Chapter 69 Uterine Cervix 1411
occurred in 3% to 7% of the patients. The most significant
determinants of severe rectal complications were the addition
of a lower vaginal tandem (p < .01), uterine tandem length >5
cm, a total biologically effective dose to the rectum of >120 Gy,
and stage III disease.
Kagei et al.727 reported on 217 patients with carcinoma of
the cervix (71 patients with stage II and 146 with stage III dis-
ease) who received whole-pelvis EBRT (40 Gy in 20 fractions or
39.6 Gy in 22 fractions) and an additional 10 Gy in five frac-
tions to the parametria followed by HDR brachytherapy. Cause-
specific 5-year survival rates were 77% for stage II and 50% for
stage III. Pelvic failure rates were 13% and 36%, respectively.
The rates of severe (grade 4) late complications were 2% for
the rectum, 1% for the small intestine or sigmoid colon, and 1%
for the bladder.
Takeshi et al.728 treated 265 patients with stage III cervical
carcinoma with external-beam radiation therapy (50.3 Gy) and
intracavitary HDR brachytherapy (19.8 Gy). The 5-year overall
survival, relapse-free survival, and locoregional eventfree
rates were 50.7%, 57.1%, and 71.2%, respectively. The 5-year
incidence of major complications was 2.6% for bladder and
8.3% for rectum. The radiation dose in the subgroup with rec-
tal complications was significantly greater than that in the sub-
group without complications.
Wang et al.729 reported treatment results in 173 patients
with cervical carcinoma treated with HDR brachytherapy and
whole-pelvis irradiation (40 to 44 Gy in 20 to 22 fractions) fol-
lowed by pelvic wall boost (6 to 14 Gy in three to seven frac-
tions with central shielding). HDR brachytherapy delivered
7.2 Gy to point A in each of three applications 1 to 2 weeks
apart. Five-year pelvic tumor control rates were 94%, 87%,
and 72% for stages IIA, IIB to IIIA, and IIIB to IVA, respectively.
Five-year actuarial survival rates were 79%, 59%, and 41%,
respectively. Sixty-six patients (38%) had rectal complications,
and 19 (11%) had bladder complications. The 5-year actuarial
rectal complication rates were 15%, 4%, and 3% for grades 2,
3, and 4, respectively.
Lorvidhaya et al.730 reported the results in 1,992 patients
with carcinoma of the cervix treated by external irradiation
and HDR brachytherapy. There were 211 patients with stage
IB, 225 with stage IIA, 902 with stage IIB, 14 with stage IIIA,
675 with stage IIIB, 16 with stage IVA, and 16 (0.8%) patients
with stage IVB. With a median follow-up of 96 months, the
actuarial 5-year disease-free survival rates were 70%, 59.4%,
46.1%, 32.3%, 7.8%, and 23,1%, respectively. The late compli-
cation rates (RTOG) for bowel and bladder combined were 7%
for grade 3 and 1.9% for grade 4 complications.
Leborgne et al.731 described a 4-year pelvic control rate of
93% and a disease-free survival rate of 88% for 59 patients
with stage IB to IIA disease. All were treated with 18 Gy to the
whole pelvis and 22 Gy to the parametria combined with six
HDR fractions (14 Gy/hour to point A) of 7 Gy to point A, two in
each treatment day, with 6-hour interfraction intervals. The
corresponding parameters for 29 patients with stage IIB dis-
ease were 79%, 75%, and 75%. The actuarial 4-year late grade
2 and 3 complication rate was 4.7%.
In 1,148 patients with squamous cell cervical cancer treated
with external RT and HDR brachytherapy with 22 years
median of follow-up, the 10-year pelvic tumor control was 93%
for stage IB, 82% for stage II, and 75% for stage III.569 Cause-
specific survival was 89%, 74%, and 59%, respectively. Major
sequelae were 4.4% in the rectosigmoid, 0.9% in the bladder,
and 3.3% in the small intestine. Nakano et al.732 subsequently
presented a study of 210 patients with stage IIIB cervical can-
cer from eight Asian countries treated from 1996 to 1998 with
radiation and brachytherapy. Though follow-up was difficult to
obtain, the reported 5-year major complication rates were 6%
in the HDR group and 10% in the LDR group. The 5-year over-
all survival rates were 51.1% in the HDR group and 57.5% in
the LDR group.
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Novetsky et al.733 presented data on 77 patients treated with
external beam with concomitant cisplatin followed by two HDR
brachytherapy fractions of 9 Gy each. Median follow-up was
3.5 years. The local control rate was 88% for stages IB2/II and
68% for stages III/IV. Grade 3/4 gastrointestinal acute symp-
toms occurred in 47%. Grade 3/4 late toxicities occurred in
5 (6%) patients. Patel et al.734 describe 104 cervical cancer
patients treated with external beam and HDR, either 9 Gy for
two fractions or 6.8 Gy for three fractions, each fraction 1 week
apart. Median follow-up was 31 months. The 3-year actuarial
local control was 81.35% with 9 Gy versus 65.18% with 6.8 Gy
(p = .04). The 3-year actuarial risk of developing any grade 3 or
worse late toxicity was 7.47% with 9 Gy and 3.57% with 6 Gy
(p = 0.3).
Prospective Trial with CT or MR Compared to X-Ray
The clinical outcome results from institutions using CT- or
Clinical Radiation Oncology
MR-based treatment planning for cervical cancer brachyther-
apy are listed in Table 69.18. The French STIC trial733 collected
data from 20 centers prospectively and stratified to 2D ver-
sus 3D (mainly with CT) brachytherapy. A total of 705 patients
were treated with one of three arms: (a) brachytherapy fol-
lowed by surgery (stage IB1, 165 patients); (b) EBRT plus che-
motherapy, BT, then surgery (305 patients); or (c) EBRT plus
chemotherapy and then BT (235 patients). For the 235 patients
treated with concurrent chemoradiation and then brachy-
therapy, 2-year overall survival was 74% for 3D versus 65%
for 2D (p = .27); disease-free survival was 60% versus 55%
(p = .09); local regional relapsefree survival was 70% versus
61% (p = .001), and local-only relapsefree survival was 79%
versus 74% (p = .003). Toxicity was reduced overall from 23%
with 2D to 2.6% with 3D (p = .002); urinary from 9% in 2D to
1% with 3D (p = .02), gastrointestinal from 9% to 0% (p = 0.17),
and gynecologic from 15% to 1% (p = .01).
Retrospective Comparison of CT to
MR-Planned Brachytherapy
Three studies compared CT to MRI contouring for HDR tandem
and ring brachytherapy. Wachter-Gerstner et al.735 compared
MR-based plans in 15 patients to those derived with either CT
or orthogonal films. CT and MR enabled higher dose to the
target volume with similar OAR dosing. Viswanathan et al.635
compared CT contours to MR contours based on a standard
set of guidelines; the CT contours were larger in width, but no
other significant differences in DVHs were identified. A report
by Eskander et al.636 of 10 patients had an MR for the first frac-
tion only and showed that CT volumes had a greater length on
the coronal plane, whereas MR images had a greater height on
the sagittal plane. No differences were found in DVH param-
eters after optimization.636 Similar to the Eskander et al.636
study, using an MR for the first fraction and CT for subsequent
fractions, Beriwal et al.652 treated 44 patients with 5- to 6-Gy
per fraction HDR after EBRT. Ninety-three percent had a com-
plete response by PET at 3 months. Of those with a CR, 2 had
a local recurrence at 6 and 8 months. With a median follow
up of 8 months (range, 2.5 to 38 months), 2-year local control,
disease-specific, and overall survival rates were 88%, 85%, and
86%, respectively.
Retrospective Results with CT-Planned Brachytherapy
Potter et al.736 reported results in 189 patients treated with
HDR brachytherapy and EBRT (48.6 to 50 Gy). Small tumors
were treated with five to six fractions of 7 Gy at point A (25 Gy
in the brachytherapy volume), which is isoeffective to 76 to
86 Gy at point A. Large tumors received three to four frac-
tions of 7 Gy after 50 Gy of EBRT, which is isoeffective to 82
to 92 Gy at point A. Three-dimensional treatment planning for
brachytherapy was based on conventional x-rays and in 181 of
189 patients on CT scan. The mean brachytherapy dose was
16.2 Gy at the ICRU rectum reference point and 14.4 Gy at the
1412 Section III Clinical Radiation Oncology Part J Gynecologic
ICRU bladder point. Taking into account the dose for EBRT, the
mean isoeffective dose at the ICRU rectum reference point was
69.9 Gy. After a mean follow-up of 34 months, the actuarial
pelvic control rate was 78% and the late complication rate for
grades 3 and 4 was 2.9% for bladder, 4% for bowel, 6.1% for
rectum, and 30.6% for the vagina (shortening and obliteration).
CT-based clinical outcomes were reported by the Addenbrooks
Hospital. Twenty-eight patients had HDR, 8 Gy 3, CT-planned
brachytherapy.737 The 3-year actuarial cancer-specific survival
rate in this group was 81%, with a pelvic control rate of 96%.
Five of the 28 patients died of para-aortic or other distant dis-
ease, 1 of them being the only one with local recurrence pre-
senting as a malignant vesicovaginal fistula. In 24 patients,
D90 74 Gy was achieved. The only patient with local recur-
rence had D90 = 63.8 Gy, which was a 20% improvement over
historical nonimage-guided controls.
At Brigham and Womens Hospital, 115 stages IB to IVA
cervical cancer patients had CT-planned brachytherapy and
were treated with 595 fractions of 5.5- to 6-Gy per fraction
HDR brachytherapy.738 The 2-year local relapse rate was 6.9%.
The 2-year disease-specific survival was 83%, and overall sur-
vival rate was 78%.
Retrospective Results with MR-Planned
LDR Brachytherapy
An initial report of MRI during intracavitary gynecologic
brachytherapy was published in 1992 from the University of
Michigan by Schoeppel et al.739 Three patients had CT and
MRI with their first of two intracavitary implants. A CT- and
MR-compatible Fletcher applicator was used. CT could not
distinguish the tumor with as much clarity as MR. Tardivon
et al.740 at Institut Gustave Roussy (IGR) treated 10 patients
with MR evaluation of the tumor during intracavitary brachy-
therapy for cervical and vaginal cancer and found that in
7 cases MR findings were concordant with clinical examina-
tion. MR was useful to determine the tumor/applicator rela-
tionship and distinguish the adjacent OAR.
A review was published of 39 patients treated at IGR with
MRI-guided LDR brachytherapy in the preoperative setting.741 A
total dose of 60 Gy to the IR-CTV was followed 6 weeks later by
extrafascial hysterectomy and bilateral salpingo-oophorectomy
with pelvic node dissection. Adjuvant chemoradiation was deliv-
ered to patients with pelvic lymph node involvement. After a
median follow-up of 4.4 years (range, 2.6 to 6.6 years), there
were no central recurrences; 1 local recurrence occurred in the
lateral pelvis (2.6%). The 4-year actuarial overall and disease-
free survival rates were 94% and 86%, respectively. The 2- and
4-year actuarial local relapsefree survival rates were 94% and
91%, respectively. Haie-Meder et al.655 subsequently published a
series of 84 patients treated with LDR MR-planned brachytherapy
after chemoradiation. With a median follow-up of 53 months
(range, 31 to 79 months), the 4-year overall survival and
disease-free survival rates were 57 (95% CI = 43 to 69) and 52%
(95% CI = 40 to 64), respectively. Thirty-nine late complications
occurred in 28 patients (33.3%): 13 bladder, 7 rectal, 5 small
bowel, 4 urethral, 3 colic, 2 vaginal, 1 pelvic fibrosis, and 4 others.
Four grade 3 delayed complications were observed, and no grade
4 complication occurred.
Retrospective Results with MR-Planned
PDR or HDR Brachytherapy
With a 0.2-T MRI at the Medical University of Vienna, 145
patients with stage IB to IVA cervical cancer were treated with
four fractions of 7-Gy HDR from 1998 to 2003.742 Complete
remission was achieved in 138 patients (95%), with 7 patients
having locally persistent or progressive disease in the central
(n = 5) or noncentral (n = 2) pelvis. With a median follow-up of
40 months, the 4-year local control rate was 83%, compared
to 63% for historical controls. A subsequent analysis of 156
patients treated from 2001 to 2008 with MR-based brachyther-
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apy was reviewed.653 Local control was 98% for tumors 2 to
5 cm and 92% for tumors >5 cm. Overall survival, however,
was 72% for tumors 2 to 5 cm and 65% for tumors >5 cm, indi-
cating that despite the increase in local control with MR-based
brachytherapy, death from distant metastases remains a prob-
lem in patients with large-volume cancer.
Investigators at the IGR reported on 45 patients treated
between 2004 and 2006 with a tandem and mold technique
using PDR brachytherapy and MR-based contouring.651 Until
recently at IGR, surgery was often performed after brachyther-
apy if disease was suspected on clinical examination. A dose of
15 Gy (after EBRT) was prescribed to the IR-CTV. The dose to
the HR-CTV was approximately 250% of the dose to the IR-CTV
(i.e., 80 Gy to the HR-CTV). With a median follow-up of 26
months, the 2-year overall and disease-free survival rates were
78% and 73%, respectively. At Tata Memorial Hospital in India,
24 patients with squamous cell carcinoma were treated with
MRI-based HDR. With a median follow-up of 12 months,743 2
patients had local failures.616 Other European centers645,654,656
and one Canadian center744 reported feasibility data for MR-based
cervical cancer brachytherapy, showing a reduction in the nor-
mal-tissue toxicity rate. When implementing 0.5- to 1.5-T
MR-based tandem/ring or tandem/ovoid brachytherapy with
MRI, specific guidelines for MR use should be followed.680
Toxicities
Table 69.18 lists general toxicities in series using CT- or
MR-planned brachytherapy. In the Medical University of Vienna
series reporting patients treated from 2001 to 2008, 73%
received concurrent cisplatin chemotherapy.653 A total of 11
grade 3 and 4 late events were recorded in 143 patients. With a
median follow-up of 3.5 years, the actuarial grade 3 and 4 late
morbidity at 3 and 5 years was respectively as follows: gastro-
intestinal, 4% and 4%; urinary, 2% and 3%; and vaginal, 1% and
3%. Two patients developed massive rectal bleeding requiring
transfusions. Three patients required stoma (grade 4) for rectal
wall ulceration, resulting in a fistula, a rectal perforation, and
a rectovaginal fistula. Three patients developed grade 3 urinary
frequency or urgency. Three patients experienced grade 3 or 4
coaptation of the vagina.
At IGR, of the 45 patients studied,651 23 and 2 developed
acute grade 1 or 2 and grade 3 complications, respectively; 21
patients presented with delayed grade 1 or 2 complications.
One other patient presented with a grade 3 vesicovaginal fis-
tula. No grade 4 or greater complications, whether acute or
delayed, were observed. In the IGR experience with LDR
brachytherapy from 2000 to 2004, 39 late complications were
reported; 13 bladder, 7 rectal, 5 small bowel, 4 urethral, 3 colic,
2 vaginal, 1 pelvic fibrosis, and 4 others. Grade 3 complications
were 1 rectal, 2 bladder, and 1 urethral. Tan et al.737 reported
on 28 patients treated with CT-guided brachytherapy for stage
IB to IIIB cervix cancer. Their overall actuarial 3-year grade
3 and 4 morbidity rate was 14%,. Two patients had grade
3 abdominal pain and 1 had a colovaginal fistula. Overall,
the data indicate that a potential reduction in morbidity appears
to be a benefit of image-guided brachytherapy.
Template-Based Interstitial Brachytherapy
Interstitial implants with 226Ra, 137Cs needles, or 192Ir afterload-
ing plastic catheters to limited tumor volumes are helpful in
specific clinical situations. Indications include large residual
bulky cervical tumors after external-beam treatment, residual
tumor with sidewall invasion, vaginal extension, presence of a
fistula and/or adjacent organ invasion, or a prior supracervi-
cal hysterectomy (Fig. 69.26). Syed-Neblett745 and Martinez746
perineal applicators are the most commonly selected. Methods
for insertion have been described.598,747 A tandem should be
inserted when a uterus is present.748 If the os is not visible,
ultrasound guidance to determine the proper placement of the

A B
tandem is advised.749 A ring applicator modified to allow simul-
taneous insertion of interstitial needles750 and ovoid applica-
tion with interstitial needles have been described.656
Traditionally, plain x-ray films are used for brachytherapy
treatment planning. Determination of normal tissue doses and
optimization is not feasible, and the risk of complications is
high. In these cases, consideration of laparoscopic approaches is
recommended.598 Syed et al.751 reported on 185 locally advanced
cervical cancer patients treated with LDR interstitial brachyther-
apy from 1977 to 1997. Patients received external-beam treat-
ment to 50.4 Gy, followed by interstitial brachytherapy to 40 to
50 Gy. Local control was 82%; 5-year disease-free survival rates
were 65%, 67%, 49%, and 17% for patients with stage IB, II, III,
and IV disease, respectively. Eighteen (10%) of the 185 patients
developed RTOG grade 3 or 4 late complications.
Clinical outcomes using traditional techniques have been
reported by several institutions. Thirty patients with stage IIB
and 37 patients with stage III carcinoma received interstitial
irradiation in the parametrium to supplement the dose deliv-
ered by external-beam treatment and intracavitary brachyther-
apy. Despite the fact that the patients treated with interstitial
implant were in a high-risk group, local tumor control was
comparable to that of patients treated with standard tech-
niques.169 Pierquin et al.752 described locoregional recurrences
in 6% of 53 patients with T1, 11% in 47 patients with T2, and
42% of 19 patients with T3 primary tumors of the uterine cer-
vix treated with a combination of external-beam irradiation
and the Creteil method for interstitial implantation of 192Ir
sources in a plastic cervical-vaginal moulage and a uterine tan-
dem. Prempree753 reported a 96% local tumor control rate and
61% 5-year disease-free survival rate in 23 patients with stage
IIIB carcinoma of the cervix treated with a combination of
external irradiation and intracavitary and interstitial implants
to the parametrium. Overall, major complications were noted
in 8% of the patients. Martinez et al.,746 using the Martinez
Universal Perineal Interstitial applicator, treated 37 patients
with advanced or recurrent carcinoma of the cervix and
26 with vaginal-urethral tumors. Doses of approximately 35 Gy
were given, in addition to external irradiation (36 Gy to the
whole pelvis and 14 Gy to the pelvic sidewall). They reported 6
local failures in the patients with cervical lesions and 5 in the
group with vaginal-urethral tumors. The overall complication
rate was 5.1%. Nag et al.754 reported on 31 patients with carci-
noma of the cervix treated with external-beam radiation ther-
apy and fluoroscopically guided interstitial brachytherapy.
With a median follow-up of 36 months, 16 patients (51%) with
cervical had local tumor control. The 5-year actuarial survival
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Chapter 69 Uterine Cervix 1413
FIGURE 69.26. A: Picture of anterior scout
computed tomography showing a template-
based interstitial brachytherapy application.
Clinical Radiation Oncology
B: Magnetic resonance imaging during inter-
stitial needle insertion in a patient with stage
IIIB cervical cancer ensures proper placement
of the catheters adjacent to the tandem. The
100% isodose line is in yellow.
rate was 34%. Only 1 patient experienced grade 3 complica-
tions (2.5%).
Recio et al.755 used laparoscopy at the time of interstitial
brachytherapy in six patients with FIGO stages IIB to IVA cervi-
cal carcinoma after completion of whole-pelvis radiation; a
total of 98 needles were inserted to deliver a median interstitial
brachytherapy dose of 20 Gy. Eleven perforations in the pelvic
peritoneum or bladder were identified during surgery in five of
the six patients, leading to immediate repositioning of needles.
No acute or short-term morbidity related to the procedure was
noted.
Sharma et al.756 presented results on 42 patients treated
from 2005 to 2007 in a prospective study of two weekly ses-
sions of 10Gy, 1 week after finishing external-beam radiation.
Median follow-up was 23 months. Delayed toxicity was 9%.
The 3-year overall survival for all stages was 47% and the
3-year recurrence-free survival for stages IIB, IIIB, and IVA
was 67%, 34%, and 20%, respectively. Sharma et al.757 also
reported on the use of transrectal ultrasound to assist with
insertion of the interstitial needles.
With image-based planning including either a CT637,638 or an
MRI630 the physician evaluates the placement of the needles
and may choose either to not treat specific catheters or to
lower the dose given through catheters close to normal-tissue
structures. An approximate 11% rate of bowel insertion and a
long-term fistula rate of 4% to 10% have been reported in stud-
ies using CT for planning after insertion.637,638 When a physi-
cian has the facility to insert the applicator in a CT or MR suite
while the patient is under anesthesia, an iterative process of
image-guided needle insertion ensures proper placement of
the catheters and prevents an inadvertent insertion into a sur-
rounding normal-tissue structure, such as the rectum, sigmoid,
or bladder.630
Dose optimization with either PDR or HDR may improve the
normal-tissue doses for interstitial therapy for some patients.
The University of Pittsburgh reported on 11 cervical cancer
patients treated with CT-guided HDR interstitial brachytherapy
(5 fractions of 3.5 Gy per fraction).758 From 1998 to 2004 inter-
stitial brachytherapy was chosen for cases with distorted anat-
omy or extensive vaginal disease. The 5-year actuarial local
control rate was 63%. No patient had acute grade 3 or 4 toxic-
ity. Grade 3 or 4 late toxicity occurred in 1 patient, with a
5-year actuarial rate of 7%. Three patients had late grade 2
rectal toxicity, and 1 patient had grade 2 small-bowel toxicity.
Dimopoulos et al.720 reported on the use of tandem/ring
with short interstitial needles and MR-planned HDR brachy-
therapy for 22 cervical cancer patients followed for a median
1414 Section III Clinical Radiation Oncology Part J Gynecologic
of 20 months; no grade 3 or 4 toxicities were noted, and 1
patient had a local recurrence. Nomden et al.721 described the
use of tandem/ovoid application with short interstitial needles
for the second insertion with MR-planned PDR brachytherapy
for 20 cervical cancer patients. They compared the first inser-
tion with just a tandem and ovoid applicator to the second
insertion, which included the addition of interstitial needles.
There was an average increase in dose of 4.4 Gy (SD 2.3), with
better coverage of the HR-CTV with the second insertion.
Mikami et al.759 analyzed needle applicator displacement in
10 patients treated with 30 Gy HDR in five fractions and found
on daily CT scans an average of 1 to 2 mm of caudal displace-
ment. Shifts of >3 mm were replanned. Shukla et al.760
presented data on 20 patients with cervical cancer treated with
interstitial brachytherapy who underwent every-other-fraction
CT imaging. The mean needle displacement was 2.5 (range, 0
to 7.4), 17.4 (range, 0 to 27.9), 1.7 (range, 0 to 6.7), 2.1 (range,
0 to 9.5), 1.7 (range, 0 to 9.3), and 0.6 mm (range, 0 to 7.8 mm)
in cranial, caudal, anterior, posterior, right, and left directions,
respectively. The mean displacement in the caudal direction
was higher between days 1 and 2 than that between days 2
and 3 (13.4 vs. 3.8 mm; p = .01). Damato et al.,761 in a study of
10 patients treated with interstitial brachytherapy, found on
average, that <1-cm displacements and deformations of the
implant occurred over the course of treatment. The most sig-
nificant dosimetric consequences were due to changes in organ
filling rather than catheter shifts. Proper quality assurance
methodologies should be in place to detect shifts that can
potentially result in inadvertent insertion into normal tissue.
Brachytherapy in the Elderly
Magn et al.762 reported on 113 patients with median age of
76 years (range, 70.7 to 94.4 years) treated by conventional
LDR BT as a part of their treatment. For rectal complications,
grades 1/2, 3/4, and 5 (fatal) crude incidences were 19.4% (22
of 113), 1.8% (2 of 113) and 0.9% (1 of 113), respectively. Acute
toxicity death occurred in 1 patient with major diarrhea associ-
ated with a hemodynamic shock. For small-bowel complica-
tions, grades 1/2 and 3/4 crude incidences were 3.5% (4 of
113) and 0.9% (1 of 113), respectively. For urinary tract com-
plications, grades 1/2 and 3/4 crude incidences were 11.5%
(13/113) and 2.7% (3/113), respectively. With a median follow-
up of 3.1 years, 10 patients developed distant metastases, and
10 others had local relapses. The 3-year specific overall sur-
vival rate was 88.6% (95% CI = 77 to 92), and the correspond-
ing disease-free survival rate was 81% (95% CI = 72 to 88). Age
did not influence the effectiveness of BT in elderly patients, and
BT should be considered whenever possible, even in elderly
patients presenting with a cervix cancer.
Image-Guided Brachytherapy Versus
External-Beam Boost
Studies of external-beam treatment as an alternative boost
instead of brachytherapy demonstrate significantly inferior
survival rates compared to those that use brachytherapy. The
use of ultrasound enables tandem placement in most cases,
even when the os cannot be identified, and should be attempted
for difficult cases. Barraclough et al.763 reported on 44 patients
with cervical cancer who did not receive brachytherapy and
were treated with EBRT to 54 to 70 Gy via a three-dimensional
conformal boost. After a median follow-up of 2.3 years, 48%
relapsed, with 16 of 21 developing a central recurrence. The
5-year overall survival rate was 49%, which is much lower
than for brachytherapy-treated patients.
The dosimetry of brachytherapy cannot be adequately mim-
icked by external-beam techniques. A treatment planning
report compared inversely planned EBRT with photons (IMRT)
and protons (IMPT) to 3D MRI-guided brachytherapy.764 EBRT
was planned to deliver the highest possible doses to the PTV
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while respecting D2cc limits from brachytherapy, assuming the
same fractionation. Volumes receiving 60 Gy (in equivalent dose
in 2-Gy fractions) were approximately twice as large for IMRT
compared with brachytherapy, and the high central tumor dose
was lower than that seen with brachytherapy. Both IMRT and
protons were inferior to 3D image-based brachytherapy.
With IMRT, there is a need for replanning due to rapid tumor
regression317319 and an increase in integral dose, with normal
tissues throughout the pelvis receiving more radiation than with
brachytherapy. Given the large movement and the increased
dose to the normal tissues resulting in an increase in normal-
tissue toxicity, highly conformal (IMRT, IGRT, SBRT) methods for
boosting the cervix are not routinely recommended. Every effort
should be made to use image guidance to insert a tandem into
the uterus in order to provide adequate brachytherapy doses for
all cervical cancer cases receiving radiation.
External-Beam Irradiation Alone
Occasionally, brachytherapy procedures cannot be performed
because of medical reasons or unusual anatomic configura-
tion of the pelvis or the tumor (i.e., extensive lesion, inability
to identify the cervical canal). These patients may be treated
with higher doses of external-beam irradiation alone, although
survival is significantly worse than when brachytherapy is imple-
mented, and normal-tissue toxicity is higher due to the excessive
dose to the rectum and bowel. Therefore, every attempt to treat
with brachytherapy should be made because brachytherapy
moves with the patient and provides high regions of dose in the
central regions of the tumor. With IMRT, a significantly higher
normal-tissue dose is administered, and the desired high central
regions of radiation cannot safely be administered.
Coia et al.,521 in an analysis of 565 patients with various
stages of cervical carcinoma treated in the Patterns of Care
Study, reported better survival (67%) and pelvic tumor control
(78%) for patients treated with external irradiation and brachy-
therapy than for patients who had no intracavitary brachyther-
apy applications (36% 4-year survival rate and 47% in-field
failure rate). Patients treated with two intracavitary applica-
tions had a higher 4-year survival rate (73%) and in-field tumor
control rate (83%) than those receiving only one application
(60% 4-year survival rate and 71% in-field tumor control rate).
Hanks et al.525 and Montana et al.524 reported a higher inci-
dence of central pelvic recurrences in patients with stage III
cervical carcinoma treated with external-beam therapy alone
than in patients receiving brachytherapy in addition to exter-
nal-beam irradiation (Table 69.21). The incidence of major
complications was similar in both groups of patients.
Akine et al.765 treated 104 patients with carcinoma of the
uterine cervix with external irradiation alone (anteroposterior
posteroanterior or four-field box techniques) because of inabil-
ity to perform intracavitary brachytherapy. Average doses
delivered were 50 Gy to the whole pelvis, followed by addi-
tional doses with reduced portals to deliver a total of 60.8 Gy in
TABLE 69.21 CARCINOMA OF THE UTERINE CERVIX: INCIDENCE OF CENTRAL/
PELVIC RECURRENCES CORRELATED WITH METHOD OF THERAPY
Incidence of Pelvic Failures
External External Beam
Author (Reference) Stage Beam Only and Intracavitary p
Hanks et al. (525) III 33/38 (86%) 55/109 (50%) .0002
Montana et al. (524) III 14/35 (40%) 12/37 (32%) .6725
Coia et al. (521) I,II,III (53%) (22%) <.0100
Longsdon and Eifel (899),a IIIB 641 (45%) 266 (24%) <.0001
a
Five-year disease-free survival.
Modified from Stehman FR, Perez CA, Kurman RJ, et al. Uterine cervix. In: Hoskins WJ,
Perez CA, Young RC, eds. Principles and Practice of Gynecologic Oncology, 3rd ed.
Philadelphia: Lippincott Williams & Wilkins, 2000:841918.

6 weeks, 72.3 Gy in 7.5 weeks, or 80.5 Gy in 8 weeks, with a
daily dose of 1.9 or 2 Gy. The local tumor control rate was 27%
for stage II, 19% for stage III, and 15% for stage IVA disease.
The 5-year survival rates were 36%, 17%, and 5%, respec-
tively. Four patients had major complications (usually proctitis)
that required surgical treatment, and 1 patient died of rectal
bleeding. Eight of 23 patients treated with conformal therapy
had control of the tumor and survived 5 years without major
complications. Saibishkumar et al.766 treated 146 patients with
cervix cancer with EBRT alone (60 to 66 Gy) because of unsuit-
ability for brachytherapy; 5-year pelvic tumor control was
21.9% and DFS was 11.6%.
Cost-Effectiveness of LDR Versus
HDR Brachytherapy
Wright et al.767 developed a questionnaire to elicit patient
preference for two brachytherapy methods (one LDR or three
HDR fractions and two HDR or five HDR fractions, assuming
both methods to be isoeffective). The questionnaire was com-
pleted by 90 female staff members at their center, 18 previ-
ously treated patients, and 20 newly diagnosed patients. When
both methods were assumed to be isoeffective, only 34% of the
38 patients preferred three HDR fractions to one LDR fraction.
However, when HDR was assumed to be 2% more curative or
6% less toxic, 50% said they would prefer the HDR therapy.
Both preference and strength of preference for LDR were sig-
nificantly associated with a greater traveling distance for treat-
ments. More studies on resource utilization768 are needed.
Alternative Isotopes
Californium has been proposed as an alternative to iridium as
the radioactive isotope. Maruyama and Muir769 reported on 41
patients with stage IB cervix cancer treated with 40 to 50 Gy to
the whole pelvis followed by a 5- to 15-Gy boost to the lateral
pelvic wall and a single 252Cf-neutron brachytherapy insertion
in approximately 8 hours. Nearly total tumor clearance was
achieved in >90% of the patients; tumor regression was more
rapid in the 252Cf group than in similar patients treated with
137
Cs and the same external-beam irradiation dose.
FOLLOW-UP
After treatment, patients should be regularly followed by both
the radiation and the gynecologic oncologist. Careful history
taking and a complete physical and pelvic/rectal examination
usually are performed every month for the first 3 months after
completion of irradiation, every 3 months for the remainder of
the first year, every 4 months the second year, every 6 months
during the third through the fifth year, and yearly thereafter.
The use of Pap smears for cervical and vaginal cytology as a
follow-up study is controversial because of postirradiation cel-
lular morphology that renders it difficult to distinguish postirra-
diation changes from residual or recurrent malignant cells.770,771
DNA analysis of postirradiation cytologic smears demonstrating
atypia or dysplasia may provide ancillary information.772
Rintala et al.773 evaluated the reliability of cytologic analysis
and atypia after radiation therapy in 89 patients treated for
cervical carcinoma. A total of 697 Pap smears were taken; dur-
ing the follow-up, 44 patients had recurrent disease, which
was local in 17 (39%) cases. The rate of false-positive samples
was only 3%. Radiation-induced atypia was detected in 28% of
the Pap smears taken during the first 4 months after radiation
therapy, and its incidence decreased thereafter. In 1,000
patients treated with either surgery or radiation therapy at the
MD Anderson Cancer Center for stage IB cervical cancer post-
treatment, Pap smears did not detect a single asymptomatic
recurrence among 133 patients with recurrent disease.774
The presence of apparently viable tumor cells in the cyto-
logic smear 3 months after irradiation should be evaluated
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Chapter 69 Uterine Cervix 1415
with cervical biopsies, dilation and curettage, and careful
examination under anesthesia, as indicated.
Complete blood counts and chemistry profile tests are
obtained as clinically indicated. Chest radiography is commonly
obtained on a yearly basis, usually for the first 5 years post-
treatment, although its value to detect curable lung metastasis
is not proven. If radiographs are consistently negative, obtain-
ing them every other year thereafter may be sufficient.
Other imaging studies, such as CT, MRI, PET scanning, or
bone scans, are obtained when clinically warranted. When
persistent or recurrent tumor is suspected, biopsies should be
obtained for histologic confirmation. If a biopsy is positive,
immediate treatment should be instituted, as is discussed later.
Usually, hematometra after radiation therapy for cervical
carcinoma is related to recurrent disease but occasionally may
be related to estrogen replacement therapy, endometrial activ-
ity, or fibrosis and obliteration of the endocervix.775
Clinical Radiation Oncology
TREATMENT OF RECURRENT CARCINOMA
OF THE CERVIX
After Previous Surgery
Radiation may salvage approximately 50% of patients with
localized pelvic recurrences after surgery alone. A combination
of whole-pelvis external irradiation (45 to 50 Gy) with concur-
rent chemotherapy followed by interstitial brachytherapy is
recommended. If the tumor lies outside of an accessible region
for brachytherapy, dose escalation with conformal or IMRT
techniques may be attempted, depending on the location of the
tumor and the need to protect bowel, with at least 65 to 70
Gy necessary for adequate control. In the setting of recurrent
disease, the total mucosal dose from the external and brachy-
therapy can approach 140 Gy to the upper vagina and 95 Gy
to the distal vagina without a high risk.776 With interstitial
brachytherapy, doses of 20 to 35 Gy are administered with sin-
gle, double-plane, or volume implants, for a total tumor dose
of approximately 80 Gy, depending on the extent of the tumor.
Larson et al.777 observed 27 recurrences (11%) in 249
patients treated with radical hysterectomy and pelvic lymph-
adenectomy for stage IB carcinoma of the cervix; 17 (63%) had
tumor recurrence in the pelvis or vulva; the other 10 patients
had recurrences outside the pelvis. Eight of 15 patients (53%)
treated with irradiation for an isolated recurrence in the pelvis
or vulvar region were tumor free between 10 and 126 months
after treatment of the recurrence (median, 48 months).
Ijaz et al.778 reported on 50 patients treated with RT for an
isolated pelvic recurrence of cervical carcinoma after radical
hysterectomy; 7 patients were treated with palliative intent
using hypofractionated RT. The remaining 43 patients were
treated with curative intent, 33 with RT only and 10 with cispl-
atin-based chemoirradiation. The overall 5-year survival rate
was 33% for all 50 patients, 39% for the 43 patients treated
with curative intent, and 25% for patients with isolated sidewall
recurrences treated with curative intent. Three patients expe-
rienced late treatment complications.
Hille et al.779 described results in 17 patients with recurrent
cervix cancer (9 had a complete microscopically incomplete
resection) treated with EBRT and brachytherapy to 50 to 65
Gy. The 5-year pelvic tumor control was 48%, and relapse-free
survival was 24%.
After Definitive Irradiation
Reirradiation of previously irradiated patients must be under-
taken with extreme caution. It is very important to analyze the
techniques used in the initial treatment (beam energy, volume,
doses delivered with external or intracavitary irradiation). In
addition, the period of time between the two treatments must
be taken into consideration because it is postulated that some
repair of the initial damage may take place in the interval. In
1416 Section III Clinical Radiation Oncology Part J Gynecologic
general, external irradiation for recurrent tumor is given to
limited volumes (40 to 45 Gy, 1.8-Gy tumor dose per fraction,
preferentially using lateral portals). Occasionally, intracavitary
or interstitial irradiation can be used to treat relatively circum-
scribed recurrences.
Sommers et al.780 described the results of retreatment in
376 patients with recurrent carcinoma of the uterine cervix.
Ninety-one patients received irradiation, mostly external
(86.8%), occasionally combined with brachytherapy (7.7%) to
control bleeding of central recurrences; brachytherapy alone
was administered in 5.5% of patients. The usual dose for recur-
rent pelvic masses was 40 to 45 Gy, and for para-aortic lymph
node metastases it was 45 to 50 Gy in 5 weeks. Other meta-
static sites were treated with 35 to 40 Gy in 3 to 4 weeks. Pelvic
exenteration was attempted in 23 patients, only 10 of whom
were deemed to be operable (43.5%), but it was completed in
only 7. The probability of 5-year survival after treatment for
recurrence was 30% with combined surgery and external
irradiation, 12% with surgery alone, and 4% with external irra-
diation alone. The 5-year survival rate for 10 patients who
underwent pelvic exenteration was 16%. Only 1% of the
untreated patients survived 5 years. Six of 140 patients (4.3%)
experienced grade 2 or 3 complications.
Selected patients with limited pelvic recurrences not fixed
to the pelvic wall and without evidence of extrapelvic metasta-
ses can be potentially salvaged by radical hysterectomy or pel-
vic exenteration. Coleman et al.781 described results in 50
patients who underwent radical hysterectomy for persistent
(18 patients) or recurrent (32 patients) cervical cancer after
primary radiation therapy. Lymph node metastases were iden-
tified in 5 of 39 patients (13%) in whom the lymph nodes were
evaluated. The 5- and 10-year survival rates were 72% and
60%, respectively.
In 65 patients on whom pelvic exenteration was carried out
at Memorial Sloan-Kettering Cancer Center, the 5-year survival
rate was 23%.782 The operative mortality rate was 9.2%. The
authors pointed out that the significant mortality and morbid-
ity associated with this procedure preclude its use as palliative
therapy.
Urinary diversion, either by nephrostomy or ileal bladder,
may be of palliative value in patients with either recurrent car-
cinoma in the pelvis or complications. It must be kept in mind
that diversion may prolong life but runs the risk of denying a
terminally ill patient with cancer the oblivion and insensibility
of uremia.
Kastritis et al.783 treated 200 patients with stage IV or
recurrent cervix cancer with cisplatin-based chemotherapy;
response rate was 43.5% in 142 patients with squamous cell
and 53.5% in 58 patients with nonsquamous tumors (p = .79).
Median survival was 11.57 and 19 months, respectively.
Tinker et al.784 treated 25 women for recurrent cervical cancer
with carboplatinpaclitaxel and noted a 20% cure rate and
20% progression rate, with median survival of 21 months.
Brewer et al.511 in 32 women, all of whom had previous che-
motherapy and 29 of whom had previous RT, used cisplatin
and gemcitabine, with a progression rate of 22% and median
time to progression of 3.5 months.
Para-Aortic Lymph Node Recurrences
Isolated recurrences in the para-aortic nodes after pelvic irra-
diation have been described in about 3% of patients, and some
may be salvaged with aggressive therapy. The advent of IMRT
makes treatment easier, with less morbidity.
Kim et al.785 treated 12 patients with isolated para-aortic
lymph node metastasis with hyperfractionated RT (60 Gy in
1.2-Gy fractions twice a day) and concurrent cisplatinpacli-
taxel. Fields extended from the superior plate of T12 to the
lower plate of L5. Three-year survival was 19%. Grade 3 or 4
hematologic toxicity developed in two patients. Singh et al.786
booksmedicos.org
detected 14 isolated para-aortic lymph node metastases in 816
patients previously treated with RT; these women were subse-
quently treated with RT to the para-aortic lymph nodes com-
bined with concurrent chemotherapy. Seven patients survived
5 years.
In a review of 1,955 patients treated with RT for cervix cancer,
Jhingran et al.,787 identified 120 patients with recurrent tumor
above the pelvic fields. Initially, 10 had common iliac and 5 had
para-aortic node involvement. In 104 patients, recurrences
were immediately adjacent to the upper borders of the RT
fields. In 15 patients treated with curative intent for the para-
aortic lymph node recurrence, 5-year survival was 25%.
Intraoperative Irradiation
Intraoperative radiation therapy (IORT) has been used for
treatment of locally advanced and recurrent carcinoma of the
cervix, with 3-year survival rates of 8% to 21% as reported
by Mah et al.788 and Garton et al.,789 and a 5-year survival
rate of 33% in 14 patients described by Kinney et al.423 Patient
selection may have had an impact on the different results. Abe
and Shibamoto790 noted that central recurrences, particularly
in nonirradiated patients, and resection of the gross recurrent
tumor in irradiated patients improve the benefit from IORT.
Significant toxicity included peripheral nerve injury and ure-
teral stenosis (with doses >15 to 20 Gy).
IORT was used in 70 patients with pelvic recurrences in a
European cooperative study.791 Complete tumor resection was
carried out in 30 patients, partial in 37, and unspecified in 3.
Sixty-five patients had electron beam therapy (12 to 25 MeV),
with mean doses of 18 Gy (10 to 25 Gy) after gross complete
resection and 19 Gy (10 to 30 Gy) after partial resection. The
3-year overall survival rate was 8%. Grade 2 or 3 toxicity was
observed in 19/70 patients (27%), with 10 complications being
related to IORT.
Martinez-Monge et al.792 reported a study of IORT in 26
patients with recurrent gynecologic tumors, some relapsing
after full-dose radiation therapy (group 1) or after surgery
(group 2). Cervical carcinoma was the initial tumor site of
involvement in 18 patients. Treatment consisted of maximal
surgical resection and IORT (10 to 25 Gy) to high-risk areas.
Patients not previously irradiated also received external-beam
irradiation (with or without chemotherapy) before or after sur-
gery. There was 1 IORT-related incidence of motor neuropathy.
The local tumor control rates were 33% and 77%; the 4-year
actuarial survival for group 1 was 7%, and the 6-year actuarial
survival rate for group 2 was 33%.
In another study, 42 patients with stages IIA to IVA cervical
cancer initially received 50.4 Gy of pelvic external-beam radia-
tion with concurrent cisplatin and 5-fluorouracil.793 Patients
then underwent radical surgery 6 to 8 weeks later with IORT.
The 5-year DFS and OS were 46% and 49%, respectively, which
are inferior to reported results with standard concurrent
chemoradiation followed by brachytherapy without surgery or
IORT. Therefore, this regimen remains of questionable value in
potentially curable patients.
URGENT BLEEDING AND
PALLIATIVE IRRADIATION
Frequently, the radiation oncologist is faced with the challenge
of treating a patient with stage IVB or recurrent carcinoma
requiring palliation of pelvic pain or bleeding. Tumors respond
rapidly to radiation, and bleeding usually resolves within a few
days of treatment. If vaginal bleeding is the main concern, sev-
eral possibilities may be effective. In a descriptive review of
eight papers that presented palliative treatment data,794 five
papers were found to report using 10 Gy per fraction, with the
best resolution of bleeding and/or pain when each 10-Gy frac-
tion was given at 3- to 4-week intervals for a total of three

fractions. Alternatively, common palliative regimens used in
other sites of the body, such as 4 Gy for five or six fractions or
3 Gy for 10 fractions, may be implemented. Patients who present
with a new diagnosis may be treated with 3 to 4 Gy for two or
three fractions, followed by standard 1.8 Gy to approximately
39.6 Gy and then brachytherapy. Alternatively, patients may
receive 1 to 2 days of 1.8 Gy twice a day, switching to once-
a-day treatment with 1.8 Gy per fraction after bleeding has
stopped on day 2 or 3, completing treatment after 45 Gy and
then commencing routine brachytherapy.
A single LDR intracavitary insertion with tandem and col-
postats for approximately 6,000 mgh (55 Gy to point A) may be
used for palliation. If irradiation was delivered previously,
lower intracavitary doses should be prescribed (4,000 to 5,000
mgh). Grigsby et al.795 used two fractions of HDR brachyther-
apy with a ring applicator (once weekly) with control of bleed-
ing in 14 of 15 patients.
Several high-dose fractionation schedules with external-
beam radiation have been used. Spanos et al.796 reported on a
phase II study of daily multifractionated split-course irradia-
tion in 142 patients with recurrent or metastatic disease in the
pelvis. Irradiation consisted of 3.7 Gy per fraction given twice
daily for 2 consecutive days, repeated at 3- to 6-week intervals
for a total of three courses, aiming at a total tumor dose of 44.4
Gy. Occasionally, this regimen was combined with an LDR
intracavitary insertion (4,500 mgh), blocking the midline for
the last 14.4-Gy external dose. Twenty-seven patients survived
>1 year. There were only 2 recorded cases of grade 3 toxicity
(lower gastrointestinal tract). This study was expanded to a
phase III protocol randomizing 136 patients between a short
(2 weeks) or a longer (4 weeks) rest period between the split
courses of irradiation.797 There was a trend toward increased
acute toxicity in patients with shorter rest periods (5 of 58 vs. 0
of 68; p = .07). Late toxicity was not significantly different in
the two groups. Pelvic tumor response was comparable in both
groups (34% vs. 26%). Spanos et al.798 reported a 6% complica-
tion rate in 290 patients treated in RTOG Protocol 8502. No
patient receiving <30 Gy experienced late toxicity. There was
no significant difference in the incidence of complications for
patients with a 2- or 4-week rest (p = .47).
IRRADIATION AND HYPERTHERMIA
Because of technical limitations in the delivery of adequate
heat to large parts of the body such as the pelvis, the use of
hyperthermia in the treatment of carcinoma of the uterine
cervix has been rare. Hornback et al.799 described a nonran-
domized study in which the combination of microwave hyper-
thermia (433 MHz) and irradiation resulted in improved pelvic
tumor control (72%) in a group of 79 patients with stage IIIB
carcinoma compared with previously irradiated historic con-
trol patients (53%). However, 5-year survival rates were com-
parable in both groups (22% to 30%).
Sharma et al.800 reported a 70% disease-free survival rate at
18 months in 20 patients with stage IIB or III carcinoma of the
uterine cervix treated with a combination of irradiation and
hyperthermia (13.5 MHz, 42C to 43C, 30 minutes before irra-
diation) in comparison with a 50% disease-free survival rate in
22 patients treated with irradiation alone. The grade 3 compli-
cation rate (8%) was similar in both groups.
Dinges et al.801 treated 18 patients with advanced carci-
noma of the cervix with RT plus hyperthermia (in the first and
fourth weeks, two regional hyperthermia treatments were
applied). The acute toxicity was low and similar to that with RT
alone. The local tumor control was 48% at 2 years.
Harima et al.802 evaluated radiation therapy or thermoir-
radiation (three sessions of hyperthermia) for stage IIIB cervi-
cal carcinoma; two groups of 20 patients each were randomly
divided. A complete response was achieved in 50% (10 of 20)
in the RT group versus 80% (16 of 20) in the thermoirradiation
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Chapter 69 Uterine Cervix 1417
group (p = .048). The 3-year overall survival and disease-free
survival rates for the patients who were treated with thermoir-
radiation (58.2% and 63.6%) were better than with RT (48.1%
and 45%), but differences were not statistically significant. The
3-year local relapse-free survival rate of the patients who were
treated with thermoirradiation (79.7%) was significantly better
than that of the patients treated with irradiation alone (48.5%;
p = .048). Thermoirradiation was well tolerated and did not
add to either acute or long-term toxicity over radiation alone.
Vasanthan et al.803 reported on 110 patients with locally
advanced cervix cancer randomized to treatment with RT
alone or combined with hyperthermia (minimum five sessions,
60 minutes each, once weekly). Overall 3-year pelvic tumor
control was 68.5% and survival was 73.2%, with no difference
in either group, although survival was lower in the patients
with stage IIB treated with hyperthermia. Acute toxicity was
18% (10 of 55) in the hyperthermia patients and 4% (2 of 55)
Clinical Radiation Oncology
with RT alone. Late toxicity was not different in the two arms.
A Cochrane database review identified six randomized, con-
trolled trials published between 1987 and 2009 comparing RT
versus combined hyperthermia and RT. The results show 74% of
patients had stage IIIB cervical cancer. A significantly higher
complete response rate (RR = 0.56, 95% CI = 0.39 to 0.79) and
lower local recurrence rate (HR = 0.48, 95% CI = 0.37 to 0.63)
and improved overall survival (HR = 0.67, 95% CI = 0.45 to 0.99)
with no difference in acute or late grade 3 to 4 toxicity were seen
for patients treated with combined therapy.804 Catheter-based
ultrasound devices provide a method to deliver heat with HDR
brachytherapy, but clinical results are not yet available.805
SIDE EFFECTS: SURGERY AND RADIATION
Descriptions of sequelae vary among institutions because
toxicity-grading scales are not uniform and the scoring system
for complications is not clearly stated in all reports. Surgical side
effects alone depend on the extent of surgery and the amount of
disease. Radical hysterectomy alone may cause long-term side
effects such as urinary retention requiring chronic suprapubic
catheter placement, sciatic nerve injury, postoperative seroma
or hematoma formation, pelvic pain, or, when lymphadenec-
tomy, is performed, life-long edema. Oophorectomy also may
induce menopause; hysterectomy removes the ability to carry
a pregnancy, and removal of a portion of the vagina may sig-
nificantly change sexual function if vaginal shortening is severe.
With improved anesthesia, surgical techniques, and antibi-
otic therapy, the mortality rate for radical hysterectomy with
pelvic lymphadenectomy has decreased to 1% or less. The
most frequent sequela after radical hysterectomy is urinary
dysfunction as a result of partial denervation of the detrusor
muscle. Patients may have various degrees of loss of bladder
sensation, inability to initiate voiding, residual urine retention,
and incontinence.
In 375 patients treated with a modified radical hysterectomy
for various gynecologic disorders, Magrina et al.,806 observed
some form of postoperative (within 42 days of surgery) compli-
cations in 89 patients (24%). Patients who had a pelvic lymphad-
enectomy experienced a greater incidence of lower-extremity
lymphedema than those who did not undergo this procedure.
Preoperative or postoperative pelvic irradiation was a significant
predisposing factor for urinary tract infection, lymphedema, and
bowel obstruction in these patients compared with those who
did not receive pelvic irradiation.
Some loss of defecatory urge associated with chronic rectal
dysfunction was observed by Barnes et al.807 after radical hys-
terectomy. Manometric studies suggest a disruption of the spi-
nal arcs controlling defecation.
Other complications include ureterovaginal fistula (the inci-
dence of which has decreased to <3%), hemorrhage, infection,
bowel obstruction, stricture and fibrosis of the intestine or
rectosigmoid colon, and bladder and rectovaginal fistulas.
1418 Section III Clinical Radiation Oncology Part J Gynecologic

Postsurgical complications are usually more amenable to cor- TABLE 69.23 CARCINOMA OF THE UTERINE CERVIX: GRADE 3 SEQUELAE
rection than are late complications after irradiation. (WASHINGTON UNIVERSITY, 19591989)
When postoperative radiation therapy is given to selected
Stage
patients, further complications of the additional therapy are
expected. The main areas of side effects due to radiation are IB IIA IIB III IVA
bowel, bladder, skin, and sexual function. Because of intestinal Total number of patients 415 137 391 326 23
adhesions to denuded surfaces in the pelvis, enteric complica- treated
tions, such as obstruction, fistula, or dysfunction, were observed Number of complica- 26 (6%) 23 (17%) 57 (15%) 45 (14%) 2 (9%)
in 24% of patients reported by Fiorica et al.808 Other investiga- tions
tors, however, have reported no increase in the incidence of RectumRectosigmoid
severe complications in patients treated with postoperative Rectovaginal fistula 4 2 8 12 1
irradiation.387,821 Rectouterine fistula 1
Lower body mass index (BMI) is correlated with an increase Colovaginal fistula 1
in toxicity. A total of 404 patients with stage IB1 cervical cancer Rectal stricture 3 4 4 2
with positive lymph nodes or stage IB2 or higher were treated Proctitis 2 2 6 2
from 1998 to 2008. A BMI of <18.5 was associated with a Rectal ulcer 1
Sigmoid perforation 1 3 1
decreased overall survival (HR = 2.37, p < .01). Grade 3 and 4
complications appeared to trend higher; overall, 17% versus Small Bowel
14%; specifically for fistula, 11% versus 9% (p = .05), for bowel Small-bowel obstruction 3 5 12 8
Small-bowel perforation 2 1
obstruction, 33% versus 4% (p < .01), and for lymphedema,
Enterocolic fistula 1
5.6% versus. 1.2% (p = .0).809 Enterocutaneous fistula 1 1
Montz et al.810 evaluated bowel obstruction in 98 patients Enterovaginal fistula 1
undergoing radical hysterectomy for a nonadnexal gynecologic Enteritis/cachexia 1
malignancy. The incidence of small-bowel obstruction was sig- Urinary
nificantly higher (p < .05) in patients who received concomitant Vesicovaginal fistula 3 2 6 9 2
radiation therapy (20%). None of these patients had recurrent Ureterovaginal fistula 1
disease at the time of small-bowel obstruction. Findings at sur- Cystitis 2
gery consisted of minimal incisional adhesions but extensive Bladder ulcer 1
matted small-bowel loops adherent to the pelvic operative sites. Ureteral stricture 5 5 9 4
When irradiation is combined with surgery, the complica- Other
tion rate tends to be somewhat higher, particularly because of Postoperative pelvic 1 1
abscess
Pulmonary embolus 1
Hemorrhage 1 2
TABLE 69.22 CARCINOMA OF THE UTERINE CERVIX: GRADE 2 SEQUELAE Pelvic infection 1
(WASHINGTON UNIVERSITY, 19591989) Neuritis 1 1
Stage
IB IIA IIB III IVA
Total number of 415 137 391 326 23 injury to the ureter or the bladder (ureteral stricture or uretero-
patients treated vaginal or vesicovaginal fistula).811 The dose of irradiation,
Number of complica- 51 (12%) 14 (10%) 65 (17%) 38 (12%) 3 (13%) technique, and type of surgical procedure performed are impor-
tions tant in determining the morbidity of combined therapy. Jacobs
RectumBowel
Rectal stricture 1 2 1 1
et al.,812 in 102 patients with invasive cervical carcinoma
Proctitis 8 1 13 6 treated with low-dose preoperative irradiation and radical hys-
Rectal ulcer 1 2 1 terectomy with lymphadenectomy or high-dose preoperative
Diverticulitis 1 irradiation and conservative extrafascial hysterectomy, noted a
Small-bowel obstruction 2 3 4 major complication rate of 5%. After combined treatment, some
Malabsorption 3 1 1 degree of lymphedema may be observed (30% to 40%).
Urinary A significant number of complications are associated with
Chronic cystitis 2 12 4 pretherapy staging laparotomy, particularly if irradiation (>55
Bladder ulcer 3 1 2 1 Gy) is given to metastatic para-aortic lymph nodes. The inci-
Incontinence 1 1
Urethral stricture 2 1
dence of complications is between 5% and 20%, depending on
Extensive cystocele 3 the extent of the para-aortic lymph node dissection, use of
transperitoneal or retroperitoneal approach for the operation,
Other
Vaginal stenosis 21 4 7 6 1
and dose of irradiation given.279
Vault necrosis 8 2 2 5
Postoperative pelvic 1 1 2 Late SequelaeOverall
abscess The incidence of major late sequelae of radiation therapy
Lymphocyst 2 2 for stages I and IIA carcinoma of the cervix ranges from 3%
Pulmonary embolus 1 to 5% and for stages IIB and III between 10% and 15%. The
Subcutaneous fibrosis 1 most frequent major sequelae for the various stages are listed
Leg edema 7 3
Hemorrhage 1
in Tables 69.22 and 69.23. Injury to the gastrointestinal tract
Thrombosis of pelvic 1 usually appears within the first 2 years after radiation therapy,
blood vessels whereas complications of the urinary tract are seen more fre-
Arteriosclerosis 1 8 2 quently 3 to 5 years after treatment.570,816 Pedersen et al.,813
Thrombophlebitis 1 in a review of morbidity of radiation therapy in 442 patients
Pelvic fibrosis 1 with cervical cancer stages IIB, III, and IVA, recommended
Acute pelvic cellulitis 1 that actuarial estimates rather than frequency of sequelae be
Neuritis 1 reported to avoid underestimation of risks of late morbidity

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 Chapter 69 Uterine Cervix 1419

8 5

16/406
Severe

8/133
Moderate Severe
4 Moderate

10/298
6

6/170

5/136
6/136
7/189
Percent

Percent
4/133
5/170
8/270

6/242
4

3/86
3/86
6/314
6/314
2

3/353

2/353
2/189
3/270

2/406
1

0/298
0/242
0
6,000 7,0017,500 8,0018,500 >9,500 0
6,0017,000 7,5018,000 8,5019,500 5,000 5,0016,000 6,0017,000 >7,000
A Dose (cGY) Dose (cGy)
FIGURE 69.28. Incidence of moderate or severe complications in small intestine correlated

Clinical Radiation Oncology

12 with doses of irradiation.

7/67
Severe
10
13/155

Moderate
rectal sequelae were cystitis and proctitis (0.7% to 3%). The
8 most common grade 3 sequelae were vesicovaginal fistula
8/131
Percent

(0.6% to 2% in patients with stage I to III tumors), rectovaginal

6
11/314

fistula (0.8% to 3%), and intestinal obstruction (0.8% to 4%). In

5/131

3/67
11/360

the bladder, doses <80 Gy correlated with a <3% incidence of

9/360
8/314

4 morbidity, which was 5% with higher doses (p = .31). In the

5/268

rectosigmoid, the incidence of significant morbidity was <4%

3/268

2/155

2 with doses <75 Gy and increased to 9% with higher doses. For

the small intestine, the incidence of morbidity was <1% with
50 Gy or less, 2% with 50 to 60 Gy, and 5% with higher doses
0
6,000 7,0018,000 8,5019,500 to the lateral pelvic wall (p = .04). Multivariate analysis showed
6,0017,000 8,0018,500 >9,500 that dose to the rectal point was the only factor influencing
B Dose (cGY) rectosigmoid sequelae, and dose to the bladder point affected
bladder morbidity.
FIGURE 69.27. Incidence of moderate or severe genitourinary (A) or rectosigmoid (B)
complications in patients with carcinoma of uterine cervix (all stages) treated with irradia-
In a review of the Patterns of Care Study, Lanciano et al.817
tion alone (external and brachytherapy). A greater frequency of complications is noted with observed a 5-year actuarial rate of 14% for major late compli-
maximum doses of >75 to 80 Gy to the bladder or rectum. cations in 1,558 patients treated with irradiation for invasive
carcinoma of the cervix. Women <40 years of age or with a his-
tory of prior surgery or laparotomy for staging had a greater
after radiation therapy in long-term survivors. In fact, Eifel incidence of significant morbidity (15% to 18% vs. 8% to 9%).
et al.,811 in 1,784 patients with stage IB carcinoma of the cer- In addition, EBRT dose per fraction of >2 Gy, paracentral doses
vix, noted that the greatest risk of sequelae is in the first 3 of 85 Gy or greater, and lateral parametrial doses >60 Gy were
years after therapy. The risk of rectal complications declined independently associated with a higher complication rate.
after the first 2 years of follow-up to 0.6%/year, whereas the Lee et al.,818 using 3-Gy fractions with EBRT, calculated the
risk of major urinary tract complications for survivors contin- rectal point dose in the anterior wall at the level of the cervical os
ued at 0.3%/year, with a 20-year actuarial risk of major com- and noted that total higher BED (142.7 Gy) was associated with
plications of 14.4%. more frequent rectal sequelae compared with BED of <131 Gy.
Montana et al.,524 Perez et al.,814 and Pourquier et al.815 Mitchell et al.124 evaluated 398 patients with stages I to III
noted a greater incidence of complications with higher doses of cervical carcinoma treated with radiation therapy. Patients
irradiation. Perez et al.816 and Pourquier et al.815 reported that were divided into nonelderly (35 to 69 years of age; n = 338)
with doses <75 to 80 Gy delivered to limited volumes, grade 2 and elderly (70 years of age; n = 60) groups. The frequency
and 3 complications in the urinary tract and rectosigmoid were and severity of acute and chronic sequelae were equivalent in
approximately 5%. However, the incidence increased to >10% both groups.
with higher doses of irradiation to these organs (Fig. 69.27).
Doses >60 Gy were also correlated with a greater incidence of Gastrointestinal Toxicity
small-bowel injury (Fig. 69.28). The same analysis showed that When late radiation proctitis occurs, initial treatment is the
patients who experienced sequelae of therapy had slightly bet- same as for acute proctitis. If the symptoms and rectal bleed-
ter survival rates than patients without any complications. This ing persist, laser treatment of rectal telangiectasis or ulcers is
was related to improved tumor control with higher doses of frequently beneficial. Roche et al.819 treated six patients with
irradiation.816 hemorrhagic radiation-induced proctitis using outpatient intra-
Perez et al.814 quantitated the effect of total doses of irradia- rectal application of formaldehyde 4%. In four cases the bleed-
tion, dose rate, and ratio of doses to bladder or rectum and ing ceased after the first formaldehyde application; two patients
point A on sequelae in 1,456 patients treated for cervical can- continued to bleed, but another application 3 weeks later defini-
cer with external-beam irradiation plus two LDR intracavitary tively controlled the hemorrhage. There were no complications,
insertions to deliver 70 to 90 Gy to point A. Median follow-up such as burns or late stenosis of the deep layers of the rec-
was 11 years. In stage IB, the frequency of grade 2 morbidity tum, and this technique was well tolerated. Rubinstein et al.820
was 9%, and in grade 3 it was 5%; in stages IIA, IIB, III, and and Seow-Choen et al.821 also reported treatment of radiation
IVA, the frequency of grade 2 morbidity was 10% to 12% and proctitis with a similar technique. Patients are sedated, a local
that of grade 3 was 10%. The most frequent grade 2 urinary/ anesthetic block is administered, and a sponge moistened with

booksmedicos.org
1420 Section III Clinical Radiation Oncology Part J Gynecologic
4% formalin is applied for 4 minutes to each bleeding area of
the rectum. Care is taken to protect the perianal skin from any
caustic effects of the formalin.
Occasionally, a colostomy is necessary if conservation man-
agement fails. The importance of performing colonoscopy in
patients with rectal bleeding to exclude other lesions in the
colon, including polyps or cancer, is emphasized. If routine
screening colonoscopy is not urgent, unless there is a medical
reason, the colonoscopy may be postponed until 1 year after
pelvic radiation to ensure no issues with poor wound healing,
bleeding, or ulceration secondary to biopsy performed at the
time of colonoscopy.
Anal incontinence is occasionally observed. This sequela
must be assessed in light of a report by Nelson et al.,822 who in a
survey of 6,959 nonirradiated patients, identified 153 (2.2%)
who reported anal incontinence, without specific etiology. Thirty
percent of incontinent subjects were >65 years of age, and 63%
were women. Of those with anal incontinence, 36% were incon-
tinent to solid feces, 54% to liquid feces, and 60% to gas.
Kim et al.823 investigated the effects of radiation on anorec-
tal function using manometry in 24 patients with carcinoma of
the uterine cervix who had late radiation proctitis. These data
were compared with those from 24 age-matched nonirradiated
female volunteers. Regardless of the severity of proctitis symp-
toms, 75% of irradiated patients exhibited abnormal mano-
metric parameters for sensory or motor functions. Radiation
damage to nerves and to the external sphincter muscle was
considered to be an important cause of motor dysfunction.
Quilty824 noted a greater incidence of pelvic complications
in patients treated with higher doses to the whole pelvis (40 to
50 Gy). The author commented that the intracavitary radium
dose was not correlated with severe complications. Similar
observations were made by Stryker et al.825 who recorded a 9%
incidence of fistulas and a 14% incidence of grade 2 and 3 com-
plications in 132 patients after delivery of 50 Gy or higher to the
whole pelvis (1.8-Gy daily dose) combined with intracavitary
insertion. They recommended that the whole-pelvis dose should
not exceed 40 to 45 Gy when doses of approximately 40 Gy are
delivered to point A with LDR intracavitary insertions.
Kuske et al.,719 reported results of therapy in 99 patients
with carcinoma of the cervix on whom minicolpostats were
used, noted a 15% incidence of grade 2 and 3 complications,
which was higher than the 8% incidence noted in a similar
group of patients treated with regular colpostats during the
same period (p = .08).
Perez et al.816 reported that the incidence and type of com-
plications with interstitial therapy were approximately the
same as in patients treated with intracavitary technique only.
In contrast, Kasibhatla et al.826 noted 6% small-bowel obstruc-
tion in 36 women with gynecologic cancer treated with EBRT
and interstitial brachytherapy, which was aggravated by previ-
ous abdominopelvic surgery. The 3-year risk of rectovaginal
fistula was 18%, and it was significantly higher in patients who
received total doses of >76 Gy (100% vs. 7%; p = .009).
Irradiation of the para-aortic lymph nodes has been reported
to cause increased morbidity, particularly if it is done after
transperitoneal staging para-aortic lymphadenectomy. In a ran-
domized study reported by Rotman et al.,827 a somewhat higher
incidence of grade 2 and 3 complications was reported in 170
patients (10 complications) given 45 Gy to the para-aortic area
in addition to standard pelvic irradiation, compared with 5
complications in 167 patients treated by pelvic irradiation only.
The incidence of fatal (grade 5) complications was 4 and 1,
respectively. In a similar randomized study by Haie et al.541 for
the EORTC, the incidence of grade 3 small-bowel injury was
2.3% in the para-aortic irradiation group and 0.9% in the pelvic
irradiationonly group. The overall incidences of severe compli-
cations were 9% and 4.8%, respectively.
Willett et al.828 reported on 28 patients with inflammatory
bowel disease (10 with Crohns disease, 18 with ulcerative coli-
booksmedicos.org
tis) who underwent external-beam abdominal or pelvic irradia-
tion. Patients were treated either by specialized techniques (16
patients) to minimize small- and large-bowel irradiation or by
conventional approaches (12 patients). The overall incidence of
severe toxicity was 46% (13 of 28 patients), and 6 patients (21%)
experienced severe acute toxicity necessitating cessation of
radiation therapy. Late toxicity requiring hospitalization or sur-
gical intervention was observed in 8 of 28 patients (29%). For
patients treated with conventional approaches, the 5-year actu-
arial rate of late toxicity was 73% versus 23% for patients
treated by specialized techniques (p = .02). In patients with
inflammatory bowel disease abdominal or pelvic irradiation,
must be used judiciously.
In contrast, Song et al.,411 in a review of 24 patients with a
history of inflammatory bowel disease who received RT
(median dose of 45 Gy in 1.8- to 3-Gy fractions) to fields encom-
passing some portion of the gastrointestinal tract, noted that 5
patients (21%) experienced acute intestinal toxicity of grade 3
or greater and 2 (8%) had grade 3 or greater late intestinal
toxicity. Fifteen patients also received concurrent chemother-
apy. The authors believed that the gastrointestinal toxicity in
these patients was more modest than generally perceived.
Tiersten and Saltz829 noted that five patients with inflammatory
bowel disease and gastrointestinal malignancy completed
planned radiation therapy (30 to 54 Gy), usually with concur-
rent 5-FU, without difficulty.
Salama et al.443 reported preliminary observations on acute
toxicity with extended-field IMRT in 13 patients with gyneco-
logic cancer. With median follow-up of 11 months, 2 patients
treated with chemoradiation experienced grade 3 or higher
morbidity and 1 (with a history of previous surgeries) devel-
oped small-bowel obstruction.
Levenback et al.830 identified 116 of 1,784 patients (6.5%)
with stage IB carcinoma of the cervix treated with irradiation
in whom hemorrhagic cystitis developed, 23% grade 2
(repeated minor bleeding) and 18% grade 3 (hospitalization
required for medical management). The median interval to
onset of hematuria was 35.5 months. The risk of severe hema-
turia requiring surgical intervention was 1.4% at 10 years and
2.3% at 20 years. Minor episodes of hematuria are managed
by antibiotic therapy. Cystoscopic, laser, or cautery treatment
of bleeding points is indicated. Clot evacuation and continuous
bladder irrigation are important elements in the acute man-
agement of patients with heavy bleeding. Occasionally, a uri-
nary diversion is required for intractable severe hematuria.
Genitourinary Toxicity
Ureteral stricture at 20 years was observed in 2.5% of 1,784
patients with stage IB carcinoma of the cervix treated with
irradiation (274 followed for up to 20 years or longer).831 The
most common presenting symptoms were flank pain and uri-
nary tract infection. In 5 patients, ureteral stricture was compli-
cated by a vesicovaginal fistula. Seven of 43 patients who had
no evidence of cancer and had hydroureter or hydronephrosis
died of radiation complications. Treatment of ureteral stenosis
may consist of stenting or resection of the fibrotic segment and
reimplantation of the ureter with either ureteroneocystostomy
or ureteroileocystostomy. In approximately half of the patients,
diversion of urinary stream and ileal conduits are necessary.
Occasionally, a nephrectomy is performed for removal of a non-
functional kidney. Buglione et al.832 reported a 10% incidence
of late urinary morbidity and 1% ureteral fibrosis, grade III or
IV, in 191 patients. They postulated the role of TGF-1 in the
activation of fibroblasts and remodeling of extracellular matrix,
which may be important in the induction of these sequelae.
Patients with gynecologic malignancies, including those
receiving radiation therapy, are prone to development of urinary
tract infections. Prasad et al.833 collected 216 urine samples from
36 patients receiving pelvic irradiation, 12 of whom had urinary
tract infection. The most common organism isolated was

Escherichia coli, followed by Enterococcus species. Appropriate
urine bacterial studies and cultures are indicated in patients
suspected of having superimposed urinary tract infection dur-
ing the course of radiation therapy.
Parkin et al.834 reported a 26% incidence of severe urinary
symptoms (urgency, incontinence, and frequency) in patients
treated with irradiation alone for cervical carcinoma. They car-
ried out urodynamic studies in 42 women and compared them
with 28 women having urodynamic evaluations before and
after treatment. There was no difference in the mean maxi-
mum flow rate or mean residual volume in the two groups.
However, mean volume of full bladder sensation was signifi-
cantly lower in the postirradiation group than in the pretreat-
ment group, as was the mean maximum cystometric capacity.
This same dysfunction may be noted in approximately 10% of
the general female population, and the incidence increases in
older women.302
Ureteroarterial fistula is a rare occurrence, and it is associ-
ated with a high mortality rate. When profuse urinary tract
bleeding occurs in patients previously diagnosed with a gyne-
cologic malignancy and treated with radiation therapy and
extensive surgery, ureteroarterial fistula should be considered
in the differential diagnoses.835
Neurologic Toxicity
Although extremely rare, lumbosacral plexopathy has been
occasionally reported in patients treated for pelvic tumors with
doses of 60 to 67.5 Gy. This syndrome was observed in 4 of
2,410 patients with cervical or endometrial carcinoma receiv-
ing 45 Gy to the para-aortic lymph nodes (without spinal cord
shielding) or external pelvic irradiation (60 Gy to the parame-
tria) and brachytherapy, with the lumbosacral plexus receiving
total doses of 70 to 79 Gy.836 Lower-extremity paralysis sec-
ondary to lumbosacral plexopathy was reported in one patient
after standard radiation therapy for cervical cancer.837
Patients previously reported as having radiation myelopa-
thy to the lumbar spine may have suffered a lumbar and sacral
nerve plexopathy instead of or in addition to the spinal cord
injury. The differential diagnosis of plexopathy with recurrent
tumors is sometimes difficult. In a comparison of 20 patients
with lumbosacral plexopathy after irradiation and 30 patients
with plexus damage from pelvic malignancy, Thomas et al.838
noted that indolent leg weakness occurred early in radiation-
induced plexopathy (pain occurred initially in 10% of patients,
although ultimately it was present in 50%), whereas pain was
most frequently associated with tumor plexopathy. Muscular
weakness, numbness, and paresthesia are common in both
groups. Electromyography showed abnormal myokymic dis-
charges in 57% of patients, whereas this finding was very
unusual in tumor-induced plexopathy. CT is extremely helpful
in the detection of pelvic masses or bone destruction caused by
tumor. The authors also reported extensive retroperitoneal
fibrosis of the lumbosacral plexus in 2 patients and femoral
nerve fibrosis with plexopathy in 1 patient. Although cystomet-
rograms have demonstrated bladder atonicity in some cases,
several authors have failed to observe bladder or rectal sphinc-
ter disturbances. Unfortunately, as in radiation myelopathy,
the neurologic deficit is irreversible, and no effective therapy
other supportive care has been found.
Sexual Function
Other types of clinically significant sequelae have been
described. Bruner et al.,839 in 90 patients treated with intracavi-
tary irradiation for either carcinoma of the cervix (42 patients)
or endometrial carcinoma (48 patients), 78 of whom also
received external pelvic irradiation (44.5-Gy mean dose), noted
that vaginal length decreased in most patients (at 24 months,
in endometrial carcinoma from 8.8 to 7.8 cm, and in cervical
carcinoma from 7.6 to 6.2 cm). Pretreatment sexual activity
was reported by 31% of women in comparison with 43% after
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Chapter 69 Uterine Cervix 1421
treatment. However, 22% of women reported a decrease in sex-
ual frequency and 37% a decrease in sexual satisfaction. This
was correlated with increased dyspareunia, which was noted
in 31% of women treated for carcinoma of the cervix and 44%
of those treated for endometrial carcinoma. Grigsby et al.840
described complex problems with sexual adjustment in women
with gynecologic tumors treated with radiation therapy, with
decreased frequency of sexual intercourse, desire, orgasm, and
enjoyment of intercourse in 16% to 47% of patients.
Regular vaginal dilation is widely recommended to maintain
vaginal health and sexual functioning; however, the compliance
rate with this recommendation is not consistent. In a study to test
the effectiveness of an information-motivation-behavior skills
model, the intervention improved the use of vaginal dilation after
radiotherapy, and decreased fear about sex after treatment841
There was no evidence that the experimental intervention
improved global sexual health. Jensen et al.842 described persis-
Clinical Radiation Oncology
tent sexual dysfunction throughout 2 years after RT in 118
women; 85% had low or no sexual interest, 35% had lack of
vaginal lubrication, and 55% had mild to severe dyspareunia.
However, 63% of the sexually active patients before RT remained
active, although with decreased frequency.
Radiation causes ovarian failure with a cessation of menses
over a 6-month to 1-year period after treatment. Radiation also
causes uterine fibrosis in a dose-dependent fashion. The dose
required for radical cervical cancer treatment causes sufficient
uterine fibrosis that even if a woman were to become pregnant
through embryo donation, the pregnancy terminates as a still-
birth due to insufficient uterine distensibility.586,843
Bone Toxicity
Grigsby et al.,844 in 1,313 patients with gynecologic tumors
treated with radiation therapy, identified 207 who received pel-
vic irradiation to the inguinal areas, including the hips. Femoral
neck fractures developed in 10 patients (4.8%); 4 were bilat-
eral. The cumulative actuarial incidence of fracture was 11%
at 5 years and 15% at 10 years. Most of the fractures occurred
in patients receiving 45 to 63 Gy, and although radiation dose
could not be correlated with the occurrence of fracture, no frac-
tures were noted in patients receiving <42 Gy. Cigarette smok-
ing and osteoporosis were significant prognostic factors for
increased risk of fracture.
A retrospective cohort study using SEER cancer registry data
linked to Medicare claims data analyzed 6,428 women of age 65
years and older diagnosed with pelvic malignancies from 1986
through 1999, and compared results for women who did (n =
2,855) with those who did not (n = 3,573) undergo radiation ther-
apy. Results demonstrated that women who underwent radia-
tion therapy were more likely to have a pelvic fracture than
women who did not undergo radiation therapy. The cumulative
5-year fracture rate was 8.2% versus 5.9% in women with cervi-
cal cancer; the difference was statistically significant, and most
fractures (90%) were hip fractures.845 Concurrent chemoradia-
tion may result in a higher risk than for patients treated with RT
alone because the highest fracture rates were seen in patients
with anal carcinoma treated with concurrent chemoradiation.
Blomlie et al.846 reported radiation-induced insufficiency
fractures of the pelvis on MRI (characterized by edema on
T1-weighted images) in 16 of 18 women (9 premenopausal and
9 postmenopausal) with advanced cervical carcinoma. During
the study, the fractures associated with edema subsided without
treatment in 41 of 52 (79%) lesions in 15 of 16 (94%) patients.
Moreno et al.847 described eight patients with pelvic cancer who
developed insufficiency fractures after pelvic irradiation, with an
average onset 13.7 months after treatment. The bone and CT
scan showed abnormalities in the sacroiliac joint in all cases and
in the pubis in three cases. In five patients, the initial diagnosis
was incorrectly labeled as bone metastases.
Huh et al.848 reported on 463 patients treated for cervical
cancer with RT alone, 1.7% of whom developed insufficiency
1422 Section III Clinical Radiation Oncology Part J Gynecologic
fractures between 7 and 19 months (median, 12 months) after
treatment. All had resolution of symptoms within <1 year with
conservative therapy, including nonsteroidal anti-inflammatory
medication and rest.
The most common complaint is persistent low back pain.
Insufficiency fractures may be falsely diagnosed as metastases
on PET/CT. The most common form of treatment is conserva-
tive management, followed by sacroplasty with polymethyl-
methacrylate. Bye et al.849 assessed health-related quality of
life (HRQOL) at 3 to 4 years after pelvic radiation therapy for
carcinoma of the endometrium and cervix in 94 survivors, 79
(84%) of whom answered a survey. The treated women scored
lower than the general population on role functioning (81.5 vs.
90.6; p < .01) and higher on diarrhea (23.8 vs. 9.5; p < .01).
Compared with pretreatment conditions, an increase in cases
with pain in the lower back, hips, and thighs was seen and was
associated with deterioration in HRQOL.
Toxicities Related to Brachytherapy
Descriptions of sequelae vary among institutions because tox-
icity-grading scales are not uniform and the scoring system for
complications is not clearly stated in all reports. It is helpful
to institute preventive measures when initiating radiation; for
example, Dusenbery et al.850 reported 21 (6.4%) life-threatening
complications in 327 of 462 patient implants. Lanciano et al.,851
in 95 tandem and ovoid insertions for cervical cancer in
91 patients and for endometrial cancer in 4, observed 2 uterine
perforations and a vaginal laceration in 2 patients. Twenty-four
percent of implants in 16 patients were associated with tem-
peratures >100.5F. Five implants (5%) were removed because
of presumed sepsis, pulmonary disease, arterial hypotension,
change in mental status, and myocardial infarction.
Jhingran and Eifel,852 in 4,043 patients with carcinoma of
the cervix who had undergone 7,662 intracavitary procedures,
observed 11 (0.3%) documented or suspected thromboembo-
lisms, resulting in 4 deaths; the incidence of postimplant throm-
boembolism did not decrease significantly with the routine use
of minidose heparin prophylaxis. Other life-threatening periop-
erative complications included myocardial infarction (1 death
in 5 patients), cerebrovascular accident (2 patients), congestive
heart failure (3 patients), and halothane liver toxicity (2 deaths).
Intraoperative complications included uterine perforation
(2.8%) and vaginal laceration (0.3%), which occurred more fre-
quently in patients 60 years of age or older (p < .01).
Wollschlaeger et al.853 reported morbidity during hospital-
ization in 128 patients with cervical carcinoma undergoing 110
LDR intracavitary brachytherapy insertions. Forty-two implants
(24.7%) were associated with acute problems; the most com-
mon were fever/infection (14.1%) or gastrointestinal problems
(5.9%).
Acute gastrointestinal side effects of pelvic irradiation include
diarrhea, abdominal cramping, rectal discomfort, and occasion-
ally rectal bleeding, which may be caused by transient entero-
proctitis. Patients with hemorrhoids may experience discomfort
earlier than other patients. Diarrhea and abdominal cramping
can be controlled with the oral administration of diphenoxylate
hydrochloride, with loperamide, atropine sulfate, or opium
preparations or emollients such as kaolin and pectin. Proctitis
and rectal discomfort can be alleviated by small enemas with
hydrocortisone and anti-inflammatory suppositories containing
bismuth, benzyl benzoate, zinc oxide, or Peruvian balsam. Some
suppositories contain cortisone. Small enemas with cod liver oil
are also effective. A low-residue diet with no grease or spices
and increased fiber in the stool (psyllium, polycarbophil) usually
helps to decrease gastrointestinal symptoms.
Genitourinary symptoms secondary to cystourethritis are
dysuria, frequency, and nocturia. The urine is usually clear,
although there may be microscopic or even gross hematuria.
Methenamine mandelate and antispasmodics such as phenazo-
pyridine hydrochloride or a smooth muscle antispasmodic such
booksmedicos.org
as flavoxate hydrochloride, hyoscyamine sulfate, oxybutynin
chloride, or tolterodine tartrate can relieve symptoms. Fluid
intake should be at least 2,000 to 2,500 mL daily. Urinary tract
infections may occur; diagnosis should be established with
appropriate urine culture studies, including sensitivity to sulfon-
amides and antibiotics. Therapy should be promptly instituted.
Erythema and dry or moist desquamation may develop in
the perineum or intergluteal fold. Proper skin hygiene and top-
ical application of petroleum jelly, petrolatum, or lanolin should
relieve these symptoms. U.S.P. zinc oxide ointment and inten-
sive skin care may be needed for severe cases.
Management of acute radiation vaginitis includes douching
every day or at least three times weekly with a 1:5 mixture of
hydrogen peroxide and water. Douching should be continued
on a weekly basis until the mucositis has resolved or for 2 or
3 months as necessary. Superficial ulceration of the vagina
responds to topical (intravaginal) estrogen creams, which stimu-
late epithelial regeneration within 3 months after irradiation.
Use of vaginal dilators several times daily, started during the
course of treatment, prevents vaginal stenosis. Psychoeducational
intervention and motivation improve the compliance in use of
dilators.854 More-severe necrosis may require debridement on a
weekly basis until healing takes place. Judicious use of biopsies
is recommended to rule out persistent or recurrent cancer.
Petereit et al.855 reported 16 acute events (9.5%) in 169
patients treated with HDR brachytherapy (128 with cervical
cancer also receiving external irradiation, and 41 medically
inoperable endometrial carcinomas). The overall 30-day mor-
bidity rate for the patients with cervical cancer was 5.5%, and
the 30-day mortality rate was 1.6% (2 patients; 1 died of pul-
monary edema 12 days after first HDR insertion and the other
had enteritis and died in a nursing home).
The complication rates for HDR and LDR techniques are
usually equivalent.608,610 Petereit et al.606 observed a 12% 3-year
actuarial overall toxicity (2.6% genitourinary and 5.6% rectum)
with LDR, compared to 15% overall (3% genitourinary and
4.6% rectum) with HDR brachytherapy. However, in the series
by Cikaric,711 the rectal complication rate was significantly
higher in the LDR group. Bladder complication rates reported,
in general, are lower than rectal complication rates; again,
except for the series by Cikaric711 showing a higher complica-
tion rate with the LDR technique, there were no significant dif-
ferences with the two techniques.
Ogino et al.,856 in 253 patients with invasive carcinoma of
the cervix treated with HDR brachytherapy, noted that grade 4
rectal complications were not observed in patients with a time
dose factor of <130 or biologic equivalent dose of <147, assum-
ing an / ratio of 3 Gy for late reactions.
Spontaneous intraperitoneal rupture of the urinary bladder,
an extremely rare event, was reported by Fujikawa et al.857
after radiation therapy for cervical cancer in 6 of 148 patients
treated with HDR intracavitary brachytherapy combined with
EBRT. All 6 patients underwent laparotomy and repair of the
perforation; however, rerupture of the bladder occurred in 3 of
these patients.
Clark et al.858 reported on 43 patients treated with pelvic
EBRT (46 Gy) and three HDR intracavitary treatments given
weekly combined with concomitant chemotherapy (cisplatin,
30 mg/m2 weekly) for advanced carcinoma of the cervix. At 40
months after treatment, 9 of 13 patients who received a dose to
the rectal reference point greater than the prescribed point A
dose had a 46% actuarial rate of serious (grade 3 and 4) rectal
complications, compared with 14% in the remainder. A strong
dose response was observed, with a threshold for complica-
tions at a brachytherapy dose of 8 Gy per fraction.
Hyperbaric Oxygen
In 13 patients with hemorrhagic cystitis treated with hyper-
baric oxygen, all but 1 experienced durable cessation of hema-
turia.859 Lee et al.860 also noted that, in 16 of 20 patients (80%)

with hemorrhagic radiation cystitis, significant improvement
was observed after treatment with hyperbaric oxygen at 2.5 atm
(44 sessions).
Several reports evaluated the efficacy of hyperbaric oxygen
combined with irradiation in the treatment of a variety of human
tumors, including carcinoma of the uterine cervix. Watson
et al.,861 in a randomized clinical trial of 320 patients (stages III to
IVA), reported a 5-year survival rate of 33% in the oxygen-treated
group in contrast to 27% in the control group treated in normal
air (p = .08). The local recurrence rate was 33% in the 161
patients treated with oxygen and 53% in 159 patients treated in
normal air (p < .001). Morbidity in the patients treated with oxy-
gen was greater (20 severe and 13 moderate complications) than
in those treated in normal air (6 severe and 8 moderate compli-
cations, respectively). The difference was particularly striking in
the bowel (13 and 2 severe complications, respectively).
Dische et al.862 reviewed the data in a randomized study of
patients with advanced carcinoma of the cervix treated with
radiation therapy and hyperbaric oxygen or air and noted that
the patients treated with oxygen had improved survival at
Mount Vernon and Glasgow but not at Cape Town. Data from
the three centers were merged, and analysis showed that local
tumor control was significantly worse in patients treated in
normal air who had a prior blood transfusion, but in the oxy-
gen group this effect was reversed. The same interaction was
noted in the survival results (p = .042).
A trial reported by Fletcher165 in which 233 patients with
stages IIB, III, and IV carcinoma of the cervix were randomized
to be treated with irradiation in normal air or with hyperbaric
oxygen demonstrated no significant benefit in survival or
tumor control (20 of 109 patients treated with oxygen failed in
the pelvis, in contrast to 29 of 124 treated in normal air).
Furthermore, morbidity was greater (26 complications) in
patients treated with hyperbaric oxygen compared with the
control group (15 complications).
Dische et al.862 published results of a four-arm randomized
trial of hyperbaric oxygen and radiation therapy of stages IIB
and III carcinoma of the cervix in which 335 patients were ran-
domized to treatment in 10 or 28 fractions in hyperbaric oxy-
gen or in normal air. Data from 327 cases were analyzed.
There was no advantage in tumor control with the use of
hyperbaric oxygen. There was an increase in late radiation
morbidity when treatment was given in hyperbaric oxygen
rather than in normal air, and when using 10 fractions, a total
dose of 45 Gy rather than 40 Gy was administered.
No definite conclusions can be drawn concerning the use of
hyperbaric oxygen in carcinoma of the cervix. It is possible
that hyperbaric oxygen administered with fewer high-dose
fractions may be more efficacious than when combined with
conventional dose and fractionation schemes. The trials
reported have not shown an increased incidence of distant
metastasis, which has been observed in a clinical study and in
some animal experiments.863
Hormonal Replacement After Treatment
of Cervical Cancer
After pelvic irradiation or bilateral salpingo-oophorectomy,
usually carried out with a radical hysterectomy in patients
treated for carcinoma of the uterine cervix, symptoms of
menopause may occur. They can be treated with replacement
hormones, although some gynecologists have expressed res-
ervations. During the past 25 years, hormonal replacement
therapy has been shown to reduce the risk of cardiovascular
diseases, osteoporotic fractures, and colon carcinoma. On the
other hand, there is a significant increase of the risk in breast
cancer with prolonged use of estrogen plus progesterone for
>5 years. Consideration may be given to progesterone alone,
which does not increase the risk of endometrial cancer but has
potential thromboembolic risks.864
booksmedicos.org
Chapter 69 Uterine Cervix 1423
Burger et al.865 concluded that squamous cell cancers of the
cervix, vulva, and vagina are unlikely to be influenced by hor-
monal replacement therapy. In a study of women 50 years of
age or younger with ovarian cancer, estrogen replacement
therapy did not have a negative influence on disease-free sur-
vival. Long-term hormonal replacement therapy in women
treated for a gynecologic cancer must be based on the medical
history of and discussion of risk with the individual patient
(and her family when warranted). Usually, 0.625 to 1.25 mg of
coagulated estrogen daily is sufficient.866
Second Malignancy
The risk for induction of secondary primary cancers by pelvic
irradiation is low, and many potential confounders are either
unknown or may not be fully accounted for, given available
information.867 Using the population-based cancer registries
Clinical Radiation Oncology
of Denmark, Finland, Norway, Sweden, and the United States,
Chaturvedi et al.868 found a significantly increased cancer risk
in both SCC and AC survivors, with standardized incidence
ratio of 1.31 (95% CI = 1.29 to 1.34) and 1.29 (95% CI = 1.22
to 1.38), respectively. The risk of smoking-related lung can-
cer was higher in the SCC than in the AC population, whereas
second malignancies of the colon, soft tissue, melanoma, and
non-Hodgkin lymphoma were higher in the AC population.
Similarly, 1-year survivors of cervical cancer had an increased
risk of HPV-related cancers, including pharynx, genital, and
anal cancers. Higher hazard ratios for second cancer of the
rectum, anus, bladder, and genital sites was seen for younger
patients, with a 40-year cumulative risk of any second cancer
of 22% for women diagnosed with cervical cancer before age
50 years versus 16% for those diagnosed at age >50 years.869
In contrast, Lee et al.870 observed no significant increase in
the incidence of second malignancies in patients irradiated for
carcinoma of the cervix in comparison with the Connecticut
Tumor Registry prevailing rates.
Boice et al.,339 in a review of 68,730 women with carcinoma
of the cervix treated with radiation therapy, observed a second
malignant tumor in 3,324, compared with 3,063 expected
(4.8% increase; p < .001). The excess was concentrated in the
lung, other genital organs, bladder, and rectum. In addition, in
10,817 women with invasive cervical cancer not treated with
irradiation, 479 secondary malignant tumors were observed
versus 435 expected (4.4%; p = .02). Thus, the incidence of
secondary tumors in women treated for carcinoma of the cer-
vix with or without irradiation is only slightly greater than in
the general population. Pelvic organs receiving a high dose of
irradiation appear to have a somewhat greater incidence of a
second primary.
Storm,871 in a comprehensive analysis of the Danish Cancer
Registry data of 24,970 women with invasive cervical cancer
and 19,470 with carcinoma in situ of the cervix treated between
1943 and 1982, noted a small overall excess of secondary pri-
mary cancers in the lung, stomach, pancreas, rectum, and blad-
der and connective tissue sarcomas, although there was a
decreased incidence of breast cancer in the irradiated patients
compared with nonirradiated patients (attributable to ovarian
ablation by radiation therapy). In the patients irradiated for
invasive carcinoma, there was an excess of 64 cases per 10,000
women per year of tumors in organs close to or at an intermedi-
ate distance from the cervix, reaching a maximum after 30 years
or longer of follow-up. A high risk for development of acute non-
lymphatic leukemia was observed in irradiated patients with
carcinoma in situ but not in those with invasive lesions. This
could be explained by the lower doses of irradiation delivered to
the bone marrow in the in situ tumors treated with brachyther-
apy alone, with greater induction of mutations and less cell kill-
ing, which may be responsible for the leukemogenic effect.
Decreased risk was noted for tumors of the brain, myeloma of
the skin, and tumors of the colon other than rectal.
1424 Section III Clinical Radiation Oncology Part J Gynecologic
In a study of 117,830 women diagnosed with cervical carci-
noma in situ and 17,556 with invasive cervical carcinoma in
Sweden, treatment not specified and in situ lesions traditionally
treated with surgery alone, there was an increased incidence
(RR = 2.3 to 3) of second primary tumors in the anus, rectum,
urinary bladder, pancreas, esophagus, and lung compared with
the standardized incidence rate for all women.872 The data
showed consistent increases in suggested targets for HPV at
tobacco-related sites. A contributing role for a depressed
immune response was considered.
Werner-Wasik et al.,873 in an analysis of 125 women with
stages I and II carcinoma of the cervix treated with radiation
therapy, observed 11 secondary primary tumors in 10 patients
(4 breast, 2 lung, and 1 each of myeloma, non-Hodgkin lym-
phoma, bladder, thyroid, and vulva). All secondary primary
tumors were located outside the irradiation fields. The increased
relative risk of breast cancer in these patients was 2.64, higher
than reported by Boice et al.339
In an analysis of 199,268 individuals by Wright et al.,874 the
risk of secondary leukemia increased 72% in patients who
received pelvic radiotherapy, with a peak at 5 to 10 years after
treatment; there was no increased risk of multiple myeloma.
Mark et al.875 identified 13 of 114 patients diagnosed with uterine
sarcoma who had a prior history of pelvic irradiation (doses of
40 to 80 Gy). Criteria for radiation-induced sarcomas included a
prior history of pelvic irradiation, a latent period of several years,
development of sarcoma within previously irradiated field, and
histologic confirmation of malignancy. Histologic types of tumor
were mixed Mllerian in 6, leiomyosarcoma in 4 patients, endo-
metrial stroma sarcoma in 1, fibrosarcoma in 1, and angiosar-
coma in 1. Sarcoma developed in the uterus in 12 patients and
at the vaginal cuff in 1 patient. Ten patients were treated with
surgery and 2 with radiation therapy. The 5-year disease-free
survival rate after salvage therapy was 17%.
In a theoretical analysis of IMRT risk in postoperative cases
relative to three-dimensional conformal radiotherapy, the esti-
mated increase in second cancer risk was 6% for 6-MV IMRT
and 26% for 18 MV IMRT, with large increases in organs away
from the primary beam and skin because with IMRT a much
larger volume of skin was exposed.876
Seidman et al.877 reviewed 15 cases of second malignancies
after pelvic radiation; 5 were HPV-related vaginal primary
tumors. The average latency period for development was
approximately 20 years.
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776. Hintz BL, Kagan AR, Chan P, et al. Radiation tolerance of the vaginal mucosa. Int
J Radiat Oncol 1980;6:711716.
811. Eifel PJ, Levenback C, Wharton JT, et al. Time course and incidence of late com-
plications in patients treated with radiation therapy for FIGO stage IB carcinoma
of the uterine cervix. Int J Radiat Oncol Biol Phys 1995;32:12891300.
814. Perez CA, Grigsby PW, Lockett MA, et al. Radiation therapy morbidity in carci-
noma of the uterine cervix: dosimetric and clinical correlation. Int J Radiat Oncol
Biol Phys 1999;44:855866.
827. Rotman M, Pajak TF, Choi K, et al. Prophylactic extended-field irradiation of
para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas.
Ten-year treatment results of RTOG 7920. JAMA 1995;274:387893.
839. Bruner DW, Lanciano R, Keegan M, et al. Vaginal stenosis and sexual function
following intracavitary radiation for the treatment of cervical and endometrial
carcinoma. Int J Radiat Oncol Biol Phys 1993;27:825830.
845. Baxter NN, Habermann EB, Tepper JE, et al. Risk of pelvic fractures in older
women following pelvic irradiation. JAMA 2005;294:25872593.
851. Lanciano R, Corn B, Martin E, et al. Perioperative morbidity of intracavitary
gynecologic brachytherapy. Int J Radiat Oncol Biol Phys 1994;29:969974.
852. Jhingran A, Eifel PJ. Perioperative and postoperative complications of intracavi-
tary radiation for FIGO stage I-III carcinoma of the cervix. Int J Radiat Oncol Biol
Phys 2000;46:11771183.
876. Zwahlen DR, Ruben JD, Jones P, et al. Effect of intensity-modulated pelvic radio-
therapy on second cancer risk in the postoperative treatment of endometrial and
cervical cancer. Int J Radiat Oncol Biol Phys 2009;74:539545.
899. Logsdon MD, Eifel PJ. Figo IIIB squamous cell carcinoma of the cervix: an
analysis of prognostic factors emphasizing the balance between external beam
and intracavitary radiation therapy. Int J Radiat Oncol Biol Phys 1999;43:
763775.
1426 Section III Clinical Radiation Oncology Part J Gynecologic
Chapter 70
Endometrial Cancer
Kaled M. Alektiar
ANATOMY
The uterus is a hollow, muscular organ located in the true pel-
vis between the bladder and the rectum. The average adult
uterus is about 8 cm long, 5 cm wide, and 2.5 cm thick. It is
divided into the fundus, body (corpus), and cervix. The junction
between the body and cervix is called the isthmus. The fundus
is pierced at each cornu by the fallopian tubes. The uterine
surface is partially covered by peritoneum. The uterine cavity
is lined by endometrium, made up of columnar cells forming
many tubular glands. The thickness of the endometrium var-
ies during the menstrual cycle, but by the end of menstruation
it should be 2 to 3 mm in thickness. The wall of the uterus is
composed of myometrium, consisting of smooth muscle fibers.
The major supports of the uterus are the broad, round, utero-
sacral and cardinal ligaments. The major blood supply to the
uterus is the uterine artery, which enters the uterus at the
isthmus after it crosses over the ureter. The lymphatic drain-
age for the body of the uterus is mainly to the obturator and
internal and external iliac lymph nodes. The lymphatics from
the fundus accompany the ovarian artery and drain into the
para-aortic lymph nodes.
EPIDEMIOLOGY AND RISK FACTORS
Endometrial cancer is the most common gynecologic cancer
and the fourth most frequently diagnosed cancer in women
in the United States. According to 2011 cancer statistics, the
estimated number of newly diagnosed cases is 46,470, with a
probability of 1 of every 39 women (2.58%) developing it dur-
ing her lifetime.1 Although it is a cancer that affects predomi-
nantly postmenopausal women, 5% to 30% of women are <50
years of age at the time of diagnosis.2,3 The expected number of
deaths from endometrial cancer in 2011 was 8,120, making it
the eighth-leading cause of death from cancer in women. Prior
estimates on the death rate from endometrial cancer seemed to
indicate that the rate was on the rise, but the most recent data
show that the death rate of 4.18 per 100,000 women did not
change from the year 1990 to 2007.1
The age-standardized rate per 100,000 for endometrial
cancer in more developed areas of the world is 12.9, with a
cumulative risk of 1.6% (age 0 to 74 years), compared to 5.9
and 0.7%, respectively, in less developed areas, indicating a
possible influence of environmental factors on the incidence of
this disease.4 The exact etiology of endometrial cancer remains
unknown, but several risk factors have been associated with it,
chiefly unopposed estrogen. It is well established that endome-
trial cancer risk is increased among women who have high
circulating levels of bioavailable estrogens and low levels of
progesterone, so that the mitogenic effect of estrogens is insuf-
ficiently counterbalanced by the opposing effect of progester-
one.57 The source of unopposed estrogen could be endogenous
or exogenous. In a casecontrol study, the association between
endogenous estrogen and endometrial cancer was demon-
strated. In that study there was correlation between high blood
concentrations of estrogens and increased risk of endometrial
cancer.7 Lifetime cumulative number of menstrual cycles, that
is, menstruation span, is associated with increased risk of
developing endometrial cancer. This is due to the fact that
endometrial cell proliferation increases during the follicular
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phase, which is the longest in the menstrual cycle. Thus, early
age at menarche (estimated relative risk [RR], 1.5 to 2) and
late age at menopause (RR, 2 to 3), examples of increased
menstruation span, are risk factors for endometrial cancer.8,9
Nulliparity (RR, 3) is also associated with increased risk of
endometrial cancer8 due in part to anovulatory menstrual
cycles. Obesity increases endometrial cancer risk (RR, 5)
mainly through changes in endogenous hormone metabolism.
After menopause, when ovarian production of both estrogen
and progesterone ceases, the major source of estrogen is via
peripheral conversion, mostly within adipose tissue, of andro-
gens that continue being produced by the adrenal glands and
ovaries. Thus with obesity there is an increase in the amount
of bioavailable estrogens in the circulation and the endometrial
tissue.7,10,11 Obesity may also influence endometrial cancer risk
via chronic hyperinsulinemia, which appears to be a key factor
for the development of ovarian hyperandrogenism, associated
with anovulation and progesterone deficiency, especially for
premenopausal women.10 Noninsulin-dependent diabetes
mellitus and hypertension (RR, 13) also increases the risk of
endometrial cancer. This is often believed to be secondary to
obesity, but there are data showing that these risk factors could
be independent of obesity.12,13,14 With regard to exogenous
estrogen, it is well established that the use of estrogen-only
hormone-replacement therapy and sequential oral contracep-
tives greatly increases endometrial cancer risk (RR, 10 to 20),
whereas combined preparations, that is, those that contain a
progestogen as well as estrogen throughout the treatment
period, have a protective effect (RR, 0.3 to 0.5).1516,17 The use
of tamoxifen in patients with breast cancer has been associ-
ated with increased risk (RR, 3 to 7) of endometrial cancer.18,1920
The mechanism of action of tamoxifen is in competition with
that of endogenous estrogen for estrogen receptors. In pre-
menopausal women, tamoxifen has an antiestrogenic effect,
but in postmenopausal women it has a weak estrogenic effect
because of the upregulation of estrogen receptors. In a recent
meta-analysis on adjuvant tamoxifen and endometrial cancer,
for patients who were <55 years of age there was little absolute
risk compared to patients in of 55 to 69 years of age, for whom
the 15-year incidence was 3.8% in the tamoxifen group versus
1.1% in the control group (absolute increase 2.6% [standard
error 0.6], 95% confidence interval [CI] = 1.4 to 3.8), highlight-
ing the influence of age on the risk of endometrial cancer from
tamoxifen use.21 Initial data seemed to indicate that the major-
ity of endometrial cancers associated with tamoxifen use were
of early stage with favorable features.22 More recent data, how-
ever, show a change in the profile of these endometrial can-
cers, with a rise in the rate of serous, clear-cell, carcinosar-
coma, and sarcoma types.23,24 Inherited genetic predisposition,
especially in the setting of hereditary nonpolyposis colorectal
cancer (HNPCC), probably accounts for <5% of all endometrial
cancer cases. Mutations in one of the four mismatch repair
genes hMLH1, hMSH2, hMSH6, or hPMS2 have been identified
in patients with Lynch syndrome. Although HNPCC is thought
of primarily in terms of risk of developing colorectal cancer, it
is important to note that lifetime cumulative risk of endome-
trial cancer for women with HNPCC is 40% to 60%, which
equals or exceeds their risk of colorectal cancer.25 There seems
to be a high rate of lower uterine segment involvement in
patients with HNPCC-associated endometrial cancer.26

CLINICAL PRESENTATION AND
NATURAL HISTORY
The most common presentation for endometrial cancer is
postmenopausal vaginal bleeding, which is reported by 80%
to 90% of patients. The incidence of endometrial cancer in
women presenting with postmenopausal bleeding is only 10%
to 15%. This incidence, however, could range from 1% up to
25%, depending on patient age and the presence of other risk
factors. In a recent repot of a total of 3,548 women present-
ing with postmenopausal vaginal bleeding, 201 (6%) had a
diagnosis of endometrial carcinoma. Use of a multiple logistic
regression model showed that recurrent episodes of bleeding
(odds ratio [OR], 3.64), a history of diabetes (OR, 1.48), older
age (1.06), and high body-mass index (OR, 1.07) increased
the risk of endometrial malignancy when corrected for other
characteristics.27 Other patterns of presentations include vagi-
nal discharge, abnormal Papanicolaou smear, or thickened
endometrium on routine transvaginal ultrasound. For patients
with advanced disease, they may present with urinary or rec-
tal bleeding, constipation, pain, lower-extremity lymphedema,
abdominal distension due to ascites, and cough and/or or
hemoptysis.
The International Federation of Gynecology and Obstetrics
(FIGO) annual report28 showed that the 5-year survival rate for
8,110 patients with endometrial cancer treated between 1999
and 2001 was 80%. Such excellent outcome is a reflection of
the fact that the majority of patients are diagnosed with early-
stage disease. The tumor was limited to the corpus uteri in
71% of cases, involved the cervix in 12%, and extended beyond
the uterus, but short of distant spread, in 13%. For patients
with disease limited to the endometrium or with <50% myome-
trial invasion, the 5-year survival rate was 91%. However, the
rate dropped to 66% when disease extended to adnexa/serosa/
positive peritoneal cytology, to 57% with regional lymph node
involvement, to 25.5% with bladder or rectal involvement, and
to 20% with distant spread. For clinically staged patients, the
5-year survival rate ranged from 67% for early-stage disease
down to 15% for advanced disease. Mass screening for endo-
metrial cancer in women at average risk or increased risk due
to a history of unopposed estrogen therapy, tamoxifen therapy,
late menopause, nulliparity, infertility or failure to ovulate,
obesity, diabetes, or hypertension is not recommended.
American Cancer Society (ACS) recommends that women at
average and increased risk should be informed about risks and
symptoms (in particular, unexpected bleeding and spotting) of
endometrial cancer at the onset of menopause and should be
strongly encouraged to immediately report these symptoms to
their physician. However, screening has been recommended
A B
FIGURE 70.1. Sagittal view of the uterus on transvaginal ultrasound. A: Normal thin endometrium (arrow). B: Thickened endometrium (arrow).
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Chapter 70 Endometrial Cancer 1427
by the ACS for women who carry, or are related to carriers of,
the HNPCC mutation, starting at age 35 years, including annual
transvaginal ultrasound and endometrial biopsy.29 Prophylactic
hysterectomy and bilateral salpingo-oophorectomy once child-
bearing is completed have been shown to effectively reduce the
risk of endometrial cancer in patients with HNPCC and should
be strongly considered.30
DIAGNOSTIC WORKUP
Endometrial tissue sampling remains the gold standard by
which the diagnosis of endometrial cancer is established.
This is achieved via biopsy or dilatation and curettage (D&C).
Endometrial biopsy, which can be easily performed in the office
with a Pipelle or similar device, is the preferred approach. Its
sensitivity in detecting endometrial cancer in postmenopausal
women is 99.6% compared to 91% in premenopausal women.
Clinical Radiation Oncology
Its specificity is >98% for both groups.31 If the patient is under-
going hysterectomy, routine D&C is not necessary after an
office Pipelle sampling has documented malignancy. However,
if symptoms persist, the office sampling is inadequate, or the
patient is being considered for conservative fertility-sparing
approaches, a D&C should be performed. In addition, D&C pro-
vides more reliable assessments of final pathologic findings in
hysterectomy specimens, mainly with regard to tumor grade.32
Given that the incidence of endometrial cancer in women with
postmenopausal bleeding is only 10% to 15%, it is unclear how
feasible it is to perform endometrial sampling on every patient.
Transvaginal ultrasonography (TVU) may be considered as a
useful tool to assess patients vaginal bleeding.33 Normal endo-
metrium looks thin and homogeneously hyperechoic, but it is
thickened and heterogeneous, with hyperplasia, polyps, and
cancer,34 as shown in Figure 70.1. The consensus statement
from the Society of Radiologists in Ultrasound defines an endo-
metrial thickness of 5 mm or greater as being abnormal.35 If
the thickness of the endometrium is <5 mm, the risk of endo-
metrial cancer is minimal; the false-negative rate is about 4%.
Under such circumstances, endometrial sampling may be fore-
gone if no further episodes of vaginal bleeding occur.33 Recent
meta-analysis seems to indicate that perhaps a cut-off of 3-mm
thickness rather than <5 mm provides even better diagnostic
accuracy.36 If the TVU is abnormal but the biopsy is negative/
nondiagnostic or the uterine cavity is inaccessible, then saline-
infusion sonography or hysteroscopy should be considered to
help exclude intracavitary lesions, especially polyps that might
contain cancer.37,38 In addition, these methods are also helpful
in premenopausal women, for whom the accuracy of TVU is
limited because the endometrial thickness fluctuates, depend-
ing on the level of female hormones. The potential downside to
1428 Section III Clinical Radiation Oncology Part J Gynecologic
A B
FIGURE 70.2. Sagittal magnetic resonance imaging view of the uterus. A: Normal uterus. B: Deep myometrial invasion (arrows).
saline infusion or hysteroscopy is that there have been reports
that the insufflation of the distending medium into the canal
has been associated with an increase in positive peritoneal
cytology, although the prognostic implications are unclear of
such positive cytology induced by sampling.39 Several imag-
ing studies are available to define the extent of disease pre-
operatively. Good-quality pelvic computed tomography (CT)
scans obtained with oral and intravenous contrast can dem-
onstrate the extent of the endometrial tumor. The endometrial
carcinoma is a hypodense mass relative to the normal myo-
metrium and may be seen as a diffuse, circumscribed vegeta-
tive or polypoidal mass within the uterine cavity. If myometrial
invasion is seen, it usually implies involvement of greater than
one-third to one-half of the myometrial thickness. Involvement
of the cervix is seen on CT as cervical enlargement >3.5 cm
in diameter with heterogeneous low-attenuation areas within
the fibromuscular stroma. Parametrial or sidewall extension is
seen by the loss of periureteral fat in the former and <3 mm
of intervening fat between the soft tissue mass and the pelvic
sidewall in the latter. Involvement of the fallopian tubes and
ovaries is detected in the usual fashion, and for lymph nodes
is >1 cm in diameter in the short axis.40,41 Magnetic resonance
imaging (MRI) is considered the most accurate imaging study
to assess tumor extension in endometrial cancer, especially
myometrial invasion. Dynamic contrast-enhanced MRI is the
optimal MRI method for detecting myometrial invasion,42 with
an accuracy of 85% to 93%. A clear junctional zone or preser-
vation of a sharp delineation between the tumor and the myo-
metrium implies disease limited to the endometrium. Disease
characterized by disruption of the junctional zone, increased
signal-intensity tumor in the inner half of the myometrium
with preservation of the outer myometrium, or both correlate
with superficial myometrial invasion. If there is extension of
the highsignal-intensity tumor into the outer myometrium
with preservation of a peripheral rim of normal, intact myo-
metrium, then that is considered deep myometrial invasion
(Fig. 70.2). MRI also helps to delineate tumor extension into
the cervix. The normal cervical stroma is hypointense on
T2-weighted images and is replaced by intermediatesignal-
intensity tumor in cases of invasion.34 The reported sensitiv-
ity of MRI in detecting lymph node metastasis is 27% to 66%
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and the specificity is 73% to 94% in surgically staged patients.43
Positron emission tomography/computed tomography (PET/
CT) is also being used in endometrial cancer. There seems to
be little benefit in assessing the primary tumor extension. With
regard to regional lymph node metastasis, the reported sen-
sitivity is 50% to 100%, the specificity is 87% to 100%, and
the accuracy is 78% to 100%. The main limitation of PET/CT
is its inability to detect metastasis in lymph nodes 5 mm in
size.43 The FIGO staging for endometrial cancer is a surgical
staging, and thus preoperative imaging studies (except chest
x-rays) are not part of the staging. Cancer antigen 125 (CA
125) serum levels could be elevated in patients with endome-
trial cancer. Kim et al.,44 in a review of 413 patients, found that
23.9% of patients had >35 U/mL serum CA 125 levels. Hsieh
et al.45 found that preoperative levels of >40 U/mL correlated
significantly with regional lymph nodes metastasis and sug-
gested that such levels could be used as an indication for full
pelvic and periaortic lymphadenectomy at the time of surgical
staging in the absence of metastatic disease.
Pathologic Classification
Endometrial Hyperplasia
The diagnostic criterion for hyperplasia is an increase in the
number and size of proliferating glands. The International
Society of Gynecologic Pathologists standardized the subclas-
sification of endometrial hyperplasia. In simple hyperplasia,
there is only glandular proliferation and enlargement with
increased stromal cellularity. This rarely progresses to carci-
noma (<1%). Complex hyperplasia is characterized by back-to-
back proliferation of glands with intraluminal papillae, epithe-
lial pseudostratification, and few mitotic figures. If there is no
cytologic atypia, the risk of malignant degeneration is again
quite low, on the order of 3%. Any proliferation demonstrating
cytologic abnormalities (in cellular or nuclear morphology) is
classified as atypical hyperplasia. Atypical hyperplasia has a
much higher risk of progression to an invasive carcinoma8%
for simple atypical hyperplasia, increasing to 29% for complex
hyperplasia associated with atypia.46 The GOG conducted a
prospective trial in which all patients with atypical hyperplasia
of the uterus underwent an immediate hysterectomy. The rate
 Chapter 70 Endometrial Cancer 1429

TABLE 70.1 PATHOLOGIC CLASSIFICATON OF ENDOMETRIAL CANCERS proliferation with back-to-back proliferation of glands and lit-
tle intervening stroma (Fig. 70.3A). The name endometrioid is
Endometrioid adenocarcinoma derived from resemblance to proliferative-phase endometrium.
Not otherwise specified
Architectural grading is determined by the amount of solid
Villoglandular
Secretory adenocarcinoma
mass of tumor cells compared to well-defined glands. Grade 1
Ciliated carcinoma is an endometrioid cancer in which <5% of the tumor growth
Adenocarcinoma with squamous differentiation is in solid sheets. Grade 2 is an adenocarcinoma in which 6%
Uterine papillary serous to 50% of the tumor is composed of solid sheets of cells. Grade
Clear cell carcinoma 3 occurs when >50% of the tumor is made up of solid sheets.
Mucinous carcinoma Nuclear grading is determined by the nuclear shape, size,
Squamous cell carcinoma chromatin distribution, and size of the nucleoli. The grading
Transitional cell carcinoma is primarily driven by the architectural grading, but if there is
Mixed-cell type marked nuclear atypia in an otherwise grade 2 architectural
Undifferentiated carcinoma
Metastatic carcinoma to the endometrium
grading, it should be increased to grade 3. Within endome-
trioid adenocarcinoma, the subtypes are endometrioid carci-
noma not otherwise specified (NOS), endometrioid carcinoma
with squamous differentiation, villoglandular endometrioid
of underlying concurrent carcinoma in the uterus was 42.6%

Clinical Radiation Oncology

in these patients.47 The standard recommended treatment for
atypical hyperplasia of the uterus is hysterectomy if childbear-
ing is complete and the patient has no other contraindications
to surgery. In patients who desire future fertility or have an
absolute contraindication to surgery, progestational therapies
may be used with caution.48
Carcinoma of the Endometrium
Endometrioid Carcinoma
Endometrioid adenocarcinoma is the most common endome-
trial carcinoma, constituting 75% to 80% of all cases (Table 70.1).
The classic histologic appearance is that of marked glandular
carcinoma, secretory carcinoma, and a ciliated cell variant.49
Most of the endometrioid adenocarcinomas are designated
NOS. Foci of squamous differentiation are often found with
endometrioid adenocarcinoma. The squamous component
could be benign, with the designation of adenoacanthoma, or
malignant, in which case it is called adenosquamous carci-
noma. Such designations have not been very useful, however,
because the degree of differentiation of the squamous com-
ponent parallels that of the glandular architectural grading.
Therefore, most gynecologic pathologists use the term adeno-
carcinoma with squamous differentiation. Other subtypes of
endometrioid adenocarcinoma include the relatively common
villoglandular carcinoma, which grows in a papillary fashion.

A B

C FIGURE 70.3. Different histologic types of endometrial cancer. A: Endometrioid. B: Papillary

serous. C: Clear cell.

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1430 Section III Clinical Radiation Oncology Part J Gynecologic
The prognosis of this subtype is similar to that of low-grade
endometrioid cancer, and it must not be confused with serous
carcinoma because of its papillary features. Secretory carci-
noma, which represents <2% of all endometrial carcinomas, is
characterized by a very well differentiated glandular pattern
with much intracellular glycogen, thus resembling early secre-
tory endometrium. Although the cells have clear cytoplasm,
their histologic and cytologic features are different from those
of clear-cell carcinoma. Ciliated carcinoma is a very rare sub-
type, characterized by the presence of ciliated cells comprising
>75% of the tumor specimen. It is usually associated with a
history of prior estrogen use, and the prognosis is quite good,
since most are well differentiated.
Mucinous Carcinoma
This designation requires >50% of the tumor cells to be muci-
nous. These cells are carcinoembryonic antigen positive and
are laden with mucin, which stains positively with mucicar-
mine and periodic acidSchiff stains but is diastase resistant.
Because of the resemblance to endocervical adenocarcinoma,
it is essential to exclude it by endocervical curettage. Mucinous
carcinomas are usually well differentiated and have the same
prognosis as ordinary endometrioid carcinomas.
Serous Carcinoma
Serous carcinomas, also known as papillary serous cancers,
resemble ovary cancer in terms of histology and to some extent
in terms of behavior. The mere presence of papillary struc-
ture is not diagnostic because other histologic types may have
papilla as well. However, the presence of marked cellular atypia
in addition to papilla distinguishes serous carcinoma from oth-
ers (Fig. 70.3B). Psammoma bodies are found in up to 33% of
cases. The incidence of serous endometrial cancer is about 10%
that of endometrial carcinomas. This is a very aggressive sub-
type, with a high propensity for early lymphatic and intraperi-
toneal dissemination, often despite little myometrial penetra-
tion.50 In the FIGO annual report, the 5-year survival rate was
52.6% compared to 83.2% for endometrioid carcinoma.28
Clear-Cell Carcinoma
Clear-cell carcinoma of the endometrium resembles renal car-
cinoma, but its origin from Mllerian structures is now well
established. Unlike vaginal and cervical clear-cell carcinoma,
it is not related to intrauterine diethylstilbestrol exposure. The
microscopic structure may vary from solid patterns to glandu-
lar differentiation (Fig. 70.3C). In the latter pattern, small cells
resembling hobnail cells line spaces and glands. These are
cells that extruded their cytoplasm, leaving bare nuclei that pro-
trude into the glandular lumens. The prognosis of this cancer is
somewhat similar to that of serous cancer. In the FIGO annual
report, the 5-year survival rate was 62.5% compared to 83.2%
for endometrioid carcinoma and 52.6% for serous carcinoma.28
Squamous Carcinoma
This type of cancer is extremely rare, and the diagnosis has
to be made after the exclusion of cervical origin. The 5-year
survival rate based on the FOGO report is 68.9% overall, but
the prognosis is poor for patients with extrauterine disease or
distant spread.28
Undifferentiated Carcinoma
The World Health Organization classification describes endo-
metrial undifferentiated carcinomas as malignant poorly
differentiated endometrial carcinomas, lacking any evidence
of differentiation without any further characterization.51
Undifferentiated carcinomas can also be associated with an
endometrioid carcinoma component, and such tumors have
been referred to as dedifferentiated carcinomas, which is
being recognized with increased frequency. Some of these
tumors may belong to the spectrum of gynecologic neoplasms
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seen in the setting of microsatellite instability and possibly
Lynch syndrome.52
Mixed Histology
Mixed-cell-type endometrial cancer composed of two or more
pure types is not uncommon. By convention, in order to be des-
ignated as mixed, the other cell-type component has to com-
prise at least 10% of the tumor. Except for mixed endometrioid
and serous or clear-cell carcinoma, the clinical significance of
mixed cell type is questionable.
Simultaneous Tumors
Cancers of identical type may be discovered in the ovary and
endometrium simultaneously. Usually, the site of the largest
tumor is assigned the primary origin, but occasionally true
primary endometrial and ovarian malignancies may coexist.
This field effect of the Mllerian system may occur in as much
as 15% to 20% of ovarian endometrioid tumors.53 If the endo-
metrial tumor is <5 cm in diameter, well differentiated, with
no vascular invasion, limited to less than the middle one-third
of the myometrium, and the ovarian lesions are bilateral, it is
more likely that there are two concomitant primary tumors.
Genetic profiling may represent a powerful tool in clinical prac-
tice for distinguishing between metastatic and dual primaries
in patients with simultaneous ovarian/endometrial cancer and
for predicting disease outcome.54
Molecular Biology
Several investigators pointed out that there are two distinct
types of endometrial cancer.55,56 In type I endometrial cancer
there is strong correlation with prior estrogen stimulation. The
cancers in this category are often indolent in nature, with mini-
mal myometrial invasion and low-grade histology. They affect
premenopausal and perimenopausal women. Type II endome-
trial cancer often affects postmenopausal women with no prior
history of estrogen stimulation. The histology of the tumors is
often high grade, such as serous or clear-cell cancers with deep
invasion, and at a more advanced stage at the time of presen-
tation. What is intriguing is the fact that at the molecular level,
the existence of two distinct types of endometrial cancer seems
to be validated. In a recent review by Dedes et al.,57 the com-
piled data from the literature show that the most frequently
altered molecular pathway in type I endometrial carcinomas is
the PI3 K/PTEN/AKT pathway, which is dysregulated by onco-
genic mutations, PTEN loss of function, and/or overexpression
of upstream tyrosine kinase growth factor receptors, leading to
uncontrolled cell proliferation and survival. On the other hand,
the main pathway alterations in type II endometrial cancers
involve the tumor suppressors p53 and/or p16, which cause
cell cycle dysregulation and genetic instability. Other features
frequently observed in type II cancer are loss of E-cadherin
expression and the amplification and overexpression of HER2.
Inactivation of the p53 tumor suppressor gene is seen in
almost 90% of cases of serous carcinoma.58,59 Mutation in the
p53 gene, however, is encountered in only 10% of endometri-
oid adenocarcinoma, with most occurring in grade 3 tumors.
Inactivation of the cell cycle regulator p16 is also more frequent
in type II (40%) than in type I (10%). The underlying mechanism
is not clear but probably involves deletion and promoter hyper-
methylation.60 Reduction in the levels of the adhesion molecule
E-cadherin is more frequent in type II (62% to 87%) than in type
I (5% to 53%) tumors.61,62 HER2 overexpression or amplification
is seen in 17% to 32% of type II compared to 3% to 10% in type I
tumors.6364,65 In contrast, mutation in the PTEN tumor suppres-
sor gene is found in 30% to 50% of type I endometrial cancer.
PTEN mutations have been detected in endometrial hyperpla-
sia with and without atypia (19% and 21%, respectively), which
suggests that PTEN mutations are early events in the develop-
ment of endometrial cancer.60 Mutations in PIK3CA occur in
36% of type I endometrial cancer and coexist frequently with

PTEN mutations.60 Mutation in K-ras proto-oncogene is seen
in 10% to 30% of endometrial cancer patients.59 Microsatellite
instability (MSI), which is found in patients with HNPCC, is
also seen in approximately 20% of sporadic endometrial can-
cers.66,67 MSI, mutations in PTEN/ PIK3CA, and mutations in
K-ras frequently coexist within the same tumor.68 B-Catenin is
important for cell differentiation, maintenance of normal tissue
architecture, and signal transduction. B-Catenin mutations are
seen in 25% to 40% of type I endometrial cancer. Of interest,
the mutations do not usually coexist with MSI and mutations in
PTEN/PIK3CA and K-ras. This suggests that type I endometrial
cancers with B-catenin mutations may develop via a unique
pathway.68 Microarray analysis has further revealed distinct
gene expression profiles among different histologic types of
endometrial cancer.69,70
STAGING
Before 1988, the staging system for endometrial cancer was
clinical. Stage I was tumor limited to the uterus, with IA desig-
nation if the length was 8 cm and IB if it was >8 cm. Stage II
was for when cervix was involved, stage III when disease exten-
sion beyond uterus/cervix was limited to the true pelvis, and
stage IV when it extended beyond the true pelvis or involved
bladder or rectum (IVA) or distant spread (IVB). This system is
applicable to the few patients who cannot have surgery and are
treated with definitive radiation. Creasman et al.71 reported a
Gynecologic Oncology Group (GOG) study on 621 patients with
clinically stage I endometrial cancer, that is, confined to the
corpus, who underwent total abdominal hysterectomy/bilat-
eral salpingo-oophorectomy, peritoneal cytology, and selective
pelvic and para-aortic lymphadenectomy. Of the 621 patients,
144 (22%) were found to have disease outside the uterus. The
rate of positive peritoneal cytology was 12%, that of adnexal
involvement was 5%, and that of regional lymph node involve-
ment was 11%. Pelvic node metastases were found in <3% of
patients with grade 1 endometrium-confined disease but in
>30% when grade 3 disease penetrated the outer one-third of
the myometrium. Aortic nodal disease, although rare in grade 1
disease or in the absence of pelvic node metastasis, was seen in
14% and 23% of patients with deeply invasive grade 2 or 3 dis-
ease, respectively. This highlighted some of the shortcomings
of the clinical staging system and led to the adoption of a surgi-
cal staging system by FIGO in 1988 in order to better estimate
5-year prognoses for patients and to better tailor adjuvant ther-
apy to those patients most likely to benefit from it (Table 70.2).
TABLE 70.2 ENDOMETRIAL CANCER SURGICAL STAGING SYSTEM:
INTERNATIONAL FEDERATION OF GYNECOLOGY AND
OBSTETRICS 1988
Stages/Grades Definition
Stage I Tumor limited to the uterus
IA grades 13 Tumor limited to the endometrium
IB grades 13 Invasion to <50% of the myometrium
IC grades 13 Invasion to 50% of the myometrium
Stage II Extension to the cervix but not beyond the uterus
IIA grades 13 Endocervical glandular involvement only
IIB grades 13 Cervical stromal invasion
Stage III Extension outside of the uterus/cervix with/without regional
metastasis
IIIA grades 13 Tumor invades serosa or adnexum or positive peritoneal
cytology
IIIB grades 13 Vaginal metastasis
IIIC grades 13 Metastasis to pelvic and/or periaortic lymph nodes
Stage IV
IVA grades 13 Tumor invades bladder and/or bowel mucosa
IVB grades 13 Distant metastasis including intra-abdominal and/or inguinal
lymph nodes
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Chapter 70 Endometrial Cancer 1431
TABLE 70.3 REVISED ENDOMETRIAL CANCER SURGICAL STAGING SYSTEM:
INTERNATIONAL FEDERATION OF GYNECOLOGY AND
OBSTETRICS 2009
Stage I
IA grades 13 Tumor limited to the endometrium or invasion to <50%
of the myometrium (includes endocervical glandular
involvement)
IB grades 13 Invasion to 50% of the myometrium (includes endocervical
glandular involvement)
Stage II
II grades 13 Cervical stromal invasion
Stage III
IIIA grades 13 Tumor invades uterine serosa or adnexae (positive cytology
has to be reported separately without changing the stage)
IIIB grades 13 Tumor involving the vagina and/or parametria
IIIC grades 13 Pelvic or para-aortic lymph nodal involvement
IIIC1 grades 13 Pelvic nodal involvement only
Clinical Radiation Oncology
IIIC2 grades 13 Para-aortic nodal involvement with or without pelvic nodal
involvement
Stage IV
IVA grades 13 Invasion of bladder, bowel mucosa, or both
IVB Distant metastases, including intra-abdominal spread or
inguinal lymph nodes
In 2009 the FIGO staging system was modified again.72
Patients who formerly were staged as IB, that is, <50% myome-
trial invasion, are now considered IA. Patients with >50% myo-
metrial invasion are designated as stage IB. Endocervical glan-
dular involvement no longer affects staging; only patients with
cervical stromal invasion are considered stage II. Having posi-
tive peritoneal cytology no longer affects staging. Parametrial
extension is now considered IIIB. Patients with stage IIIC are
now subdivided into IIIC1 if pelvic nodes are involved and IIIC2
if para-aortic nodes are involved (Table 70.3). The discriminat-
ing power of the new FIGO staging system is being debated.
Page et al.73 evaluated 10,839 cases from 1998 to 2006 using
the Surveillance, Epidemiology, and End Results (SEER)
Program. The analysis demonstrated the usefulness of two
divisions rather than three for stage I in the new FIGO staging
system. In contrast, a study from Memorial Sloan-Kettering
Cancer Center (MSKCC) of 1,307 patients with FIGO 1988 stage
I disease showed that the revised system for stage I did not
improve its predictive ability over the 1988 system.74
Prognostic Factors
Several clinicopathologic factors have been identified in
patients with endometrial carcinoma to help predict the prog-
nosis and individualize the treatment plan. At MSKCC, a nomo-
gram was developed for predicting overall survival of women
with endometrial cancer (n = 1,735) after primary therapy.75
Use of five prognostic factorsage, grade, histologic type, num-
ber of lymph nodes removed, and FIGO 1988 surgical stage
predicted OS with high concordance probability (Fig. 70.4).
Age
The influence of older age on worse outcome has been well
established. The adverse impact of older age is often explained
by pointing out that older patients tend to present with aggres-
sive histology and more-advanced disease and are generally
treated less aggressively. What is intriguing, however, is that
the strongest correlation between older age and poor out-
come is seen in patients with favorable characteristics. Age
60 years has been shown to be predictive of local-regional
recurrence (hazard ratio [HR], 3.9; p = .0017) and death (HR,
2.66; p = .01) in a randomized trial limited to stage I and in
which patients with deep myometrial invasion grade 3 were
excluded.76 The adverse impact of advanced age on outcome
persists even when elderly patients are treated as aggressively
as their younger counterparts.77
1432 Section III Clinical Radiation Oncology Part J Gynecologic

0 10 20 30 40 50 60 70 80 90 100
Points

Age at diagnosis
20 50 60 80 90 100

Neg lymph nodes#

100 10 0

IB IC IIIA IVA/B
Stage
IA IIA IIB IIIB/C

2
Final grade
1 3

PapS/CleC
Histologic subtype
Adeno MMMT

Total points
0 20 40 60 80 100 120 140 160 180 200 220 240

FIGURE 70.4. Nomogram for predicting overall Prob of 3 year OS

survival in patients with endometrial cancer. 0.99 0.95 0.9 0.8 0.70.6 0.4 0.2 0.05

Race Myometrial Invasion

White women tend to fare better than African Americans, inde-
pendent of other prognostic factors.78 It is important to note
that although the prevalence of endometrial cancer is lower in
African American women, the incidence of high-risk tumors in
this group is higher.79
Histologic Subtype
According to the FIGO annual report, the 5-year survival rate
was 83.2% for endometrioid adenocarcinoma, compared to
52.6% for serous cancer and 62.5% for clear-cell cancer in
8,033 surgically staged patients. Patients with endometrioid
histology have surgical stage III to IV disease only in 13.8%
of patients, compared to 41.7% with serous and 33% with
clear-cell carcinoma, which could explain the worse outcome.
However, the influence of histology was seen even in patients
with surgical stage I disease (n = 5,285), for whom 5-year sur-
vival dropped from 90% for endometrioid histology to 79.9%
with serous and 85.1% with clear-cell carcinoma.28
Grade
Tumor grade is one of the most sensitive indicators of prog-
nosis. Grade directly affects the depth of myometrial penetra-
tion and the frequency of lymph node involvement. Most grade
1 tumors are limited to the endometrium or have superficial
myometrial penetration, and the overall risk of pelvic and
para-aortic lymph nodal metastases is 3% and 1.5%, respec-
tively. Only 10% of grade 1 tumors have deep myometrial inva-
sion, and pelvic and para-aortic lymph nodal involvement in
these is 12% and 6%, respectively. Conversely, >50% of grade
3 tumors have >50% myometrial invasion, and these have pel-
vic and para-aortic nodal involvement on the order of 30%
and 20%, respectively.71 In the FIGO annual report,28 grade 3
was an independent predictor of poor survival on multivariate
analysis within each stagestage I (HR, 2.45), II (HR, 2.14), III
(HR, 2.44), and IV (HR, 2.55).
Regardless of grade, only 1% of tumors limited to the endo-
metrium had lymph nodal involvement, as compared with
25% pelvic and 17% para-aortic involvement with deep pen-
etration.71 Before the 1988 FIGO staging system, the depth of
invasion had been reported as none or inner, middle, or outer
one-third of the myometrium. The 1988 FIGO staging system
subdivided myometrial invasion into none or inner or outer
half. Under that staging system, for patients with <50% myome-
trial invasion, it seems that invasion to less than versus greater
than one-third is not a significant predictor of outcome.80 In the
current 2009 FIGO staging system, depth of invasion in stage I
is divided into two categories: A (no or <50% myometrial inva-
sion) and B (>50% invasion).
Lymphovascular Invasion
This is seen in about 15% of the cases of endometrial can-
cer. The GOG study found that lymphovascular invasion (LVI)
positive tumors were associated with a 27%, or fourfold,
increase in the pelvic lymph nodal metastases, and a 19%,
or sixfold, increase in para-aortic nodal metastases.71 This
translates into more frequent relapses, including vaginal recur-
rences,81 and a poorer outcome.82
Lower Uterine Segment Involvement
The GOG study of surgical-pathologic spread patterns found a
doubling of the incidence of pelvic nodal involvement from 8%
to 16% and an increase in para-aortic nodal involvement from
4% to 14% when the tumor arose from or involved the isth-
mus.71 There seems to be a high rate of lower uterine segment
involvement in patients with HNPCC-associated endometrial
cancer.26
Cervical Involvement
In the 1988 FIGO staging system, cervical involvement was
divided into IIA when limited to endocervical glandular

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involvement and IIB when it involves the cervical stroma.
According to the FIGO report, the 5-year survival for stage IIA
was very good (89.9% for grade 1 and 83.7% for grade 2). In
contrast, the corresponding figures for stage IIB were 81.2%
and 76.9%, respectively.28 This led to a change in the 2009
FIGO staging system, in which only cervical stromal invasion
is considered stage II. Although the prognosis of the old stage
IIA grades 1 and 2 approximated stage I rather than stage IIB,
it is important to note that in the same FIGO annual report,
patients with stage IIA grade 3 did not fare as well; their 5-year
survival was 68.3%, which was worse than that for IC grade 3
(74.9%) and similar to that for IIB grade 3 (64.9%).
Peritoneal Cytology
Peritoneal fluid positive for malignant cells is found in 12% to
15% of all patients undergoing surgical staging. This is associ-
ated with 25% pelvic lymph node involvement and 19% para-
aortic node involvement.71 The data suggest a higher rate of
positive cytology for patients undergoing laparoscopic-vaginal
hysterectomy, in which there is manipulation of the uterine
cavity, compared to total abdominal hysterectomy, in which
there is no such manipulation.84 The literature regarding the
true impact of positive peritoneal cytology is mixed. One con-
founding factor, mainly in patients with no other risk factors,
is whether all endometrial cancer cells that gained access to
the peritoneal cavity are capable of independent growth. In
a review of the literature, Wethington et al.85 found that the
overall incidence of positive washings is approximately 11%.
Patients with grade 1 or 2 disease, no evidence of cervical
involvement, <50% myometrial invasion, and no LVI were con-
sidered low risk. In patients with positive peritoneal cytology,
the rate of recurrence for low-risk patients was 4.1% compared
to 32% for those considered high risk (p < .001). This indicates
the association of malignant cytology with other adverse prog-
nostic factors. In the recent FIGO staging (2009), having posi-
tive peritoneal cytology is no longer considered stage IIIA.
Adnexal/Serosal Involvement
About 5% of patients with stage I and occult stage II disease
have adnexal involvement.71 This is associated with a fourfold
increase in lymph node metastases; thus, pelvic lymph nodal
positivity rises to 32% (as compared with 8% without adnexal
spread), and para-aortic nodal involvement is seen in 20%
(as opposed to only 5% in patients with no adnexal spread).
The incidence of serosal involvement is less common. Jobsen
et al.86 reported on 46 patients with isolated adnexal involve-
ment and 21 with isolated serosal involvement. There was no
statistically significant difference in outcome between adnexal
and serosal involvement. The 5-year disease-free survival was
76.4% versus 59.6% (p = ns), and the disease-specific survival
was 76.3 % and 75.4%, respectively.
Pelvic and Para-Aortic Lymph Node Involvement
The pattern of lymphatic spread in endometrial cancer is dif-
ferent than that in cervical cancer. In endometrial cancer, a
simultaneous spread to both pelvic and para-aortic nodes
could occur, whereas in cervical cancer the spread to para-
aortic nodes is almost always secondary to pelvic lymph node
involvement. Overall, about 11% of patients with stage I and
occult stage II endometrial cancer have pelvic nodal involve-
ment. This increases to 25%, 30%, and 50% with deep myome-
trial invasion, adnexal involvement, and extrauterine spread,
respectively.71 Lymph node involvement is a major predictor of
outcome; the 5-year disease-free survival rates drop to 65% to
70% in patients with pelvic lymph node involvement as their
only risk factor.87 The rate of para-aortic nodal metastases is
about 5% of all patients with stage I and occult stage II dis-
ease. The biggest risk factor for para-aortic node involvement
is the presence of pelvic nodal metastases; more than 30% of
patients with pelvic nodal involvement have para-aortic dis-
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Chapter 70 Endometrial Cancer 1433
ease. The 5-year disease-free survival rates drop to about 30%
in this subpopulation.87
Molecular Prognostic Factors
The application of molecular biology tools to endometrial can-
cer has provided insights into the pathogenesis of the disease
and may lead to early detection, as well as to development of
novel therapeutic strategies.88 Mutations of the tumor sup-
pressor gene p53 have been most extensively studied. There
is a consistent observation linking the overexpression of p53
with advanced stage and poorer outcome.89,90 Overexpression
of HER-2 is also associated with more advanced disease and
poor outcome.65 PTEN mutation is associated with early-stage,
nonmetastatic disease and more favorable survival outlook.91
Data in the literature suggest a favorable survival outlook asso-
ciated with microsatellite instability in endometrioid endo-
metrial cancers.92 As our knowledge regarding the molecular
Clinical Radiation Oncology
biology of endometrial cancer matures, risk stratification may
soon be based on molecular alterations rather than pathologic
variables.
SURGICAL MANAGEMENT
Surgery is the main treatment for endometrial cancer. It con-
sists of simple hysterectomy, bilateral salpingo-oophorectomy
(BSO), and inspection of the pelvic and abdominal cavities,
with biopsy of any suspicious extrauterine lesions, accompa-
nied in most cases by peritoneal washings. Surgical assessment
of lymph nodes ranges from palpation, biopsy of suspicious
nodes, to pelvic and para-aortic lymphadenectomy.
Hysterectomy
There are several approaches to simple hysterectomy, also
known as extrafascial hysterectomy, but in the main it con-
sists of removal of the entire uterine corpus and cervix with-
out contiguous parametrial tissue. The pubocervical fascia is
entered, and the ureters are not unroofed. Total abdominal
hysterectomy/BSO (TAH/BSO) is the most prevalent and time-
tested form of simple hysterectomy in endometrial cancer. It
is an abdominal approach, usually via a vertical midline inci-
sion that allows thorough exploration of intra-abdominal and
pelvic cavities. The main drawback of TAH/BSO is, that it is a
laparotomy-based approach, in a group of patients with pre-
existing comorbidities such as obesity, hypertension, and dia-
betes. Therefore, it is not surprising that minimally invasive
surgery, whether laparoscopically or robotically, has gained a
great deal of acceptance in the surgical management of endome-
trial cancer. In laparoscopic vaginal hysterectomy/BSO (LAVH/
BSO) the uterus is removed vaginally rather than abdominally.
The benefit of using the laparoscope is to enable the surgeon
to have a thorough intra-abdominal exploration and to per-
form BSO, which is difficult to accomplish with just a vaginal
hysterectomy. The GOG completed a trial in which patients
with clinical stage I to occult IIA uterine cancer were ran-
domly assigned to laparoscopy (n = 1,696) or open laparotomy
(n = 920), including hysterectomy, salpingo-oophorectomy, pel-
vic cytology, and pelvic and para-aortic lymphadenectomy. The
main study endpoints were 6-week morbidity and mortality,
hospital length of stay, conversion from laparoscopy to laparot-
omy, recurrence-free survival, site of recurrence, and patient-
reported quality-of-life outcomes.93 Laparoscopy had fewer
moderate to severe postoperative adverse events than lapa-
rotomy (14% vs. 21%, respectively; p < .0001). Hospitalization
of >2 days was significantly lower in laparoscopy than in lapa-
rotomy patients (52% vs. 94%, respectively; p < .0001). The
conversion rate to laparotomy was 25.8%. With a median fol-
low-up time of 59 months for 2,181 patients still alive, there
were 309 recurrences (laparoscopy, 210, laparotomy, 99) and
350 deaths (laparoscopy, 229; laparotomy, 121). The estimated
1434 Section III Clinical Radiation Oncology Part J Gynecologic

5-year recurrence rate was 11.61% in the laparotomy arm and
13.68% for laparoscopy. The estimated 5-year overall survival
rate was 89.8% for laparoscopy and 89.8% for laparotomy.
The study demonstrated that surgical treatment of endometrial
cancer can be performed laparoscopically with relatively small
differences in recurrence rates (estimated difference at 3 years,
1.14%). These results, combined with improved quality of life
and decreased complications associated with laparoscopy,
are reassuring to patients and allow surgeons to reasonably
suggest this method as a means to surgically treat and stage
patients with presumed early-stage uterine cancers.94 In recent
years, robotic-assisted hysterectomy/BSO has emerged as an
alternative minimally invasive surgery in endometrial cancer.
It affords many advantages, including three-dimensional visu-
alization, increased freedom of instrument movement, and
enhanced ergonomics and surgeon comfort. The question of
difference in cost is under debate debatable.95 Radical hys-
terectomy is not routinely performed in endometrial cancer
due to low incidence of parametrial involvement. There is no
evidence to show that the cure rates are any better with such
radical operations. The possible exception to this might be in
patients with gross cervical involvement.96
Lymphadenectomy
The question of which patients need routine surgical lymph
nodal staging and, if so, to what extent is a matter of great
debate. The uncertainty about lymphadenectomy relates to
whether the benefit from it is prognostic rather than thera-
peutic. Those who advocate for no lymphadenectomy and
limit nodal assessment to inspection and removal of any
enlarged/suspicious pelvic or para-aortic nodes cite the lack
of documented survival advantages to lymphadenectomy.
Furthermore, patients who have adverse pathologic features
that increase the risk of microscopic lymph node metastasis
are generally offered adjuvant pelvic radiation. Advocates for
full pelvic and para-aortic lymph node sampling reason that
surgical staging is the most accurate method to assess the
extent of disease and that the sensitivity and specificity of pal-
pation of lymph nodes are only 72% and 81%, respectively.97
Lymphadenectomy in endometrial cancer includes removal of
the fat pads surrounding the major vessels in the abdomen and
pelvis without skeletonizing them. According to the GOG surgi-
cal guidelines, pelvic lymph nodes are to be removed from the
distal one-half of the common iliac artery down to the circum-
flex iliac vein, and nodal tissue is to be removed anterior to the
obturator nerve and surrounding the iliac arteries and vein.
The para-aortic nodes include those overlying the vena cava,
between the vena cava and aorta, and to the left of the aorta.
The cephalad boundary of the para-aortic specimen is gener-
ally, but not limited to, the inferior mesenteric artery, and the
distal boundary is the midpoint of the common iliac artery.93
For the sampling to be adequate, five lymphatic stations need
to be removedpara-aortic, common iliac, internal iliac, exter-
nal iliac, and obturatoror total of 10 nodes. Optional lymph-
adenectomy is another approach, in which preoperative tumor
grading with intraoperative assessment of depth of myome-
trial invasion, as well as histologic subtype, is frequently used
to decide whether lymph node dissection is necessary at the
time of hysterectomy. With such a policy, patients with grade
3 disease or serous or clear-cell histology and those with deep
myometrial invasion on frozen section will undergo lymphad-
enectomy. Opponents of selective lymphadenectomy point out
that depth of invasion on frozen section correlated with final
pathology in only 67% of cases.98 With regard to grade, pre-
operative FIGO grade 1 diagnosis correlates with final grade
diagnosis in only 85% of cases of endometrial cancer.32
Despite the misgivings about optional or no lymphadenec-
tomy, many surgeons have not embraced full lymphadenec-
tomy. In a study of 27,063 women with unstaged endometrioid
uterine cancer, lymphadenectomy was performed in only 30%
of patients.99 Two trials addressed the role of lymphadenec-
tomy. The first was an Italian study100 in which 514 eligible
patients with preoperative FIGO stage I endometrial carcinoma
were randomly assigned to undergo pelvic lymphadenectomy
(n = 264) or no lymphadenectomy (n = 250). The median num-
ber of lymph nodes removed was 30 in the pelvic lymphade-
nectomy arm. Both early and late postoperative complications
occurred more frequently in patients who had received pelvic
systematic lymphadenectomy (81 patients in the lymphadenec-
tomy arm and 34 patients in the no-lymphadenectomy arm;
p = .001). Lymphadenectomy improved surgical staging, as sta-
tistically significantly more patients with lymph node metasta-
ses were found in the lymphadenectomy arm than in the no-
lymphadenectomy arm (13.3% vs. 3.2%; p < .001). At a median
follow-up of 49 months, the 5-year disease-free and overall
survival rates in an intention-to-treat analysis were similar
between arms (81.0% and 85.9% in the lymphadenectomy arm
and 81.7% and 90.0% in the no-lymphadenectomy arm,
respectively). In the second trial (Medical Research Council
[MRC]/A Study in the Treatment of Endometrial Cancer
[ASTEC]) patients with endometrial cancer believed preopera-
tively to be confined to the uterine corpus were first random-
ized to standard surgery consisting of hysterectomy-BSO, pel-
vic washing, and palpation of para-aortic nodes (n = 704) or to
lymphadenectomy (n = 704). In the lymphadenectomy group
patients underwent standard surgery plus systematic dissec-
tion of iliac and obturator nodes.101 If the nodes could not be
dissected, sampling of suspect nodes was recommended.
Whether to dissect the para-aortic nodes was left to the discre-
tion of the surgeon. After a median follow-up of 37 months,
191 women (88 standard surgery group, 103 lymphadenec-
tomy group) had died, with an absolute difference in 5-year
overall survival of 1% (95% CI = 4 to 6) and an absolute differ-
ence in 5-year recurrence-free survival of 6%. The conclusion
from both trials was that pelvic lymphadenectomy significantly
improved surgical staging, that is, it is a good prognosticator,
but it did not improve disease-free or overall survival. As a
trade-off between lymphadenectomy and no surgical assess-
ment at all in patients with endometrial cancer, there has inter-
est in adopting a sentinel lymph node approach similar to that
in breast cancer (Fig. 70.5). In a recent report from MSKCC,
FIGURE 70.5. Sentinel lymph node. Solid arrow points to the blue dye in an external iliac
node. Dashed arrow points to a lymphatic channel draining to the sentinel node.

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266 patients with endometrial cancer underwent sentinel
lymph node (SLN) mapping. At least one sentinel node was
identified in 223 (84%) cases. Location of SLN was in the pelvis
in 94% of cases, in the pelvis and para-aortic in 5%, and in the
para-aortic in 1%. Positive nodes were diagnosed in 32 of 266
(12%) patients.102 In a prospective trial from France, at least
one SLN was detected in 111 of the 125 eligible patients. Of the
111 patients, 19 (17%) had pelvic-lymph-node metastases.
Three patients had false-negative results (two had metastatic
nodes in the contralateral pelvic area and one in the para-aor-
tic area), giving a negative predictive value of 97% (95% CI = 91
to 99) and sensitivity of 84% (95% CI 62 to 95). SLN biopsy up-
staged 10% of patients with low-risk and 15% of those with
intermediate-risk endometrial cancer.103 The results from these
two studies suggest that SLN mapping is feasible and that add-
ing SLN mapping to surgical staging procedures seems to
increase the likelihood of detecting metastatic cancer cells in
regional lymph nodes. Whether sentinel lymph node mapping
will replace lymphadenectomy needs to be determined.
ROLE OF RADIATION
Radiation therapy plays a significant role in the management
of endometrial cancer. It is often used as an adjuvant treat-
ment after surgery (which will be discussed here) or as defini-
tive treatment for patients who are medically inoperable or
with local recurrence (which will be discussed later). In the
past, most patients were treated with preoperative intracavi-
tary brachytherapy with or without external-beam radiother-
apy, followed by hysterectomy. This approach is not without
its merit, especially in patients with gross cervical involve-
ment. However, most patients nowadays undergo surgery first;
then, depending on the prognostic features obtained from the
pathology review, the need for radiotherapy is determined. In
recent years there has been a plethora of data from prospec-
tive, randomized trials addressing several aspects of the man-
agement of endometrial cancer. However, unlike in cervical
cancer, for which the data from the majority of the randomized
trials pointed in the same direction, that is, chemoradiation is
better than radiotherapy (RT) alone, the data in endometrial
cancer are less conclusive. Therefore, it is important for radia-
tion oncologists to be familiar with the methodology of these
studies so that objections to the use of any form of adjuvant RT
can be addressed with facts.
Role of RT in Stages I and II
Treatment options for patients with early-stage endometrial
cancer after hysterectomy include observation, intravaginal
RT, or pelvic RT. At MSKCC, intravaginal RT is the preferred
approach for most patients because it provides the best thera-
peutic ratio. As the discussion will demonstrate, observation
may have the best morbidity profile, but it does not provide
the best therapeutic ratio because of the increased risk of local
recurrence. Pelvic RT, on the other hand, although very effec-
tive in reducing recurrence, has a higher morbidity profile than
intravaginal RT. The results of prospective, randomized trials
will be discussed first, and then treatment recommendations
based on risk factors will follow.
Results of RT Randomized Trials
There are six randomized trials regarding the role of adju-
vant RT in early-stage endometrial cancer, mainly pertaining
to endometrioid histology and conducted in the modern era.
Observation Versus Pelvic RT
Three randomized trials compared pelvic RT to observation
in early-stage endometrial cancer. The first trial was the
Postoperative Radiation Therapy in Endometrial Cancer
(PORTEC) trial, which randomized 715 patients after total
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Chapter 70 Endometrial Cancer 1435
abdominal hysterectomy and bilateral salpingo-oophorectomy
(TAH/BSO) to observation or pelvic RT.104 Patients included
were those with stage (FIGO 1988) IB grades 2 and 3 and those
with IC grades 1 and 2. Those with IB grade 1 and those with
IC grade 3 were excluded because it was felt that adjuvant RT
was not indicated for the former and most physicians would
not omit it for the latter. No lymph node sampling was done,
and the dose of pelvic RT was 46 Gy at 2 Gy per fraction. At
5 years there was a statistically significant difference in the
rates of vaginal/pelvic recurrence in favor of adjuvant pelvic
RT (14% vs. 4%; p < .001). Overall survival, however, was not
different between the two groups (81% RT vs. 85% surgery;
p = .31), and the complications with pelvic RT were signifi-
cantly higher (25% vs. 6%; p < .0001). In addition, many of
the patients who relapsed locally after surgery alone were suc-
cessfully salvaged with subsequent definitive RT. The second
randomized trial was GOG 99. There were 190 patients with
Clinical Radiation Oncology
stage (FIGO 1988) IB to IIB (grades 1 to 3), who all underwent
TAH/BSO, pelvic washing, and pelvic/para-aortic lymph node
sampling and then were randomized to observation versus pel-
vic RT to a dose of 50.4 Gy at 1.8 Gy per fraction.105 At 2 years
there was a statistically significant difference in the rates of
relapse in favor of the adjuvant pelvic RT arm (3% vs. 12%; p =
.007). The 2-year estimated incidence of isolated vaginal/pelvic
recurrence was 1.6% in the RT group and 7.4% in the surgery-
alone group. There was, however, no significant difference in
4-year overall survival (92% RT vs. 86% with surgery alone;
p = .557), but there were more complications with pelvic RT.
The third trial consisted of two trials with separate random-
izations consolidated into one intergroup trial. One trial was
conducted by the MRC and the other by the National Cancer
Institute of Canada (NCIC). Furthermore, the MRC ASTEC trial
in itself consisted of two trials with separate randomizations
designed to answer a surgical as well as a radiation question.106
The surgical question was discussed earlier and regarded the
need for lymphadenectomy in clinical localized endometrial
cancer.101 The radiation question was whether pelvic RT is
needed. Intermediate- or high-risk early-stage patients were
then randomized to observation or pelvic RT. Intermediate risk
included stage (FIGO 1988) IA grade 3, IB grade 3, IC grades 1
and 2, and IIA grades 1 and 2. High risk included IC grade 3,
IIA grade 3, and IA to IIA serous and clear-cell tumors. Patients
who had positive pelvic nodes (stage IIIC) were allowed but not
those with cervical stromal invasion (IIB). The pelvic RT was
given to a total dose of 40 to 46 Gy in 20 to 25 fractions over
4- to 5 weeks. Intravaginal RT was permitted regardless of the
pelvic RT randomization as long as it was the stated policy for
the treating center to do so. The recommended dose was 4 Gy
in two fractions prescribed to a depth of 0.5 cm treating the
upper one-third of the vagina when using high dose rate and
15 Gy when using low dose rate. The NCIC had a similar design
but with a few exceptions. Patients with stage IIA serous or
clear-cell carcinoma were excluded, as were those with posi-
tive nodes. The dose of pelvic RT was 45 Gy in 25 fractions,
and intravaginal brachytherapy was permitted in accordance
with local practice.
Of the 905 patients (789 MRC and 116 NCIC) in the trial,
453 were randomized to observation and 452 to pelvic RT. The
two arms were balanced except for more high-risk patients
(113; 25%) in the observation arm than in the pelvic RT arm
(89; 20%). There were 137 (32%) patients in the observation
arm in whom nodes were removed, and 5 (4%) had positive
nodes. In the pelvic RT arm, 159 (38%) had nodes removed,
and 6 (4%) were positive. In the observation arm, 228 (51%)
patients received intravaginal RT, 7 (2%) received pelvic and
intravaginal RT, 3 (1%) received pelvic RT, and 3 (1%) were
unknown. Only 212 (47%) received no form of adjuvant RT.
Conversely, in the pelvic RT arm, 24 (5%) did not receive any
adjuvant RT, 10 (2%) received intravaginal RT, and 2 (0.4%)
were unknown. Combined intravaginal and pelvic RT was
1436 Section III Clinical Radiation Oncology Part J Gynecologic
given to 232 (52%) patients, and only 184 (41%) received pelvic
RT alone. The primary endpoint of this study was overall sur-
vival. With a median follow-up of 58 months, the 5-year overall
survival was 84% in both arms (p = .77). The 5-year cumulative
incidence for isolated vaginal or pelvic recurrence was 6.1% in
the observation group and 3.2% in the pelvic RT group. This
difference was statistically significant (p = .2) with a HR of 0.46
(95% CI = 0.24 to 0.89). The rate of any acute toxicity was 27%
in the observation arm compared to 57% for pelvic RT.
Similarly, late toxicity was more prevalent in the pelvic RT
compared to observation (61% vs. 45%, respectively).
The triad of lack of overall survival advantage, increased
toxicity, and high salvage rate of local recurrence for patients
who are observed have led many to conclude that all forms of
adjuvant RT, not simply pelvic RT, should be abandoned. The
morbidity of pelvic RT and the validity of omitting adjuvant RT
in favor of RT for salvage policy will discussed later in the
chapter. With regard to overall survival it is considered the
gold standard for primary endpoint in many randomized trials
in oncology, but for early-stage endometrial cancer it is per-
haps unattainable with adjuvant RT for two reasons. First,
many of the patients have other, competing causes of death
such as hypertension, diabetes, and obesity. In the PORTEC
trial the 8-year actuarial rates of intercurrent death were
19.7% in the RT arm and 15.6% in the surgery-alone arm.107
Endometrial cancerrelated deaths in comparison were only
9.6% and 7.5%, respectively. Similarly, in the GOG 99 trial,105
approximately half of the deaths were due to causes other than
endometrial cancer or treatment (surgery alone, 19 of 36; RT,
15 of 30). This led the authors of GOG 99 to write, With this
number of intercurrent deaths in both arms, even if RT reduces
the risk of endometrial cancer-related deaths, the size of this
trial is not adequate to reliably detect an overall survival differ-
ence. That is why overall survival was not the primary end-
point in GOG99 but rather the disease-free interval, which was
significantly different in favor of adjuvant pelvic RT over sur-
gery alone.105 Therefore, it is not unreasonable to conclude that
neither PORTEC nor GOG 99 was large enough to conclusively
show whether adjuvant pelvic RT affected overall survival. The
second difficult hurdle for adjuvant RT to overcome when dis-
cussing overall survival has to do with its localized nature. In
the MRC/NCIC trial, the rate of first vaginal/pelvic recurrence
was reduced from 11.4% (n = 37 of 453) in the observation arm
to 2.8% (n = 13 of 452) with pelvic RT. Adjuvant pelvic RT, how-
ever, did not affect distant spread; the rate of first distant
spread was 8.1% (n = 37 of 453) in the observation compared
to 9% (n = 41 of 452) in the pelvic RT arm.106 One would expect
adjuvant RT to make a difference in overall survival only when
systemic therapy makes has an effect on the rate of distant
spread. This is exactly the story learned from postoperative
chest wall irradiation in breast cancer. Because pelvic RT sig-
nificantly improved local control, albeit with increased toxicity,
why not replace it with intravaginal RT rather than advocating
observation for all early-stage endometrial cancer?
Observation Versus Intravaginal RT
In a trial reported by Sorbe et al.,108 645 patients with stage
(FIGO 1988) IA to IB grades 1 and 2 endometrioid adenocarci-
noma were randomized after surgery to observation (n = 326)
or intravaginal RT (n = 319). Surgery consisted of TAH/BSO
(laparoscopic surgery was allowed), pelvic washing, and
removal of enlarged nodes. The dose and type of intravaginal
RT varied among the six centers participating in this trial, but
347 of 645 patients were treated with high dose rate (HDR) to
18 Gy in six fractions. The proximal upper two-thirds of the
vagina was treated with the dose prescribed to 0.5 cm from
the surface of the cylinder. The rate of vaginal recurrence was
3.1% in the observation arm compared to 1.2% for the intra-
vaginal RT arm (p = .114). The rate of pelvic recurrence was
0.9% in the observation arm and 0.3% in the treatment arm
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(p = .326). No significance difference was seen between the two
arms in terms of overall survival. There was significantly more
grade 1 vaginal toxicity with intravaginal RT (8.8% vs. 1.5%;
p = .00004). There was no significant difference in gastrointes-
tinal (GI) or genitourinary toxicity.
Pelvic RT Versus Intravaginal RT
In the PORTEC-2 trial, 427 patients were randomized to pelvic
RT (n = 214) or intravaginal RT (n = 213). Patients enrolled
were those with stage (FIGO 1988) IB grade 3 and >60 years
old, IC grades 1 and 2 and >60 years old, and IIA grades 1
and 2 of all ages but with <50% myometrial invasion. During
surgery patients underwent TAH/BSO, pelvic washing, and
removal of suspicious pelvic or para-aortic lymph nodes.
Routine lymphadenectomy was not performed. The dose of
pelvic RT was 46 Gy given in 23 fractions. Intravaginal RT was
delivered using a cylinder to treat the upper half of the vagina.
The dose was prescribed to 0.5 cm from the surface of the cyl-
inder. Three types of brachytherapy were used: HDR to 21 Gy in
three fractions, low dose rate to 30 Gy at 0.5 to 0.7 Gy/hr, and
medium dose rate to 28 Gy at 1 Gy/hr. With a median follow-up
of 36 months, the 3-year vaginal recurrence rates were 0.9% in
the intravaginal RT arm and 1.9% in the pelvic RT arm (p = .97).
The pelvic recurrence was significantly different; the 3-year
rate was 3.5% in the intravaginal RT arm compared to 0.6% in
the pelvic RT arm (p = .03). The corresponding rates of isolated
pelvic recurrence, however, were not significant: 0.6% versus
1.2%, respectively (p = .54). There was no significant difference
in disease-free or overall survival between the two arms. The
rate of grades 1 and 2 acute GI toxicity was 53% versus 12% in
favor of intravaginal RT (p < .001). This trial showed that intra-
vaginal RT alone is sufficient to control vaginal recurrence even
in patients with intermediate- to high-risk features.109
In a more recent Swedish trial reported by Sorbe et al.110
patients with stage (FIGO 1988) I endometrioid adenocarci-
noma with at least one of the risk factors grade 3, 50% myo-
metrial invasion, or DNA aneuploidy were randomized to adju-
vant intravaginal RT (IVRT; n = 263) or pelvic and IVRT (n =
264). Lymphadenectomy was required. There was no differ-
ence in vaginal recurrence, which was 2.7% (7 of 263) in the
IVRT-alone arm compared to 1.9% (5 of 264) in the combined
arm (p = .555). Pelvic recurrence rate, however, was different:
5.3% in the IVRT arm compared to 0.4% in the pelvic plus
IVRT arm (p = .0006). There was no significant difference in
overall survival between the two arms (90% vs. 89%, respec-
tively). The toxicity was significantly higher in the combined
arm compared to IVRT alone.
Radiation Treatment Recommendations for
Early-Stage Disease Based on Risk Factors
Based on the results of these trials in early-stage endometrial
cancer, it is clear that pelvic RT is an excessive treatment for
most of those patients. Therefore the treatment recommen-
dations should be individualized based on risk factors. When
deciding on whether to recommend observation, intravagi-
nal RT, or pelvic RT, the risk of vaginal recurrence and pelvic
recurrence should be assessed separately. With respect to vagi-
nal recurrence, the data from randomized trials indicate that
adjuvant intravaginal RT alone is sufficient to control potential
microscopic disease in the vagina. The PORTEC-2 trial showed
that intravaginal RT is as good as pelvic RT in controlling vagi-
nal recurrence (0.9% vs. 1.9%, respectively; p = .97) despite
the fact that patients included in this trial were at high risk for
vaginal recurrence based on age 60 years old, deep myome-
trial invasion, or endocervical gland involvement.109 The data
from a recent Swedish randomized trial further confirmed that
when it comes to vaginal control, IVRT alone is sufficient.110
The vaginal recurrence was 2.9% in the IVRT arm compared
to 1.9% (p = .555) in the pelvic plus intravaginal RT arm. How

best to reduce pelvic recurrence is more controversial. For
patients at low risk of having pelvic lymph node involvement,
that is, endometrioid grade 1 or 2 with no or minimal myo-
metrial invasion, neither lymphadenectomy nor pelvic RT is
likely to be of significant benefit.111 Those who are at higher
risk of having lymph node involvement may need to have
their lymph nodes surgically assessed to ensure that they are
pathologically negative or receive pelvic RT to control poten-
tial microscopic disease. However, the two PORTEC trials, as
well as the Swedish trial, showed that the risk of pelvic recur-
rence was only 2% to 6% even in the absence of lymphadenec-
tomy.104,109,110 This low rate of pelvic recurrence, coupled with
the lack of survival advantage to lymphadenectomy and pelvic
RT, raises the question of whether either approach is needed
for the majority of patients with early-stage endometrial can-
cer. In the eyes of many, having LVI is almost indicative of
nodal involvement. Cohn et al.112 correlated LVI and the risk of
positive pelvic nodes in 366 surgically staged patients. The rate
of LVI was 25%, and the rate of positive pelvic nodes was 13%.
Patients with LVI were significantly more likely to have nodal
metastasis (35 of 92 vs. 11 of 274; p < .001). However, the
influence of LVI on pelvic nodal metastasis was the strongest in
patients with deep myometrial invasion and high grade. Data
from MSKCC on 126 patients with endometrioid FIGO (1988)
stages IB to IIB and LVI also showed that the mere presence of
LVI should not be a trigger for giving pelvic RT, especially when
patients had lymphadenectomy. Patients were divided into two
groups: those from the old era, when treatment was often pel-
vic RT, and those from the modern era, when patients were
more often treated with lymphadenectomy and intravaginal
RT.113 The rate of pelvic relapse for patients with LVI was 7% in
the old era compared to 3% (p = .3) in the modern era.
No Myometrial Invasion, Grades 1 and 2
The risk of vaginal recurrence is almost negligible. Straughn
et al.114 reported no vaginal recurrence in 103 such patients
treated with surgery alone. Pelvic lymph nodal positivity was
3%. The 5-year progression-free survival rate in this group was
on the order of 95% to 98%. It is unlikely that postoperative pel-
vic or intravaginal RT would add anything to the final outcome,
and therefore radiation is not routinely recommended to this
group of patients.
No Myometrial Invasion, Grade 3
In GOG study 33, there were only eight patients with stage IA
grade 3 disease, making it difficult to draw any meaningful con-
clusion.87 There were no relapses in the three patients receiv-
ing postoperative radiation as compared with one failure in the
five patients who received no postoperative therapy. Straughn
et al.114 reported on eight patients with stage IA grade 3 disease
treated with surgery alone, with two of patients developing iso-
lated vaginal recurrence. The risk of lymph node metastasis in
this group of patients is not very high. At MSKCC, these patients
are offered either intravaginal RT alone or observation.
Less Than 50% Myometrial Invasion, Grades 1 and 2
This group of patients constitutes the most common stage sub-
group of all endometrial cancers. Straughn et al.114 reported a
3% (9 of 296) risk of vaginal recurrence when surgery alone
was done. In the surgery alone arm of the PORTEC-1 trial115 the
5-year vaginal recurrence rate for patients with <50% myome-
trial invasion grade 2 was 5%. In a randomized trial reported
by Sorbe et al.108 the vaginal recurrence rate was 3.1% for
those in the observation arm compared to 1.2% for those in the
intravaginal RT arm (p = .114). The trial was designed to detect
a difference of 1% versus 5% in the vaginal recurrence rate in
the two groups. The data were not reported separately based
on whether myometrial invasion was present or not, making it
difficult to determine the true impact of intravaginal RT on the
rate of vaginal recurrence in patients with myometrial inva-
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Chapter 70 Endometrial Cancer 1437
sion. Data from MSKCC on 233 patients with <50% myome-
trial invasion grade 1 or 2 showed a vaginal recurrence rate
of only 1% using intravaginal RT alone.116 In addition, Sorbe
et al.117 reported on 110 patients with IB grade 1 or 2 who were
part of a prospective, randomized trial evaluating two differ-
ent intravaginal RT doses; the rate of vaginal recurrence was
0.9%. The risk of pelvic recurrence was only 1.8%, even though
lymphadenectomy was not required. This low rate of pelvic
recurrence is similar to those reported by Straughn et al.114 of
0.3% (1 of 296) and by Horowitz et al.118 of 0% (0 of 62) in the
setting of lymphadenectomy. This indicates that pelvic RT is of
limited use, and therefore it seems reasonable to suggest that
either observation or intravaginal RT is a reasonable option for
patients with grade 1 or 2 and <50% myometrial invasion.
However, when deciding on whether adjuvant RT is needed,
it is important to address two issues. First, older patients tend
to have higher rates of relapse. In the study by Straughn et al.114
Clinical Radiation Oncology
8 of the 10 vaginal/pelvic recurrences were in patients 60
years old. In the randomized trial by Sorbe et al.108 comparing
adjuvant intravaginal RT to observation, patients with vaginal
recurrences were significantly (p = .018) older (mean age, 68.6
years) than patients without vaginal recurrences (mean, 62.6
years). Second, patients with LVI have a higher chance of vagi-
nal recurrence, as demonstrated by Mariani et al.,81 who
reported on 508 patients with endometrial cancer limited to the
corpus treated with surgery alone. The presence of LVI signifi-
cantly increased the vaginal relapse rate from 3% to 7% (p =
.02). The rate of vaginal relapse would have been even higher if
patients without myometrial invasion (152 of 508) had been
excluded because LVI is exceedingly rare in patients without
myometrial invasion. At MSKCC, patients who are 60 years
old or have LVI are recommended to have intravaginal RT.
Greater Than 50% Myometrial Invasion, Grade 3
Some advocate observation for patients with <50% myome-
trial invasion grade 3, yet the 5-year vaginal recurrence rate
in PORTEC-1 was 14% for such patients treated with surgery
alone compared to 0% for those treated with pelvic RT.115
Perhaps a better choice for those patients is intravaginal RT.
The incidence of positive pelvic lymph nodes at time of sur-
gery in this subset of patients is not negligible. In the GOG 33
study the rate was 9% (5 of 54 of patients with inner one-third
myometrial invasion), and in the study by Chi et al.119 the rate
was 7% (3 of 42) based on <50% myometrial invasion.71 Yet
the rate of pelvic recurrence, when the pelvic nodes are not
surgically assessed, does not reflect these incidences. In the
PORTEC-1 trial, none of the 37 patients with grade 3 disease
and <50% myometrial invasion who were treated with TAH/
BSO alone relapsed in the pelvis.115 Horowitz et al.118 (n = 31)
and Fanning120 (n = 21) reported no vaginal or pelvic recur-
rence in their series of patients with <50% myometrial invasion
grade 3 treated with hysterectomy and lymphadenectomy fol-
lowed by intravaginal RT. At MSKCC, intravaginal RT is rec-
ommended for this subset of patients irrespective of whether
lymphadenectomy was performed.
Fifty Percent or Greater Myometrial Invasion,
Grades 1 and 2
The risk of vaginal recurrence with surgery alone in this group
of patients is not minimal. In the PORTEC-1 trial, the 5-year
vaginal recurrence for patients with 50% myometrial inva-
sion treated with surgery alone was 10% for those with grade
1 and 13% for grade 2. The corresponding 5-year vaginal
recurrence rates for patients treated with pelvic RT were 1%
and 2%, respectively.115 Vaginal control with intravaginal RT
alone in this group of patients is about 1.8% based on several
series.118,121122,123 This highlights the fact with regard to vaginal
control, pelvic RT is not superior to IVRT in patients with 50%
myometrial invasion grade 1 or 2. With regard to pelvic con-
trol, in the PORTEC-1 trial115 the 5-year pelvic recurrence for
1438 Section III Clinical Radiation Oncology Part J Gynecologic
TABLE 70.4 OUTCOME FOR ENDOMETRIAL CANCER WITH 50% MYOMETRIAL
INVASION (GRADES 1 AND 2) AFTER LYMPHADENECTOMY AND
INTRAVAGINAL RADIOTHERAPY ALONE
Number of Vaginal
Author Year Patients Recurrence Pelvic Recurrence
Ng et al.121 2000 34 2.9% (1/34) 2.9% (1/34)
Horowitz et al.118 2002 41 2.4% (1/41) 4.8% (2/41)
Solhjem et al.122 2005 30 0% (0/30) 0% (0/30)
Long et al.122 2011 61 1.6% (1/61) 0% (0/61)
Total 166 1.8% (3/166) 1.8% (3/166)
patients with 50% myometrial invasion treated with surgery
alone was 2% for grade 1 and 6% for grade 2. The data from
the PORTEC-2 trial109 and the Swedish trial,110 in which patients
with 50% myometrial invasion grade 1 or 2 were included,
indicate that the omission of pelvic RT increased the risk of pel-
vic recurrence. In PORTEC-2 trial109 the 3-year rate was 3.5%
in the intravaginal RT arm compared to 0.6% in the pelvic RT
arm (p = .03). In the Swedish trial110 the pelvic recurrence rate
was 5.3% in the IVRT arm compared to 0.4% in the pelvic plus
intravaginal RT arm (p = .0006). The risk of pelvic recurrence
for this subset of patients with lymphadenectomy is about 1.8%
on average118,121122,123 from data in the literature (Table 70.4).
At MSKCC, most of these patients undergo lymphadenectomy
or SLN mapping, and if the nodes are pathologically negative,
they undergo intravaginal RT alone.
Fifty Percent or Greater Myometrial
Invasion and Grade 3
In the study by Chi et al.119 the risk of finding positive lymph
nodes in this group of patients was 28% (8 of 29). Such patients
were not enrolled in the PORTEC trials because it was felt
that omitting pelvic RT when lymphadenectomy was not per-
formed could not be justified. In the registry study reported by
Creutzberg et al.115 99 patients with 50% myometrial invasion
grade 3 were treated with postoperative pelvic RT. The 5-year
rate of vaginal recurrence was 5%, that of pelvic recurrence
was 8%, and that of distant relapse was 31%. Very few inves-
tigators would recommend surgery alone for these patients. In
fact an argument could be made that pelvic RT might be needed
even after a negative lymphadenectomy, especially for older
patients and those with LVI. In GOG 99 trial, factors associ-
ated with an increased recurrence rate (25% at 5 years) were
identified using proportional hazards regression modeling of
historical data from GOG 33.105 These factors were (a) increas-
ing age, (b) moderate to poorly differentiated tumor grade,
(c) presence of lymphovascular invasion, and (d) outer one-
third myometrial invasion. From the results of that analysis
a subgroup of patients with high intermediate risk (HIR) was
defined as follows: (a) at least 70 years of age with only one of
the other risk factors, (b) at least 50 years of age with any two
of the other risk factors, or (c) any age with all three of the other
risk factors. Those on the RT arm demonstrated a somewhat
lower overall death rate when compared to those on the obser-
vation arm (relative hazard [RH] = 0.73, 90% CI = 0.43 to 1.26)
in the HIR subgroup. AT MSKCC, patients with deep myometrial
invasion grade 3 who are high to intermediate risk per GOG 99
would be offered postoperative pelvic RT even in the setting of
negative lymphadenectomy. If they are not HIR, then intravagi-
nal RT could be considered, but only in the setting of adequate
lymphadenectomy, that is, sampling the obturator, external ili-
acs, internal iliacs, common iliacs, and para-aortic lymph node
stations and a minimum of 10 nodes.
Cervical Involvement
It is important to recognize the distinction between gross and
occult cervical involvement. Gross involvement increases the
risk of parametrial extension as well as spread to pelvic lymph
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TABLE 70.5 TREATMENT RECOMMENDATIONS AT MEMORIAL SLOAN-
KETTERING CANCER CENTER FOR STAGE I AND II PATIENTS
WITH ENDOMETRIOID ADENOCARCINOMA
Extent/Grade 1 2 3
No MI invasion Observation Observation IVRT or observationa
<50% MI IVRT or IVRT or IVRT
observationa observationa
50% MI IVRT IVRT IVRT or IMRTb
Endocervical gland IVRT IVRT IVRT or IMRTb
CSI <50% IVRT IVRT IVRT or IMRTb
CSI >50% IMRT IMRT IMRT
CSI, cervical stromal invasion; IMRT, intensity-modulated radiotherapy; IVRT, intravagi-
nal radiotherapy; MI, myometrial invasion.
a
Observation is offered to patients <60 years old and without lymph node invasion.
b
IMRT if high to intermediate risk.
nodes in a fashion similar to primary cervical cancer. Patients
with gross cervical involvement from endometrial cancer could
undergo radical hysterectomy and pelvic lymph node dissec-
tion or preoperative radiation including pelvic radiation and
intracavitary brachytherapy followed by simple hysterectomy.
For occult cervical involvement, the treatment often consists
of simple hysterectomy with or without lymphadenectomy
and adjuvant radiation. The type of radiation most often used
is pelvic RT and intravaginal RT. Pitson et al124 reported on
120 patients treated with such a combination. The 5-year dis-
ease-free survival rate was 68% and the rate of pelvic relapse
was 5.8% (7 of 120).
There are also emerging data on the role of intravaginal RT
alone in some patients with occult cervical involvement who also
had surgical lymph node staging. The average rate of vaginal
recurrence was 1.47% (1 of 68), and pelvic recurrence was also
1.47%. It is important to note that in these series patients treated
with intravaginal RT alone were highly selected.118,125126,127
Patients with endocervical glandular involvement are no longer
considered stage II in the new FIGO staging system. In PORTEC-2
trial patients with glandular cervical involvement were random-
ized to pelvic RT or intravaginal RT.109 At MSKCC patients with
endocervical glandular involvement are treated with IVRT alone,
especially if there are no other adverse features or if they had
lymphadenectomy. For patients with cervical stromal invasion
grade 1 and 2 and the depth of cervical stromal invasion is
<50%, intravaginal RT could be offered if they underwent ade-
quate lymphadenectomy. For those with grade 3 or deep cervi-
cal stromal invasion, pelvic RT is recommended irrespective of
lymphadenectomy. Table 70.5 shows overall treatment recom-
mendations for early-stage endometrioid adenocarcinoma at
MSKCC.
Role of RT in Stage III
The outcome of patients with isolated adnexal involvement
treated with pelvic RT is reasonably good. Connell et al.128
reported on 12 patients treated with postoperative pelvic
radiation with a 5-year disease-free survival of 70.9%. The
weighted average of 5-year disease-free and overall survival
rates from literature review in that study was 78.6% and
67.1%, respectively. Jabson et al.86 reported 5-year disease-
free and disease specific survival of 76.4% and 76.3%, respec-
tively, in 46 patients with isolated adnexal involvement treated
with postoperative RT. The rate of local/regional recurrence
was 2.2% (1 of 46) and that of distant relapse was 26.1% (12
of 46). In the same report, the outcome of patients with iso-
lated serosal involvement (n = 21) was somewhat similar: the
5-year disease-free and disease-specific survival rates were
59.6% and 75.4.3%, respectively. The rate of local/regional
recurrence was 14.3% (3 of 21) and that of distant relapse
was 33.3% (7 of 21). If pelvic node involvement (IIIC) is the
only major risk factor, treatment with postoperative pelvic

radiotherapy can yield a 60% to 72% long-term survival
rate in these patients.87 Patients with stage IIIC disease, by
virtue of para-aortic node involvement, represent a particu-
larly high-risk group. After surgery, these patients are gen-
erally treated with extended-field radiation to encompass
the pelvis and the para-aortic regions. With this aggressive
approach, several investigators reported 30% to 40% survival
rates in small patient populations.87 The question of whether
it is safe to omit radiation even after adequate surgical lymph
node staging in patients with stage IIIC endometrial can-
cer was addressed in a study from the Mayo Clinic. Mariani
et al.129 reported on 122 patients with node-positive disease;
at 5 years the risk of pelvic recurrence was 57% after inad-
equate lymph node dissection and/or no RT compared to 10%
with adequate lymph node dissection (>10 pelvic nodes and
5 para-aortic nodes) and RT. This difference was statistically
significant on univariate (p < .001) and multivariate analysis
(p = .03) indicating the need for postoperative radiation even
after adequate surgical staging.
The recognition that a significant number of patients with
stage III disease fail in the abdomen has prompted a number of
investigators to evaluate whole-abdomen irradiation (WAI) in
these patients. The GOG did a pilot study (GOG study 94) on
patients with maximally debulked stages III and IV disease
using whole-abdomen radiotherapy to a total dose of 30 Gy at
1.5 Gy per fraction followed by a pelvic boost for an additional
19.8 Gy at 1.8 Gy per fraction.130 The 3-year disease-free and
overall survival rates for the 58 patients with stage III typical
adenocarcinoma were both 34.5%, and for stage IV the corre-
sponding rates were 10.4% and 21.1%, respectively.
ROLE OF SYSTEMIC THERAPY
Hormonal therapy has been used in the treatment of recurrent/
advanced endometrial cancer for many years. Agents used
include megestrol acetate (Megace), medroxyprogesterone
acetate (Provera), and to a lesser extent tamoxifen.131133 The
response rate rages from 9% to 33%, with an overall survival
of 6 to 14 months. In GOG 107, doxorubicin was compared
to doxorubicin and cisplatin.134 The response rate was 42%
vs. 25% (p = .004), and the progression-free interval was 5.7
versus 3.8 months (p = .014) in favor of combination chemo-
therapy. However, this did not translate into overall survival
advantage (9 vs. 9.2 months). In GOG 177 trial135 doxorubicin/
cisplatin was compared doxorubicin/cisplatin/paclitaxel. The
three-drug regimen was superior in terms of response rate
(57% vs. 34%, p < .01), progression-free interval (8.3 vs. 5.3
months, p < .01), and survival (15.3 vs. 12.3 months, p = .037).
With the widespread use of chemotherapy in the recurrent/
advanced setting, its use in the adjuvant setting has also started
to increase and to challenge the role of adjuvant RT. There are
several randomized trials addressing the role of adjuvant che-
motherapy in advanced endometrial cancer.
Chemotherapy Versus RT Trials
There are three randomized trials comparing adjuvant che-
motherapy to radiation. The Japanese Gynecology Oncology
Group (JGOG) trial randomized 385 patients with stage (FIGO
1988) IC to III (25% with stage III) endometrial cancer to pelvic
radiation (193 patients) or to chemotherapy (192 patients).136
The surgery was hysterectomy with optional lymphadenec-
tomy. The dose of pelvic RT was 45 to 50 Gy using open antero-
posterior/posteroanterior (AP/PA) fields. Chemotherapy con-
sisted of cyclophosphamide (333 mg/m2), cisplatin (50 mg/m2),
and doxorubicin (40 mg/m2) every 4 weeks for three cycles or
more. There was no significant difference in progression-free
(p = .726) or overall survival rate (p = .462) between the two
groups. A trial from Italy had a similar design, in which 340
patients with stage (FIGO 1988) IC grade 3, stage II grade 3,
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Chapter 70 Endometrial Cancer 1439
and stage III (two-thirds of patients) were randomized to
radiation or to chemotherapy.137 With a median follow-up of
95.5 months, the 5-year disease-free survival rate was 63% in
both arms (p = .44) and the 5-year overall survival rate was
69% in the radiation arm and 66% in the chemotherapy arm
(p = .77). Again there was no significant difference in outcome
despite using five cycles of Cytoxan, cisplatin, and doxorubi-
cin. In GOG 122, 396 patients with stage (FIGO 1988) III to
IV disease were randomized to whole-abdomen radiation
(n = 202) versus doxorubicin/cisplatin (n = 194) for eight cycles.
Progression-free survival was the primary endpoint of this
study. With a median follow-up of 74 months, there was sig-
nificant improvement in both progression-free (50% vs. 38%;
p = .007) and overall survival rate (55% vs. 42%; p = .004),
respectively, in favor of chemotherapy. However, before con-
cluding that chemotherapy alone is the answer, a closer exami-
nation of the data is warranted. The overall absolute rate of
Clinical Radiation Oncology
relapse was 54% in the radiation arm compared to 50% in the
chemotherapy arm, a small difference, if any, and yet the corre-
sponding 5-year progression-free survival rates were 38% and
50% (p = .007), respectively. The reason for the discrepancy is
that in this study, there was stage imbalance, in which there
were more stage IIIA patients in the RT arm (28.2%) than in the
chemotherapy arm (18%). Conversely, there were more patients
with stage IIIC disease in the chemotherapy arm (51.5%) than
in the RT arm (44.6%). Therefore, the 5-year disease-free sur-
vival rate for the chemotherapy arm was increased from 42%
to 50%, which became significantly different than the RT arm
(50 vs. 38%, p = .007) rather than 42% versus 38%, which is not
likely to be significant. The 5-year overall survival rate in the
chemotherapy arm was 55% compared to 42% for the RT arm
(p = .004). What are we to make of the significant difference in
overall survival? There were 15 deaths unrelated to endome-
trial cancer or protocol treatment in the radiation arm com-
pared to only to 6 in the chemotherapy arm, raising a question
about whether the two arms of the study were truly balanced,
especially since no stratification was performed in that trial.138
The results of GOG 122 have led to the adoption of adjuvant
chemotherapy as the preferred treatment for stage III endo-
metrial cancer. It is important to note, however, that GOG 122,
JGOG, and the Italian study all showed no significant difference
in the patterns of relapse between RT and chemotherapy. If one
were to use the unadjusted progression-free survival from GOG
122, then all three randomized trials failed to show that adju-
vant chemotherapy is superior to adjuvant RT.
Chemoradiation Versus RT Trials
In a trial from Finland,139 156 patients with stage (FIGO 1988) IA
or IB grade 3 (n = 28) or stage IC to IIIA grade 1 to 3 (n = 128) were
postoperatively randomized to receive radiotherapy (56 Gy)
only (n = 72) or radiotherapy combined with three cycles of
cisplatin (50 mg/m2), epirubicin (60 mg/m2), and cyclophos-
phamide (500 mg/m2) chemotherapy (n = 84). The disease-
specific overall 5-year survival was 84.7% in the RT arm versus
82.1% in the chemoradiation arm (p = 0.148). Hogberg et al.140
reported on two trials (Mario Negri Gynecologic Oncology
Group [MaNGO] and Nordic Society of Gynecological Oncology
[NSGO]/European Organisation for Research and Treatment of
Cancer [EORTC]) combined in one report. In the MaNGO trial
there were 157 patients (two-thirds were stage III); 76 were
randomized to postoperative pelvic RT (45 Gy) and 80 to che-
motherapy followed by pelvic RT. The chemotherapy consisted
of three cycles of doxorubicin (60 mg/m2) and cisplatin (50 mg/
m2). The 5-year progression-free survival (PFS) was 61% in the
RT group compared to 74% for the chemoradiation group, but
that difference was not significant (p = .1). The 5-year overall
survival (OS) was also not significant (73% vs. 78%, respec-
tively; p = .41). In the NSGO/EORTC trial 383 patients were
randomized to RT (n = 191) versus RT and chemotherapy
(n = 187). The type of chemotherapy varied, and only a handful
1440 Section III Clinical Radiation Oncology Part J Gynecologic
TABLE 70.6 EFFECT OF ADJUVANT CHEMOTHERAPY ON OUTCOME IN
HIGH-RISK ENDOMETRIAL CANCER
JGOG Italian GOG 122 Finland NSGO MaNGO
Relapse
PFS Unadjusted
Adjusted
OS , OS not primary
endpoint
The Japanese Gynecology Oncology Group (JGOG), the Italian trial, and Gynecologic
Oncology Group (GOG) 122 compared chemotherapy to radiotherapy. The Finland
trial, Nordic Society of Gynecological Oncology (NSGO), and Mario Negri Gynecologic
Oncology Group (MaNGO) compared chemotherapy/radiotherapy to radiotherapy.
OS, overall survival; PFS, progression-free survival.
, chemotherapy equivalent to radiotherapy; , chemotherapy better than
radiotherapy.
of patients were stage III. The 5-year PFS was better for the
chemoradiation arm (79% vs. 72% for RT; p = .04), but OS
was not significantly better (83% vs. 76%, respectively; p = .1).
Greven et al.141 reported the results of RTOG 9708 phase II
study on 44 patients with stages (FIGO 1988) I to III endo-
metrial cancer who were treated with pelvic radiation and
intravaginal RT given concurrently with cisplatin 50 mg/m2 on
days 1 and 28 of radiation followed by four cycles of cisplatin
(50 mg/m2) and Taxol (175 mg/m2). The 4-year disease-free
and overall survival rates for those with stage III disease (66%
of patients) were 72% and 77%, respectively.
It is clear from the foregoing discussion that the role of
adjuvant chemotherapy is gaining ground and that at least the
results are equivalent to those with adjuvant RT (Table 70.6).
However, adjuvant chemotherapy should not be promoted at
the expense of RT, because the rate of relapse is still high even
with chemotherapy.142,143 The GOG is comparing chemoradia-
tion (similar to RTOG 9708) to six cycles of carboplatin/pacli-
taxel in patients with stage III disease. PORTEC 3 is a random-
ized trial comparing chemoradiation to RT alone. Until the
results of these trials are available, the decision on whether to
give chemoradiation or chemotherapy alone should be based
on risk factors.
Systemic Therapy Recommendations
Based on Risk Factors
Isolated Positive Peritoneal Cytology
In the 2009 FIGO staging system, having positive peritoneal
cytology is no longer considered stage IIIA. The true benefits of
treatment when adverse features such as high grade or deep
invasion are lacking are debatable. Eltabbakh et al.144 reported
on 29 patients with FIGO grade 1 or 2 and <50% myometrial
invasion who were treated with intravaginal brachytherapy
and megestrol acetate (Megace). None of the patients relapsed
or died from their disease. Megace was given for 1 year, and at
the end of therapy, 24 patients underwent second-look laparos-
copy and peritoneal cytology. In 23 patients, the cytology was
negative, and the remaining patient, with persistent positive
cytology, received an additional year of Megace, after which
cytology was confirmed to be negative. At MSKCC, we gener-
ally recommend intravaginal RT and Megace for such patients.
Early-Stage Serous and Clear-Cell Cancer
Serous cancer and to a lesser extent clear-cell cancer tend to
spread in a fashion similar to ovarian cancer, with a high pro-
pensity for upper abdominal relapse. Therefore, it is important
to perform comprehensive surgical staging because of the high
rate of surgical up-staging. With such pattern of spread, it is
not surprising that whole-abdomen radiation has been exten-
sively studied in this group of patients. Lim et al.145 reported
on 78 patients with stages I to IIIA papillary serous carcinoma:
booksmedicos.org
58 were treated with whole-abdomen radiation and 20 were
not. The corresponding 5-year disease-specific survival rates
were 74.9% and 41.3%, respectively (p = .04). The data from
GOG 94 were less impressive.146 The 5-year progression-free
survival for stages (FIGO 1988) I and II papillary serous cancer
was 38.1% and for clear-cell carcinomas was 53.9%. Alektiar
et al.147 reported on 25 patients with stages I and II serous
endometrial cancer who underwent surgical staging, intravagi-
nal RT, and six cycles of carboplatin/paclitaxel. With a median
follow-up of 30 months, the 5-year progression-free and over-
all survival rates were 88%. None of the patients developed
vaginal recurrence. In a recent update on a larger number of
patients (n = 41) with a median follow-up time of 58 months,
the 5-year disease-free and overall survival rates were 85%
and 90%, respectively.148 The 5-year actuarial recurrence rates
were 9% in the pelvis, 5% in the para-aortic nodes, and 10%
at distant sites. None of the patients developed vaginal recur-
rence. At MSKCC patients with early-stage disease who are
surgically staged are being treated with intravaginal RT with
concurrent carboplatin/paclitaxel.
Early-Stage High-Risk Endometrioid Adenocarcinoma
The 5-year rate of distant metastasis from the PORTEC regis-
try study of patients with grade 3 and deep invasion was 31%
despite the use of postoperative pelvic RT.115 The rate of relapse
was also 28.9% (90% distant) in a study from MSKCC despite
an aggressive surgical and adjuvant RT approach.123 Thus it is
not surprising that there is an inclination toward recommend-
ing adjuvant chemotherapy in addition to RT in this group of
patients. The GOG is conducting a randomized trial for patients
with high to intermediate risk, as well as serous and clear-cell
carcinoma, in which patients are randomized to pelvic RT ver-
sus intravaginal RT and three cycles of carboplatin/paclitaxel.
Stage IIIA
The results of postoperative external-beam RT in patients
with isolated adnexal or serosal involvement are gener-
ally good. However, the rate of distant relapse is still 26% to
33%, indicating the need for adjuvant systemic therapy.86 At
MSKCC, we recommend concurrent chemoradiation followed
by carboplatin/Taxol in a similar fashion to the RTOG 9708.
Although the results of isolated involvement with postoperative
RT are good, patients with more than one site of involvement do
worse. Jobson et al.149 reported on 141 patients with IIIA endo-
metrioid adenocarcinoma (patients with isolated positive perito-
neal cytology were excluded) treated with postoperative RT. The
risk of abdominal relapse was 12.4% (11 of 89) for patients with
one site of involvement compared to 36.5% (19 of 52) for more
than one site (p < .001). Distant metastasis rate was 23.9% (21
of 89) compared to 34.6% (18 of 52), respectively. The 5-year
disease-specific survival (DSS) was 70.4% for one involved site
compared to 43.3% for more than one (p = .001). On multivari-
ate analysis, grade 3 (HR, 2.5; p = .045) and more than one site
involvement (HR, 2.2; p = .012) were independent predictors
of poor DSS. In the ongoing debate on whether chemotherapy
alone is better than chemoradiation in patients with stage III,
it is in this group of patients with multiple sites of involvement
and grade 3/aggressive histology in which chemotherapy alone
might be a better choice.
Stage IIIC
The outcome of patients with isolated lymph node involvement
(especially pelvic nodes), treated with postoperative pelvic RT
is relatively good. At MSKCC, we recommend chemoradiation
followed by carboplatin/paclitaxel to try to reduce the risk of
recurrence even further. Similar to patients with IIIA, having
more than one site of involvement has been shown to be a
predictor of poor outcome.150 In a recent SEER review, Garg
et al.151 showed that for patients with stage IIIC disease (n =
2,559), the 5-year disease-specific survival was 67%, which

dropped to 43% when extranodal involvement (i.e., positive
washing, adnexa/serosal, and vaginal/parametrial involve-
ment) was present (p < .001). Again, perhaps in this subset of
patients with stage IIIC chemotherapy alone might be better.
RADIATION THERAPY TECHNIQUES
Intravaginal Radiation
The purpose of this treatment modality is to deliver the high-
est dose of radiation to the vaginal mucosa while limiting the
dose to the surrounding normal structures such as the blad-
der, rectum, and small intestines. HDR brachytherapy using
192
Ir sources is the preferred method of delivering intravagi-
nal RT. The type of applicator used is generally a cylinder. The
treatment is given on an outpatient basis without the need for
anesthesia and without the radiation exposure to medical per-
sonnel. At MSKCC, patients start their treatment 4 to 6 weeks
postoperatively, depending on the vaginal cuff healing. It takes
longer for the vaginal cuff to heal after LAVH/BSO and robotic
hysterectomy than after TAH/BSO. The treatment is given in
three fractions of 7 Gy to a total dose of 21 Gy. The interval
between each fraction is 1 to 2 weeks. The dose is prescribed
to 0.5-cm depth from the mucosal surface (Fig. 70.6). The
treatment is usually delivered using a 3-cm-diameter cylinder
to treat a 4- to 7-cm length of the vagina, depending on depth
of invasion and tumor grade. For patients with grade 3, serous
or clear-cell carcinoma, the length of vagina treated is gener-
ally 7 cm (assuming an average length of vagina after simple
hysterectomy of about 10 cm). This is done to account for
potential submucosal extension that may lead to relapse in the
distal periurethral region with these aggressive histologies. For
patients with grade 1 or 2 endometrioid adenocarcinoma, the
treated vaginal length increases from 4 cm if myometrial inva-
sion is <50%, to 5 cm for >50% myometrial invasion, and to
6 cm for cervical involvement. Occasionally, the dose per frac-
tion is lowered to 6 Gy instead of 7 Gy if the diameter of the
cylinder is <3 cm. This is usually done to avoid a very high dose
of radiation to the vaginal mucosa. The dose per fraction is also
lowered to 4 to 5 Gy when pelvic radiation is added. Intravaginal
RT could be delivered with lowdose-rate 137Cs sources, which
requires admission to the hospital for a few days. The dose is
usually 60 Gy prescribed to the vaginal mucosa or 30 to 35 Gy
prescribed to a 0.5-cm depth from the vaginal mucosa.
A B
FIGURE 70.6. Dose distribution with intravaginal radiation therapy (prescription dose 7 Gy in solid yellow). A: Sagittal view. B: Axial view.
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Chapter 70 Endometrial Cancer 1441
External-Beam Radiation
Pelvic Radiation
Conventional Pelvic RT
At the time of simulation, the small bowel is opacified using
oral contrast, a vaginal marker is used to define the vaginal
cuff, and the rectum is opacified with barium or CT-compatible
contrasts. Patients are usually placed in the prone position to
displace the small intestines from the radiation field. The tar-
get volume consists of the pelvic lymph nodes, including obtu-
rator, external, internal, and lower common iliac groups, and
the proximal two-thirds of the vagina. The presacral nodes are
not included unless patients have gross cervical involvement.
High-energy linear accelerators (15 MV) are preferred because
of their sparing of the skin and subcutaneous tissue. The ideal
beam arrangement with conventional radiation is the four-field
pelvic-box technique to reduce the dose to the small intestines
Clinical Radiation Oncology
and to some extent the bladder and rectum. For AP/PA fields,
the superior border is L5-S1, the inferior border is the bot-
tom of the obturator foramina, and the lateral border is 2 cm
beyond the widest point of the inlet of the true bony pelvis.
For lateral fields, the anterior border is in front of the pubis
symphysis and the posterior border at least at S2-3. The supe-
rior and inferior borders are the same for the AP/PA fields.
All fields are treated daily to a dose of 1.8 Gy. A total dose of
50.4 Gy is generally used when pelvic radiation is used alone
or 45 Gy when combined with intravaginal brachytherapy.
Intensity-Modulated RT
At MSKCC, postoperative intensity-modulated RT (IMRT) is
used for most patients with endometrial cancer who need pel-
vic RT (Fig. 70.7). At the time of simulation patients are placed
in the supine position and immobilized using Aquaplast. Oral
and rectal contrasts are used to better visualize the small and
large intestines. In addition, contrast is inserted in the vaginal
cuff to better visualize the upper vagina. Because pelvic lymph
nodes are poorly visualized by CT when normal, they should be
defined by encompassing the contrast-enhanced blood vessels.
Taylor et al.152 found that a modified 7-mm margin around con-
trast-enhanced vessels offers a good surrogate target for pelvic
lymph nodes. Small et al.153 reported on consensus guidelines
for delineation of clinical target volume for intensity-modulated
pelvic radiotherapy in postoperative treatment of endometrial
1442 Section III Clinical Radiation Oncology Part J Gynecologic
50.4 40.0 30.0 20.0 10.0 5.0 Gy
FIGURE 70.7. Pelvic intensity-modulated radiation therapy dose distribution. Outlined iliac
vessels are shown in pink and nodal planning target volume in yellow.
and cervical cancer. A modified 7-mm margin (excluding bowel
and muscles) is recommended around the iliac vessels to cre-
ate nodal clinical target volume (CTV). To create nodal plan-
ning target volume (PTV), an additional expansion of 7 mm
all around nodal CTV is generally recommended. At MSKCC
vaginal PTV is created by outlining the contrast enhanced vagi-
nal cuff and adding a 3-cm margin to account for the impact of
bladder and rectal filling, as well as of vaginal motion.154
Extended Field
This technique is mainly used for patients with documented
positive para-aortic nodes. CT simulation is crucial when treat-
ing extended fields for accurate delineation of the kidneys, small
bowel, and liver in addition to nodal target. The latter should
include, in addition to the pelvic nodes, the pericaval, interaor-
tocaval and para-aortic areas, defined by contrast-enhanced
blood vessels. The preferred approach is the four-field box
technique rather than AP/PA in order to lower the dose to the
small intestines. However, attention should be paid to the dose
that the kidneys might receive with the four-field arrangement.
The lower border is the same as in pelvic radiation, but the
upper border is extended usually to the T12-L1 interspace. The
typical dose is 45.0 Gy at 1.8 Gy or 1.5 Gy if patients develop
acute gastrointestinal toxicity. At MSKCC, IMRT is also the pre-
ferred choice for extended-field radiation.
Whole-Abdomen Radiation
The target is the whole peritoneal cavity, which requires adequate
coverage of the diaphragm with adequate margin during all
phases of normal respiration with minimal to no liver shielding.
The standard approach is AP/PA open fields with five half value
layer kidney blocks placed over the PA field only (if the patient is
lying supine) from the start of the treatment. The dose is usually
30.0 Gy at 1.5 Gy per fraction, followed by 19.8-Gy boost to the
pelvis at 1.8 Gy per fraction. The upper border is usually placed 1
cm above the diaphragm, and the lateral borders should extend
beyond the peritoneal reflections. The lower border is usually at
the bottom of the obturator foramen. The para-aortic region gen-
erally receives a cone down to a total dose of 45 Gy and the pelvis
to 50 Gy. IMRT may allow higher and more uniform doses to be
delivered with potentially less toxicity.155,156
COMPLICATIONS OF TREATMENT
Surgery
In PORTEC-1 trial104 the rate of complications in the surgery-
alone arm was very low (6%). Surgical toxicity data were
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generally collected within 30 days of surgery, that is, before
patients were enrolled in the trial. Therefore it is important to
assess surgical toxicity from trials addressing a surgical ques-
tion. In the GOG LAP2 trial comparing laparotomy to lapros-
copy93 the rate of intraoperative complications was 8% versus
10%, respectively (p = .106). More important, the rate of post-
operative (within 6 weeks of surgery) grade 2 or greater com-
plications was 21% for laparotomy versus 14% for laparoscopy
(p < .001). In the Italian randomized trial comparing hyster-
ectomy to hysterectomy and lymphadenectomy, both early and
late postoperative complications occurred significantly more
frequently in the lymphadenectomy patients (81 of 264; 30.6%)
than for hysterectomy alone (34 of 250, 13.6%; p = .001). Most of
the difference in morbidity was due to lymphocysts and lymph-
edema, which occurred in 35 patients in the lymphadenectomy
arm and 4 patients in the no-lymphadenectomy arm.100
Radiation
Pelvic Radiation
In the PORTEC-1 randomized trial157 the overall (grades 1 to 4)
rate of late complications was 26% in the RT group compared to
4% in the observation group (p < .0001). Most of the late com-
plications in the RT group, however, were grades 1 and 2 (22%),
and only 3% were grades 3 and 4. It is also important to note
that many patients in this trial were treated with AP/PA fields,
for which the overall rate of complications was 30%, compared
to 21% for those treated with the four-field box (p = .06). Noute
et al.158 reported on the quality of life for patients enrolled in
PORTEC-1. Patients treated with pelvic RT reported significant
(p < .01) and clinically relevant higher rates of urinary inconti-
nence, diarrhea, and fecal leakage, leading to more limitations
in daily activities. Increased symptoms were reflected by the
frequent use of incontinence materials after pelvic RT (day and
night use, 42.9% vs. 15.2% for surgery alone; p < .001). Patients
treated with pelvic RT reported lower scores on physical func-
tioning (p = .004) and role-physical (p = .003). In GOG 99
when lymphadenectomy was performed, chronic lymphedema
was seen in 2.5% of the patients randomized to surgery alone
compared to 5% with postoperative pelvic RT.105 There is an
increased awareness of sacral insufficiency fractures (SIFs) as
a potential complication of pelvic RT in gynecologic cancers. In
a recent report from MSKCC, 13 of 223 (5.8%) patients treated
with postoperative pelvic RT developed SIF (median time, 11
months after completing pelvic RT). Eight patients (62%) pre-
sented with pain, and 5 patients (38%) were diagnosed on
incidental imaging. Treatment of SIF included observation in 7
patients (53%), bisphosphonate therapy in 5 patients (38%), and
surgery in 1 patient (8%). On multivariate analysis, only osteo-
porosis was independently associated with SIF (p = .04), with a
relative risk of 4.0 (95% CI 1.1 = 15.4). The rate of SIF was 5.5%
(8 of 145) for the subset of patients with endometrial cancer.159
The morbidity of rate conventional pelvic radiation could be
reduced by using IMRT. Mundt et al.160,161 demonstrated sig-
nificant reduction in acute and chronic gastrointestinal toxicity
when IMRT was compared to conventional radiation. In a
recent study from MSKCC,162 the use of IMRT was associated
with less bowel obstruction (BO) than with conventional RT.
There were 223 patients; 145 (65%) had endometrial cancer.
With a median follow-up of 48 months, the overall 5-year actu-
arial rate of BO was 7.2%. The rate in the IMRT group was
1.2%, compared to 9.6% for conventional RT (p = .025). This
was seen despite the fact that more patients in the IMRT group
had prior laparotomy (37% vs. 28%; p = .03), had more nodes
removed (22 vs. 13 median lymph nodes; p = .001), and
received more adjuvant chemotherapy (79% vs. 64%; p = .016).
On multivariate analysis the use of IMRT (relative risk, 0.12,
95% CI = 0.015 to 0.987) and body mass index of >30 (relative
risk, 0.12, 95% CI = 0.014 to 0.96) were associated with less
bowel obstruction.

RTOG 0418 is a recently completed a phase II study on the
feasibility of postoperative pelvic IMRT in cervical and endo-
metrial cancers.163 In the subset of evaluable patients with
stages I to IIIC endometrial cancer (n = 43), with a median
follow-up of 3.5 years, the 3-year DFS and OS rates were 92%
and 95%, respectively. Intestinal complications were the most
common; 10 patients (23%) had grade 1, 3 (7%) had grade 2,
and 1 (2%) had grade 3.
Whole-Abdomen Radiation
The toxicity of whole-abdomen radiation is more pronounced
than that of pelvic radiation but not as high as expected. In the
radiation arm of GOG study 122, the GI toxicity did not exceed
2% for grade 4 and 11% for grade 3, whereas in the chemo-
therapy arm the corresponding figures were 7% and 13%.
Grade 4 liver toxicity was seen in 1% of patients in the radia-
tion arm, and the grade 4 cardiac grade toxicity was 4% in the
chemotherapy arm.138
Intravaginal RT
The main advantage of intravaginal brachytherapy is its ability
to deliver a relatively high dose of radiation to the vagina while
limiting the dose to the surrounding normal structures, such as
the bowels and bladder. This advantage is manifested with the
low rate of severe late toxicity seen with this treatment tech-
nique, ranging from 0% to 1% in several series.116,118,122 In the
intravaginal RT arm of the Swedish trial110 the rate of late
intestinal toxicity was 2.3% for grade 1 and 0.4% for grade 2.
Urinary tract toxicity was as follows: 20.2% grade 1, 2.7%
grade 2, and 0.8% grade 3. Vaginal toxicity rate was 4.1%
grade 1, 0.8% grade 2, and 0.8% grade 3. However, such a
low rate of severe complications cannot be taken for granted
because special attention needs to be paid to the depth of pre-
scription, the dose per fraction, the length of vagina treated,
and the diameter of the cylinder used. Sorbe and Smeds164
reported a 15% late complication rate and a very high inci-
dence of vaginal stenosis after postoperative highdose-rate
intravaginal irradiation. This was attributed to the high dose
per fraction of 6 to 9 Gy; moreover, this dose was prescribed at
a depth of 10 mm from the surface of the cylinder, resulting in
very high vaginal mucosal, bladder, and rectal doses.
In PORTEC-2, intravaginal RT patients reported better social
functioning (p = .005) and lower symptom scores for diarrhea,
fecal leakage, need to stay close to a toilet, and limitation in
daily activities due to bowel symptoms (p = .001) compared to
pelvic RT. There were no differences in sexual functioning or
symptoms between the treatment groups; however, sexual
functioning was lower and sexual symptoms more frequent in
both treatment groups compared to the norm population.165
Definitive Radiation for Inoperable Disease
Patients with medically inoperable stage I or II uterine cancer
are usually treated in a fashion similar to those with cervical
cancer by using intracavitary applicators with or without pelvic
radiation. For patients with clinical stage I grade 1 or 2 and
no evidence of myometrial invasion or lymph node metastasis
on MRI, intracavitary brachytherapy alone is sufficient. Usually
a Fletcher-Suit or Henschke applicator with one or two tan-
dems (depending on uterus size) and ovoids is used to deliver
70 to 75 Gy to point A. The loading of the tandems is usually
different than that in cervical cancer. This is done in order to
provide wider coverage of the uterus laterally and superiorly.
When pelvic radiation is added, the dose is usually 45 to 50 Gy
supplemented with 30 to 35 Gy from intracavitary brachyther-
apy to bring the total dose to point A to 80 to 85 Gy. Rouanet
et al.166 treated 250 patients with endometrial cancer according
to this approach, which yielded a 5-year disease-specific survival
of 76.5%. HDR intracavitary brachytherapy is being used with
increased frequency.167,168 The American Brachytherapy Society
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Chapter 70 Endometrial Cancer 1443
established general guideline recommendations regarding HDR
alone or in combination with external-beam RT in terms of pre-
scription point (2 cm from the central axis at the midpoint along
the intrauterine sources), number of fractions, dose per fraction,
combination with EBRT, and optimization.169 Patients with stage
IIIB disease (vaginal involvement), an uncommon presentation,
are usually not surgical candidates and are also treated with
definitive radiation, including a combination of external-beam
and intracavitary/interstitial radiotherapy tailored to the extent
of their disease.
Radiation Therapy for Local Recurrence
Radiation therapy can be curative in a select group of patients
with small vaginal recurrences who have not received prior
radiation.170172 The 5-year local control rate ranges from 42%
to 65% and the 5-year overall survival rate from 31% to 53%.
Creutzberg et al. reported on survival after relapse based on
Clinical Radiation Oncology
the PORTEC-1 randomized trial.107 In patients who were ini-
tially randomized to surgery alone (n = 46 of 360), the 5-year
survival after vaginal relapse was 65%. However, before adopt-
ing salvage radiation as a treatment policy for all early-stage
endometrial cancer, a few aspects of this trial need to be
addressed. First, the 5-year survival rate from the PORTEC
trial is much higher than what is reported in the literature.
Most likely, the vaginal recurrences in this trial were detected
very early, unlike the situation for patients in the community.
The extent and size of local recurrence in endometrial can-
cer are very significant predictors of outcome.173 Second, this
high rate of salvage pertains only to isolated vaginal recur-
rence. The rate of survival at 3 years for pelvic recurrence in
the PORTEC-1 trial107 was 0%. Third, although the trial does
not mention any data on complications, it is not unrealistic to
expect a higher complication rate than what is normally seen
with adjuvant radiation. With salvage radiation, external-beam
RT and brachytherapy are often combined, and the doses of
radiation required are much higher than those used with adju-
vant radiation. The study from MD Anderson Cancer Center by
Jhingran et al.170 clearly highlights these issues. They reported
on 91 patients who were treated with definitive radiation for
isolated vaginal recurrence. The 5-year local control and over-
all survival rates were 75% and 43%, respectively. The median
dose of radiation was 75 Gy, which often included external
radiation and brachytherapy. The rate of grade 4 complica-
tions (requiring surgery) was 9%. Thus, when talking with a
patient about adjuvant radiation versus radiation reserved for
salvage, these issues need to be addressed and compared to
the excellent local control and low morbidity obtained with
adjuvant intravaginal brachytherapy.
UTERINE SARCOMA
Uterine sarcomas are uncommon, representing about 3% to 7%
of all uterine cancers.174 The World Health Organization (WHO)
classification includes endometrial stromal tumors, smooth
muscle tumors, and miscellaneous mesenchymal tumors. In
the mixed epithelial and mesenchymal tumors category, the
WHO classification includes adenosarcoma and malignant
mixed Mllerian tumors or carcinosarcoma.51 Age-related inci-
dences vary among the histologic types. The mean age at diag-
nosis for endometrial stromal sarcoma is 41 years, for leio-
myosarcoma 53.5 years, for adenosarcoma 57.4 years, and for
carcinosarcoma 65 years. Little is known about the risk factors
for uterine sarcomas, except for history of prior radiation and
carcinosarcoma.175 Most uterine sarcomas present with vagi-
nal bleeding, especially carcinosarcomas. Leiomyosarcomas
are more commonly discovered incidentally after simple hys-
terectomy for presumed uterine leiomyomata.
Nodal metastases are seen in approximately 14% of carci-
nosarcomas at the time of surgical staging but are rarely
1444 Section III Clinical Radiation Oncology Part J Gynecologic
(<5%) seen in leiomyosarcoma unless there is obvious extra-
uterine disease. For stromal sarcomas, dos Santos et al.176
reported a 19% (7 of 36) rate of nodal metastasis. The rate of
occult metastasis was only 10%. The corresponding rates
from the literature review were 10.1% and 8.1%, respectively.
Pathology and Staging
Endometrial stromal sarcomas are generally divided into
endometrial stromal sarcomas, which are low grade by defi-
nition, and undifferentiated endometrial sarcoma, which
are high grade. Tumor cells in endometrial stromal sarcoma
resemble those found in the stroma of proliferative endome-
trial lining. In contrast, tumor cells in undifferentiated endo-
metrial stromal sarcoma do not resemble endometrial stroma.
Leiomyosarcomas of the uterus have a fleshy appearance,
often with areas of necrosis. They display nuclear atypia,
high mitotic rates, and areas of coagulative tumor necrosis.
Adenosarcomas have two componentsa benign epithelial
tumor and a malignant mesenchymal component (gener-
ally low-grade sarcoma that resembles endometrial stroma).
Sarcomatous overgrowth, defined as the presence of pure sar-
coma, usually of high grade and without a glandular compo-
nent, occupying at least 25% of the tumor, has been reported
in 8% to 54% of uterine adenosarcomas.174 Tumors containing
both malignant epithelium, that is, carcinoma, and malignant
soft-tissue tumors, that is, sarcomas, are called carcinosarco-
mas or malignant mixed Mllerian tumors. These neoplasms
are often bulky, necrotic, and deeply invasive. The epithe-
lial component is generally serous carcinoma. Homologous
tumors have stroma that contains cell types normally seen
in the uterus, in contrast to heterologous tumors, which may
contain striated muscle cells (rhabdomyosarcoma) cartilage
(chondrosarcoma), and bone (osteogenic sarcoma). Whether
carcinosarcomas are epithelial tumors or sarcomas contin-
ues to be debated. Gene profiling may shed some light on that
intriguing question.177 The 2009 FIGO staging recognizes the
uniqueness of each uterine sarcoma. For leiomyosarcomas and
endometrial stromal sarcomas, the staging system recognizes
the importance of tumor size on outcome. For adenosarcomas,
the new staging system recognizes the importance of depth of
myometrial invasion. For carcinosarcomas, the 2009 staging
system for carcinomas of the endometrium is used, recogniz-
ing the similarity in patterns of spread.174
Management
The main treatment for uterine sarcoma is surgery in a similar
fashion to endometrial adenocarcinoma. The extent of surgical
staging varies, depending on the risk of lymph node involve-
ment. Patients with carcinosarcoma should undergo compre-
hensive surgical staging similar to that with serous cancer.
Patients with endometrial stromal sarcomas and adenosarco-
mas might benefit from lymph node sampling. On the other
hand, for patients with leiomyosarcomas the rate of nodal
involvement is too low to justify routine lymphadenectomy.178
A GOG clinicopathologic study of 453 patients with uterine
sarcomas reported a 53% recurrence rate in carcinosarcoma
and 71% in leiomyosarcoma, with the site of first recurrence
being the pelvis in 21% of carcinosarcomas (19% in homolo-
gous and 24% in heterologous types) and 14% of leiomyosarco-
mas, respectively. Distant failure, as the first site, occurred in
14% of carcinosarcoma and 41% of leiomyosarcoma patients,
respectively. Forty percent of patients with carcinosarcoma
received adjuvant pelvic RT compared with 22% of leiomyosar-
coma patients. The pelvic failure was 17% in patients receiving
RT compared with 24% for those who did not.179
With regard to the role of adjuvant radiation, the EORTC
performed a prospective, randomized trial addressing the
role of postoperative pelvic RT in stages I to II uterine sarco-
mas. There were a total of 224 patients in the trial who
booksmedicos.org
underwent TAH/BSO, and 166 who had peritoneal washings.
Lymphadenectomy was optional. There were 103 leiomyosar-
comas (LMSs), 91 carcinosarcomas, and 28 endometrial stro-
mal sarcomas. The 5-year cumulative incidence of locoregional
recurrence was 18.8% in the pelvic RT arm compared to 35.9%
in the surgery-alone arm. That difference was statistically sig-
nificant (p = .0013). The 5-year cumulative incidence of distant
relapse was 45.3% for the pelvic RT and 33.6% for surgery
alone, but the difference was not statistically significant
(p = .2569). There was no significant difference in progression-
free (p = .3254) or overall survival (p = .923) between the two
arms. For patients with carcinosarcoma, the rate of pelvic
recurrence only was 4% in the pelvic RT arm compared to 24%
for the surgery-alone arm. The corresponding rates for any
local recurrence were 24% and 47%, respectively. For LMS
patients, the rate of pelvic recurrence only was 2% in the pelvic
RT compared to 14% in patients treated with surgery alone,
and for any local recurrence it was 20% versus 24%. This
seems to indicate that the pelvic control benefit is mainly seen
in carcinosarcoma.180 It is important to note that the primary
endpoint of this trial was pelvic control, which it met (p =
.0013). The study was not powered to detect a significant dif-
ference in PFS or OS. Sampath et al.181 performed a retrospec-
tive review of uterine sarcoma patients using the National
Oncology Database. The impact of adjuvant radiation was
assessed in patients who presented with nonmetastatic disease
and underwent definitive surgery (n = 2,206). In patients with
carcinosarcoma, the 5-year local-regional failure-free survival
was 90% for those who received adjuvant RT (n = 490) com-
pared to 80% for those who received surgery alone (n = 638;
p <.001). For endometrial stromal sarcoma, the rate was 97%
with RT (109) versus 93% for surgery alone (n = 252; p < .05).
For LMS it was 98% for RT (n = 131) compared to 84% with
surgery alone (n = 398; p < .01).
The role of adjuvant chemotherapy has been evaluated
mainly in carcinosarcoma. Sutton et al.182 reported on 65
patients with completely resected stage I or II carcinosarcoma
of the uterus treated with adjuvant ifosfamide and cisplatin.
Overall 5-year survival was 62%. None of the patients received
adjuvant RT in this GOG trial. Initial site of relapse was vagi-
nal apex in 6 of 65 and pelvis in 4 of 64, suggesting that a
combined chemoradiation approach might be ideal. GOG-150
is a phase III randomized study of WAI versus three cycles of
cisplatin, ifosfamide, and Mesna (CIM). Eligible patients (n =
206) included those with stages I to IV uterine carcinosar-
coma, no greater than 1-cm postsurgical residuum, and/or no
extra-abdominal spread. Stage distribution was as follows: I,
64 (31%); II, 26 (13%); III, 92 (45%); IV, 24 (12%). The esti-
mated crude probability of recurring within 5 years was 58%
for WAI and 52% for CIM. Adjusting for stage and age, the
recurrence rate was 21% lower for CIM patients than for WAI
patients (RH, 0.789, 95% CI = 0.530 to 1.176; p = .245, two-
tailed test). The estimated death rate was 29% lower in the
CIM group (RH, 0.712, 95% CI = 0.484 to 1.048; p = .085,
two-tailed test). The conclusion was that there was not a sta-
tistically significant advantage in recurrence rate or survival
for adjuvant chemotherapy over WAI in patients with uterine
carcinosarcoma. However, the observed differences favor the
use of combination chemotherapy in future trials. The rate of
vaginal recurrence was 4 of 105 (3.8%) in the WAI compared
to 10 of 101 (9.9%). The corresponding abdominal relapse
rates were 27.6% (29 of 105) and 18.8% (19 of 101). There
was no difference in pelvic recurrence between the two arms.
The rates of lung metastasis (14 of 105 vs. 14 of 101, respec-
tively) or other distant sites (13 of 101 vs. 10 of 101, respec-
tively) were similar. Analysis of the patterns of relapse from
this trial also indicates the need for chemoradiation in
patients with stages I to III carcinosarcoma.183 At MSKCC,
patients with surgical stages I or II carcinosarcoma are
treated with intravaginal RT and chemotherapy. Stage III

patients are treated with concurrent pelvic RT/cisplatin fol-
lowed by carboplatin/paclitaxel.
For patients with leiomyosarcomas the main treatment is
surgery, and the role of adjuvant treatment, whether RT or
chemotherapy, is not well defined. The high rate of distant
relapse in these patients overshadows any local control benefit
attained with adjuvant RT. These patients should be encour-
aged to participate in trials assessing the role of chemotherapy
and/or targeted therapy. For patients with endometrial stromal
sarcomas (low grade) observation is feasible. For those with
undifferentiated endometrial sarcomas adjuvant pelvic RT is
reasonable. For patients with adenosarcomas, especially with
sarcomatous overgrowth, adjuvant pelvic RT is also reason-
able. Carcinosarcomas should be treated in a similar fashion to
other high-risk endometrial cancers. For early-stage compre-
hensively staged patients, intravaginal RT and chemotherapy
is recommended. Patients with stage III could be treated with
concurrent pelvic RT and cisplatin followed by carboplatin/
paclitaxel.
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cancer. Br J Cancer 2009;100:8995.
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gression. Int J Clin Exp Pathol 2009;2:411432.
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71. Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread pat-
terns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987;
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72. International Federation of Gynecology and Obstetrics. Revised FIGO staging for
carcinoma of the vulva, cervix, and endometrium. Int J Gynecol Obstet 2009;
105:103.
73. Page BR, Pappas L, Cooke EW, et al. Does the FIGO 2009 endometrial cancer
staging system more accurately correlate with clinical outcome in different his-
tologies? Revised staging, endometrial cancer, histology. Int J Gynecol Cancer
2012;22(4):593598.
74. Abu-Rustum NR, Zhou Q, Iasonos A, et al. The revised 2009 FIGO staging system
for endometrial cancer: should the 1988 FIGO stages IA and IB be altered? Int J
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75. Abu-Rustum NR, Zhou Q, Gomez JD, et al. A nomogram for predicting overall
survival of women with endometrial cancer following primary therapy: toward
improving individualized cancer care. Gynecol Oncol 2010;116(3):399403.
76. Creutzberg CL, Nout RA, Lybeert ML, et al. Fifteen-year radiotherapy outcome of
Clinical Radiation Oncology
the randomized PORTEC-1 Trial for endometrial carcinoma. Int J Radiat Oncol
Biol Phys 2011;81(4):631638.
82. Guntupalli SR, Zighelboim I, Kizer NT, et al. Lymphovascular space invasion is
an independent risk factor for nodal disease and poor outcomes in endometrioid
endometrial cancer. Gynecol Oncol 2012;124(1):3135.
83. Kizer NT, Gao F, Guntupalli S, et al. Lower uterine segment involvement is asso-
ciated with poor outcome in early-stage endometrioid endometrial carcinoma.
Ann Surg Oncol 2011;18(5):14191424.
85. Wethington SL, Barrena Medel NI, Wright JD, et al. Prognostic significance and
treatment implications of positive peritoneal cytology in endometrial adenocarci-
noma: unraveling a mystery. Gynecol Oncol 2009;115(1):1825.
86. Jobsen JJ, Naudin Ten Cate L, Lybeert ML, et al. Outcome of endometrial cancer
stage IIIA with adnexa or serosal involvement only. Obstet Gynecol Int 2011;
2011:962518.
94. Walker JL, Piedmonte MR, Spirtos NM, et al. Recurrence and survival after ran-
dom assignment to laparoscopy versus laparotomy for comprehensive surgical
staging uterine cancer: Gynecology Oncology Group LAP2 study. J Clin Oncol 2012;
30(7):695700.
95. Wright JD, Burke WM, Wilde ET, et al. Comparative effectiveness of robotic
versus laparoscopic hysterectomy for endometrial cancer. J Clin Oncol 2012;
30(8):783791.
100. Benedetti Panici P, Basile S, Maneschi F, et al. Systematic pelvic lymphadenec-
tomy vs. no lymphadenectomy in early-stage endometrial carcinoma: random-
ized clinical trial. J Natl Cancer Inst 2008;100(23):17071716.
101. ASTEC Study Group. Efficacy of systematic pelvic lymphadenectomy in endo-
metrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009;373(9658):
125136.
102. Khoury-Collado F, Murray MP, Hensley ML, et al. Sentinel lymph node mapping
for endometrial cancer improves the detection of metastatic disease to regional
lymph nodes. Gynecol Oncol 2011;122(2):251254.
103. Ballester M, Dubernard G, Lcuru F, et al. Detection rate and diagnostic accuracy
of sentinel-node biopsy in early stage endometrial cancer: a prospective multi-
centre study (SENTI-ENDO). Lancet Oncol 2011;12(5):469476.
104. Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radio-
therapy versus surgery alone for patients with stage-1 endometrial carcinoma:
multicentre randomised trial. PORTEC Study Group. Post Operative Radiation
Therapy in Endometrial Carcinoma. Lancet 2000;355:14041411.
105. Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or
without adjunctive external pelvic radiation therapy in intermediate risk endo-
metrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol
2004;92(3):744751.
106. Blake P, Swart AM, Otron J, et al. Adjuvant external beam radiotherapy in the
treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised
trials): pooled trial results, systematic review, and meta-analysis. Lancet 2009;
373(9658):137146.
108. Sorbe B, Nordstrm B, Menp J, et al. Intravaginal brachytherapy in FIGO
stage I low-risk endometrial cancer: a controlled randomized study. Int J Gynecol
Cancer 2009;19(5):873878.
109. Nout RA, Smit VT, Putter H, et al. PORTEC Study Group. Vaginal brachytherapy
versus pelvic external beam radiotherapy for patients with endometrial cancer of
high-intermediate risk (PORTEC2): an open-label, non-inferiority, randomised
trial. Lancet 2010;375(9717):816823.
110. Sorbe B, Horvath G, Andersson H, et al. External pelvic and vaginal irradia-
tion versus vaginal irradiation alone as postoperative therapy in medium-risk
endometrial carcinomaa prospective randomized study. Int J Radiat Oncol Biol
Phys 2012;82(3):12491255.
113. Croog VJ, Abu-Rustum NR, Barakat RR, et al. Adjuvant radiation for early
stage endometrial cancer with lymphovascular invasion. Gynecol Oncol 2008;
111(1):4954.
115. Creutzberg CL, van Putten WL, Warlam-Rodenhuis CC, et al. Outcome of high-
risk stage IC, grade 3, compared with stage I endometrial carcinoma patients:
the Postoperative Radiation Therapy in Endometrial Carcinoma Trial. J Clin
Oncol 2004;22:12341241.
117. Sorbe B, Straumits A, Karlsson L. Intravaginal high-dose-rate brachytherapy for
stage I endometrial cancer: a randomized study of two dose-per-fraction levels.
Int J Radiat Oncol Biol Phys 2005;62(5):13851389.
123. Long KC, Zhou Q, Hensley ML, et al. Patterns of recurrence in 1988 FIGO stage IC
endometrioid endometrial cancer. Gynecol Oncol 2012;125(1):99-102.
127. Cannon GM, Geye H, Terakedis BE, et al. Outcomes following surgery and adju-
vant radiation in stage II endometrial adenocarcinoma. Gynecol Oncol 2009;
113(2):176180.
136. Susumu N, Sagae S, Udagawa Y, et al. Randomized phase III trial of pelvic radio-
therapy versus cisplatin-based combined chemotherapy in patients with inter-
mediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology
Group study. Gynecol Oncol 2008;108(1):226233.
1446 Section III Clinical Radiation Oncology Part J Gynecologic
139. Kuoppala T, Menp J, Tomas E, et al. Surgically staged high-risk endometrial
cancer: randomized study of adjuvant radiotherapy alone vs. sequential chemo-
radiotherapy. Gynecol Oncol 2008;110(2):190195.
140. Hogberg T, Signorelli M, de Oliveira CF, et al. Sequential adjuvant chemotherapy
and radiotherapy in endometrial cancerresults from two randomised studies.
Eur J Cancer 2010;46(13):24222431.
141. Greven K, Winter K, Underhill K, et al. Final analysis of RTOG 9708: adjuvant
postoperative irradiation combined with cisplatin/paclitaxel chemotherapy fol-
lowing surgery for patients with high-risk endometrial cancer. Gynecol Oncol
2006;103(1):155159.
143. Klopp AH, Jhingran A, Ramondetta L, et al. Node-positive adenocarcinoma of
the endometrium: outcome and patterns of recurrence with and without external
beam irradiation. Gynecol Oncol 2009;115(1):611.
147. Alektiar KM, Makker V, Abu-Rustum NR, et al. Concurrent carboplatin/pacli-
taxel and intravaginal radiation in surgical stage I-II serous endometrial cancer.
Gynecol Oncol 2009;112(1):142145.
148. Kiess A, Damast S, Makker V, et al. Adjuvant carboplatin/paclitaxel and intra-
vaginal radiation for stage I-II serous endometrial cancer. Radiother Oncol 2012;
103:S101S102.
149. Jobsen JJ, ten Cate LN, Lybeert ML, et al. The number of metastatic sites for
stage IIIA endometrial carcinoma, endometrioid cell type, is a strong negative
prognostic factor. Gynecol Oncol 2010;117(1):3236.
151. Garg G, Morris RT, Solomon L, et al. Evaluating the significance of location of
lymph node metastasis and extranodal disease in women with stage IIIC endo-
metrial cancer. Gynecol Oncol 2011;123(2):208213.
153. Small W Jr, Mell LK, Anderson P, et al. Consensus guidelines for delineation of
clinical target volume for intensity-modulated pelvic radiotherapy in postopera-
tive treatment of endometrial and cervical cancer. Int J Radiat Oncol Biol Phys
2008;71(2):428434.
157. Creutzberg CL, van Putten WL, Koper PC, et al. The Postoperative Radiation
Therapy in Endometrial Carcinoma. The morbidity of treatment for patients with
stage I endometrial cancer: results from a randomized trial. Int J Radiat Oncol
Biol Phys 2001;51(5):12461255.
Chapter 71
Ovarian and Fallopian Tube Cancer
Larissa Lee, Ross Berkowitz, and Ursula Matulonis
Ovarian neoplasms encompass a wide array of benign and
malignant tumors with diverse histologic cell types, clinical
features, and survival outcomes. Primary malignant tumors
of the ovary include the epithelial ovarian cancers, germ
cell tumors, and sex cord tumors. Low malignant poten-
tial (LMP) tumors of the ovary are noninvasive epithelial
tumors often confined to the ovary, although extraovarian
tumor implants may be detected. Metastases to the ovary
occur from other primary malignancies including uterine,
gastrointestinal (Krukenberg tumors), and breast cancers.
Primary lymphoma, sarcoma, and melanoma of the ovary
are rare. Relative to its incidence, epithelial ovarian cancers
have substantially high mortality because effective screening
tools are lacking; only 25% are detected as stage I at diag-
nosis, and current therapies for advanced cancer, although
improving, have reached a therapeutic plateau. Surgery is
the mainstay for diagnosis, staging, and the initial treat-
ment for ovarian cancer. Platinum-based chemotherapy is
indicated for patients with high-risk or advanced disease.
Novel agents, such as antiangiogenics and poly (ADP-ribose)
polymerase (PARP) inhibitors, are under active investigation
in the adjuvant and/or recurrent setting. The use of whole-
abdomen irradiation (WAI) or intraperitoneal (IP) radioiso-
topes is primarily historical, and radiation therapy now has a
limited role in the management of ovarian cancer. Nonethe-
less, palliative radiotherapy may be of significant benefit for
symptomatic disease relapse or select patients with localized
recurrence.
ANATOMY
In premenopausal women, the ovaries are almond-shaped,
gray-pink solid organs that measure approximately 4 2.5
booksmedicos.org
158. Nout RA, van de Poll-Franse LV, Lybeert ML, et al. Long-term outcome and qual-
ity of life of patients with endometrial carcinoma treated with or without pelvic
radiotherapy in the post operative radiation therapy in endometrial carcinoma
1 (PORTEC-1) trial. J Clin Oncol 2011;29(13):16921700.
159. Shih K, Abu-Rustum NR, Sonoda Y, et al. Sacral insufficiency fractures after post-
operative pelvic radiation therapy in gynecologic malignancy. Presented at the
93rd Annual Meeting of the American Radium Society, Palm Beach, FL, 2011.
162. Shih K, Frey M, Chi D, et al. Impact of postoperative intensity-modulated radia-
tion therapy on the rate of bowel obstruction in gynecologic malignancy. Gynecol
Oncol 2012;125(Suppl 1):S147S148.
163. Jhingran A, Wnter K, Portelance L, et al. Efficacy and safety of IMRT after sur-
gery in patients with endometrial cancer: RTOG 0418 phase II study [Abstract].
Int J Radiat Oncol Biol Phys 2011;81(25, Suppl):S45.
165. Nout RA, Putter H, Jrgenliemk-Schulz IM, et al. Five-year quality of life of
endometrial cancer patients treated in the randomised Post Operative Radiation
Therapy in Endometrial Cancer (PORTEC-2) trial and comparison with norm
data. Eur J Cancer 2012;48:16381648.
174. DAngelo E, Prat J. Uterine sarcomas: a review. Gynecol Oncol 2010;116(1):131139.
176. Dos Santos LA, Garg K, Diaz JP, et al. Incidence of lymph node and adnexal
metastasis in endometrial stromal sarcoma. Gynecol Oncol 2011;121(2):319
322.
180. Reed NS, Mangioni C, Malmstrm H, et al. European Organisation for Research
and Treatment of Cancer Gynaecological Cancer Group. Phase III randomised
study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of
uterine sarcomas stages I and II: an European Organisation for Research and
Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874). Eur
J Cancer 2008;44(6):808818.
181. Sampath S, Schultheiss TE, Ryu JK, et al. The role of adjuvant radiation in uter-
ine sarcomas. Int J Radiat Oncol Biol Phys 2010;76(3):728734.
182. Sutton G, Kauderer J, Carson LF, et al. Gynecologic Oncology Group. Adjuvant
ifosfamide and cisplatin in patients with completely resected stage I or II carci-
nosarcomas (mixed mesodermal tumors) of the uterus: a Gynecologic Oncology
Group study. Gynecol Oncol 2005;96(3):630634.
1 cm, with an average weight of 4 to 5 g. After menopause,
the ovaries atrophy and become nonfunctional and smaller in
size. When normally positioned, the ovary is attached by the
meso-ovarium to the broad ligament that covers the uterus
and fallopian tubes. The infundibular pelvic, or suspensory,
ligament extends from the surface of the ovary to the lateral
pelvic wall, forming the superior and lateral aspect of the
broad ligament (Fig. 71.1). The blood supply of the ovary is
derived from the ovarian arteries, which arise from the aorta
immediately below the level of the renal arteries and course
through the retroperitoneum and infundibular pelvic liga-
ments. The venous return of the ovary empties to the renal
vein on the left and directly to the vena cava on the right. The
primary lymphatic drainage of the ovary parallels the course
of the ovarian veins, with secondary lymphatic flow passing
through the inguinal canal and to the iliac nodal system.1
Histologically, the outer cortex of the ovary is covered by a
layer of pseudocolumnar or cuboidal epithelium, termed the
germinal epithelium of Waldeyer or ovarian surface epithe-
lium (OSE). The inner medulla consists of a superficial tunica
albuginea and dense stromal tissue filled with blood vessels
and spindled, muscle-like connective tissue. Within the
medulla, maturing follicles are present throughout the various
layers.
The fallopian tubes are positioned horizontally within the
superior part of the broad ligament and extend from the supe-
rior posterior portion of the uterine fundus to the ovaries. The
fallopian tubes are hollow, muscular viscera that are in direct
communication with the peritoneal cavity. The ovarian artery
anastomoses with the uterine artery to supply the fallopian
tube, and venous drainage is through the pampiniform plexus
to the ovarian vein and uterine plexus. The mucosa of the fal-
lopian tube contains a rich network of intercommunicating

Fallopian tube Isthmus
Ampulla
Infundibulum
Fimbria
Abdominal Secondary
opening of oocyte
fallopian tube Perimetrium (serosa)
Corpus luteum
of menstruation (glandular mucosa)
Cervical canal
FIGURE 71.1. Anatomy of the ovary and female reproductive tract. (Asset provided by the Anatomical Chart Company.)
lymphatic sinusoids that anastomose with adjacent organs and
drain into the ovarian lymphatics and para-aortic and iliac
lymph nodes.2 The fallopian tubes consist of four separate his-
tologic layers: the mucosa, submucosa, muscularis (external
longitudinal and inner circular layers), and outer serosal layer,
which is continuous with the visceral peritoneum of the uterus.
The mucosa is intricately folded, with the number of folds
increasing from the interstitial portion to the ampulla. The epi-
thelium is composed mainly of ciliated cells and secretory cells.
Cyclic changes are evident in the tubal epithelium, similar to
those of the endometrium, in response to estrogen and proges-
terone.
EPIDEMIOLOGY
Ovarian cancer is the second most common gynecologic
malignancy in the United States after endometrial cancer.
Approximately 22,280 women in the U.S. received a diagno-
sis of epithelial ovarian cancer in 2012, and 15,500 died of
the disease3,4 (Fig. 71.2). Ovarian cancer represents the fifth
leading cause of cancer-related death in U.S. women, following
lung, breast, colorectal and pancreatic cancers. The lifetime
risk of ovarian cancer is approximately 1 in 72 women with
a median age at diagnosis of 63 years; >80% of women are
diagnosed after the age of 40 years.5 The incidence of ovar-
ian cancer rises with increasing age and peaks in the eighth
decade of life. Differences in race and ethnicity are apparent in
the age-adjusted annual incidence per 100,000 women, which
in 2005 to 2009 was highest for White women (13.4), followed
by Hispanic (11.3), American Indian/Alaska Native (11.2),
Black (9.8), and Asian/Pacific Islanders (9.8).5 The incidence of
Chapter 71 Ovarian and Fallopian Tube Cancer 1447
Suspensory
ligament of ovary
Fundus of uterus
Ovarian
ligament Ovary
Cavity of uterus Vesicular
appendix
Clinical Radiation Oncology
Broad ligament
Uterus Internal os of cervix
Myometrium Cervix
Endometrium
Vagina
External os
Labium minus
ovarian cancer also varies significantly by geography, with the
highest rates in North America and northern Europe, which
are three to seven times higher than that observed in Japan.6
Mortality rates for ovarian cancer have been decreasing in
the United States since 1975, when the 5-year survival rate
reported by the Surveillance, Epidemiology, and End Results
(SEER) Program was 37%. Between 2001 and 2007, 5-year
survival increased to 44%, predominantly driven by survival
gains among White women. Black women have disproportion-
ately lower 5-year survival rates, estimated at 34% in the same
time period.5
Primary cancer of the fallopian tube was once considered a
rare disease, accounting for 0.2% to 0.5% of female gyneco-
logic malignancies. However, the true incidence has likely been
underestimated considering a large proportion of extrauterine
high-grade serous carcinomas may actually originate in the
fimbriated end of the fallopian tube.7,8 Precursor lesions,
known as tubal intraepithelial carcinomas (TICs) have been
detected in the fallopian tubes of prophylactic salpingo-oopho-
rectomy specimens from high-risk patients. The model of the
fallopian tube as the primary site of origin for extrauterine
high-grade serous carcinoma is supported by epidemiologic,
morphologic, and genetic data, as discussed later.
PATHOGENESIS
The female reproductive tract originates from the Mllerian
ducts, which are paired embryologic structures of mesodermal
origin that give rise to the fallopian tubes, uterus, cervix, and
upper vagina. Ovarian tissue is composed of embryonic yolk
sac cells that give rise to the ova or germ cells, stromal cells
booksmedicos.org
1448 Section III Clinical Radiation Oncology Part J Gynecologic
Ovarian Cancer incidence and Deaths in the USA, 20052012*
25000
20000
# Cases
15000
10000
5000
0
2005
FIGURE 71.2. Ovarian cancer incidence and
deaths in the United States from 2005 to 2012.
(Courtesy of the American Cancer Society.)
that produce the steroid hormones, and mesothelium that pro-
vides the epithelial covering for the follicle cysts. These cell types
give rise to germ cell tumors, sex cordstromal tumors, and the
epithelial tumors of the ovary, respectively. The traditional view
of ovarian cancer pathogenesis is that all tumor subtypes arise
from the OSE. In the incessant ovulation hypothesis, ovarian
cancer develops from an aberrant repair process as a result of
repeated rupture of the surface epithelium during each ovulatory
cycle, thought to produce inflammation and scarring that serves
as a nidus for carcinogenesis.911 A second proposed mechanism
is related to hormonal and reproductive factors such as persis-
tent exposure to gonadotropins and elevated estradiol levels that
stimulate malignant transformation.12,13 Strong evidence exists
that many borderline tumors and low-grade carcinomas of the
ovary arise from cortical inclusion cysts (CICs) within the ovar-
ian parenchyma. These benign cysts are composed of Mllerian
epithelium that closely resembles the fallopian tube. CICs are
thought to result from invaginations of the OSE into the ovar-
ian stroma through repeated ovulation and aging, acquiring a
Mllerian phenotype through metaplasia.8 An alternate expla-
nation is that remnants of Mllerian-derived epithelia from the
fallopian tube may adhere to the ovarian surface and become
incorporated into CICs in a process known as endosalpingiosis.
Nonetheless, as a result of hormone exposure, damage repair
processes, and inflammation within the ovary, neoplastic trans-
formation gives rise to a variety of Mllerian-cell type differenti-
ations, including serous carcinomas that resemble the fallopian
tube, mucinous tumors as seen in the endocervix, endometrioid
tumors from the endometrium, and glycogen-rich clear cell can-
cers similar to secretory-phase endometrial glands.
High-grade serous ovarian carcinomas are infrequently asso-
ciated with benign or borderline precursor lesions within the
ovary, a contradiction of the OSE-CIC model. Furthermore, high-
grade serous carcinomas of the ovary share distinct morpho-
logic and genetic characteristics with high-grade serous carcino-
mas of other extrauterine sites, including serous fallopian tube
carcinoma and primary peritoneal serous carcinoma. In this
context, a second model of ovarian carcinogenesis has emerged
with the recognition of the distal fallopian tube as the primary
site of origin for many high-grade serous carcinomas. With rig-
orous pathologic processing, occult fallopian tube cancer has
been detected in the fimbria of prophylactic salpingo-oophorec-
tomy specimens from high-risk patients.14,15 Furthermore, TICs
have been found in a large proportion of high-grade serous car-
cinomas initially designated as primary ovarian cancers.16 An
booksmedicos.org
2006 2007 2008 2009 2010 2011 2012
*Source: American
Ovarian Cancer Incidence Ovarian Cancer Deaths
Cancer Society
adenoma-carcinoma sequence has since been described that
involves a dysplastic tubal precursor lesion with loss of p53
detectable by immunohistochemical staining (p53 signature)
with progression to a TIC characterized by increased prolifera-
tion, followed by the development of frank invasive serous carci-
noma.7,17 The concept of the fallopian tube as the primary site of
high-grade serous carcinoma suggests that previously unde-
tected serous TICs may spread to the adjacent ovary or perito-
neal cavity early in the disease process of serous carcinogenesis.
In the two-pathway model of ovarian carcinogenesis, type I
tumors include all major histologic subtypes (serous, endome-
trioid, mucinous, clear cell, and transitional) with low nuclear
and architectural grade that may be linked to well-defined
benign precursor lesions, and type II tumors account for the
bulk of high-grade serous carcinomas (Table 71.1). The type I
tumors are associated with distinct molecular alterations, such
as mutations in KRAS, BRAF, and PTEN, which are rarely
found in type II serous tumors.18 Mutually exclusive KRAS and
BRAF mutations, both of which activate the oncogenic MAPK
signaling pathway, are observed in 65% of serous borderline
tumors but are rarely seen in high-grade serous carcinomas.19
KRAS mutations also occur in Mllerian histologic subtypes,
including 60% of mucinous, 5% to 16% of clear cell, and 4% to
5% of endometrioid carcinomas.18 Mutations in PTEN, which
lead to constitutive activation of the related PI3 kinase signal-
ing pathway, have been detected in 20% of endometrioid carci-
nomas,20 whereas activating mutations in PIK3CA have been
TABLE 71.1 TWO-PATHWAY MODEL OF EPITHELIAL OVARIAN CARCINOGENESIS
Type 1 Type 2
All Mllerian subtypes (serous, endometri- High-grade serous carcinoma
oid, mucinous, clear cell, transitional)
Usually low grade High grade
Linked to benign or borderline precursor Associated with tubal intraepithelial
lesions carcinomas (TICs)
KRAS or BRAF mutation (MAPK pathway) Inactivation of BRCA pathway
PTEN or PIK3CA mutation (PI3K pathway)
ARID1A mutation, loss of BAF250a
expression
Wild-type p53 status High frequency of p53 mutation
Chromosomally stable Widespread DNA copy number change
Frequently platinum insensitive Usually platinum sensitive
Adapted from Bowtell DD. The genesis and evolution of high-grade serous ovarian
cancer. Nat Rev Cancer 2010;10(11):803808.

identified in 30% of clear cell cancers.21 Somatic mutations in
ARID1A, a novel tumor suppressor gene, were recently identi-
fied in 46% of ovarian clear cell cancers and 30% of endometri-
oid cancers. ARID1A mutation and corresponding loss of
BAF250a expression, a key component in chromatin remodel-
ing, were also seen in preneoplastic lesions and may represent
an early event in the transformation of endometriosis.22 In con-
trast, type II tumors exhibit a high frequency of p53 mutation
and widespread DNA copy number change. Inactivation of the
BRCA pathway, a critical component of DNA repair by homolo-
gous recombination, is also a hallmark of high-grade serous
carcinomas.23 Disruption of the BRCA pathway by germline or
somatic mutation, epigenetic silencing, or microRNA regula-
tion has been observed in >50% of serous cancers,24 and func-
tional assays show defective formation of homologous recom-
bination repair foci following DNA damage.25
Angiogenesis plays an important role in normal ovarian
function, as heavy vascularization occurs at the beginning of
each ovulatory cycle with predictable variation in the serum
levels of vascular endothelial growth factor (VEGF). Epithelial
ovarian cancers frequently overexpress VEGF, fibroblast growth
factor, platelet-derived growth factor (PDGF), and angiopoi-
etin.26 In preclinical models, expression of VEGF provides a
survival advantage to transformed cells of the ovary. Other
studies have found an association between preoperative
serum VEGF level and clinical outcome.27 Targeting the tumor
microenvironment in ovarian cancer is an attractive treatment
strategy given the inherent genomic instability of high-grade
serous cancers.
RISK FACTORS
Epidemiologic studies have identified hormonal, genetic, and
environmental factors that may play an important role in ovar-
ian carcinogenesis (Table 71.2). The OSE-CIC model is con-
sistent with well-established epidemiologic data indicating
that suppression of ovulation results in substantial reduction
of ovarian cancer risk. New insights into the pathogenesis of
high-grade serous carcinomas have emerged through the study
of high-risk populations with a genetic predisposition for the
development of ovarian cancer. Nevertheless, the pathogenic
mechanisms are not well understood and likely multifactorial,
associated with both patient-related and environmental factors.
TABLE 71.2 FACTORS INFLUENCING THE RISK OF OVARIAN CANCER
Factor Estimated Risk (%) Estimated Relative Risk
Baseline lifetime risk 1.4
Race
White 13.4 per 100,000
Hispanic or American Indian 11.3 per 100,000
African American 9.8 per 100,000
Risk factors
Family history 9.4
BRCA1 mutation 3546
BRCA2 mutation 1323
Lynch II/HPNCC 314
Infertility
Obesity
Nulliparity
Late menopause
Early menarche
Unopposed estrogen use
Protective factors
Multiparity
Oral contraceptive use
Hysterectomy or tubal ligation
HPNCC, hereditary nonpolyposis colorectal cancer.
Adapted from Holschneider CH, Berek JS. Ovarian cancer: epidemiology, biology, and
prognostic factors. Semin Surg Oncol 2000;19(1):310.
Chapter 71 Ovarian and Fallopian Tube Cancer 1449
Patient-Related Factors
Risk factors associated with a higher frequency of ovulatory
events, such as advancing age, low parity, infertility, early men-
arche, and late menopause, support the proposed mechanism
of incessant ovulation.2831 Although infertility is associated
with ovarian cancer, the use of fertility drugs has not been con-
clusively linked.3234 Suppression of ovulatory events from preg-
nancy, breast-feeding, and oral contraceptive use may explain
the observed protective benefit.30,31,35 With oral contraceptive
use for 4, 8, or 12 years, the risk of ovarian cancer is reduced
by 40%, 53%, and 60%, respectively.36 In a collaborative meta-
analysis of 45 epidemiologic studies from 21 countries, the
use of oral contraceptives was significantly associated with a
decreased risk of ovarian cancer in ever users (hazard ratio
[HR] 0.73, p <.0001), with larger reductions observed for lon-
ger duration of use.37 The authors conclude that 200,000 ovar-
ian cancers and 100,000 deaths have been prevented since the
Clinical Radiation Oncology
introduction of oral contraceptives 50 years ago.
Other patient-related risk factors such as polycystic ovarian
disease and endometriosis may act through hormonal mecha-
nisms attributable to elevated gonadotropins or by chronic
inflammation. In a meta-analysis of eight case-control studies,
women with polycystic ovarian disease had a 2.5-fold increase in
ovarian cancer risk.38 Endometriosis has been shown to be an
independent risk factor for ovarian cancer with an estimated rate
of malignant transformation of 2.5%.39 Ovarian cancers that
arise from endometriosis are most often low-grade tumors with
endometrioid or clear cell histology and are associated with a
better prognosis.40 Altered hormonal levels such as elevated
androgens may also increase risk, whereas progestins have been
shown to be protective.41 Large prospective cohort studies have
demonstrated an increase in ovarian cancer risk and mortality
with the use of exogenous estrogen and hormone replacement
therapy.4244 Surgical procedures, including hysterectomy and
tubal ligation, are independently associated with a 34% reduc-
tion each in ovarian cancer risk, although the protective mecha-
nism is unknown.29,4547 Chronic inflammatory conditions such
as pelvic inflammatory disease and tuberculous salpingitis were
once believed to be causative factors in the development of fallo-
pian tube malignancies, although this theory remains unproven.
Genetic Factors
Heredity tumors account for 10% to 15% of all ovarian cancers,
and family history is the strongest risk factor after increasing
age.48,49 The risk of developing ovarian cancer in the general
population is approximately 1.4%, whereas the lifetime risk for
a woman with one first-degree family member with ovarian
1 cancer is 5% and climbs to 7% with two first-degree relatives.
If a hereditary syndrome is present, the lifetime risk is on the
order of 25% to 50% with an age of diagnosis approximately
10 years younger than women with sporadic disease.50
Three distinct familial ovarian cancer syndromes have been
identified by pedigree analysis with autosomal dominant pat-
57 terns of inheritance.51,52 BRCA1 and BRCA2 mutations are the
1829
most common genetic alterations, with up to 90% of all heredi-
1619
67 tary cases associated with a deleterious mutation of the BRCA1
25 gene, located on chromosome 17q21, or the BRCA2 gene, located
1.14 on chromosome 13q22. The lifetime risk of ovarian cancer is
23 approximately 40% in BRCA1 mutation carriers and 18% in
1.52 BRCA2 mutation carriers.53 BRCA-associated ovarian cancers
11.5 are most frequently invasive serous adenocarcinomas and less
1.22 likely borderline or mucinous tumors.54 Mutation carriers are
also more likely to present with advanced stage disease and
0.40.6 have poorly differentiated tumors.55 Nonetheless, BRCA1 or
0.7 BRCA2 mutation carriers have a more favorable clinical course
0.60.7 with a significantly longer recurrence-free and overall survival
compared to noncarriers. The improved outcome appears related
to a higher sensitivity to platinum chemotherapy across first
and subsequent lines of treatment.56,57,5859,60
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1450 Section III Clinical Radiation Oncology Part J Gynecologic
The importance of the fallopian tube in the pathogenesis of
extrauterine serous carcinoma was initially recognized in
BRCA1 and BRCA2 mutation carriers. In a prospective study of
483 BRCA1 mutation carriers, the incidence of fallopian tube
cancer was reported as 120 times that of the general popula-
tion.61 High-grade serous primary peritoneal carcinomas are
also frequently observed in mutation carriers.62 Further atten-
tion was focused on the fallopian tube as the primary site of
origin following reports of epithelial dysplasia and occult
serous carcinomas in prophylactic salpingo-oophorectomy
specimens from mutation carriers.6366 In contrast to the stan-
dard pathologic sampling of the ampullary region of the fallo-
pian tube in ovarian cancer cases, more extensive complete
sectioning of the tube revealed an abundance of lesions in the
fimbria of the distal tube.14,1516 The detection of early serous
carcinomas, or TICs, lent further support to the emerging con-
cept of the fallopian tube as the primary site for extrauterine
serous carcinoma. In this context, the National Comprehensive
Cancer Network (NCCN) guidelines recommend that any
woman with a diagnosis of ovarian, fallopian tube, or primary
peritoneal carcinoma be referred to a cancer genetics professional
for consideration of BRCA mutation testing.67 BRCA screening
in a population of women with non-mucinous ovarian cancer
detected germline mutations in 14% of women, including 22%
with high-grade serous cancer, reinforcing the importance of
offering testing to all patients.68
Hereditary nonpolyposis colorectal syndrome, or Lynch
type II cancer syndrome, is responsible for the remaining 10%
of hereditary ovarian cancers.69 In this syndrome, germline
mutations of DNA mismatch repair genes lead to an increased
risk of colorectal, stomach, endometrial, and ovarian cancer
owing to underlying microsatellite instability. A total of seven
mismatch repair genes have been identified with mutations in
MLH1 and MSH2 accounting for 90% of the observed muta-
tions in Lynch syndrome families.70,71 Mutations in MSH6 and
PMS2 have been reported in the remaining 10% of families,
whereas alterations in the remaining three identified genes are
uncommonly observed. Inactivating mutations in specific genes
may modify the underlying cancer predisposition. Women with
MSH6 mutations are twice as likely to develop endometrial
cancer compared to carriers of MSH2 or MLH1 gene muta-
tions, which are the most common alterations underlying
colorectal cancer risk.72 Women with MSH2 gene mutations
have been shown to have a risk of epithelial ovarian cancer
twice that of MLH1 carriers. In contrast to BRCA1 and BRCA2
mutation carriers, women with Lynch syndrome may present
with a variety of nonserous epithelial tumor types, including
endometrioid and clear cell histologies. Ovarian cancer associ-
ated with Lynch syndrome is more often diagnosed at an ear-
lier stage with well to moderately differentiated tumor grade.
The lifetime risk of ovarian cancer in women with Lynch syn-
drome is estimated at 3% to 14% and is most commonly diag-
nosed in the fifth decade of life.73 In women with a family or
personal history suggestive of Lynch syndrome, tumor testing
may be performed by microsatellite instability analysis or
immunohistochemistical staining for mismatch repair genes.
Direct sequencing of the mismatch repair genes is used for
detection of germline mutations. Other less common germline
mutations have been identified by genomic sequencing and
involve the following genes: BARD1, BRIP1, CHEK2, MRE11A,
NBN, PALB2, RAD50, RAD51C, and TP53.74
Other genetic disorders linked with nonepithelial ovarian
cancers include Peutz-Jeghers syndrome, which is associated
with an increased risk of sex cordstromal tumors, and gonadal
dysgenesis, associated with dysgerminomas and gonadoblas-
tomas.
Environmental Factors
Environmental or physical causes of ovarian cancer have been
investigated through numerous case-control studies. Women in
booksmedicos.org
developing countries have a lower incidence of ovarian cancer
than those living in industrialized nations,75 although to date,
no specific chemical carcinogens have been identified. Chronic
exposure to asbestos-related products, including talc products,
have long been implicated in the development of ovarian can-
cer.76 The Nurses Health Study reported a modestly elevated
risk of invasive serous cancers with talc use (relative risk [RR]
1.4), although no association was detected with overall ovar-
ian cancer risk.77 The development of mucinous ovarian cancer
has been found to be associated with cigarette smoking (RR 2
to 2.2) but not other epithelial subtypes.78,79
Dietary and metabolic factors have also been explored in
large population-based studies as possible contributors to ovar-
ian cancer risk. To date, there have been no consistent associa-
tions of coffee or alcohol consumption with increased risk. Large
epidemiologic studies also showed no relationship between con-
sumption of animal fat and the development of ovarian can-
cer.80,81 In a recent Swedish population-based cohort study of the
effect of body mass index on cancer risk in >35,000 women, a
36% higher risk of cancer was observed in obese women (body
mass index 30) relative to women with body mass index in the
normal range (18.5 to 25); cancer sites most strongly related to
obesity were endometrium, ovary (risk for top quartile 2.09;
95% confidence interval [CI], 1.13 to 4.13), and colon.82 Obesity
has also been associated with increased ovarian cancer mortal-
ity in a large prospective study of adults in the U.S.83 There is no
clear relationship between exercise and ovarian cancer risk.
SCREENING
In the absence of a reliable screening test, most women with
ovarian cancer are diagnosed with advanced-stage disease. In
contrast to women with localized disease (stage I/II) who have
estimated 5-year survival rates of 70% to 90%, overall survival
for women with advanced disease (stage III/IV) is poor, ranging
from 20% to 45% (Table 71.3). The low sensitivity and speci-
ficity of the available screening modalities and the low preva-
lence of the disease in the general population have hindered
the development of a robust screening test. Recent screening
approaches have been associated with a low positive predictive
value and unacceptable false-positive rates without impacting
disease mortality in the general population or high-risk groups.
Several screening strategies have been investigated, includ-
ing pelvic exam, the serum tumor marker CA-125, and trans-
vaginal ultrasound (TVUS), either alone or in combination.84
CA-125 values >35 U/mL are observed in 80% of patients with
epithelial ovarian cancer, including 90% of women with
advanced-stage disease, but only in 50% of early-stage
patients.85 CA-125 is nonspecific for ovarian cancer, as it can be
elevated in benign gynecologic and nongynecologic conditions
as well as nongynecologic cancers. Screening with CA-125
TABLE 71.3 EPITHELIAL OVARIAN CANCER STAGE DISTRIBUTION AND
SURVIVAL BY STAGE
FIGO Stage Patients (n = 4,825) (%) 5-Year Overall Survival (%)
IA 13 90
IB 1 86
IC 14 83
IIA 2 71
IIB 2 66
IIC 5 71
IIIA 3 47
IIIB 6 42
IIIC 42 33
IV 13 19
FIGO, International Federation of Gynecology and Obstetrics.
Adapted from Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary.
FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J
Gynaecol Obstet 2006;95(Suppl 1):S161S192.
 Chapter 71 Ovarian and Fallopian Tube Cancer 1451

alone has been found to lack specificity in an average-risk pop-

ulation of postmenopausal women. Ultrasound alone is able to
detect early-stage disease in an average-risk population,8688
although the significant false-positive rate remains a concern.
In a United Kingdom multimodality screening study, diagnostic
surgeries were performed nine times more frequently to detect
one cancer in the group screened by TVUS alone compared to
multimodality screening (CA-125 and TVUS).89
Several large screening trials currently in progress in the
United States, United Kingdom, and Japan have been designed
to assess reduction in mortality with early detection of ovarian
cancer. The Prostate, Lung, Colorectal, and Ovarian Cancer
(PLCO) screening trial in the United States randomized 78,216
women aged 55 to 74 to annual screening with CA-125 and
TVUS versus usual medical care. Following baseline screening,
570 surgical procedures, including 325 laparotomies, were
performed; 29 tumors were detected, 9 of which were of LMP.90
HISTOLOGIC CLASSIFICATION
The World Health Organization and International Federation of
Gynecology and Obstetrics (FIGO) have adopted a unified classifi-
cation of the common epithelial, germ cell, sex cord, and stromal
tumors99 (Table 71.4). Most ovarian malignancies (60% to 65%)
are epithelial, with germ cell tumors (20%), sex cordstromal
TABLE 71.4 WORLD HEALTH ORGANIZATION CLASSIFICATION
OF OVARIAN TUMORS
Epithelial tumors
Serous
Adenocarcinoma
Surface papillary carcinoma
Adenocarcinofibroma (malignant adenofibroma)
Mucinous

Clinical Radiation Oncology

The positive predictive value for the detection of invasive ovar- Adenocarcinoma
ian cancer was 3.7% for an abnormal CA-125, 1.0% for an Adenocarcinofibroma (malignant adenofibroma)
abnormal TVUS, and 23.5% for both. Publication of the mortal- Mucinous cystic tumor with mural nodules
ity data with 12-year follow-up showed no difference in the Mucinous cystic tumor with pseudomyxoma peritonei
stage of cancer detected by screening (90% stage III or IV) and Endometrioid
no reduction in cause-specific or overall mortality for women Adenocarcinoma NOS
who underwent screening.91 Furthermore, diagnostic evalua- Adenocarcinofibroma (malignant adenofibroma)
tion for women with false-positive screening resulted in a seri- Malignant Mllerian mixed tumor (carcinosarcoma)
ous complication rate of 15%. Adenosarcoma
Endometrioid stromal sarcoma
A second trial, the United Kingdom Collaborative Trial of
Undifferentiated ovarian carcinoma
Ovarian Cancer Screening (UKCTOCS), has accrued >200,000
postmenopausal women to evaluate multimodality screening Clear cell carcinoma
Adenocarcinoma
with TVUS and serum CA-125. In the prevalence screen, the
Adenocarcinofibroma (malignant adenofibroma)
sensitivity, specificity, and positive predictive values of multimo- Transitional cell carcinoma
dality screening for invasive epithelial ovarian and tubal cancers Squamous cell tumors
were 89.5%, 99.8%, and 35.1%, respectively.89 The initial results Mixed epithelial tumors
of baseline screening were more promising than the U.S. study, Undifferentiated and unclassified tumors
with 43% of invasive cancers detected as stage I or II, which Germ cell tumors
may reflect differences in study design and the diagnostic Dysgerminoma
algorithm. The effect of multimodality screening on mortality is Endodermal sinus tumor
awaiting further follow-up. The multicenter, randomized Embryonal carcinoma
Japanese study utilizes a similar screening strategy with TVUS Polyembryoma
and CA-125 and has accrued >80,000 women. Unlike the U.S. Choriocarcinoma
and UK trials, there was a nonsignificant trend for the detection Teratoma
Immature
of more stage I cancers in the screened population (63% vs.
Mature
38%), although mortality rates have not yet been reported.92 Solid
The present data do not support routine screening for ovar- Cystic
ian cancer in the general population. All of the North American Dermoid cyst with malignant transformation
expert groups, including the U.S. Preventive Services Task Monodermal
Force, the American College of Obstetricians and Gynecologists Mixed
(ACOG), the Society of Gynecologic Oncologists (SGO), and the Tumors composed of germ cells and sex cordstromal derivative
Canadian Task Force on the Periodic Health Examination, rec- Gonadoblastoma
ommend against routine screening in asymptomatic women. Mixed germ cell-sex cord-stromal tumor
The incidence of ovarian cancer is relatively low in the general Sex cord tumors
population; thus, the concerns for false-positive screening and Granulosa-stromal cell tumors
the associated risks of exploratory surgery are significant.93 Granulosa cell tumor
However, women at high risk for ovarian cancer with BRCA1 or Adult type
BRCA2 mutations or hereditary nonpolyposis colorectal syn- Juvenile type
drome could potentially benefit from chemoprevention; screen- Thecoma-fibroma group
Thecoma
ing with pelvic examinations, TVUS, and CA-125 on a biannual
Fibroma-fibrosarcoma
or annual basis; or prophylactic surgery.94 Although the efficacy Sclerosing stromal tumor
of screening has been disappointing in the high-risk popula- Sertoli-stromal cell tumors
tion,95 the ACOG, SGO, and NCCN guidelines recommend rou- Sertoli cell tumor
tine screening with pelvic exam, CA-125 and TVUS for women Leydig cell tumor
with hereditary ovarian cancer syndromes beginning at the age Sertoli-Leydig cell tumor
of 30 to 35, or 5 to 10 years earlier than the age of diagnosis of Sex cord tumor with annular tubules
ovarian cancer in the family. The U.S. National Institutes of Steroid cell tumors
Health Consensus Development Panel recommends that pro- Stromal luteoma
phylactic salpingo-oophorectomy be considered in women with Leydig cell tumor
ovarian cancer syndromes at age 35 years or after childbearing Steroid cell tumor NOS
is complete, as the risk reduction with salpingo-oophorectomy Unclassified
Gynandroblastoma
is 80%.96,97 Removal of the ovaries also reduces the risk of
breast cancer in BRCA mutation carriers.98 NOS, not otherwise specified.

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1452 Section III Clinical Radiation Oncology Part J Gynecologic
A B
FIGURE 71.3. Serous tumor of low malignant potential of the ovary at low power (A) and high power (B). At low power, note the progressively
branching papillary fronds with fibrovascular support and detached papillary clusters; at high power, note the serous epithelium with nuclear
hyperchromasia and cytologic atypia. By definition, there is no destructive stromal invasion.
tumors (5%), and metastases to the ovary (5% to 10%) account-
ing for the remainder.100 Serous tumors are most common, com-
prising 50% to 60% of epithelial tumors. Other subtypes include
mucinous carcinoma in 10%; endometrioid carcinoma, 8%; clear
cell carcinoma, 3% to 5%; transitional, 3% to 5%; and undifferen-
tiated carcinoma, 1%. Bilateral presentation occurs frequently in
epithelial tumors, most commonly in serous tumors followed by
endometrioid (15%) and mucinous tumors (5% to 10%).
High-grade serous carcinomas are often widely dissemi-
nated at diagnosis and account for most deaths from ovarian,
tubal, and peritoneal cancers. In contrast, 5-year survival for
low-grade serous carcinoma is 85%. Most serous tumors pres-
ent as large ovarian masses and grossly appear nodular with
multiple papillary projections and cysts filled with clear serous
fluid. A two-tiered grading system separates high-grade serous
carcinomas from low-grade tumors,101,102 which have a similar
prolonged natural history to noninvasive borderline tumors, or
tumors of LMP.103 As discussed previously, there is increasing
evidence that high grade serous carcinomas originate in the
fimbria of the fallopian tube and may spread rapidly to the
adjacent ovary and peritoneal sites. Low-grade tumors appear
to follow a stepwise progression from borderline tumor to
invasive carcinoma and involve molecular pathways distinct
from their high-grade counterparts.104106 Although treatment
is similar for all serous tumors, low-grade tumors have been
shown to be less responsive to chemotherapy.103,107,108
LMP or borderline tumors have nuclear abnormalities and
mitotic activity intermediate between benign and malignant
tumors of similar cell type but lack stromal invasion (Fig. 71.3).
Borderline tumors are a subcategory of ovarian malignancies
that account for 10% to 20% of all epithelial neoplasms.109,110
The prognosis, surgical approach, and postoperative treatment
recommendations are vastly different as compared with those
of their invasive counterparts. The majority of LMPs (75%)
present with stage I disease, which directly contrasts with the
75% advanced stages in the invasive epithelial tumors. The 5-
and 10-year survival rates for women with LMP tumors are
>95%. Significant heterogeneity exists in the biologic behavior
of borderline tumors. Women with nonlocalized LMP tumors of
the ovary have decreased survival compared to those with
localized LMP tumors but are similar to that of women with
localized, well-differentiated epithelial ovarian carcinoma.111
Other pathologic features that affect prognosis include the cell
type, tumor stage, implant type (invasive vs. noninvasive), the
presence of micropapillary architecture, and microinvasion.
Extensive sampling of all pathologic specimens is required to
firmly establish the diagnosis.
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Most endometrioid and clear cell carcinomas arise in foci of
endometriosis and follow an adenoma to borderline tumor to
carcinoma sequence. Endometrioid carcinoma of the ovary
resembles its endometrial counterpart (Fig. 71.4), and syn-
chronous primary cancers are detected in 10% of women with
ovarian cancer and 5% of women with endometrial cancer.112
Bilateral ovarian involvement, small multinodular ovaries, and
surface and hilar spread suggest metastatic involvement from
an endometrial primary, particularly if the endometrial tumor
is high-grade, deeply invasive, and associated with lymphovas-
cular invasion. A large, cystic, unilateral tumor of low grade
arising in a focus of endometriosis likely represents a primary
ovarian tumor. Endometrioid tumors appear to have a better
prognosis than serous cancers regardless of tumor stage.113
Multiple synchronous primary tumors may represent a field
defect related to endometriosis, which is associated with
improved survival.114
Mucinous tumors follow a similar progression from cystad-
enoma to borderline tumor prior to invasion. All subtypes are
more likely to be diagnosed when confined to the ovary.
Mucinous cancers may grow to a very large size, often measur-
ing up to 20 cm in diameter and filled with large pockets of
thick, necrotic, mucinous debris.115,116 Ovarian mucinous
tumors closely resemble mucin-secreting tumors originating
from other sitesmost commonly the gastrointestinal tract.
The pathologic distinction between primary and metastatic
mucinous carcinoma may be challenging, despite the use of
immunohistochemical analysis. Further clinical evaluation is
often required to exclude a clinically occult nonovarian pri-
mary source. Secondary involvement of the ovary may also
occur in association with pseudomyxoma peritonei arising
from a low-grade tumor often of appendiceal origin.117
Clear cell carcinoma is characterized by clear and hobnail
cells with a similar histologic appearance to clear cell carci-
noma of the kidney, endometrium, and vagina. Ovarian clear
cell carcinoma is often seen in association with venous throm-
boembolism and hypercalcemia. Although more likely to be
stage I than serous carcinoma, clear cell histology is associated
with a lower response rate to platinum-based chemotherapy,
higher recurrence rate, and worse survival.118 The transitional
cell tumors, including Brenner tumors, are benign in most
cases (98%) and carry a favorable prognosis.
Ovarian germ cell tumors comprise <5% of ovarian malig-
nancies and are classified by the World Health Organization
(Table 71.4). Dysgerminomas are the most common of the germ
cell tumors and occur bilaterally in 10% to 20% of cases. The
other germ cell tumor types are typically unilateral. Endodermal

A B
FIGURE 71.4. Endometrioid adenocarcinoma of the ovary. A: At low power, note the tumor composed of back-to-back endometrioid glands.
B: At high power, note the squamous metaplasia, commonly seen in this epithelial variant. Assignment of tumor grade is based on similar criteria
as for carcinomas arising in the endometrium. This tumor would qualify as well differentiated or grade 1.
sinus tumors, also known as yolk sac tumors, are characterized
by Schiller-Duvall bodies. Embryonal carcinomas are rare and
tend to occur in younger populations; they may be seen with
nongestational choriocarcinomas as part of mixed germ cell
tumors (10% of all germ cell tumors). Immature teratomas are
characterized by immature elements from the germ layers. The
grade, treatment recommendations, and outcome are directed
by the amount of immature neural elements.
Sex cordstromal tumors are also classified by the World
Health Organization (Table 71.3), with granulosa cell tumors
being the most common (70%). Histologically, the granulosa cell
tumors are composed of granulosa cells that have a pale,
grooved, coffee bean nuclei or a rosette of cells surrounding
eosinophilic material, a Call-Exner body. Thecomas (hormonally
active) and fibromas (hormonally inactive) are both clinically
benign tumors and are most common in middle-age women.
The most common histopathology of primary fallopian tube
malignancies is papillary serous adenocarcinoma. Other less
common Mllerian subtypes include endometrioid, clear cell,
and malignant mixed Mllerian tumors.119,120 Rare reports of
squamous cell carcinoma, immature teratoma, glassy cell tumor,
and sarcoma have also been described. Benign tumors are
found even less frequently than malignant neoplasms. Metastatic
involvement of the fallopian tube is reported in up to 12% of
women with uterine cancer and 4% with cervical cancer.121,122
PATTERNS OF SPREAD
The primary mode of spread for epithelial ovarian and fallopian
tube cancers is transperitoneal, as malignant cells exfoliate into
the peritoneal cavity. Intraperitoneal spread is favored by intes-
tinal peristalsis and negative hydrostatic pressure below the
diaphragm. The exfoliated tumor cells follow the intra-abdomi-
nal fluid stream passing along the paracolic gutters toward the
diaphragm, predominately on the right side, before implanta-
tion on any peritoneal surface.123,124 Metastatic deposits are
frequently seen in the posterior cul-de-sac, paracolic gutters,
diaphragmatic surfaces, liver capsule, intestinal surfaces, and
omentum. Metastases may also be found in the uterus or con-
tralateral ovary from peritoneal spread or flow through the fal-
lopian tubes. Dense tumor caking can cause infiltration into
the abdominal organs creating a mass effect on the omentum,
ureter, bowel, liver, pancreas, spleen, or adrenals, resulting in
advanced disease stage at presentation with associated ascites.
Lymphatic drainage constitutes the second most common
pattern of spread. The lymphatic capillaries of the ovary con-
verge on the hilus and follow the ovarian blood vessels in the
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Chapter 71 Ovarian and Fallopian Tube Cancer 1453
Clinical Radiation Oncology
infundibular ligament to drain to the para-aortic nodes at the
level of the renal hilum. Lymphatics also drain along the broad
ligament to the hypogastric and external iliac nodes in the pel-
vis. Less frequently, spread can occur to the inguinal nodes via
the round ligament.125 Approximately 10% to 15% of women
with disease that appears confined to the ovary have para-aor-
tic lymph node involvement,126 which becomes increasingly
common in advanced-stage disease. Because of the rich lym-
phatic supply of the fallopian tubes, lymph node involvement is
common even in the absence of tubal musculature involve-
ment.127 Pelvic and para-aortic lymph node involvement has
been reported in 10% to 30% of women with fallopian tube can-
cer at diagnosis.128
Transdiaphragmatic spread occurs to the pleural cavity and
is the most common finding in stage IV disease. Hematogenous
spread is infrequent at the time of presentation, with only 2%
to 3% of patients with parenchymal liver or lung disease. Brain
metastasis is also rare. However, >50% of recurrences occur
both within and outside the peritoneal cavity at the time of
treatment failure.
CLINICAL PRESENTATION
As ovarian cancer has insidious growth and is asymptomatic
in early-stage disease, most women do not present until symp-
toms arise from advanced disease progression. Vague gastroin-
testinal complaints of dyspepsia, nausea, early satiety, bloating,
constipation, or obstipation are common presenting symptoms,
as are genitourinary symptoms including frequency, urgency,
or incontinence. Other ill-defined symptoms include fatigue,
back pain, pain with intercourse, and menstrual irregularities.
These nonspecific symptoms can be present for several months
but may not trigger diagnostic evaluation until after the symp-
toms fail to clear with other medical therapy.129 Detection of
early-stage disease may occur by palpation of an asymptomatic
adnexal mass on routine examination, although most adnexal
masses require moderate size for palpation. In premenopausal
women, most of these masses are benign, as ovarian cancer
represents <5% of adnexal neoplasms. An adnexal mass in a
postmenopausal woman has a higher likelihood of malignancy,
and surgical exploration is often indicated. Physical exami-
nation findings such as a fixed pelvic mass, palpable upper
abdominal mass, and ascites are highly suggestive of an ovar-
ian malignancy. According to a consensus statement on the
symptoms of ovarian cancer published by the Gynecologic
Cancer Foundation, SGO, and American Cancer Society, new
and persistent symptoms of bloating, pelvic or abdominal pain,
1454 Section III Clinical Radiation Oncology Part J Gynecologic
difficulty eating, early satiety, or urinary urgency or frequency
should prompt women to seek medical evaluation.
A portion of women with fallopian tube carcinoma may pres-
ent with early clinical signs and symptoms. Two triads have
been described as pathognomonic for fallopian tube malig-
nancy: (a) pelvic pain, pelvic mass, and leukorrhea and (b)
vaginal bleeding, vaginal discharge, and lower abdominal
pain. However, the percentage of patients presenting with either
triad of symptoms has been reported as low as 11%.130 Another
classic signhydrops tubae profluensis a sudden emptying of
accumulated fluid in the distended fallopian tube that causes
profuse, watery, serosanguineous vaginal discharge. The dis-
charge is often accompanied by a decrease in pelvic mass size
on physical examination. In a meta-analysis of 122 patients with
primary fallopian tube cancer, hydrops tubae profluens was a
presenting sign in only 9%.121 In other series,124,127 it has been
specifically reported that neither a triad nor hydrops tubae pro-
fluens was present in any of the patients reviewed. When clini-
cally apparent, the fallopian tube may be dilated and mimic more
benign pathologic processes such as hydrosalpinx, pyosalpinx,
or hematosalpinx.131 In more advanced disease with tubal wall
invasion, extension of a necrotic mass to involve the ovary may
give the initial impression of a tubo-ovarian abscess.
Germ cell and stromal cell malignancies present at an ear-
lier stage than epithelial ovarian or fallopian tube cancers,
often related to abdominal discomfort or symptoms of exces-
sive estrogen or androgen production. Granulosa cell tumors
may lead to precocious puberty in young girls, and Sertoli-
Leydig cell tumors may cause virilization.
DIAGNOSTIC WORKUP
Evaluation of a pelvic mass will be influenced by the patients
age, clinical presentation, and imaging features. An ovarian
mass is more likely to be a malignant neoplasm in the pedi-
atric, perimenopausal, and postmenopausal age groups and
benign during the reproductive years. Ultrasound is often
the first, noninvasive step for the evaluation of a pelvic mass.
Sonographic characteristics suggestive of malignancy include
irregular borders; a solid component that is not hyperechoic
and often nodular or papillary; Doppler demonstration of flow
in the solid component; dense multiple irregular septa (>2 to
3 mm); and the presence of ascites, peritoneal masses, enlarged
nodes, or matted bowel. Computed tomography (CT) and mag-
netic resonance imaging (MRI) may be useful preoperatively for
surgical planning to determine the extent of intra- and extra-
abdominal disease. Although limited as a screening tool, an
elevated CA-125 level may suggest more advanced or greater
bulk of disease and high-grade serous histology but in general
is a weak predictor of surgical resection.132,133 Human chorionic
gonadotropin (-hCG), -fetoprotein (AFP), total inhibin, and
lactate dehydrogenase levels may aid in the diagnosis of and
treatment for nonepithelial germ cell ovarian tumors.
Other conditions may mimic ovarian cancer in their presen-
tation, including colon, gastric, and appendiceal carcinomas as
well as metastatic breast cancer and primary lymphoma.
Although ideally the primary site of disease is determined in
the preoperative setting, the diagnosis often cannot be made
accurately until the time of surgery, and frozen section patho-
logic evaluation may guide surgical approach. Primary malig-
nancies of the fallopian tube have been difficult to diagnose
prior to surgical exploration, as the clinical presentation may
be similar to that of salpingitis, ovarian abscess, pelvic inflam-
matory disease, or even ectopic pregnancy. Occult tubal prima-
ries may be detected only by careful pathologic processing.
Referral to a gynecologic oncologist should be considered
for any woman with a suspicious pelvic mass, family history of
ovarian or fallopian tube cancer, or elevated CA-125.134 Initial
evaluation should include a thorough history and full physical
and pelvic examination, laboratory studies (complete blood
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count, chemistries, CA-125, carcinoembryonic antigen, CA
199), and imaging (abdominal CT/MRI, directed ultrasound,
chest x-ray). Further evaluation with mammography, upper
gastrointestinal endoscopy, or colonoscopy may be indicated in
some scenarios. Comorbid conditions may prompt additional
evaluations, including cardiac risk assessment, pulmonary
function testing, and nutritional evaluation.
SURGICAL STAGING
Surgical advances in staging and the therapeutic benefit of a
maximal safe tumor resection have improved the progression-
free and overall survival of women with ovarian cancer over
the past two decades. Traditional staging for ovarian cancer
is based on the FIGO staging system shown in Table 71.5.135 A
parallel American Joint Committee on Cancer system of TNM
staging also exists, with strong correlations between stage and
the prognostic value of these substages. Staging of primary
fallopian tube cancer was established by FIGO in 1992 based
on the ovarian cancer staging system. A proposed modifica-
tion was later published to permit staging of noninvasive tubal
carcinomas and fimbrial carcinomas as well as the inclusion of
substaging based on depth of invasion119 (Table 71.6).
Comprehensive surgical staging is the mainstay of diagnosis
and initial treatment for ovarian, fallopian tube, and peritoneal
cancers.136 In apparent early-stage cancers, surgical evaluation is
required for accurate pathologic staging to guide adjuvant treat-
ment recommendations. In patients with advanced disease, sur-
gery represents the initial treatment by providing optimal cytore-
duction. Comprehensive surgical staging begins with an
exploratory laparotomy via a vertical midline incision followed
by collection of peritoneal washings or any ascitic fluid for cytol-
ogy. The surgeon performs a thorough inspection of all visceral
and peritoneal surfaces within the abdomen and pelvis, with
particular attention to the intestinal serosal surfaces, mesentery,
TABLE 71.5 FIGO STAGING FOR OVARIAN CARCINOMA
Stage I Growth limited to the ovaries
Ia Growth limited to 1 ovary; no ascites present containing malignant cells.
No tumor on the external surface; capsule intact.
Ib Growth limited to both ovaries; no ascites present containing malignant
cells. No tumor on the external surfaces; capsules intact.
Ic Tumor either stage Ia or Ib, but with tumor on surface of 1 or both ovaries,
or with capsule ruptured, or with ascites present containing malignant
cells, or with positive peritoneal washings.
Stage II Growth involving 1 or both ovaries with pelvic extension.
IIa Extension and/or metastases to the uterus and/or tubes.
IIb Extension to other pelvic tissues.
IIc Tumor either stage IIa or IIb, but with tumor on surface of 1 or both
ovaries, or with ascites present containing malignant cells, or with
positive peritoneal washings.
Stage III Tumor involving 1 or both ovaries with histologically confirmed peritoneal
implants outside the pelvis and/or positive retroperitoneal or inguinal nodes.
Superficial liver metastases equals stage III. Tumor is limited to the true
pelvis but with histologically proven malignant extension to small bowel or
omentum.
IIIa Tumor grossly limited to the true pelvis, with negative nodes, but with histo-
logically confirmed microscopic seeding of abdominal peritoneal sur-
faces, or histologically proven extension to small bowel or mesentery.
IIIb Tumor of 1 or both ovaries with histologically confirmed implants,
peritoneal metastases of abdominal peritoneal surfaces with none
>2 cm in diameter; nodes are negative.
IIIc Peritoneal metastases beyond the pelvis >2 cm in diameter and/or positive
retroperitoneal or inguinal nodes.
Stage IV Growth involving 1 or both ovaries with distant metastases. If pleural
effusion is present, there must be positive cytology to allot a case to
stage IV. Parenchymal liver metastases equal stage IV.
FIGO, International Federation of Gynecology and Obstetrics.
Available at: http://www.igcs.org/files/TreatmentResources/FIGO_IGCS_staging.pdf.
Accessed December 27, 2011.

TABLE 71.6 MODIFIED FIGO FALLOPIAN TUBE STAGING
Stage Description
0 Carcinoma in situ (limited to tubal epithelium).
I Growth limited to the fallopian tubes.
IA Growth limited to 1 tube with extension into the submucosa and/or mus-
cularis but not penetrating the serosal surface; no ascites containing
malignant cells or positive peritoneal washings.
0b Growth limited to 1 tube with no extension into lamina propria.
1b Growth limited to 1 tube with extension into lamina propria but no exten-
sion into muscularis.
2b Growth limited to 1 tube with extension into muscularis.
IB Growth limited to both tubes with extension into the submucosa and/or
muscularis but not penetrating the serosal sursal surface; no ascites
containing malignant cells or positive peritoneal washings.
0b Growth limited to both tubes with no extension into lamina propria.
1b Growth limited to both tubes with extension into lamina propria but no
extension into muscularis.
2b Growth limited to both tubes with extension into muscularis.
IC Tumor either stage IA or IB with tumor extension through or onto the
tubal serosa; or with ascites present containing malignant cells or
positive peritoneal washings.
I (F) Tumor limited to fimbriated end of fallopian tube(s) without invasion of
tubal wall.
II Growth involving 1 or both fallopian tubes with pelvic extension.
IIA Extension and/or metastasis to the uterus and/or ovaries.
IIB Extension to other pelvic tissues.
IIC Tumor either stage IIA or IIB with ascites present containing malignant
cells or with positive peritoneal washings.
III Tumor involves 1 or both fallopian tubes with peritoneal implants outside
the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial
liver metastasis equals stage III. Tumor appears limited to the true pel-
vis but with histologically proven malignant extension to the small
bowel or omentum.
IIIA Tumor grossly limited to the true pelvis with negative nodes but with
histologically confirmed microscopic seeding of abdominal peritoneal
surfaces.
IIIB Tumor involving 1 or both tubes with grossly visible histologically con-
firmed implants of abdominal peritoneal surfaces with none >2 cm in
diameter; lymph nodes are negative.
IIIC Abdominal implants >2 cm in diameter and/or positive retroperitoneal or
inguinal nodes.
IV Growth involving 1 or both fallopian tubes with distant metastasis. If
pleural effusion is present, there must be positive cytology to be
stage IV. Parenchymal liver metastases equal stage IV.
FIGO, International Federation of Gynecology and Obstetrics.
paracolic gutters, hemidiaphragms, gallbladder, and liver.
Systematic biopsies of the bladder serosa, anterior and posterior
cul de sac, paracolic gutters, hemidiaphragms, and any suspi-
cious adhesions or implants should be obtained. Total hysterec-
tomy, bilateral salpingo-oophorectomy, infracolic omentectomy,
and pelvic and para-aortic lymph nodal sampling may be per-
formed in addition to the intact removal of the adnexal mass when
possible. Given the significant risk of contralateral involvement,
bilateral lymph node assessment is frequently performed.137,138 In
patients with advanced disease, bowel resection, diaphragm
stripping, splenectomy, nodal dissection, and radical resection of
peritoneal tumor nodules are often necessary to achieve the
desired surgical outcome of maximal debulking. Recently, the
role of routine appendectomy has been questioned and is not
recommended in the absence of visible pathology.139
In select cases, preservation of the contralateral unaffected
ovary and the uterus can be achieved in young women wishing
to retain fertility who have stage I and/or low-risk tumors
(early-stage, low-grade invasive tumors, LMP lesions, or malig-
nant stromal or germ cell tumors).136 In the setting of unilateral
salpingo-oophorectomy, comprehensive surgical staging should
be performed to exclude occult disease. Exceptions to upfront
surgical management include patients with significant medical
comorbidities who are poor operative candidates and patients
with a complex ovarian cyst where extraovarian disease has
not been excluded. Neoadjuvant chemotherapy followed by
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Chapter 71 Ovarian and Fallopian Tube Cancer 1455
interval cytoreduction may be considered in patients with bulky
stage III or IV disease. Before initiation of neoadjuvant chemo-
therapy, the pathologic diagnosis should be confirmed by
biopsy, fine-needle aspirate, or paracentesis. The NCCN guide-
lines recommend that patients who are evaluated for neoadju-
vant chemotherapy be seen by a fellowship-trained gynecologic
oncologist before being deemed a nonsurgical candidate.136
PROGNOSTIC FACTORS
Tumor stage, grade, histology, and optimal cytoreduction by a
trained gynecologic oncologist are the most important determi-
nants of survival for ovarian and fallopian tube cancer. Patients
with FIGO stage 1A disease who have negative staging lapa-
rotomy have 5-year survival rates of 80% to 90%. If extrapelvic
disease is detected at the time of surgical staging, the patient is
upstaged to stage III disease with corresponding 5-year survival
Clinical Radiation Oncology
rates of 30% to 50%. Primary or interval cytoreductive surgery
should be performed by a gynecologic oncologist based on pub-
lished evidence of a 6- to 9-month median survival benefit.140142
The volume of residual disease after primary surgery is also
an important determinant of outcome.143148 Patients who have
optimal cytoreduction of tumor have a 22-month improvement
in median survival compared to those with suboptimal resec-
tion. A meta-analysis of >6,800 women with advanced-stage
ovarian cancer treated with adjuvant platinum-based chemo-
therapy found a 5.5% increase in median survival for every
10% increase in maximal cytoreduction.144 Although the defini-
tion of maximal resection varies by study, <1 mm or no visible
disease has been associated with improved response to chemo-
therapy, less platinum resistance, and longer overall sur-
vival.143,149,150 Preoperative CA-125 measurement is not inde-
pendently prognostic, as it likely reflects disease burden. In
contrast, the half-life and nadir of CA-125 during induction che-
motherapy is associated with improved outcome in ovarian and
fallopian tube cancers.120,151155
Although a strong correlation exists between histologic grade
and stage, grade has independent prognostic significance, par-
ticularly in early-stage disease. Survival rates for stage I disease
with grade 1, 2, or 3 tumors are 96%, 78%, and 62%, respec-
tively.156 The impact of histologic subtype on survival is less
robust owing to other more important clinical variables, includ-
ing stage, grade, and volume of disease. Patients with mucinous
and endometrioid subtypes have improved survival rates com-
pared to serous adenocarcinoma, predominately related to the
earlier stage at presentation. Clear cell carcinomas appear to be
more aggressive than other epithelial malignancies. The 5-year
survival rate for stage I clear cell carcinoma is 60% and for
other stages is <15%.118
As reflected in the modified FIGO staging system, depth of
tubal invasion has been found to correlate with survival in two
large retrospective studies of fallopian tube carcinoma.120,157,158
In addition to the depth of tubal invasion, the pathology report
should provide information on tumor grade and the presence
of lymphovascular invasion.
MANAGEMENT OF EPITHELIAL TUMORS
Treatment for ovarian and fallopian tube cancer depends
largely on the stage and grade of disease at presentation. Table
71.7 presents a general schematic for treatment recommenda-
tions for women with epithelial ovarian and fallopian tube can-
cer. Although much less common, primary peritoneal cancers
are managed in a similar manner.
Early-Stage Disease
Surgical Therapy
Comprehensive surgical staging should be performed in all
women with apparent early-stage disease to confirm that the
1456 Section III Clinical Radiation Oncology Part J Gynecologic

TABLE 71.7 SCHEMATIC OF THE PRIMARY TREATMENT FOR EPITHELIAL Nonetheless, two large multi-institutional trials conducted in
OVARIAN CANCER Europe randomized women with early-stage ovarian cancer to
platinum-based chemotherapy or observation following surgery
Low risk, early stage
(Table 71.8). The International Collaborative Ovarian Neoplasm
Stage IA/B, grade 1 Observation
Stage 1A/B, grade 2 Observation or IV taxane/carboplatin for 36 cycles
1 (ICON1) trial enrolled 477 women with FIGO IA-C ovarian can-
High risk, early stage cer inclusive of all tumor grades and histologic subtypes.162
Stage 1C, all grades IV taxane/carboplatin for 36 cycles Adjuvant chemotherapy consisted of six cycles of a platinum-
Stage IA/B, grade 3 based regimen per institutional preference. With a median fol-
Stage II IV taxane/carboplatin for 68 cycles low-up of 9.2 years, 10-year recurrence-free survival was 67%
IP chemotherapy in optimally debulked patients for the chemotherapy arm and 57% for observation (HR 0.7, p =
Advanced stage .02).163 Overall survival also favored the chemotherapy group
Optimal debulked stage III IP chemotherapy (72% vs. 64%, p = 0.06). When stratified by histology and grade,
IV taxane/carboplatin for 68 cycles the largest benefit for adjuvant chemotherapy was seen in
Clinical trial patients with high-risk disease, defined as FIGO stage 1A grade
Suboptimal debulked IV taxane/carboplatin for 68 cycles 3, stages 1B or 1C grades 2 and 3, or any clear cell histology.
stage III/IV Clinical trial HRs for recurrence and death for the high-risk subset were 0.52
Interval cytoreduction if indicated by tumor
response and resectability
and 0.48, respectively (both p <.01). The second trial, Adjuvant
Chemotherapy in Ovarian Neoplasm (ACTION), assigned 448
IV, intravenous; IP, intraperitoneal. women with early-stage ovarian cancer to four to six cycles of
platinum-based adjuvant chemotherapy or observation follow-
ing surgery. Women with FIGO 1A grades 2 and 3 disease, all
cancer is confined to the adnexa. Fertility-sparing surgery stages IC-IIA, or any clear cell histology were eligible for the
with unilateral salpingo-oophorectomy may be considered in trial. Recurrence-free survival, but not overall survival, was sig-
a small subset of women with stage IA disease if the contralat- nificantly improved in the chemotherapy group (70% vs. 62% at
eral ovary is normal in appearance.159 In addition to abdomi- 10 years).164,165 The greatest benefit was seen in the subset of
nal exploration and full surgical staging, endometrial biopsy women with nonoptimal surgical staging. In a combined analy-
should be performed to sample the endometrium. sis of the ICON1 and ACTION trials, adjuvant chemotherapy was
associated with significantly improved overall survival at 5 years
Postoperative Management (82% vs. 74%) compared to observation.166
Early studies by the Gynecologic Oncology Group (GOG) and The GOG conducted a randomized trial to determine the
others have identified a small subgroup of patients with well- optimal duration of adjuvant chemotherapy in women with
to moderately differentiated (grade 1 or 2) stage IA and 1B high-risk, surgical stage I disease by comparing three versus
tumors who have a low risk of relapse and may not require six cycles of carboplatin and Taxol chemotherapy.167 Rates of
adjuvant therapy.160,161 The NCCN guidelines state that women recurrence (25% vs. 20%) and overall survival (81% vs. 83%)
with early-stage (FIGO 1A or 1B) grade 1 ovarian cancer were similar at 5 years for three and six cycles of chemo-
may be treated with surgical resection and observation with therapy, although six cycles were associated with significantly
expected 5-year survival rates on the order of 90%.136 If obser- more toxicity, including neuropathy, granulocytopenia, and
vation is considered for women with early-stage grade 2 dis- anemia. However, subset analysis revealed a significantly
ease, full surgical staging should be performed. lower risk of recurrence for women with serous tumors.168 At
5 years, recurrence-free survival for women with serous tumors
Adjuvant Chemotherapy was 83% for six cycles of chemotherapy versus 60% for three
Women with early-stage disease and a less favorable prog- cycles (HR 0.33, p = .04). Overall survival was also improved at
nosis include patients with grade 3 tumors, clear cell histol- 5 years (86% vs. 73%), although not statistically significant.
ogy, or disease extension beyond the ovarian capsule into the
abdominal wall or peritoneum (stage IC or II). Various adjuvant Adjuvant Whole-Abdomen Irradiation
treatment approaches have been investigated to improve clini- WAI was an accepted standard modality in the adjuvant post-
cal outcomes, although the optimal management remains con- operative treatment for completely resected ovarian cancer;
troversial. Few randomized trials have been conducted in this however, its use declined significantly after 1975. The practi-
population, and they have been limited by small sample size cal advantage of WAI was the ability to treat all of the peri-
and lack of power to demonstrate a survival advantage. toneal surfaces within the abdomen and pelvis, although the

TABLE 71.8 RANDOMIZED STUDIES OF ADJUVANT CHEMOTHERAPY IN EARLY-STAGE OVARIAN CANCER

Number of
Trial Stage Study Design Patients 5-Year DFS% 5-Year OS% Notes
Observation Versus Chemotherapy
GOG (1990) 1A, IB grades 12 Observation 44 91 94 No survival difference; optimal staging
Melphalan 48 98 98
ICON1 (2003, 2007) I/II Observation 236 62 70 Largest benefit for high-risk group; no surgical staging
Platinum-based 241 73a 79a
ACTION (2003, 2010) 1A, 1B grades 23 Observation 224 68 78 Optimal staging in 1/3
ICIIA all grades Platinum-based 224 76a 85
Clear cell
Duration of Chemotherapy
GOG (2006, 2010) 1A, 1B grade 3 3 cycles CT 232 75 81 No survival difference; greatest benefit for serous tumors
1CII all grades 6 cycles CT 225 80 83
Clear cell
DFS, disease-free survival; OS, overall survival; GOG, Gynecologic Oncology Group; ICON1, International Collaborative Ovarian Neoplasm 1; ACTION, Adjuvant Chemotherapy in
Ovarian Neoplasm; CT, carboplatin and paclitaxel.
a
Statistically significant.

booksmedicos.org

delivered dose was limited by the relatively low tolerance of
the liver and kidneys. Interest in WAI was established follow-
ing the publication from Princess Margaret Hospital of a ran-
domized comparison of 147 patients with FIGO 1B, II, or III
debulked ovarian cancer who received WAI with a pelvic boost
or pelvic radiotherapy followed by chlorambucil.169 WAI sig-
nificantly improved 10-year survival rates over limited pelvic
radiotherapy and chemotherapy (64% vs. 40%, respectively).
The greatest magnitude of the survival benefit was observed in
patients with <2 cm of residual disease (10-year survival 78%
vs. 51%, respectively). No significant benefit was observed in
patients with extensive residual tumor.
Subsequent randomized studies did not find a benefit for
WAI compared to combined adjuvant treatment modalities. A
multi-institutional trial by the National Cancer Institute of
Canada (NCIC) randomized 257 high-risk stage I or optimally
debulked stage II or III patients to receive melphalan, WAI, or
IP 32phosphorus (32P).170 All patients had previously received
22.5 Gy to the pelvis prior to study entry. The WAI arm deliv-
ered 22.5 Gy to the abdomen in 2.25-Gy fractions. Actuarial
10-year survival rates failed to demonstrate a statistically sig-
nificant difference among all groups.171 A second study from
the Danish Ovarian Cancer Group (DACOVA) reported similar
outcomes for women who received adjuvant WAI versus pelvic
radiotherapy with cyclophosphamide or melphalan (4-year
survival, 63% vs. 55%, respectively).172
WAI has also been shown to be comparable to single or com-
bination chemotherapy in the adjuvant setting. A prospective
study from the MD Anderson Cancer Center randomized 149
women with stage I through III ovarian cancer and <2 cm of
residual disease to WAI or melphalan.173 WAI was delivered by a
moving strip technique with a pelvic boost. Overall survival at
5 years was 71% for WAI and 72% for the melphalan arm. Severe
late gastrointestinal toxicity requiring surgical intervention was
reported in 14% of patients who received WAI, attributed to the
moving strip technique that delivered excessive pelvic dose. A
second prospective trial from the Northwest Oncologic
Cooperative Group of Italy randomized 70 women with early-
stage high-risk disease to adjuvant WAI or six cycles of cisplatin
plus cyclophosphamide. Despite protocol violations in the
assigned treatment groups, there was no difference in relapse-
free or overall survival when analyzed by treatment received.174
From these studies, WAI appears equivalent to chemotherapy
when delivered in patients with optimally debulked disease but is
no longer used. Further dose escalation of WAI to 27.5 Gy does
not appear to provide additional survival benefit.175
Adjuvant Intraperitoneal 32Phosphorous
IP instillation of 32P was extensively studied as an alternative to
external-beam radiotherapy but is no longer in clinical use. In
high-risk, early-stage ovarian cancer patients, randomized tri-
als of adjuvant IP 32P versus chemotherapy from the GOG and
Norwegian Radium Hospital found no significant differences in
disease-free or overall survival in a population with high-risk
early-stage disease.161,176,177 Given a higher incidence of bowel
toxicity and limitations of delivery, 32P has largely been replaced
by platinum and taxane combination chemotherapy as the
adjuvant treatment for early-stage and advanced disease.
Advanced-Stage Disease
Surgical Considerations
Maximal cytoreduction is one of the most important prognos-
tic factors for survival in patients with advanced-stage ovar-
ian cancer. Cytoreductive surgery in advanced-stage disease
may improve the patients disease-related symptoms such
as abdominal pain and early satiety and allow for the ability
to maintain nutritional status. Optimal debulking may also
enhance chemotherapy delivery and response by removal of
large hypoxic tumor masses. Bowel resection may be required
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Chapter 71 Ovarian and Fallopian Tube Cancer 1457
to remove metastatic implants involving the bowel mesentery
or serosa. Extensive upper abdominal surgery, including sple-
nectomy, partial hepatectomy, distal pancreatectomy, and/or
diaphragmatic resection, also results in prolonged palliation
and improved survival.178,179
Second-look laparotomy (SLL) was introduced to assess the
extent of residual disease following cytoreductive surgery and
adjuvant chemotherapy. Up to 20% to 50% of patients may
have residual disease after adjuvant therapy that was not
detected on physical examination or by CA-125 levels or imag-
ing. Although SLL demonstrated the prognostic importance of
a pathologic remission, it was not found to have a therapeutic
benefit in a GOG trial of 800 patients.180 Therefore, second-look
evaluations for the purposes of determining therapy, and not
for interval cytoreduction, should be reserved for women
enrolled in clinical trials.
Several studies have evaluated the importance of interval
Clinical Radiation Oncology
cytoreduction following an initial attempt at surgical debulk-
ing. In a randomized trial by the European Organisation for
Research and Treatment of Cancer (EORTC), 319 women with
suboptimally debulked disease (>1 cm residual) were assigned
to six cycles of cisplatin/cyclophosphamide chemotherapy or
interval cytoreduction after three cycles of chemotherapy, fol-
lowed by an additional three cycles.181 Progression-free and
overall survival were significantly improved with interval cyto-
reduction (median overall survival 26 vs. 20 months, p = .04)
without increased surgical morbidity. However, a subsequent
GOG trial of 550 women failed to reproduce these results.182
Following a suboptimal resection in the GOG trial, patients
were randomized to three cycles of cisplatin and paclitaxel fol-
lowed by interval debulking or chemotherapy alone for a maxi-
mum of six cycles in both arms. The absence of a survival ben-
efit may be attributable to differences in the chemotherapy
used or more aggressive initial surgical management by gyne-
cologic oncologists in the GOG trial.
The role of neoadjuvant chemotherapy has been explored in
a randomized EORTC/NCIC trial of 670 women with stage IIIC
and IV ovarian, fallopian tube, or primary peritoneal cancer
randomized to initial surgical debulking followed by six cycles
of cisplatin-based chemotherapy or interval debulking after
three cycles, followed by three additional cycles.183 The cohort
had extensive bulky disease, with >60% of patients with metas-
tases >10 cm. Although progression-free and overall survival
were similar between the two groups, interval surgery achieved
optimal cytoreduction more often (81% vs. 42%) and with fewer
surgical complications. A major criticism of the trial is that the
median survival was significant lower than that of recently
reported U.S. trials, which may be related to selection of higher-
risk patients. NCCN guidelines state that more data will be nec-
essary prior to recommending neoadjuvant chemotherapy in
potentially resectable patients, and upfront debulking surgery
remains the treatment of choice in the United States.136
Chemotherapy for Advanced-Stage Disease
Platinum agents are the most active class of compounds in the
adjuvant treatment for ovarian cancer. Before 1980, alkylating-
based regimens such as cyclophosphamide and doxorubicin
were used with clinical response rates of 15% to 20%. GOG 47
demonstrated an improvement in clinical complete response
rates (51% vs. 26%) and progression-free survival (13 months
vs. 8 months) with the addition of cisplatin to cyclophospha-
mide and doxorubicin. Cisplatin has since been used exten-
sively in both single-agent and multidrug studies. A meta-anal-
ysis of 49 trials from the Advanced Ovarian Cancer Trialists
Group found that platinum combination chemotherapy
improved survival rates over the same nonplatinum regimen
(HR 0.88, 95% CI 0.79 to 0.98) and nonplatinum monotherapy
(HR 0.93, 95% CI 0.83 to 1.05).184 The women in the nonplati-
num groups routinely received platinum chemotherapy at the
time of relapse, likely obscuring the magnitude of the benefit.
1458 Section III Clinical Radiation Oncology Part J Gynecologic
TABLE 71.9 RANDOMIZED STUDIES OF ADJUVANT CHEMOTHERAPY IN ADVANCED-STAGE OVARIAN CANCER
Trial Stage Study Design
GOG 172 (2006) III IP/IV cisplatin/paclitaxel
1 cm residual IV cisplatin/paclitaxel
Japanese GOG (2009) IIIV Dose-dense CT
CT (every 21 days)
GOG 218 (2010) IIIIV CT
+ c. bevacizumab
+ c./m. bevacizumab
ICON7 (2010) High risk III CT
IIIIV + c./m. bevacizumab
PFS, progression-free survival; OS, overall survival; IP, intraperitoneal; IV, intravenous; CT, carboplatin and paclitaxel; c., concurrent; m., maintenance; GI, gastrointestinal; ICON7,
International Collaborative Ovarian Neoplasm 7.
a
Statistically significant.
This meta-analysis also incorporated data from 11 trials that
directly compared carboplatin and cisplatin, either as single
agents or in combination with other drugs, which suggested
no difference in efficacy between the two agents. Carboplatin
clearly has fewer treatment-related side effects, including less
nephrotoxicity, neurotoxicity, and emetogenic potential, and is
considered standard of care. However, carboplatin does have
more associated myelosuppression, primarily thrombocytope-
nia, which is cumulative and may be dose limiting.
In addition to platinum compounds, taxanes have become a
cornerstone of the treatment schemas for women with epithe-
lial ovarian cancer. GOG 111 was a randomized study compar-
ing cisplatin and paclitaxel with cisplatin and cyclophospha-
mide in women with suboptimally debulked, large-volume
ovarian cancer. The paclitaxel-containing arm demonstrated
improved clinical response rates (73% vs. 60%), progression-
free survival (18 months vs. 13 months), and overall survival
(38 months vs. 24 months).185 A second GOG study of 614
women with advanced disease and suboptimal resection com-
pared single-agent cisplatin to 24-hour infusion of paclitaxel
and to the combination of paclitaxel and cisplatin.186 Cisplatin
alone or in combination with paclitaxel resulted in improved
clinical response rates and progression-free survival, although
overall survival was similar in the three arms. Combination
chemotherapy also had lower cumulative toxicity. As several
trials have demonstrated the comparable efficacy of cisplatin
and carboplatin, combination carboplatin and paclitaxel has
become the preferred first-line chemotherapy regimen.
Although the standard dosing of intravenous carboplatin and
paclitaxel is every 21 days, a phase III trial from Japan demon-
strated significant gains in progression-free and overall sur-
vival with a dose-dense regimen of weekly paclitaxel in combi-
nation with carboplatin given every 3 weeks187 (Table 71.9).
Grade 3 or 4 anemia was more common in the dose-dense
arm, although other toxicities were similar. Dose-dense pacli-
taxel and carboplatin is a recommended intravenous regimen
by the NCCN.136 Carboplatin and docetaxel is also an accept-
able first-line alternative and may be considered for patients at
high risk for neuropathy.188 Phase III trials have failed to show
a benefit for the addition of a third agent to the carboplatin and
paclitaxel regimen. GOG 182-ICON5 was a five-arm random-
ized trial of 4,312 women that compared the addition of gem-
citabine, liposomal doxorubicin, or topotecan to carboplatin
and paclitaxel. There were no improvements in progression-
free or overall survival with any experimental regimen.189
The role of novel biologics in the first-line treatment for
ovarian, fallopian tube, and primary peritoneal cancers is
under active investigation. Antiangiogenics have demonstrated
activity in the recurrent treatment setting, and the addition of
bevacizumab to conventional first-line chemotherapy has
recently been tested in two randomized trials. Bevacizumab is a
humanized monoclonal antibody directed against the VEGF
booksmedicos.org
Number of Median PFS Median OS
Patients (months) (months) Notes
415 23.6 65.6 Greater toxicity in IP/IV arm
18.3a 49.7a
631 28.0 More anemia with dose-dense schedule
17.2a
1,873 10.3 39.3 Higher rates of hypertension, GI perforation, and fistula
11.2 38.7
14.1a 39.7
1,528 17.4 Greatest benefit in high-risk subset
19.8a
receptor that may inhibit tumor angiogenesis and improve che-
motherapy delivery. GOG 218 reported that the addition of con-
current and maintenance bevacizumab for 15 months signifi-
cantly improved progression-free survival compared to six
cycles of carboplatin and paclitaxel alone (14.1 months vs. 10.3
months).190 The benefit was not seen in the group who received
concurrent bevacizumab without maintenance therapy. Rates of
hypertension, gastrointestinal perforation, and fistula formation
were higher with the use of bevacizumab. With a median fol-
low up of 17.4 months, overall survival was similar between
the treatment arms. The ICON7 trial also reported a progres-
sion-free but not overall survival benefit with concurrent beva-
cizumab and carboplatin/paclitaxel chemotherapy.191 The
greatest benefit was observed in patients at high risk for pro-
gression, defined as FIGO stage IV or >1 cm of residual disease
and FIGO stage III (median progression-free survival of 16
months vs. 10.5 months). Concerns about cost and lack of an
overall survival benefit have tempered the widespread adoption
of bevacizumab to the first-line chemotherapy backbone. The
NCCN Ovarian Cancer Panel had a major disagreement about
recommending the addition of bevacizumab to upfront therapy
with carboplatin/paclitaxel or as maintenance therapy, as
reflected in a category 3 recommendation.136 A phase III trial of
the oral antiangiogenic nintedanib (BIBF 1120) in combination
with carboplatin and paclitaxel is open to accrual for women
with newly diagnosed ovarian, fallopian tube, or primary perito-
neal cancer. Pazopanib, a potent multitargeted tyrosine kinase
inhibitor against VEGF receptor, PDGF receptor, and c-Kit is
being tested as maintenance therapy following surgical debulk-
ing and first-line chemotherapy.
Intraperitoneal Chemotherapy
Because of the unique peritoneal dissemination of epithelial
ovarian and fallopian tube cancer, there has been a signifi-
cant interest in evaluating IP administration of chemotherapy,
which allows for a severalfold increase in drug concentration
compared to systemic delivery. However, penetration into
tumor tissue may be limited such that therapy is best suited for
patients with minimal residual disease after surgical debulk-
ing. The National Cancer Institute published a consensus state-
ment in 2006 stating that IP chemotherapy should be offered
to every woman with optimally debulked advanced-stage ovar-
ian cancer based on the findings of GOG 172 (Table 71.9),
which showed a progression-free and overall survival benefit
to IP chemotherapy when compared with intravenous ther-
apy alone (23.6 months vs. 18.3 months and 65.6 months vs.
49.7 months, respectively).192 Only 42% of patients completed
all six cycles of IP chemotherapy owing to treatment-related
toxicity and catheter-related complications, which included
gastrointestinal events, abdominal pain, metabolic abnormali-
ties, neuropathy, catheter infection, and blockage. Despite the
higher incidence of toxicity, additional support for IP chemo-

therapy is derived from a meta-analysis of eight trials com-
paring IP to intravenous administration of platinum-based che-
motherapy. IP delivery resulted in a 22% decrease in the risk
of death, which translated into a 12-month median survival
benefit.193 NCCN guidelines state that stage II patients may
also receive IP chemotherapy, although randomized evidence
has not yet been published.136 Despite the clinical advisory, IP
chemotherapy has not been consistently adopted for treatment
in women with optimally debulked ovarian cancer given the
technical demands and increased toxicity. Patients with poor
performance status, medical comorbidities, stage IV disease, or
advanced age may not tolerate the IP regimen. The feasibility
and effectiveness of IP carboplatin will be evaluated in a phase
III GOG trial comparing a modified GOG 172 intravenous/IP
cisplatin/paclitaxel regimen to IP carboplatin/weekly paclitaxel
as well as intravenous carboplatin/weekly paclitaxel (dose-
dense regimen). All three arms will receive concurrent and
maintenance bevacizumab for 1 year.
CONSOLIDATIVE THERAPY FOR
EPITHELIAL OVARIAN CANCER
Consolidative radiotherapy was introduced in hopes of eradicat-
ing subclinical residual disease in women who remain at high
risk for relapse following surgical cytoreduction and adjuvant
chemotherapy. Despite a negative SLL, 30% to 50% of women
with confirmed clinical remission ultimately relapse, most com-
monly in the pelvis or upper abdomen. Consolidative WAI as
well as IP radiocolloid have been evaluated in several studies,
although randomized data are currently lacking. Radiotherapy
is not currently used as consolidative treatment for ovarian or
fallopian tube carcinomas, although it may have a role in the
salvage or palliative treatment of select cases.
Consolidative Whole-Abdomen Irradiation
The efficacy of WAI has been demonstrated in early-stage
patients with minimal residual disease (<2 cm) after cytoreduc-
tive surgery. A few early, prospective randomized trials have
evaluated the role of consolidative WAI compared to extended
chemotherapy in patients with advanced-stage disease (stage
III/IV) after initial surgical cytoreduction, adjuvant chemother-
apy, and SLL. In all of these trials, disease-free and overall sur-
vival rates were not found to be significantly different between
WAI and chemotherapy.194196 A possible limitation of these tri-
als was that women with macroscopic residual disease after
SLL were eligible for enrollment.
Two recent trials have evaluated consolidative WAI in
patients with complete clinical or pathologic remission follow-
ing cytoreductive surgery and adjuvant chemotherapy. A ran-
domized study from Austria demonstrated improved disease-
free and overall survival for consolidative WAI, with the greatest
benefit seen in stage III patients.197 The Swedish-Norwegian
Ovarian Cancer Study Group recently reported their long-term
results from a randomized trial of stage III patients.198 Following
primary cytoreductive surgery and four cycles of cisplatin-
based chemotherapy, women with complete remission at sec-
ond-look surgery were randomized to WAI, six additional cycles
of chemotherapy, or observation (if pathologic remission con-
firmed). In the subgroup with pathologic remission, WAI
improved progression-free survival compared to chemotherapy
or no further therapy (56%, 36%, and 35%, respectively).
Overall survival was not statistically different, although statisti-
cal power was limited because only 172 (23%) of 742 enrolled
patients were randomized to consolidative treatment.
WAI does not appear to compromise the ability for patients
to receive and tolerate salvage chemotherapy following relapse,
as recently reported in a phase II study from Princess Margaret
Hospital.199 However, the long-term complication rate using
conventional radiotherapy techniques is significant. In a multi-
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Chapter 71 Ovarian and Fallopian Tube Cancer 1459
center retrospective study from France with a median follow
up of 14 years, late symptomatic enteritis occurred in 20% of
patients, of which 8% required surgical intervention for bowel
obstruction, and death related to bowel complications occurred
in 4%.200 At this time, WAI is no longer included in the NCCN
guidelines as an option for initial or consolidative treatment in
ovarian cancer.
Consolidative Intraperitoneal 32Phosphorous
Randomized data evaluating IP 32P as consolidative treatment
following SLL are limited. The Norwegian Radium Hospital ran-
domized 50 patients with stage IA high-grade and IB through III
disease and negative SLL to 32P versus observation and found no
significant difference between the arms.176 The GOG also con-
ducted a prospective randomized trial of 202 stage III patients
with complete clinical remission and microscopically negative
disease at SLL.201 Compared with patients who received no fur-
Clinical Radiation Oncology
ther therapy, those who received 32P (15 mCi) within 10 days of
SLL did not have improved 5-year disease-free survival (36%
vs. 42%, respectively) or overall survival (63% vs. 67%, respec-
tively).
Recurrent Ovarian Cancer
Women in clinical remission following initial adjuvant treat-
ment for ovarian cancer are followed with a combination of pel-
vic examination, abdominal and pelvic CT, and serial CA-125
levels. Detection of early relapse by a rising CA-125 is fairly
specific, although the lead time between biochemical and clini-
cal progression may be >6 months. Second-line chemotherapy
is not curative; thus, the timing of salvage therapy is controver-
sial. The EORTC conducted a randomized trial of early versus
delayed treatment for relapsed ovarian cancer that showed no
difference in overall survival between the arms.202 However,
the findings have not been widely adopted in the United States
owing to criticisms regarding the study design, including lack
of stratification by known prognostic factors and nonstandard
second-line therapies. An SGO statement encourages physi-
cians to discuss with their patients CA-125 monitoring and the
implications regarding treatment and quality of life.
Chemotherapy
The selection of second-line chemotherapy for recurrent ovar-
ian cancer is based on the interval to disease relapse and
determination of platinum sensitivity or resistance. Patients
who experience an early recurrence within 6 months of the
completion of initial chemotherapy, have stable disease, or
progress during initial induction chemotherapy are consid-
ered platinum-resistant with low likelihood of cure. Women
who suffer an early recurrence do have treatment options,
including second-line chemotherapy agents (topotecan, weekly
paclitaxel, liposomal doxorubicin, gemcitabine, oral etoposide,
docetaxel), hormonal therapies, targeted therapeutics, and the
opportunity to participate in clinical trials. For women with a
late recurrence, retreatment with a platinum-based combina-
tion is a reasonable option, and the longer the disease-free
interval, the higher the response rate to the agents. With the
exception of those women who have a prolonged disease-free
interval, the opportunity for a meaningful second remission is
low, and one needs to carefully balance quality of life, chemo-
therapy-related toxicity, cost, and the patients goals of care.
Several randomized phase III studies are testing the role of
antiangiogenics in the recurrent setting with combination che-
motherapy. In the OCEANS trial, the addition of bevacizumab
to carboplatin/paclitaxel chemotherapy resulted in improved
response rates (79% vs. 57%, p <.001) and progression-free
survival (median 12.4 months vs 8.4 months, p <.001) in
women with platinum-sensitive recurrent disease.203 Phase II
studies of bevacizumab have demonstrated single-agent activ-
ity in patients with platinum-resistant recurrent ovarian cancer
1460 Section III Clinical Radiation Oncology Part J Gynecologic
with response rates of 15% to 20%.204,205 However, one of these
studies reported a gastrointestinal perforation rate of 11% in a
heavily pretreated population. A number of tyrosine kinase
inhibitors have been tested in the recurrent setting as single
agents with demonstrated response rates of 3% to 29%.27,206
These agents include cediranib (targets VEGF receptor and
c-Kit), sunitinib (targets VEGF receptor, c-Kit, PDGF receptor,
RET, and FLT-3), sorafenib (targets VEGF receptor, c-Kit, RAF,
and PDGF receptor-b), ENMD2076 (targets VEGF receptor and
aurora A), pazopanib (targets VEGF receptor, PDGF receptor,
and c-Kit), and cabozantinib (targets VEGF receptor and
c-MET). Cabozantinib had a 29% partial response rate in
patients with platinum-resistant or refractory ovarian cancer
and a 40% response rate in platinum-sensitive disease.207 A
randomized phase II study of nintedanib (BIBF 1120) with
activity against VEGF receptor, PDGF receptor, and fibroblast
growth factor receptor demonstrated a progression-free sur-
vival benefit in the maintenance setting, and a phase III study
in newly diagnosed patients is under way.
Emerging data is confirming the activity of PARP inhibitors
in select patients with recurrent ovarian cancer. This new class
of targeted therapy inhibits key enzymes involved in DNA
repair and has been shown to be particularly active in treating
cancers in BRCA mutation carriers. In the setting of BRCA defi-
ciency, PARP inhibition results in accumulation of double-
strand DNA breaks that are lethal to tumor cells through a
mechanism known as synthetic lethality. A substantial number
of patients with ovarian cancer have been found to have BRCA-
deficient tumors related to germline or somatic mutation, epi-
genetic silencing, or alteration in microRNA levels. Olaparib
has shown single-agent response rates ranging from 28% to
41% depending on dose and BRCA mutation status. In a recent
trial of 265 women with platinum-sensitive recurrent ovarian
cancer, olaparib resulted in a progression-free survival benefit
of 8.4 months compared to 4.8 months with placebo (HR 0.35,
95% CI 0.25 to 0.49).208 Further studies of PARP inhibitor
agents as single agents and in combination therapy are under
way in patients with platinum-sensitive and resistant disease.
Palliative Surgery
Secondary cytoreductive surgery with the intent of prolonging
survival may benefit a select subset of patients with a long dis-
ease-free interval, good performance status, and single or few
sites of recurrence.209 Palliative surgery may also be consid-
ered in women who present with symptomatic tumor masses
or intestinal obstruction. However, the risk of perioperative
mortality and re-obstruction is significant, and the patients
medical condition, performance status, and anticipated life
expectancy should be carefully considered before operative
intervention. For patients who are not surgical candidates,
percutaneous decompression and intravenous hydration with
consideration of palliative chemotherapy and/or hospice refer-
ral may be appropriate.
Palliative Radiation Treatment
Radiation therapy may be an effective palliative treatment
modality in settings where localized recurrences are caus-
ing significant symptoms that are unresponsive to systemic
therapy. Symptoms such as bleeding, pain, or obstruction in
the pelvis, groin, abdomen, or chest may be palliated with an
abbreviated course of radiation treatment. Clinical response
rates have been reported in the range of 70% to 100%, with
complete clinical response rates of 30% to 70% and a median
duration of 5 to 11 months.210213 Palliative radiotherapy is
effective even in patients heavily pretreated with systemic or
IP chemotherapy. Pain relief and cessation of bleeding are
achieved in >80% of patients, and symptoms from bowel or
ureteral obstruction in 65% to 75%.214 Radiation therapy deliv-
ered locally to symptomatic sites appears to be of significant
and durable benefit and should be considered for palliative
booksmedicos.org
purposes in select patients with symptomatic relapses, particu-
larly in those who are refractory to chemotherapy.
The role of salvage radiotherapy in select patients with iso-
lated pelvic recurrences has been suggested by several reports.
In a series by Firat and Erickson,215 28 patients with recurrent
or persistent disease involving the vagina and/or rectum
received palliative radiotherapy delivered by external-beam
radiotherapy, brachytherapy, or a combination of both.
Bleeding was controlled in all cases, and 79% achieved a com-
plete symptomatic response. Of the 21 patients with no evi-
dence of liver or extra-abdominal disease, 2-year survival was
57% compared to 0% for the 7 patients with liver and extra-
abdominal metastases at the time of radiotherapy. In the group
of 14 patients with pelvic-confined disease, 5 patients had
recurrences in the upper abdomen and 4 patients were long-
term survivors >5 years after radiotherapy administration. A
second study by Albuquerque et al.216 evaluated the outcomes
of 20 women treated with salvage radiotherapy for isolated
extraperitoneal recurrence. Most recurrences were in the pel-
vis, although 3 patients had regional nodal recurrences and 1
patient had an abdominal wall recurrence. The median delivered
dose to a tumor-directed volume was 50.4 Gy, and a brachyther-
apy boost was delivered in select cases. Local recurrence-free
survival at 2 years was 89% for patients with optimal debulking
prior to radiotherapy compared to 42% for patients with subop-
timal debulking or gross residual disease. The corresponding
disease-free survival rates at 3 years were 72% and 22%, and
overall survival rates at 5 years were 50% and 19%, respectively.
Given the exceptional local control rates, minimal toxicity, and
long-term survival, select patients with isolated extraperitoneal
recurrences may be appropriate candidates for salvage involved-
field radiation treatment.
Ovarian cancer metastatic to the brain is a rare occurrence
reported in <1% of patients in autopsy cases and in 2% of clini-
cal series.217,218 More recent series have suggested an increased
incidence as chemotherapy regimens have become more effec-
tive.218 Nonetheless, long-term prognosis is poor, as brain
metastases are often a late manifestation of advanced disease,
with a median survival time <12 months. In a series of 24
patients with metastatic brain disease treated with whole-brain
radiotherapy, stereotactic radiosurgery (SRS), or a combination
of whole-brain radiotherapy and SRS, median survival was 8.5
months. Patients with solitary metastatic lesions had signifi-
cantly improved survival compared to those with multiple
metastases of 17 months versus 6 months, respectively.219
Platinum sensitivity was also recently identified as an important
prognostic factor in women with metastatic brain involvement
from ovarian cancer. In an analysis of 4,277 women treated at
six German hospitals, 74 patients (1.7%) had clinical documen-
tation of brain metastases, of which 61 patients received radio-
therapy alone or in combination with surgical resection and
chemotherapy.220 On multivariate analysis, platinum sensitivity
(HR 0.23) and good performance status (HR 0.45) were associ-
ated with improved survival, whereas multiple lesions (HR 4.4)
and low tumor grade (HR 3.1) were associated with adverse
outcome. Although the extent of extracranial disease was not
associated with outcome in this study, it is unclear whether the
prognostic importance of platinum sensitivity was related to
control of intracranial or systemic disease.
RADIATION THERAPY TECHNIQUES
Whole-Abdominal Radiation Therapy
The clinical target volume for WAI includes the entire perito-
neum from the diaphragm to the pelvic floor, encompassing
both the visceral and parietal surfaces as well as the pelvic
and para-aortic nodes. Conventionally, large anterior and pos-
terior fields have been used. The simulation technique requires
attention to the excursion of the diaphragm at the superior
margin during respiration to ensure appropriate coverage. The

field should encompass the pouch of Douglas inferiorly as well
as the lateral extent of the peritoneal margins, which may be
located outside the pelvic brim in obese patients. Fluoroscopy
may be used to assess the range of quiet respiratory motion.
Alternatively, image fusion of CT scans obtained at inspira-
tion and expiration or throughout the respiratory cycle (four-
dimensional [4D] CT) may be used to design the treatment
fields. Extended source to skin distance may be required in
some patients to ensure adequate coverage. Organs at risk that
are dose limiting include the kidneys, liver, small and large
bowel, and bone marrow. Kidney doses are limited to 15 Gy
with customized blocking, and whole-liver tolerance is 30 Gy.
The standard whole-abdomen dose is 30 Gy delivered in 1.2-
to 1.5-Gy fractions. An additional boost may be delivered to
the pelvis and para-aortic lymph nodes to 45 to 50 Gy, depend-
ing on the clinical requirements. Patients will need to be moni-
tored for acute gastrointestinal and hematologic toxicity as well
as nutritional support.
The use of intensity-modulated radiation therapy (IMRT) to
deliver WAI has been proposed as a means to reduce the radia-
tion dose to the bone marrow and kidneys to decrease the inci-
dence of myelotoxicity and renal damage. Dosimetric analysis
has demonstrated improved planning target volume (PTV) cov-
erage and significant dose reductions to bones with equivalent
kidney sparing using dynamic multileaf collimator IMRT when
compared with conventional fields.221 The PTV receiving 95%
of the prescribed dose improved from 72% to 84%, and the
volume of pelvic bones receiving >21 Gy was reduced by a rela-
tive 60% from 86% to 35%. Dose inhomogeneity, however,
increased slightly, with small regions of underdosing near the
kidneys. Similar improvements in PTV dose coverage were
reported in a study using IMRT arc therapy.222 It remains to be
seen whether the dosimetric advantages gained from WAI-
IMRT will translate to a significant and clinically relevant ben-
efit. Furthermore, technical considerations must be considered
with great care given the complex anatomy and delineation of
the peritoneal cavity boundaries. Patient breathing motion and
setup uncertainties will also need to be addressed.
Intraoperative Radiation for Ovarian Cancer
Several studies have suggested that intraoperative radiation
therapy (IORT) as part of salvage surgery for locally recurrent
gynecologic cancers, including ovarian cancer, may improve
locoregional control and overall survival.223,224227 The larg-
est IORT retrospective study to date that reported results of
22 ovarian cancer patients treated with IORT (median dose,
12 Gy; range, 9 to 14 Gy) suggests that the addition of IORT
to cytoreductive surgery may potentially improve locoregional
control and achieve palliation in highly selected patients with
locally recurrent ovarian cancer.223 Various sites were treated,
most commonly the pelvic sidewall. Most patients received
additional treatment after IORT, including WAI, pelvic and/or
inguinal radiation, and chemotherapy. Locoregional control
was achieved in 68% of patients, with a median time to recur-
rence of 14 months and 5-year disease-free survival of 18%
and overall survival of 22%. Overall treatment-related grade
3 toxicities occurred in 41%. Bowel obstruction occurred in
seven patients, all of whom received postoperative WAI and
two of whom also had a component of locoregional relapse. No
long-term neurologic sequelae were reported.
SEQUELAE OF TREATMENT
Acute Toxicity
Acute toxicity from WAI is common but rarely severe. The use
of large radiation fields that encompass multiple abdominal
organs, including the liver, kidneys, gastrointestinal tract, blad-
der, spleen, lungs, and pancreas, contributes to the develop-
ment of predictable side effects. Gastrointestinal side effects are
the most common acute and subacute toxicities encountered
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Chapter 71 Ovarian and Fallopian Tube Cancer 1461
with WAI given the large volume of bowel within the treatment
field. Up to 75% of patients treated with WAI experience mild
to moderate diarrhea; severe diarrhea requiring hospitalization
and intravenous hydration is seen in 10% of patients. Limiting
bowel exposure through the use of shielding or appropriately
timed field reductions can minimize or prevent this toxicity.
Approximately 60% to 70% may also experience nausea, par-
ticularly early during treatment, although emesis occurs infre-
quently. Premedication with antiemetic therapy 30 to 60 minutes
prior to treatment may help to mitigate this side effect. Routine
intravenous hydration to prevent dehydration is also recom-
mended. Appetite loss accompanied by weight loss is a frequent
concern. It is thus essential to closely monitor and ensure proper
nutrition to avoid malnourishment and dehydration that may
result in hospitalization and treatment interruption.
Clinically significant liver damage is extremely rare with
appropriate shielding.228 Approximately 50% of patients will
Clinical Radiation Oncology
develop transiently elevated alkaline phosphatase levels; how-
ever, symptomatic hepatitis occurs in <1%.229 Hematologic tox-
icity including leukopenia and thrombocytopenia occurs in
10% to 20% of patients, although significant drops in blood
counts causing treatment interruption are rare. Splenic dam-
age may occur even at low radiation doses because of the
exquisite radiosensitivity of the spleen, resulting in transient
reduction in platelet counts.
Urethritis and bladder spasm from pelvic irradiation may
occur and should be treated symptomatically. Adequate and
careful shielding of the kidneys to limit the delivered dose to
<15 Gy is critical to minimize renal damage and failure. Stricture
of the ureters or urethra is rare, occurring in <1% of cases and is
usually not seen until 3 to 6 months postradiation. Because
treatment to the entire peritoneal cavity with adequate margins
requires extension of fields above the diaphragm, inclusion of
the lung bases bilaterally is required. Chest radiographs may
show fibrosis or bibasilar pneumonitis in 5% to 20% of patients
but is generally self-limited and rarely symptomatic.
Late Toxicity
Late toxicities were more common with the moving strip tech-
nique than with the open-field technique, primarily because
of the higher doses and hot spots that were generated. High
radiation doses can exceed normal organ tolerances, leading to
permanent organ damage and failure. Chronic gastrointestinal
damage (i.e., bloating, intermittent diarrhea) occurs in <5% of
treated patients. The overall incidence of bowel obstruction has
been reported to be 5% to 10% at 5 years in cases in which IP
32
P or WAI is used independently. Approximately 50% of these
patients who develop bowel obstructions will require surgical
intervention (incidence, 3% to 5%); however, recent data sug-
gest that this incidence may be higher and closer to 10% in
long-term survivors at 10 years.200 Bowel obstructions occur
more frequently with doses >45 Gy and in patients with gapped
or abutted split fields. In addition, adhesions in the peritoneal
cavity and the combination of additional pelvic radiation to 32P
or WAI may double the risk of significant bowel complications
up to 20% to 25%.170,176 As with most anatomic sites, escalating
doses of radiation come with an increase in rate and degree of
toxicity. Major bowel complications from 10 pooled series of
1,098 patients reported an incidence of 1.4% with abdominal
dose of 22.5 Gy compared with 14% with 30 Gy.229
MANAGEMENT OF GERM CELL TUMORS
In general, the presentation and management of nonepithelial
tumors are similar to those of their epithelial counterparts, as
patients usually experience vaginal bleeding, abdominal bloat-
ing, or pain and typically require surgical intervention and che-
motherapy. On presentation, routine workup is identical to that
for other ovarian cancers as outlined previously. Pretreatment
AFP and -hCG levels are of particular importance in diagnosis
1462 Section III Clinical Radiation Oncology Part J Gynecologic
TABLE 71.10 SERUM MARKERS FOR OVARIAN GERM CELL TUMORS
Tumor Type AFP hCG LDH
Dysgerminoma +/ + including stage I grade 2 and 3 immature teratoma, should be
Choriocarcinoma + treated with three cycles of BEP chemotherapy. Because of the
Endodermal sinus tumor + low number of diagnosed cases, large-scale studies comparing
Immature teratoma +/
Mixed germ cell tumor +/ +/ +/
Embryonal carcinoma +/ + peutic regimens in treatment for nonseminomatous testicular
Polyembryoma +/ + germ cell tumors has had a great impact on treatment in
AFP, -fetoprotein; hCG, human chorionic gonadotrophin; LDH, lactate dehydrogenase.
and treatment. An elevated -hCG with a normal AFP is
strongly suggestive of dysgerminoma. Lactate dehydrogenase
and CA-125 levels should also be drawn, as the germ cell
tumors may have several tumor markers that can be followed
(Table 71.10). Variations in surgical management and adjuvant
chemotherapy and radiation do exist among the nonepithelial
tumors, and treatments should consider the patients desire to
maintain fertility while offering the greatest chance for cure.
Most ovarian neoplasms diagnosed in children and adoles-
cents are germ cell tumors, with approximately two-thirds of
these tumors being malignant at the time of diagnosis. Germ
cell tumors comprise 20% of all ovarian neoplasms and 2% to
5% of all ovarian malignancies. The most common germ cell
tumor is the mature cystic teratoma (also the most common
ovarian neoplasm); however, fortunately only the minority con-
tain a malignancy or immature elements.
Dysgerminoma
Dysgerminoma is the most common of the malignant germ
cell tumors and also has the highest bilaterality rate (20%),
with 10% of the ovaries being grossly involved and 10% being
microscopically involved. As shown in Table 71.10, dysgermi-
nomas may secrete lactate dehydrogenase and have elevated
hCG levels. Most women with dysgerminomas receive a
diagnosis of early-stage disease, and 80% present before the
age of 30 years. In many instances, young women affected by
this disease wish to maintain fertility after therapy. The high
rate of contralateral disease confers a greater risk with conser-
vative surgical therapy.
Postoperative therapy for patients with dysgerminoma can
be separated into those women with stage I disease and those
with disease of a more advanced stage. Women with stage IA
disease following careful surgical staging can be monitored
closely without compromising cure. Approximately 15% to
25% of these women will experience a recurrence, although
successful salvage treatment with chemotherapy results in sur-
vival rates close to 100%. For women with more advanced
stage disease, chemotherapy with three to four cycles of BEP
(bleomycin, etoposide, and cisplatin) is recommended.231 In a
report from MD Anderson Cancer Center, >95% of the patients
with ovarian dysgerminoma were free from relapse at a
median of 7 years follow-up.230, Of the 16 women treated with
fertility-sparing surgery, 10 patients maintained menstrual
function during chemotherapy and 13 patients returned to
their prechemotherapy baseline. Five pregnancies were
reported, and two of the women had difficulty conceiving.
Dysgerminomas are unique in that they are exquisitely radio-
sensitive tumors. Radiotherapy may be considered for patients
who are not candidates for platinum-based chemotherapy. The
appropriate radiation dose for dysgerminoma is 25 Gy in 12 to
14 fractions with a boost of 10 Gy for gross residual disease.
However, radiotherapy will affect ovarian function and fertility,
which must be taken into consideration when recommending
adjuvant radiation therapy in a young patient.
Other Germ Cell Tumors
Nondysgerminomas are almost always unilateral. For apparent
early-stage disease, unilateral salpingo-oophorectomy appears
booksmedicos.org
to be as effective as more extensive surgery. Patients with
stage I grade 1 immature teratomas usually require no further
therapy after unilateral salpingo-oophorectomy. All others,
adjuvant therapy are uncommon.
Extrapolation of data regarding the efficacy of chemothera-
patients with nondysgerminoma ovarian germ cell tumors.
Patients with less well differentiated tumors and all those with
endodermal sinus tumor, embryonal carcinoma, choriocarci-
noma, or mixed germ cell tumors should receive adjuvant post-
operative chemotherapy. Various regimens have been used,
including VAC (vincristine, dactinomycin, and cyclophospha-
mide), PVC (cisplatin, vincristine, and cyclophosphamide), and
CVB (cyclophosphamide, vincristine, and bleomycin). The BEP
regimen was prospectively evaluated by the GOG in patients
with completely resected, surgically staged I, II, and III disease
and resulted in a 96% disease-free survival rate.232 NCCN guide-
lines recommend three to four courses of BEP as the standard
treatment for well-staged patients with resected ovarian germ
cell tumors. Six cycles of chemotherapy may be considered for
patients with gross residual or stage IV disease.
Management of Sex CordStromal Tumors
Sex cordstromal tumors derive from the intraovarian matrix
of mesenchymal and connective tissue elements that supports
the germ cells. The most common sex cordstromal tumors
are the granulosa cell tumors, derived from the sex cord cells
along with Sertoli cell tumors. The mesenchymal derivatives
include fibromas, thecal cell tumors, and Leydig cell tumors.
These tumors are responsible for <5% of all ovarian malignan-
cies but account for 90% of all functioning ovarian neoplasms.
One-third of the tumors will produce estrogen, progesterone,
testosterone, or other androgens. This hormonal expression
may lead to presenting signs and symptoms such as precocious
puberty, postmenopausal bleeding, hirsutism, or virilization.
Sex cordstromal tumors can develop in women of any age
(with the granulosa cell tumors having a bimodal age distribu-
tion) with a peak incidence in postmenopausal women around
50 years of age. These tumors typically behave in a benign
fashion with LMP. Surgery remains the mainstay of treat-
ment; however, occasionally, postoperative therapy is required,
although these tumors are considered relatively insensitive.
Adult granulosa cell tumors account for 95% of all granulosa
cell tumors. Most women are diagnosed after 30 years of age,
with a median age of 52 years. Abdominal pain, distention, and
vaginal bleeding are the most common signs and symptoms.
Because of the relative state of estrogen excess produced by
these tumors, 25% of women will also have concomitant endo-
metrial pathology, such as hyperplasia or adenocarcinoma.233
These tumors tend to be large with an average diameter of
12 cm. If a granulosa cell tumor is suspected preoperatively,
inhibin A and B levels may be elevated and useful in narrowing
the differential diagnosis. Ninety percent of patients present
with stage I disease, and the tumors are typically unilateral in
90% of cases. Stage is the most important prognostic factor for
granulosa cell tumors; other factors include tumor rupture,
stage IC disease, poorly differentiated tumor, and tumor size
>10 to 15 cm. The 10-year survival for women with stage I dis-
ease is approximately 90%, with 15% to 25% of stage I patients
ultimately suffering a disease recurrence. The 10-year survival
for women with advanced-stage disease is 26% to 49%.
Juvenile granulosa cell tumors are rare, although they
account for 90% of the granulosa cell tumors that occur in pre-
pubertal girls and women <30 years of age.234 Similar to the
adult form, the juvenile tumors may also secrete estrogen;
therefore, the prepubertal girls may present with isosexual

precocious puberty. This may be the most dramatic presenta-
tion; however, the most common presentation is that of an
abdominal mass. As with the adult variant, the juvenile variant
is rarely bilateral, with bilaterality occurring in only 5% of
cases. More than 90% of cases will be stage I at the time of
diagnosis, and other prognostic factors apply as with the adult
variant. The 5-year survival rate is 95%, and the prognosis
remains poor with advanced-stage or recurrent disease.
Most granulosa cell tumors are unilateral and can be treated
with fertility-preserving therapy consisting of unilateral sal-
pingo-oophorectomy and appropriate surgical staging. Given
the rarity of pelvic and para-aortic nodal involvement, lymph-
adenectomy may be omitted. Endometrial sampling should be
performed in all women retaining their uterus, as these tumors
may be associated with concomitant hyperplasia or adenocarci-
noma. In women not wishing to preserve fertility or those who
are postmenopausal, complete hysterectomy with bilateral sal-
pingo-oophorectomy is the procedure of choice. Surgery alone
is typically curative. However, risk factors for relapse that
should be considered in adjuvant treatment for stage 1 disease
include tumor rupture, stage IC disease, poorly differentiated
tumor, and tumor size >10 to 15 cm. Adjuvant treatment options
for high-risk stage I and advanced-stage disease include obser-
vation, radiation therapy for localized disease, and BEP chemo-
therapy. Inhibin levels, if initially elevated, may be a useful
tumor marker for surveillance of patients under observation.235
FUTURE DIRECTIONS
Ovarian cancer represents a spectrum of distinct disease pro-
cesses, ranging from noninvasive borderline tumors to dissem-
inated high-grade serous carcinomas. The cell of origin may
be extraovarian in a large proportion of cases, as many high-
grade serous carcinomas appear to originate in the distal fallo-
pian tube. Clear cell, endometrioid, and mucinous cancers may
arise from metaplastic transformation of the OSE, although an
extraovarian origin has been proposed. Recent insights from
molecular and genomic studies also support the concept of
distinct biologic subtypes of ovarian cancer. Gene expression
profiling has revealed greater similarity between ovarian clear
cell carcinoma and renal clear cell carcinoma than other ovar-
ian subtypes.236 High-grade serous carcinoma shares genomic
and transcriptional features with the basal subtype of breast
cancer, characterized by a BRCA-deficient phenotype.23 Driver
mutations that activate the PI3 kinase signaling pathway and
mutations in the tumor suppressor ARID1A have been iden-
tified in endometrioid and clear cell ovarian cancers, which
share a strong epidemiologic link with endometriosis.
The recognition of distinct ovarian cancer subtypes has
implications for prevention, early detection, clinical trial design,
and the identification of new therapeutic targets, particularly
for advanced stage and recurrent disease. Results from the
large screening trials of postmenopausal women in the United
States, United Kingdom, and Japan using CA-125 and TVUS do
not at present support routine screening for ovarian and fallo-
pian tube cancer in the general population. Future screening
strategies may focus on women at greatest genetic risk by high
throughput sequencing and mutation testing. Genome-wide
association studies have recently identified new ovarian cancer
risk loci.237,238 Novel screening strategies will also be needed to
detect precursor lesions within the fallopian tube, particularly
for high-grade serous carcinomas. It is not yet known whether
prophylactic salpingectomy without removal of the ovaries is an
acceptable prevention strategy for premenopausal women with
familial ovarian cancer syndromes. Clinical trials will soon
incorporate targeted therapies with blood and imaging bio-
markers to assess pathway inhibition and accurately measure
disease response. Trial end points should also include robust
quality-of-life tools to assess the effect of palliative chemother-
apy on symptom control as well as evaluation of its toxicity.
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Chapter 71 Ovarian and Fallopian Tube Cancer 1463
Although no longer used in the initial management of ovarian
cancer, the role of radiation therapy in palliation remains of
significant importance for symptomatic recurrence, particularly
for women with chemotherapy-refractory disease.
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180. Greer BE, Bundy BN, Ozols RF, et al. Implications of second-look laparotomy
in the context of optimally resected stage III ovarian cancer: a non-randomized
comparison using an explanatory analysis: a Gynecologic Oncology Group study.
Gynecol Oncol 2005;99(1):7179.
181. Van der Burg ME, van Lent M, Buyse M, et al. The effect of debulking surgery
after induction chemotherapy on the prognosis in advanced epithelial ovarian
cancer. Gynecological Cancer Cooperative Group of the European Organization
for Research and Treatment of Cancer. N Engl J Med 1995;332(10):629634.
182. Rose PG, Nerenstone S, Brady MF, et al. Secondary surgical cytoreduction for
advanced ovarian carcinoma. N Engl J Med 2004;351(24):24892497.
183. Vergote I, Trope CG, Amant F, et al. Neoadjuvant chemotherapy or primary sur-
gery in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363(10):943953.
184. Chemotherapy for advanced ovarian cancer. Advanced Ovarian Cancer Trialists
Group. Cochrane Database Syst Rev 2000;(2):CD001418.
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185. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin com-
pared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian
cancer. N Engl J Med 1996;334(1):16.
187. Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in
combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase
3, open-label, randomised controlled trial. Lancet 2009;374(9698):13311338.
188. Vasey PA, Jayson GC, Gordon A, et al. Phase III randomized trial of docetaxel-
carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian
carcinoma. J Natl Cancer Inst 2004;96(22):16821691.
189. Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new platinum-based
treatment regimens in advanced-stage ovarian cancer: a phase III trial of the
Gynecologic Cancer Intergroup. J Clin Oncol 2009;27(9):14191425.
190. Burger R, Brady M, Bookman M, et al. Incorporation of bevacizumab in the pri-
mary treatment of ovarian cancer. N Engl J Med 2011;365(26):24732483.
191. Perren T, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian
cancer. N Engl J Med 2011;365(26):24842496.
192. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel
in ovarian cancer. N Engl J Med 2006;354(1):3443.
193. Jaaback K, Johnson N. Intraperitoneal chemotherapy for the initial manage-
ment of primary epithelial ovarian cancer. Cochrane Database Syst Rev 2006;
(1):CD005340.
197. Pickel H, Lahousen M, Petru E,, et al. Consolidation radiotherapy after carbopla-
tin-based chemotherapy in radically operated advanced ovarian cancer. Gynecol
Oncol 1999;72(2):215219.
198. Sorbe B. Consolidation treatment of advanced (FIGO stage III) ovarian carcinoma
in complete surgical remission after induction chemotherapy: a randomized,
controlled, clinical trial comparing whole abdominal radiotherapy, chemother-
apy, and no further treatment. Int J Gynecol Cancer 2003;13(3):278286.
199. Dinniwell R, Lock M, Pintilie M, et al. Consolidative abdominopelvic radiotherapy
after surgery and carboplatin/paclitaxel chemotherapy for epithelial ovarian
cancer. Int J Radiat Oncol Biol Phys 2005;62(1):104110.
200. Petit T, Velten M, dHombres A, et al. Long-term survival of 106 stage III ovarian
cancer patients with minimal residual disease after second-look laparotomy and
consolidation radiotherapy. Gynecol Oncol 2007;104(1):104108.
202. Rustin GJ, van der Burg ME, Griffin CL, et al. Early versus delayed treatment of
relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet
2010;376(9747):11551163.
203. Aghajanian C, Finkler N, Rutherford T, et al. OCEANS: a randomized, double-
blinded, placebo-controlled phase III trial of chemotherapy with or without beva-
cizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian
(EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC). J Clin Oncol
2011;29(Suppl):LBA5007.
206. Horowitz N, Matulonis UA. New biologic agents for the treatment of gynecologic
cancers. Hematol Oncol Clin North Am 2012;26(1):133156.
207. Vergote I, Sella A, Bedell C, et al. Phase II study of XL184 in a cohort of ovarian
cancer patients with measurable soft tissue disease. Proceedings of the 22nd
EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics
conference, Berlin, Germany, November 18, 2010.
208. Ledermann J, Harter P, Gourley C, et al. Phase II randomized placebo-controlled
study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous
ovarian cancer. J Clin Oncol 2011;29(Suppl):5003.
209. Hauspy J, Covens A. Cytoreductive surgery for recurrent ovarian cancer. Curr
Opin Obstet Gynecol 2007;19(1):1521.
210. Gelblum D, Mychalczak B, Almadrones L, et al. Palliative benefit of external-
beam radiation in the management of platinum refractory epithelial ovarian car-
cinoma. Gynecol Oncol 1998;69(1):3641.
211. May LF, Belinson JL, Roland TA. Palliative benefit of radiation therapy in
advanced ovarian cancer. Gynecol Oncol 1990;37(3):408411.
212. Tinger A, Waldron T, Peluso N, et al. Effective palliative radiation therapy in
advanced and recurrent ovarian carcinoma. Int J Radiat Oncol Biol Phys 2001;
51(5):12561263.
213. Corn BW, Lanciano RM, Boente M, et al. Recurrent ovarian cancer: effective radio-
therapeutic palliation after chemotherapy failure. Cancer 1994;74(11):29792983.
215. Firat S, Erickson B. Selective irradiation for the treatment of recurrent ovarian
carcinoma involving the vagina or rectum. Gynecol Oncol 2001;80(2):213220.
218. Albuquerque KV, Singla R, Potkul RK, et al. Impact of tumor volume-directed
involved field radiation therapy integrated in the management of recurrent ovar-
ian cancer. Gynecol Oncol 2005;96(3):701704.
219. Ratner ES, Toy E, OMalley DM, et al. Brain metastases in epithelial ovarian and
primary peritoneal carcinoma. Int J Gynecol Cancer 2009;19(5):856859.
220. Sehouli J, Pietzner K, Harter P, et al. Prognostic role of platinum sensitivity in
patients with brain metastases from ovarian cancer: results of a German multi-
center study. Ann Oncol 2011;21(11):22012205.
221. Hong L, Alektiar K, Chui C, et al. IMRT of large fields: whole-abdomen irradia-
tion. Int J Radiat Oncol Biol Phys 2002;54(1):278289.
222. Duthoy W, De Gersem W, Vergote K, et al. Whole abdominopelvic radiotherapy
(WAPRT) using intensity-modulated arc therapy (IMAT): first clinical experience.
Int J Radiat Oncol Biol Phys 2003;57(4):10191032.
223. Yap OW, Kapp DS, Teng NN, et al. Intraoperative radiation therapy in recurrent
ovarian cancer. Int J Radiat Oncol Biol Phys 2005;63(4):11141121.
229. Thomas GM, Dembo AJ. Integrating radiation therapy into the management of
ovarian cancer. Cancer 1993;71(4 Suppl):17101718.
230. Brewer M, Gershenson DM, Herzog CE, et al. Outcome and reproductive function
after chemotherapy for ovarian dysgerminoma. J Clin Oncol 1999;17(9):26702675.
231. Williams SD, Blessing JA, Hatch KD, et al. Chemotherapy of advanced dysgermi-
noma: trials of the Gynecologic Oncology Group. J Clin Oncol 1991;9(11):19501955.
232. Williams S, Blessing JA, Liao SY, et al. Adjuvant therapy of ovarian germ cell
tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic
Oncology Group. J Clin Oncol 1994;12(4):701706.
236. Zorn KK, Bonome T, Gangi L, et al. Gene expression profiles of serous, endome-
trioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res
2005;11(18):64226430.
237. Bolton KL, Tyrer J, Song H, et al. Common variants at 19p13 are associated with
susceptibility to ovarian cancer. Nat Genet 2010;42(10):880884.
238. Song H, Ramus SJ, Tyrer J, et al. A genome-wide association study identifies a new
ovarian cancer susceptibility locus on 9p22.2. Nat Genet 2009;41(9):9961000.

Chapter 72
Vaginal Cancer
Josephine Kang and Akila N. Viswanathan
Primary vaginal cancer is a rare malignancy, constituting
1% to 2% of all gynecologic malignancies. According to the
American Cancer Society estimates for 2010, there were
approximately 2,300 new cases and 780 deaths from this
disease.1 The majority of malignant lesions in the vagina
are metastatic from other gynecologic malignancies or
involve direct extension from adjacent sites, which excludes
diagnosis as a primary vaginal malignancy. According to
the staging system set by the International Federation of
Obstetrics and Gynecology (FIGO), a diagnosis of primary
vaginal cancer excludes any tumors involving the cervix or
vulva.2 According to one study of 141 vaginal carcinoma
cases, only 26% met the criteria of being a primary vaginal
cancer,3 defined as a lesion that arises in the vagina without
involving the cervix or vulva.
The majority of primary vaginal malignancies are squa-
mous cell carcinomas (SCC). According to a National Cancer
Data Base (NCDB) report4 based on 4,885 patients with pri-
mary vaginal cancer registered from 1985 to 1994, approxi-
mately 92% of patients were diagnosed with in situ or invasive
SCC or adenocarcinomas, 4% with melanomas, 3% with sarco-
mas, and 1% with other or unspecified types of cancer. Sixty-six
percent of all vaginal cancers were invasive, with SCC repre-
senting 79% of all invasive cases.
The peak incidence of primary vaginal cancer is in the
sixth and seventh decades of life. According to data from the
Surveillance, Epidemiology, and End Results (SEER) program,1
2,149 women in the United States were diagnosed with pri-
mary vaginal cancer from 1990 to 2004. The mean age at
diagnosis was 65.7 14.3 years and incidence rates increased
with age. Vaginal cancer incidence is increasing in younger
women, possibly due to an increase in human papilloma virus
(HPV) infection or other sexually transmitted diseases.
However, there has been an overall decrease in the incidence
of primary vaginal tumors, possibly attributable to earlier
detection and to implementation of strict exclusion criteria in
the FIGO staging system. At the same time, there has been a
steady increase in the diagnosis of vaginal intraepithelial neo-
plasia (VAIN) over the past several decades, due to expanded
cytologic screening and increased awareness.5 Due to infre-
quent presentation, treatment recommendations are based on
results from relatively small retrospective series, the majority
of which are based on heterogeneous patient populations and
treatments.
ANATOMY
The vagina is a fibromuscular tube that extends from the cer-
vix down to the vestibule, or cleft, between the labia minora
(Fig. 72.1). It lies dorsal to the urethra and bladder base and
ventral to the rectum. Superiorly, it joins the uterine cervix at
an angle and, as a result, the posterior vaginal wall is longer
than the anterior wall, with an overall average length of 7.5
cm. The upper aspect of the posterior vaginal wall is separated
from the rectum by a reflection of peritoneum, the pouch of
Douglas. The cervix projects into the upper lumen of the vagina,
creating invaginations between the vaginal mucosa and the cer-
vix, which are termed the anterior, posterior, and lateral fornices.
Inferiorly, the vagina extends through the urogenital diaphragm
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Chapter 72 Vaginal Cancer 1465
and lies directly adjacent to the rectum up to where the fibro-
muscular perineal body tissue separates the vagina from the anal
canal. Laterally, the vagina is adjacent to the pelvic fascia and
levator ani muscles. At the introitus, the vagina has a perforated
fold of thin connective tissue and mucous membrane known as
the hymen.
The vaginal wall is composed of three layers: the mucosa,
muscularis, and adventitia. The inner lining of the vagina is
Clinical Radiation Oncology
formed by a nonkeratinizing stratified squamous epithelium
overlying a basement membrane with many papillae. The epi-
thelium lacks glandular structures and instead receives lubri-
cation from mucous secretions originating in the cervix.
Underneath the mucosa is connective tissue composed of elas-
tin and a thick muscularis layer composed of two layers of
smooth muscle. The inner layer is arranged circularly,
whereas the outer layer is arranged longitudinally. This mus-
cular layer is covered by a thin adventitia that merges with
neighboring organs. At the vaginal introitus, skeletal muscle
forms a sphincter.
Proximally, the vagina is supplied by the vaginal artery,
which arises from the cervical branch of the uterine artery
and runs lateral to the vagina until it anastomoses with
the inferior vesical and middle rectal arteries. The venous
plexus runs parallel to the arteries, draining into the inter-
nal iliac vein. The vaginal vault is innervated by the lumbar
plexus and pudendal nerve, with branches from sacral roots
2 to 4.6
The vagina has a complex, extensive network of lymphatic
drainage, with vessels that course through the submucosal and
muscularis layer. The uppermost portion drains primarily via
cervical lymphatics. The superior anterior vagina drains along
cervical channels to the interiliac and parametrial nodes, and
the posterior upper vagina drains into the inferior gluteal, pre-
sacral, and anorectal nodes (Fig. 72.2). The inferior aspect of
the vagina drains into the inguinal and femoral nodes and ulti-
mately to the pelvic nodes, following drainage patterns of the
vulva. Lesions in the midvagina have been shown to drain
either way.7 Lesions infiltrating the rectovaginal septum may
spread to the pararectal and presacral nodes. There are mul-
tiple interconnections between lymphatic channels, and pat-
tern of drainage cannot be reliably predicted based on location
of the primary tumor. Embryologically, the vagina is believed to
be of dual origin, with the upper third derived from the uterine
canal, while the lower two-thirds are derived from the uro-
genital sinus.8
EPIDEMIOLOGY, PRESENTATION,
AND GENERAL MANAGEMENT
Vaginal Intraepithelial Neoplasia
Epidemiology
Incidence of VAIN is estimated to be 0.2 to 0.3 cases per
100,000, with peak incidence between 40 and 60 years of
age.5,9,10 Most studies do not report differences in mean age
between women with low-grade and those with high-grade
VAIN,1115 although a few series have reported that patients
with VAIN-1 or -2 were younger than patients with VAIN-3.1619
Incidence of in situ vaginal cancer is estimated to be 0.1 per
1466 Section III Clinical Radiation Oncology Part J Gynecologic

Suspensory
ligament of ovary
Broad ligament
of uterus

Round ligament
of uterus
Visceral pelvic
fascia
Vesicouterine
pouch Rectouterine
fold and pouch
Pubic symphysis
Sigmoid colon
Urethra
Levator ani
Cervix
Rectum
Anal canal

Vesicouterine
pouch Posterior vaginal
fornix
Bladder Rectouterine
pouch
(peritoneal
Pubovesical cavity)
ligament
External os
Pubic of uterus
symphysis
Anterior
FIGURE 72.1. Median section of the female pelvis. The vaginal
vagina is a fibromuscular tube situated posterior to the blad- Clitoris
der and urethra and anterior to the rectum. The anterior fornix
and posterior fornices are formed by protrusion of the cer- Vestibule
vix into the vaginal canal. (From Moore KL. Clinical oriented of vagina Minor
anatomy, 4th ed. Baltimore: Lippincott Williams & Wilkins, labium
Vagina Major
1999, with permission.)

100,000 women, with peak incidence between ages 70 to 79,
according to data from the U.S. Centers for Disease Control and
Preventions National Program of Cancer Registries, and the
National Cancer Institutes SEER program.20 Risk factors for
VAIN include low sociocultural level, history of genital warts,
hysterectomy at an early age, history of cervical intraepithelial
neoplasia, immunosuppression, prior pelvic radiation, smok-
ing, exposure to diethylstilbestrol (DES), and history of sexu-
ally transmissible diseases (STDs) or HPV infection.15,17,21,22
The diagnosis of VAIN is associated with prior or concur-
rent neoplasia elsewhere in the lower genital tract. Multiple
series suggest approximately 50% to 90% of patients with VAIN
have concurrent or prior history of intraepithelial neoplasia or
carcinoma of the cervix or vulva.9,16,17 Immunosuppression
from human immunodeficiency virus (HIV) is also a risk factor
for both VAIN and HPV, although a higher incidence of invasive
vaginal cancer in infected women has not been demon-
strated.2325 The role of pelvic radiation in the development of
secondary vaginal neoplasia is unclear, with conflicting data
suggesting a history of ionizing radiation may predispose to
VAIN or vaginal cancer after a latency period of many
years.12,26,27 In utero exposure to DES may double the risk of
VAIN, thought to be due to transformation zone enlargement,
increasing the risk of HPV infection.28
Natural History
Although the likelihood of VAIN progressing to invasive dis-
ease is not fully understood, several clinical series have dem-
onstrated a significant increase in risk of invasive vaginal
cancer after a diagnosis of VAIN.12,16,29,30 Similar risk factors
for VAIN and invasive vaginal cancer, as well as the younger
average age at presentation of VAIN compared with invasive
disease, add support to the theory that VAIN may be a precur-
sor lesion to invasive SCC. In one series, 23 patients with VAIN,
with a mean age of 41 years, were followed for at least 3 years
without treatment;16 this included multifocal lesions as well as
lesions associated with cervical intraepithelial neoplasia (CIN)
or vulvar dysplasia. Two cases (9%) progressed to invasive can-
cer; one patient had VAIN-1 and progressed to stage I vagi-
nal carcinoma in 5 years, and the second patient had VAIN-3
and progressed to stage I vaginal carcinoma in 4 years. The
overall spontaneous regression rate was 78%, with the major-
ity (78%) occurring in patients with VAIN-1 or -2. Similarly,
several additional studies have demonstrated a range of 2%

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 Chapter 72 Vaginal Cancer 1467

Posterior wall of abdomen and inguinal region

Superficial lymph vessels to

axillary nodes Abdominal aorta
Right suprarenal node Diaphragm
Right lumbar trunk Cisterna chyli
Intestinal trunk
Left lumbar trunk

Renal lymph vessels

Right ovarian artery and vein
Ovarian lymph vessels to Superior mesenteric artery
lumbar nodes Left lumbar nodes
Inferior mesenteric artery
and nodes

Clinical Radiation Oncology

Right lumbar nodes
Left colic lymph vessels
Superficial lymph vessels to
inguinal nodes
Right common iliac
artery and nodes Medial common iliac node
External iliac nodes

Internal iliac artery

and node

Obturator node
Superficial inguinal
nodes
Uterine artery and node
Deep inguinal nodes
Superficial subinguinal
nodes
Deep femoral lymph
vessels

Superficial lymph vessels

FIGURE 72.2. Lymphatic drainage of the vagina to the inguinal and pelvic lymph nodes. (Asset provided by the Anatomical Chart Company.)

to 20% of patients with VAIN progressing to invasive vaginal
cancer.12,16,29,3133
The rate of occult invasive disease in patients with VAIN-3
has been reported to be as high as 28%.34 The risk of malig-
nant transformation in VAIN-1 and -2 is less clearly elucidated;
there have been reports of patients with low-grade VAIN sub-
sequently developing invasive vaginal carcinoma.14,15
Pathology
VAIN is defined as the presence of squamous cell atypia with-
out evidence of invasion (Fig. 72.3). VAIN is further classified
according to depth of epithelial involvement, with involvement
of the lower one-third, two-thirds, and greater than two-thirds
of the epithelium classified as VAIN-1, -2 and -3, respectively.
Carcinoma in situ encompasses the full epithelial thickness
and is included under VAIN-3. Excluded from diagnosis of
VAIN is the presence of glandular intraepithelial dysplasia or
atypical vaginal adenosis; these entities are associated with
in utero DES exposure and are deemed to be precursors of
DES-associated clear cell adenocarcinoma.35 VAIN is frequently
multifocal and most commonly involves the upper portion of
the vagina.
Histopathologically, most lesions are epidermoid and
exhibit full-thickness alterations with atypical mitoses and
hyperchromatism (Fig. 72.3).36 Punctation and mosaic patterns
are often noted with high-grade VAIN.14 Most lesions are multi-
focal and can involve all surfaces of the vagina, although the
superior one-third of the vagina is most common.12,16
VAIN is associated with HPV infection.37 A review of 232
published VAIN cases documented a high prevalence of HPV
using polymerase chain reaction or hybrid capture assays for
detection, with 98.5% and 92.6% of VAIN-1 and VAIN-2 or -3
cases positive for HPV.38 A series by Sugase and Matsukura39
examining 71 biopsy specimens of VAIN found HPV in 100% of

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1468 Section III Clinical Radiation Oncology Part J Gynecologic

A B

FIGURE 72.3. Normal vaginal epithelium (A), vaginal intraepithelial neoplasia (VAIN)-2 (B)
and VAIN-3 (C). Compared with normal vaginal mucosa, VAIN lesions display architectural
and cytologic abnormalities, such as nuclear hyperchromasia, pleomorphism, undifferentiated
cells scattered within the epithelium, and cellular crowding. In VAIN-3, dysplastic cells involve
C the full epithelial thickness without stromal invasion. (Courtesy of Marisa R. Nucci and Carlos
Parra-Herran.)

samples. Fifteen different known subtypes were identified
(HPV-16, -18, -30, -31, -35, -40, -42, -43, -51, -52, -53, -54, -56,
-58, -66). Types HPV-16 or -18 comprised 9%, 7%, and 67% of
VAIN-1, -2, and -3 cases, respectively.
Clinical Presentation
VAIN is usually asymptomatic12 and most commonly
detected after cytologic evaluation as part of surveillance
in patients with a history of CIN or invasive cervical carci-
noma. According to the American Cancer Society guidelines
from 2002, surveillance cytology for VAIN in posthysterec-
tomy patients is recommended if there is a history of cervi-
cal pathology.40 However, evidence does not support routine
surveillance in patients without a history of CIN or invasive
cervical cancer.
Prognostic Factors
A study by So et al.41 on 48 women with VAIN reports a signifi-
cant association between higher viral load of HPV and the like-
lihood of persistent disease after treatment. There is also an
association between a history of pelvic radiation and develop-
ment of VAIN,33,42,43 with up to 20% of patients with prior radi-
ation developing vaginal dysplasia. A retrospective review of
33 patients with VAIN treated at the University of Pennsylvania
found patients with a history of radiation therapy to be more
refractory to treatment, with a significantly higher likelihood of
recurrence after surgical and ablative therapy.31 Patients with
a history of radiation had an odds ratio of 3.6 for recurrent
disease (95% confidence interval, 1.5 to 9.0) compared with
patients without a history of radiation.
Treatment Options
The management of VAIN is heterogeneous, with a wide
variety of treatments available. There is currently no con-
sensus on optimal treatment modality, as reported data are
generally retrospective and based on decades of experience
with varied treatments and patient characteristics; thus it
is difficult to compare different treatment modalities (Table
72.1). Treatment approaches include local excision, partial
or total vaginectomy, laser vaporization, electrocoagulation,
topical 5% fluorouracil (5-FU) administration, and radia-
tion.14,15,1719,47,54,64,66,67 Reported success rates for different
approaches range from 48% to 100% for laser vaporiza-
tion,50,68,69 52% to 100% for colpectomy,34,47,51 75% to 100%
for topical 5-FU,53,54,55,56,70,71,72,73 and 83% to 100% for radia-
tion.61,62,65,67,74 Given the breadth of available therapies, an
individualized approach to patient management is advised,
with consideration given to the patients overall health, desire
to preserve sexual function, candidacy for surgery, disease
multifocality, and prior treatment failures.
Most patients with VAIN-1 are offered close surveillance.
Lesions often regress spontaneously; in one study by Aho
et al.,16 78% of patients with VAIN-1 or -2 had spontaneous
regression of disease without treatment. Appropriate treatment
for VAIN-2 should be determined on an individual basis, based
on disease extent and associated patient factors. Therapy for

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 Chapter 72 Vaginal Cancer 1469

TABLE 72.1 LOCAL CONTROL OF VAGINAL INTRAEPITHELIAL NEOPLASIA BY TREATMENT MODALITY

Series (Reference) Year Number of Patients Recurrence (%) Follow-Up Treatment Notes
Surgery
Benedet and Sanders (44) 1984 136 25 >5 yr WLE, PV, TV
Lenehan et al. (12) 1986 19 16 5112 mo PV, TV
Ireland and Monaghan (45) 1988 25 4 3 mo11 yr PV, TV
Hoffman et al. (34) 1992 32 17 673 mo PV; 28% invasive cancer
Fanning et al. (46) 1999 15 0 1.8 yr PV; 6.6% invasive cancer
Cheng et al. (9) 1999 35 34 1124 mo WLE
Dodge et al. (15) 2001 13 0 >7 mo PV
Indermaur et al. (47) 2005 105 12 29 mo PV, 12% invasive cancer
Laser Therapy
Jobson and Homesley (48) 1983 24 17 627 mo
Audet-LaPoint et al. (49) 1990 32 28 785 mo 3.8% invasive cancer at
excision 3 of 11 w/invasive
cancer at recurrence
Hoffman et al. (50) 1991 26 42 2.2 yr (mean)

Clinical Radiation Oncology

Diakomanolis et al. (51) 1996 25 32 3582 mo
Campagnutta et al. (52) 1999 39 23 1390 mo
Dodge et al. (15) 2001 42 38 >7 mo
Topical 5-FU
Woodruff et al. (53) 1975 9 11 37 yr 1%2% 5-FU every mo
Petrilli et al. (54) 1980 15 20 260 mo BID 5 d
Kirwan and Naftalin (55) 1985 14 7 442 mo Every week 10 wk
Krebs (56) 1989 37 19 1284 mo Every week 10 wk
Audet-Lapointe et al. (49) 1990 12 17 942 mo Every d 5 d
Dodge et al. (15) 2001 22 59 >7 mo
Topical Imiquimod
Buck and Guth (57) 2003 56 14 0.25 g every wk 3 wk
Diakomonolis et al. (58) 2002 3 See note 3 weekly 8 wk
3 pts with high-grade disease,
therapy revealed regres-
sion to VAIN1 (n = 2) or
cure (n = 1)
Radiation
Prempree et al. (59) 1977 7 0 ICB 7080 Gy
Chyle et al. (60) 1996 37 17 ICB or orthovoltage radiation
MacLeod et al. (61) 1997 14 14 46 mo (mean) HDR-ICB, 3445 Gy to vaginal
surface, 410 fx
Ogino et al. (62) 1998 6 0 13153 mo HDR-ICB, mean dose 23.3 Gy
Perez et al. (63) 1999 20 6 ICB 6070 Gy
Graham et al. (64) 2007 22 14 77 mo MDR-ICB, 48 Gy to point Z
Blanchard et al. (65) 2011 28 7 79 mo LDR, 60 Gy to 5 mm below
(median) mucosa
WLE, wide local excision; PV, partial vaginectomy; TV, total vaginectomy; ICB, intracavitary brachytherapy; HDR, high-dose rate; MDR,
medium-dose rate; LDR, low-dose rate.

VAIN-3 should be more aggressive, as there is a higher likeli-
hood of progression to invasive disease, including occult inva-
sive disease.34,47
Surgical and Ablative Therapies
Surgical approaches include local excision, partial vaginectomy,
and, in rare cases, total vaginectomy for highly extensive dis-
ease, which provides the advantage of obtaining a complete
pathologic diagnosis. Most resections can be performed through
a transvaginal approach. Location of VAIN in the vaginal vault
or posthysterectomy suture recesses may require partial vagi-
nectomy for complete resection.
Local therapy is achieved through a cold-knife approach,
electrosurgical loop excision, laser, or via ultrasonic surgical
aspiration.7577 The carbon dioxide laser has been used for
ablation of local tissue, with multiple treatments required in
approximately one-third of patients.49,50,52,56,69,78,79 Complications
include postoperative pain, scarring, and bleeding; however,
the treatment is overall fairly well tolerated, with minimum
impact on sexual function.80 Diakomanolis et al.51 reported on
52 patients who underwent laser treatment or partial vaginec-
tomy and found results to favor laser ablation for multifocal
disease and partial vaginectomy for unifocal disease. Ultrasonic
surgical aspiration is another technique that has shown efficacy
similar that of to laser ablation; in one series of 110 patients,
1-year recurrence-free survival rates were 24% and 26%,
respectively.47
Series on surgical treatment of VAIN report recurrence rates
in the range of 0% to 50%, with follow-up times ranging from
3 months to 18 years.9,12,17,34,44 Overall, series looking specifi-
cally at upper vaginectomy report control rates of 68% to
88%.19,29,34,47,51 For example, Hoffman et al.34 reported that 83%
of patients with VAIN-3 remained free of disease with a mean
follow-up time of 38 months. Of note, 28% of all patients were
found to have occult invasive disease upon upper vaginectomy.
A subsequent study by Indermaur et al.,47 which retrospectively
reviewed 36 patients treated with upper vaginectomy for VAIN,
reported 88% to be free of recurrence with a mean follow-up
time of 25 months. Thirteen patients (12%) were found to have
invasive cancer; 8 of 13 had frank invasive disease, while 5
patients had microinvasive carcinoma. Complication rates of
upper vaginectomy have been variably reported; in the series
by Indermaur et al.,47 there was a 9% complication rate.
Potential complications from surgery depend on the extent and

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1470 Section III Clinical Radiation Oncology Part J Gynecologic
method of surgical resection, and they range from vaginal
shortening and stenosis to standard postoperative morbidity
associated with abdominal procedures. It should be noted that
patients with a history of radiation treatment are at higher risk
of postoperative complications, with a higher rate of fistula
formation reported in one study.9
Topical Treatments
Topical therapies have been utilized in patients with early-stage
lesions, multifocal disease, or multiple comorbidities, render-
ing them nonideal surgical candidates. Topical applications
have also been utilized prior to surgery to reduce lesion size
and improve stripping of neoplastic epithelial cells from under-
lying stroma.17 Treatments include topical 5-FU and 5% imiqui-
mod cream, with response rates in 71% to 78% of patients
for imiquimod and 41% to 88% for 5-FU.53,55,56,57,58,67,71,72,81,82
Imiquimod increases levels of interferon-alfa, interleukin-12,
and tumor necrosis factor,58 resulting in immunomodulation of
the vaginal mucosa. Side effects of topical treatments include
local irritation, with burning and ulceration being the most
commonly reported adverse events.53,71
Radiation Therapy
Radiation therapy is an alternate treatment with a long history
of efficacy, with several small series over the past 20 to 30 years
reporting control rates ranging from 80% to 100%.12,18,49,62,64,
65,67,74,83,84
High-dose-rate (HDR), medium-dose-rate (MDR),
and low-dose-rate (LDR) techniques have been reported with
acceptable results, although it is difficult to compare regimens
due to small patient numbers, generally short follow-up times,
and overall nonuniformity among series. Generally, radiation
is reserved for patients who relapse after more conservative
treatments. Drawbacks to radiation include potential under-
treatment of occult invasive disease, the risk of secondary
malignancy, and long-term morbidity, although there are no
prospective data available regarding the impact of treatment
on sexual function and quality of life.
LDR treatment is most commonly delivered with an intra-
cavitary vaginal cylinder using cesium-137. Typically, a dose of
60 Gy is prescribed to the vaginal mucosa, but a wide range of
doses, depending on depth of dose prescription, as well as a
variety of techniques, have been reported.63,65,67,74,84 Chyle et al.60
prescribed 70 to 80 Gy to the vaginal surface and reported a
17% recurrence rate at 10 years in their series of 37 patients.
Perez et al.63 treated patients to the vaginal surface with a dose
of 60 to 70 Gy, and reported 1 recurrence in 20 patients. The
recurrence occurred in the distal vagina and was noted to be a
marginal recurrence. Blanchard et al.65 reported on a series of
28 patients with VAIN-3 treated at Institut Gustave Roussy from
1985 to 2008. Patients were treated with LDR brachytherapy,
using a vaginal mold technique, to a dose of 60 Gy prescribed
5 mm below the vaginal surface; 18 patients received treatment
to the upper half of the vagina, 6 were treated to the upper two-
thirds, and 4 were treated to the whole vaginal length. With a
median follow-up time of 41 months, the authors report only
one in-field recurrence, with a 10-year local control rate of 93%.
Treatment with LDR brachytherapy is overall well tolerated; in
the Blanchard et al.65 series, there were no grade 3 or 4 late
toxicities and only one grade 2 gastrointestinal toxicity noted.
This is consistent with the Perez et al.63 series, in which there
was only one grade 3 urinary complication among 40 patients
with VAIN-3 or stage I vaginal cancer treated with LDR. Overall,
excellent local control and low toxicity have been reported for
LDR brachytherapy.
Graham et al.64 reviewed their experience using MDR intra-
cavitary brachytherapy for VAIN-3 at the Beatson Oncology
Centre in Glasgow, UK. Using a MDR Selectron (Nucletron,
Holland), 48 Gy was prescribed 0.5 cm lateral to the ovoid sur-
face (point Z) over two insertions, spaced 1 week apart. Ovoids
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were chosen over vaginal cylinder placement in order to ade-
quately cover epithelium sutured into the superolateral vagina
at hysterectomy. With a median follow-up duration of 77
months, recurrent or residual VAIN-3 was documented in
three patients, and two of these patients subsequently devel-
oped invasive or microinvasive vaginal carcinoma. One other
patient developed late progression 14 years after treatment.
There were minimal acute effects during treatment; however,
with longer follow-up, all patients were noted to have grade
12 mucosal atrophy, dryness and telangiectasia. Four patients
developed grade 3 toxicity with severe vaginal stenosis, and
one patient developed grade 4 toxicity, with a vaginal ulcer that
presented 2 years after treatment. An additional patient devel-
oped grade 3 urinary toxicity with urethral stricture requiring
intermittent self-catheterization.
HDR brachytherapy has been used for patients with VAIN-3.
Ogino et al.62 reported their experience treating six patients with
VAIN-3 at Kanagawa Cancer Center from 1983 to 1993, with a
mean dose of 23.3 Gy (range, 15 to 30 Gy); most treatments
were delivered in 5 fractions using two ovoids, with dose calcu-
lated to a point 1 cm superior to the vaginal apex. Lesions distal
to the vaginal vault had doses calculated 1 cm beyond the plane
of the vaginal cylinder in order to deliver adequate dose to the
entire vagina. Median follow-up was 90.5 months, and there
was no evidence of disease recurrence in the treated patients.
Two patients developed moderate to severe vaginal stenosis,
and three patients developed rectal bleeding, which resolved.
MacLeod et al.61 reviewed their experience treating 14 patients
with VAIN-3 from 1985 to 1995. Total dose was 34 to 45 Gy to
the vaginal surface, in 8.5-Gy fractions delivered twice a week or
4.5-Gy fractions delivered 4 times a week. One patient devel-
oped invasive cancer, and one patient had persistent VAIN-3.
There were no major acute toxicities, and two patients devel-
oped late grade 3 vaginal atrophy and stenosis. Mock et al.83
reported treatment of six patients with HDR intracavitary
brachytherapy, with 100% 5-year disease-specific survival.
Malignant Tumors of the Vagina:
Squamous Cell Carcinoma
Epidemiology
A review of five series, including a total of 1,375 cases of
vaginal cancer, reported a FIGO stage distribution as follows:
26% stage I, 37% stage II, 24% stage III, and 13% stage IV.85
Consistent with these data, the NCDB review by Creasman
et al.,4 for the period of 1985 to 1994, revealed 3,244 cases
of invasive primary vaginal carcinoma, with 24% of patients
presenting with American Joint Committee on Cancer (AJCC)
stage I disease, 20% AJCC stage II, 24% AJCC stages III an IV,
and 32% unknown. Most tumors were moderately (28%) or
poorly (28%) differentiated at presentation.
According to the SEER study by Shah et al.,1 most women
diagnosed with primary vaginal cancer are non-Hispanic
whites (66%), followed by African Americans (14%), Hispanic
whites (12%), Asian/Pacific Islanders (7%), and others (1%).
Incidence rates were highest for African American women
(1.24/100,000 person-years) and lowest for Asian/Pacific
Islanders (0.64/100,000 person-years). The greatest propor-
tion of women (36%) presented with stage I disease, and 65%
had squamous histology, consistent with other reports.
Risk Factors
Primary vaginal SCC shares similar risk factors with VAIN and,
in general, with cervical neoplasia. Potential risk factors for
SCC include HPV infection, history of CIN, vulvar intraepithelial
neoplasia, immunosuppression, and possibly history of pelvic
radiation, although this is controversial. In a population-based
case-control study of 156 women with VAIN or invasive can-
cer, risk factors included early onset of intercourse, increased

number of lifetime sexual partners, and current smoking. HPV
DNA was detectable in 80% of patients with in situ disease
and 60% of those with invasive disease, and 30% of patients
reported a history of treatment for invasive malignancy, most
commonly cervix or in situ anogenital neoplasia.30 A case-
control study of 41 women with in situ disease or invasive
carcinoma identified low socioeconomic status, history of geni-
tal warts, vaginal discharge or irritation, history of abnormal
cytology, prior hysterectomy, and vaginal trauma as potential
risk factors.86 A larger case-control study of 36,856 women
found an increased risk of vaginal cancer in alcoholic women,
likely associated with a higher incidence of lifestyle factors,
such as promiscuity and smoking, which are also associated
with a higher incidence of HPV infection. Early hysterectomy
appears to be a risk factor in some studies, if performed for
malignant or premalignant disease.30,87
Patients with a history of cervical cancer have a significantly
higher risk of developing in situ as well as invasive carcinoma.
Studies suggest that 10% to 50% of patients with a history of
VAIN or invasive carcinoma of the vagina have undergone
treatment for in situ or invasive cervical carcinoma,12,60,8894
with the interval from treatment of cervical disease to develop-
ment of vaginal carcinoma averaging approximately 14
years.90,95 HIV-infected women are also at higher risk of devel-
oping vaginal carcinoma, which tends to behave more aggres-
sively in this setting than in HIV-negative patients.96
The role of ionizing radiation to the pelvis in the develop-
ment of vaginal carcinoma is unclear, with conflicting reports.
According to one study that analyzed 1,200 patients treated
over a 20-year period for carcinoma of the cervix, prior radia-
tion therapy was not shown to result in increased secondary
pelvic neoplasms.27 A second study by Boice et al.,26 however,
reported a 14-fold increased risk of vaginal cancer in women
with a history of pelvic irradiation before the age of 45, with a
significant doseresponse relationship.
Other proposed causes include chronic irritation of the vag-
inal mucosa, resulting in chronic inflammation, hyperkerato-
sis, thickening, and acanthosis,96 with subsequent metaplastic
and dysplastic changes. Although older studies showed that
more vaginal cancers arise from the posterior vaginal wall,
other studies report approximately equal distribution of inva-
sive carcinomas on the anterior and posterior walls,29,90,9798,99
arguing against the theory that pooling of irritating substances
in the posterior fornix contributes to development of vaginal
cancers, particularly on the posterior wall. Chronic irritation
A B
FIGURE 72.4. Invasive squamous cell carcinoma of the vagina at 10X (A) and 40X (B) magnification. (Courtesy of Marisa R. Nucci and Carlos
Parra-Herran.)
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Chapter 72 Vaginal Cancer 1471
from use of vaginal pessaries has also been implicated as a
contributor in vaginal cancer development.100,101
Clinical Presentation
Vaginal tumors can spread along the vaginal walls to involve
the cervix or vulva, but involvement of the cervix or vulva at
the time of diagnosis excludes classification as a primary vagi-
nal cancer. Lesions can extend radially, either into the lumen
to form exophytic masses or through the vaginal wall to invade
surrounding musculature and organs. Anterior wall lesions can
infiltrate the vesicovaginal septum or urethra. Posterior wall
lesions can infiltrate the rectovaginal septum and involve the
rectal mucosa. Advanced disease can extend laterally toward
the parametrium and paracolpal tissues or into the urogenital
diaphragm, levator ani muscles, or pelvic fascia, and eventu-
ally to the pelvic side wall.
Grossly, SCC of the vagina can present as nodular, ulcer-
Clinical Radiation Oncology
ated, indurated, exophytic, or endophytic lesions, and it is dif-
ficult to histologically distinguish a primary vaginal SCC from
recurrent cervical or vulvar carcinoma. Histologically, tumors
are graded as well, moderate, or poorly differentiated and
have been described as keratinizing, nonkeratinizing, basa-
loid, warty, or verrucous. The majority of these lesions are
nonkeratinizing and moderately differentiated (Fig. 72.4).102
Vaginal carcinoma most frequently involves the superior
one-third of the vaginal canal, with series reporting 50% to
83% of cases occurring in this region.29,98,99,103106 A high pro-
portion of patients have a history of prior hysterectomy. There
is approximately equal involvement of the middle and inferior
thirds,29 although some studies suggest that involvement of the
lower third is more common than involvement of the middle
third.90,99 Older series report involvement of the posterior vagi-
nal wall to be more common, although other series suggest
involvement of the anterior and posterior walls occurs at equal
frequencies.90,98,99 The lateral walls are less frequently involved.
Tumors may exhibit an exophytic or ulcerative, infiltrating
growth pattern.
HPV has been implicated in the pathogenesis of vaginal SCC.
Fuste et al.107 examined histopathologic patterns of HPV infection
and vaginal SCC. They did not find any association between the
type of HPV and histology (keratinizing, basaloid, warty). Overall,
75% of specimens were positive for HPV. HPV-16 was identified
in 72% of positive samples. Ferreira et al.108 also noted a high
percentage of HPV-positive tumors, with 81% of SCC specimens
positive for HPV and HPV16 found in the majority of tumors.
1472 Section III Clinical Radiation Oncology Part J Gynecologic
Verrucous carcinoma is a distinct histologic variant of vagi-
nal SCC that commonly presents as a well-circumscribed, soft,
cauliflower-like mass that is microscopically well differenti-
ated, with a papillary growth pattern and acanthotic epithe-
lium.109 There is surface maturation with parakeratosis or
hyperkeratosis without koilocytosis. This variant of SCC exhib-
its less aggressive behavior and rarely metastasizes.109112
Therefore, it should be considered a distinct entity from other
vaginal SCC.
Up to 65% of patients present with irregular vaginal bleed-
ing as their primary symptom.90,113,114 Vaginal discharge is the
second most common symptom, occurring in 10% to 15% of
patients. Less frequent symptoms, associated with locally
advanced disease, include the presence of a mass; pain; uri-
nary symptoms, including frequency, dysuria, or hematuria;
or gastrointestinal complaints such as tenesmus, constipa-
tion, or melena. Due to the proximity of anterior wall lesions
to the urethra and bladder, urinary symptoms can be seen
more commonly in vaginal cancer than in cervical cancer. Up
to 20% of women are asymptomatic at the time of diagno-
sis,90,115 with lesions detected via cytologic screening or by
speculum examination.
Patterns of Lymphatic Drainage
The lymphatic system of the vagina is complex, with many
interconnections. Lymphatic channels in the mucosa run par-
allel to networks of channels in the submucosa and muscu-
lar layer, ultimately converging to form trunks at the vaginal
wall periphery, which subsequently drain to major pelvic nodal
groups. The upper vagina drains to the obturator and hypo-
gastric nodes, similar to the cervix. The lower vagina drains
to the inguinal, femoral, and external iliac nodes, and posteri-
orly situated lesions can drain to the inferior gluteal, presacral,
or perirectal nodes. Due to considerable crossover drainage,
the location of the primary tumor is not a reliable indicator of
drainage site.
Frumovitz et al.116 utilized lymphoscintigraphy to determine
patterns of lymphatic drainage in 14 women diagnosed with
primary vaginal cancers and found a substantial degree of
anomalous drainage, resulting in a change in radiation treat-
ment for 33% of patients. For example, among four women
with lesions located in the upper third of the vagina, which is
predicted to drain along the cervical lymphatic chains to the
pelvis, two (50%) were found to have a sentinel node in
the inguinal region. Among five women with lesions located at
the vaginal introitus, a location predicted to drain along the
vulvar lymphatic chains to the inguinal triangle, three (60%)
were found to have a sentinel node in the pelvis.
The risk of nodal metastasis appears to increase signifi-
cantly with stage, although the true incidence of positive
lymph nodes is difficult to determine because most patients
receive treatment with radiation therapy and do not undergo
surgical lymphadenectomy. Sparse data on nodal metastases
are derived from series in which exploratory laparotomies
and lymphadenectomies were performed.95 The incidence of
lymph node involvement has been reported to be 0% to 14% in
stage I and 21% to 32% in stage II disease.95,117,118 The inci-
dence of nodal involvement in stages III and IV has been
reported to be as high as 78% and 83%, respectively.99 At diag-
nosis, up to 20% of patients have clinically positive inguinal
nodes, with reported ranges of 5.3% to 20%.63,93 The risk of
nodal failure increases significantly with local recurrence.
Chyle et al.60 reported 10-year inguinal and pelvic failure rates
of 16% and 28%, respectively, in patients with local recur-
rence, in contrast to 2% and 4%, respectively, in patients with-
out local recurrence.
Distant metastases can occur with advanced disease at pre-
sentation or upon recurrence after primary therapy. The most
frequent site of hematogenous metastasis is the lung, with less
commonly noted sites being liver and bone.60 In a series by
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Perez et al.,93 the incidence of distant metastasis was 16% for
stage I, 31% for stage II, 46% for stage IIB, 62% for stage III, and
50% for stage IV. Some histologies may have a higher likelihood
of distant metastases than others. Chyle et al.60 noted a higher
incidence of distant metastases in patients with adenocarcinoma
(48%) than in those with SCC (10%), with correspondingly lower
10-year survival rates (20% vs. 50%). Leiomyosarcomas are also
aggressive; they undergo early hematogenous dissemination,
frequently occur locally,4,119 and demonstrate frequent pulmo-
nary metastases.120 Vaginal melanoma and neuroendocrine
small cell tumors are highly malignant, and both have a propen-
sity for early hematogenous spread.121,122
Diagnostic Workup
The diagnostic workup should start with a thorough history
and physical examination, with careful attention given to the
pelvis. Examination under anesthesia is recommended for
complete assessment of tumor extent and assessment of vagi-
nal walls. During speculum examination, the speculum blades
can obscure the anterior and posterior walls, so it is essential
to rotate the speculum for visualization of all four walls from
the introitus to the apex. Bimanual examination, with careful
digital palpation, should be performed.
A definitive diagnosis is achieved with biopsy of suspected
lesions, which can present as an exophytic mass, plaque, or
ulcer. Up to 20% of vaginal malignancies are detected inciden-
tally as a result of cytologic surveillance.90 If a lesion is not vis-
ible in the setting of abnormal cytology, colposcopy with acetic
acid, followed by Lugols iodine stain, is conducted. Biopsies of
white epithelium or atypical vascularity should be obtained
after application of acetic acid. Iodine will identify Schiller-
positive regions, which are nonstaining and should correspond
with areas identified following application of acetic acid.
Adequate biopsies should include the cervix, if present, to rule
out a cervical primary. Patients can present with multiple
regions of abnormality. Inguinal nodes should be palpated for
disease involvement, particularly if the primary lesion is situ-
ated in the lower portion of the vagina, as 5% to 20% of patients
have been reported to have involved inguinal nodes at presen-
tation.63,93 Suspicious nodes warrant a biopsy. Laboratory tests
include a complete blood count with differential and assess-
ment of renal and hepatic function.
FIGO staging of vaginal cancer is clinical and allows chest
x-ray, intravenous pyelography (IVP), barium enema, cystos-
copy, and proctosigmoidoscopy. Cystoscopy or proctosigmoid-
oscopy may be necessary in patients with symptoms suggestive
of bladder or rectal infiltration. Computed tomographic (CT)
imaging and magnetic resonance imaging (MRI) do not affect
FIGO stage assignment and are commonly used. CT of the pel-
vis is obtained in place of IVP to assess the renal parenchyma
and also to obtain information on the extent of local disease
and lymph node status. MRI can provide salient treatment
planning information by characterizing extent of invasion and
differentiating malignant tumor, which is isointense to muscle
on T1 and hyperintense on T2, from normal structures or
fibrosis.123 Advantages of MRI over other imaging modalities
include superior soft tissue contrast resolution, allowing accu-
rate assessment of tumor volume and extent of local invasion,
and accurate assessment of pelvic-nodal involvement. In gen-
eral, MRI is regarded as superior to CT for staging of gyneco-
logic malignancies and should be obtained when available.
Positron emission tomography (PET) has shown efficacy in
detecting the extent of primary tumor and abnormal lymph
nodes in vaginal cancer with higher sensitivity than CT,124 as is
the case with cervical carcinoma. Primary vaginal carcinoma
and metastatic lesions demonstrate avid uptake of
2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG). In one study,
23 patients with primary vaginal carcinoma received both PET
and CT during staging. CT identified the primary tumor in only
43% of patients, whereas PET identified the tumor in 100%.
 Chapter 72 Vaginal Cancer 1473

PET identified suspicious uptake in groin and pelvic nodes in 8 TABLE 72.3 INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS
of 23 patients, compared with 4 of 23 with CT. Treatment plan- STAGING SYSTEM FOR CARCINOMA OF THE VAGINA
ning was modified in 14% of patients due to findings from PET,
Stage Description
and the authors concluded that PET detects primary tumor and
abnormal lymph nodes more often than CT.124 It is important Stage I Carcinoma that is limited to vaginal wall
that the patient have an empty bladder prior to imaging, as Stage II Carcinoma that has involved the subvaginal tissue but has not
physiologic FDG activity in a filled bladder can potentially extended to the pelvic walla
interfere with accurate estimation of vaginal involvement. In Stage III Carcinoma that has extended to the pelvic wall
practice, most patients undergoing planning for radiation Stage IV Carcinoma that has extended beyond the true pelvic or has
involved the mucosa of the bladder or rectum; bullous edema
treatment are assessed with CT as well as MRI or PET, based as such does not permit a case to be allotted to stage IV
on extrapolation from studies of other gynecologic malignances Stage IVA Tumor invades bladder and/or rectal mucosa and/or direct
as well as these studies. extension beyond the true pelvis
Stage IVB Tumor has spread to distant organs
Staging a
Pelvic wall is defined as muscle, fascia, neurovascular structures, or skeletal portions
The AJCC125 and FIGO2 systems are used to stage vaginal of the bony pelvis.
cancer (Tables 72.2 and 72.3). FIGO is a clinical staging sys- From FIGO Committee on Gynecologic Oncology. Current FIGO staging for cancer
tem that allows chest x-ray, IVP, barium enema, cystoscopy, of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J

Clinical Radiation Oncology

and rectosigmoidoscopy for staging purposes. Vaginal cancer Gynaecol Obstet 2009;105:1, with permission.
is a diagnosis of exclusion, with involvement of the cervix or
vulva classified as primary cervical or vulvar cancers, respec-
tively. Primary vaginal melanomas and lymphomas are staged adopted into FIGO staging; however, some investigators con-
according to the AJCC staging systems for melanomas and sider the distinction to be prognostically relevant.59,93
lymphomas, respectively.125
For patients with a prior gynecologic malignancy, a 5-year Prognostic Factors
period free of disease is generally considered adequate to allow The most significant prognostic factor is stage at time of pre-
for distinction between recurrent disease and a new primary sentation;1,63,91,126129 the NCDB, the largest population-based
vaginal cancer. FIGO no longer recognizes carcinoma in situ as series on vaginal cancer thus far, reports 5-year survival rates
stage 0. of 96% for stage 0, 73% for stage I, 58% for stage II, and 36%
Stage I disease is defined as limited to the vaginal wall, and for stages III and IV disease.4 The series by Shah et al.,1 based
stage II disease involves subvaginal tissue without extension to on SEER data for women diagnosed between 1990 and 2004,
the pelvic wall. Discriminating between stages I and II can be also reveals the correlation between stage and outcome, with
subjective; thin tumors <0.5 cm are generally classified as 5-year disease-specific survival rates of 84% for stage I, 75%
stage I, with thicker infiltrating tumors or those with paravagi- for stage II, and 57% for stages III and IV; the adjusted hazard
nal nodularity classified as stage II. Perez et al.63 proposed a ratio for mortality, on multivariate analysis, was 4.67. In the
modification to the FIGO system in 1973, distinguishing tumors Perez et al.93 series, 165 patients with primary vaginal cancer
with paravaginal submucosal extension only (stage IIA) from were treated with definitive radiation therapy and had 10-year
tumors with parametrial infiltration (stage IIB). The study actuarial disease-free survival rates of 94% for stage 0, 75% for
reported a 20% 5-year survival difference (55% vs. 35%) stage I, 55% for stage IIA, 43% for stage IIB, 32% for stage III,
between stages IIA and IIB. This modification has not been and 0% for stage IV. Lymph node involvement also carries an
unfavorable prognosis.130
Size of the initial lesion is a prognostic factor that has
TABLE 72.2 AMERICAN JOINT COMMITTEE ON CANCERS STAGING OF shown significance in several series. The SEER database
VAGINAL CANCER study,1 which included 2,149 women with primary vaginal
cancer, noted a significantly lower 5-year survival rate in
Primary Tumor (T)
women with tumors 4 cm than in women with tumors <4 cm
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor (65% vs. 84%); however, size information was missing for 52%
Tis/0 Carcinoma in situ of women. After multivariate analysis, the women with the
T1/I Tumor that is confined to the vagina larger tumors had an adjusted hazard ratio of 1.71 for mortal-
T2/II Tumor that invades paravaginal tissues but not to the pelvic wall ity. Chyle et al.,60 in their review of 301 patients treated at the
T3/III Tumor that extends to the pelvic walla MD Anderson Cancer Center (MDACC) from 1953 to 1991,
T4/IVA Tumor that invades mucosa of the bladder or rectum and/or found that women with lesions >5 cm in maximum diameter
extends beyond the pelvis (Bullous edema is not sufficient to had a significantly higher 10-year local recurrence rate than
classify a tumor as T4) those with smaller lesions (40% vs. 20%). The series by
Regional Lymph Nodes (N) Hellman et al.,128 with 314 patients treated at the Karolinska
Nx Regional lymph nodes cannot be assessed University Hospital from 1956 to 1996, found only three fac-
N0 No regional lymph nodes tors to independently predict for poor survival on multivariate
N1 Pelvic or inguinal lymph node metastasis
analysis: advanced age, tumor size 4 cm, and advanced
Distant Metastasis (M) stage. Tumors comprising two-thirds or more of the vagina
Mx Distant metastasis cannot be assessed
and tumors growing circumferentially were associated with
M0 No distant metastasis
M1/IVB Distant metastasis an extremely poor prognosis. The series by Tran et al.,131
which reviewed records of 78 patients with SCC treated at
Stage Groupings
Stage 0 Tis N0 M0
Stanford University Medical Center from 1959 to 2005, also
Stage I T1 N0 M0 found size to be a prognostic factor for disease-free survival
Stage II T2 N0 M0 on multivariate analysis, along with stage, prior hysterectomy,
Stage III T13 N1 M0, T3 N0 M0 and pretreatment hemoglobin level. Smaller series by Tjalma
Stage IVA T4, any N, M0 et al.132 and Kirkbride et al.91 also describe adverse outcomes
Stage IVB Any T, any N, M1 with larger tumor size. Other series have failed to show sig-
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, nificance, but they likely were hindered by small numbers, dif-
Illinois. The original source for this material is the AJCC Cancer Staging Manual, 7th ed ficulties in accurate assessment of size, and treatment hetero-
(2010) published by Springer Science and Business Media LLC, www.springer.com. geneity. Frank et al.114 reviewed data on 193 patients treated

booksmedicos.org
1474 Section III Clinical Radiation Oncology Part J Gynecologic
at MDACC between 1970 and 2000 for vaginal SCC and found
a nonsignificant difference in disease-specific survival rates
between patients with tumors 4 cm in diameter and those
with tumors >4 cm (82% vs. 60%, respectively). Extent of vagi-
nal canal involvement has also been examined, as a surrogate
for tumor size, in the assessment of tumor burden. In a series
by Stock et al.,98 which examined 100 cases of primary vaginal
carcinoma treated at Magee Womens Hospital from 1962 to
1992, patients with involvement of one-third of the vaginal
canal or less had a significantly higher 5-year disease-free
survival rate (61%) than patients with more extensive involve-
ment (25%).
There is conflicting evidence on the impact of lesion location
on prognosis; it has been noted in some60,103,133135 but not
all93,106,136 reports. In an analysis of 110 patients by Kucera et
al.,137 5-year survival rates were 60% for lesions of the upper
third of the vagina, 37.5% for lesions of the middle third, and
37% for the lower third. Chyle et al.60 noted a 17% rate of pelvic
relapse in patients with tumors in the upper third of the vagina,
36% for patients with tumors in the middle or lower third, and
42% for patients with whole vaginal involvement. Lesions in the
posterior wall were also noted to be associated with a worse
prognosis than lesions involving the anterior vaginal wall,60
with 10-year recurrence rates of 32% versus 19% on univariate
analysis (<.007). The Hellman et al.128series found no difference
in prognosis between anterior and posterior tumors.
Histologic grade has been found to be an independent sig-
nificant predictor of survival in several series91,103,135 but not
others. Hellman et al.128 evaluated the impact of tumor grade
and other histopathologic variables (mitotic activity, koilocyto-
sis, growth in vessels, lymphocytic reactions) and found no
correlation with survival.
Age at diagnosis correlated significantly with poor survival
in both univariate and multivariate analysis in the Hellman
et al.128 series. Age was also noted to be a significant prognos-
tic factor in the Urbanski et al.135 series, with 5-year survival
rates of 83% for patients younger than 60 compared with 25%
for those 60 years of age or older (P <.0001); other series have
failed to demonstrate the statistical significance of age.63,138
Tran et al.131 reviewed records of 78 patients with primary
SCC of the vagina treated at Stanford University Hospital and
found a hemoglobin level <12.5 g/dL prior to definitive treat-
ment to be prognostic for worse pelvic control and disease-
specific survival;117 5-year disease-specific survival rates were
55% for women with hemoglobin levels <12.5 g/dL and 76%
for those with levels 12.5 g/dL. This remained significant
after multivariate analysis, along with prior hysterectomy,
stage, and tumor size.
Up to 62% of patients with primary vaginal cancer have had
a prior hysterectomy.139 This high rate reflects the proportion of
patients with a history of cervical pathology as well as the
increased hysterectomy rate in the general female population.140
The study by Tran et al.131 is the first to identify prior hysterec-
tomy as a favorable prognostic factor on multivariate analysis.
This may reflect more rigorous surveillance in posthysterectomy
patients, resulting in tumors discovered at an earlier stage, or
may be a reflection of less overall vaginal tissue as a substrate
for tumorigenesis. Two studies have identified hysterectomy as a
significant prognostic factor in univariate analysis.60,128
The prognostic role of HPV was examined by Brunner
et al.141 in their series of 35 patients with primary invasive SCC
of the vagina. Using in situ hybridization, HPV was detected in
51.4% of cases. There was no significant influence on clinical
stage, grade, or tumor size nor did prognosis differ between
HPV-positive and HPV-negative tumors. However, in a subset of
patients with FIGO stage III or higher disease, HPV positivity was
found to correlate with improved disease-free and overall sur-
vival (P .004 and .023, respectively). In contrast, Fuste et al.107
found a trend toward longer survival in women with HPV-positive
tumors in their series of 32 patients, with median survival times
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of 113.9 months versus 19.7 months for women with HPV-
positive and HPV-negative tumors, respectively (P = .15).
For patients treated with radiation, treatment time may be
a significant factor impacting tumor control.142,143 Lee et al.143
found overall treatment time of 9 weeks to be associated with
a pelvic tumor control rate of 97% as compared with 57% for
treatment time >9 weeks (P <.01). Pingley et al.142 also noted a
correlation between treatment time and outcome; patients
receiving brachytherapy within 4 weeks of external-beam radi-
ation therapy (EBRT) had a 5-year disease-free survival rate of
60%, compared with a 30% rate in patients who had an inter-
val >4 weeks.
Treatment: Surgery
For most patients with invasive vaginal cancer, radiation
is the treatment of choice. Surgery is considered for highly
selected patients who have early-stage lesions, when a poten-
tially curative resection can be achieved without extensive
functional morbidity. Surgery is also used for previously irra-
diated patients who cannot receive further radiation. A wide
local excision is reserved only for carcinoma in situ or small,
superficially invasive lesions that are well demarcated. More
extensive lesions in the proximal aspect of the vaginal canal
require radical hysterectomy, upper vaginectomy, and bilateral
pelvic lymphadenectomy, and patients with positive margins
require adjuvant radiation. Lesions that extend to the inferior
vagina require a total vaginectomy with radical hysterectomy,
pelvic lymphadenectomy, and possibly vulvovaginectomy and
inguinofemoral lymphadenectomy.89,90,98,99 It is not uncommon
for relatively small lesions to invade the rectum or urethra
early in the disease course, given the close proximity of the
vagina to these structures. Older surgical series often required
pelvic exenteration in 40% to 50% of cases to obtain negative
margins.95,99 Anterior exenteration removes the vagina, ure-
thra, and bladder and is often necessary to achieve negative
margins for invasive anterior wall lesions. Posterior exentera-
tion requires resection of the vagina and rectum. Deeply inva-
sive, circumferential lesions may require a total exenteration in
order to achieve clear margins. Given the potentially devastat-
ing functional results associated with radical surgery, defini-
tive radiation is the treatment of choice for most patients with
invasive vaginal cancer and has largely replaced surgery as the
primary therapeutic modality.
In select stage I patients, surgery can offer excellent results,
with series reporting 5-year survival rates ranging from 56% to
100% for women with stage I disease.4,89,95,98,132,144 The NCDB
review for cancers of the vagina noted superior survival rates in
patients treated with surgery,4 although this likely reflects selec-
tion of healthier patients with good performance status for radi-
cal surgery. A more recent analysis utilizing the SEER database1
found that women with stage I disease who underwent surgery
only, had a lower risk of mortality than those treated with radia-
tion only, combined modalities, or no treatment; however, this
difference did not reach statistical significance. For stage II vagi-
nal cancer patients, there was a similar trend toward increased
mortality in women who did not have surgery alone as their pri-
mary treatment modality, but values once again did not reach
statistical significance in their multivariate adjusted model.
In a review of 100 cases by Stock et al.98 surgical treatment
was noted to be a significantly favorable prognostic factor for
disease-free survival, versus treatment with radiation alone, in
stage II patients but not stage I patients. For stage I patients,
survival rates were 56% and 80% for patients treated with sur-
gery versus radiation, respectively. For stage II patients, survival
rates were 68% and 31% after surgery and radiation, respec-
tively, although this likely reflects selection bias, with patients
with more extensive involvement offered radiation. Overall 5-
year survival was 47%. Stock et al.98 concluded that surgery that
consists of radical hysterectomy, pelvic lymphadenectomy, and
upper vaginectomy could be reasonable for stage I lesions and

select stage II lesions, with radiation being the preferred pri-
mary modality for patients with stage IIB disease. It should be
noted, however, that 23 of 33 stage II patients (70%) treated with
surgery required a total vaginectomy or exenterative procedure,
which carries significant morbidity and functional impairment.
Other series also report excellent results with primary surgi-
cal therapy, although authors acknowledge bias resulting from
selection of healthier patients with less extensive disease for
primary surgery over radiation. Tjalma et al.132 reported on 55
cases of primary vaginal SCC. Of 27 patients with stage I dis-
ease, 26 received surgery, with 4 subsequently receiving some
form of adjuvant radiation. With a median follow-up time of 45
month, 5-year survival was reported to be 91%. Otton et al.,144
in their retrospective review of 70 patients with stage I
or II vaginal carcinoma treated at Queensland Centre for
Gynaecological Cancer between 1982 and 1998, report that
patients treated with surgery alone, or a combination of sur-
gery and radiation, had significantly longer survival times than
patients treated with radiation alone. The authors suggest that
surgery may be effective in a select subset of patients with
small, localized tumors that permit clear surgical margins.
Peters et al.106 reviewed records of 86 patients with vaginal
carcinoma, including 68 SCC cases, treated at University of
Michigan Medical Center. Twelve selected patients had surgery
as primary therapy, with a 75% survival rate. Similarly, Rubin
et al.99 reported on eight patients with stage I or II disease who
received surgery as primary treatment; 5-year survival was
75%, and the overall local control rate for the stage I patients
was 80%, suggesting that highly selected patients can achieve
excellent outcomes with surgery. Davis et al.95 reported on 89
patients with vaginal carcinoma treated primarily at the Mayo
Clinic from 1960 to 1987. A total of 52 patients were treated
with surgery as primary therapy, with 5-year survival of 85%
compared with 65% for patients who received radiation alone.
In the stage II patients, the 5-year survival rates were 49%,
50%, and 69% for surgery, radiation, and combined treatment
with surgery and radiation, respectively. However, treatment
modalities cannot be effectively compared using retrospective
series, which reflect strong selection biases.
Ling et al.,145 in a small series with 4 patients who had stage
I disease, report their experience using laparoscopic radical
hysterectomy with vaginectomy and reconstruction of the
vagina. With follow-up times ranging from 40 to 54 months,
they reported all patients to be free of disease, with satisfactory
sexual function. The authors suggest that laparoscopic surgery
can be an option for select patients with early-stage disease,
with good outcomes.
Several series report their experience using surgery for
advanced stage III or IV patients, with most cases requiring
pelvic exenteration.89,90,98,99 Control rates at best were 50% in
highly selected patients. In practice, given the overall poor
prognosis and morbidity associated with surgery, advanced-
stage patients should receive treatment with definitive radia-
tion, typically in combination with chemotherapy.
Neoadjuvant chemotherapy followed by radical surgery has
been proposed for selected patients with vaginal cancer.146,147
Benedetti et al.147 reported results on 11 patients with stage II
SCC of the vagina, using 3 cycles of neoadjuvant paclitaxel and
cisplatin. Ninety-one percent of patients obtained a partial or
complete response to neoadjuvant chemotherapy; 27%
achieved a complete response. All patients had disease-free
resection margins after surgery, and only one patient had posi-
tive lymph nodes. At a median follow-up time of 75 months, 10
of 11 patients (91%) were alive, and of those, 8 (73%) were free
of disease. Postoperative complications were mild. A case
report documented the use of neoadjuvant chemotherapy, con-
sisting of bleomycin and cisplatin, followed by radical surgery
in one patient with stage II SCC of the vagina.146 The patient
was free of disease, with satisfactory sexual function, at
30 months. However, larger series of patients treated with this
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Chapter 72 Vaginal Cancer 1475
approach, with longer follow-up, are necessary to further eval-
uate the feasibility of this treatment.
Treatment: Radiation
Stage I
It is difficult to compare results for stage I and stage II disease
from different series, as the distinction between them is made
clinically, based on physical examination, and can be subject to
variability. In general, stage I lesions are 0.5 to 1 cm in thick-
ness. It is important to individualize radiation therapy tech-
niques based on size, depth, and location of the lesion.
Selected patients with small, superficial tumors may be ade-
quately treated with brachytherapy alone, with reported local
control rates of 67% to 100%.92,93,97,103,114,135,148,149 Perez et al.63
reported pelvic tumor control of 88% in patients with stage I
disease who received brachytherapy alone, using a dose of 60
to 70 Gy, prescribed 5 mm beyond the plane of the implant or
Clinical Radiation Oncology
vaginal mucosa, with a vaginal surface dose of 80 to 120 Gy.
Frank et al.114 reported on 21 patients with stage I disease who
were treated with local radiation only, without regional node
coverage. Nine received brachytherapy alone, 11 received
EBRT with or without brachytherapy, and 1 received local
EBRT using a transvaginal orthovoltage cone. Three of 9
patients treated with brachytherapy alone developed recurrent
disease in the pelvis, resulting in a 10-year pelvic disease con-
trol rate of 67%. Patients who had received EBRT with or with-
out brachytherapy did not have pelvic recurrences. In the
series by Dancuart et al.,148 patients treated with brachyther-
apy or transvaginal cone irradiation alone had a local failure
rate of 18%. A pelvic relapse rate of 18% at 10 years was noted
by Frank et al.,114 with all pelvic failures occurring in patients
treated with brachytherapy alone.
Typically, the entire length of the vagina is treated to a
mucosal dose of 60 to 65 Gy, with an additional mucosal dose
of 20 to 30 Gy delivered to the area of tumor involvement.150
With LDR, treatment can be delivered in two applications, with
the first designed to treat the entire vaginal wall and a second
application to cover the tumor volume. This can be delivered
with a shielded vaginal cylinder to treat the tumor with a 2-cm
margin and block uninvolved mucosal surfaces. HDR can also
be used to treat superficial lesions. In general, the vaginal
mucosa is treated to a dose of 21 to 25 Gy, prescribed to a
depth of 5 mm, in weekly fractions of 5 to 7 Gy each. An addi-
tional 21 to 25 Gy, prescribed to a depth of 5 mm, is delivered
to the tumor via shielded vaginal cylinder, with weekly frac-
tions of 5 to 7 Gy, to bring the total dose to 42 to 50 Gy. For
lesions thicker than 5 mm, a combination of intracavitary and
interstitial brachytherapy can be utilized. For such lesions, a
vaginal cylinder typically delivers 45 Gy (LDR) or 21 to 25 Gy
(HDR) to a depth of 5 mm into the vaginal mucosa. Subsequent
therapy is delivered via interstitial implant, to deliver an addi-
tional dose of 25 to 35 Gy (LDR) to the tumor volume.
A combination of EBRT and brachytherapy is suggested for
more extensive stage I lesions that exhibit greater infiltration or
poor differentiation. Perez et al.63 noted that tumor control in
stage I vaginal carcinoma was approximately the same with
brachytherapy alone as when given in combination with EBRT,
consistent with observations made by some groups137,151 but not
others.114 Given possible underestimation of submucosal disease
or nodal disease, resulting in a potentially high likelihood of
recurrence with brachytherapy alone, some groups recommend
incorporating EBRT into treatment of all stage I patients, except
for those with very small, superficial lesions.114 Frank et al.,114 in
their series of patients with vaginal cancer treated at MDACC
between 1970 and 2000, noted an increased trend toward
increasing use of EBRT for stage I vaginal SCC over time.
Actuarial 5-year survival rates for stage I disease range
from 60% to 85%.1,93,114,131 Disease-specific survival rates for
stage I disease, treated with definitive radiation, range from
75% to 95%.63,60,94 The 10-year pelvic-relapse rate, comprising
1476 Section III Clinical Radiation Oncology Part J Gynecologic
local, pelvic nodal, and inguinal nodal failures, was noted to be
16% by Frank et al.114 for stage I patients. Distant metastases
are uncommon and occur in about 5% of patients.63,95,148
Stage II
Radiation is the primary treatment for stage II disease and
involves a combination of EBRT and brachytherapy. Perez
et al.63 noted a 36% pelvic tumor control rate in stage II patients
treated with brachytherapy alone, compared with 67% in
patients treated with a combination of EBRT and brachytherapy.
The benefit of combining EBRT and brachytherapy, as opposed
to using either alone, has been shown in other series as well.60,98
Generally, patients with stage II disease are treated with
EBRT followed by interstitial or intracavitary brachytherapy.
The pelvis receives 45 to 50.4 Gy in 1.8 Gy fractions, with con-
sideration of a parametrial boost if there is extensive primary
infiltration or high suspicion of nodal disease. Inguinal lymph
nodes are included in a modified whole pelvic field for lesions
involving the distal vaginal canal.
Chyle et al.60 reported an 89% local-control rate in the
vagina for patients treated with brachytherapy alone, although
the rate of pelvic wall relapse was not reported in this cohort.
Of 28 patients treated with EBRT alone, with carefully designed
shrinking fields, three (11%) developed vaginal recurrences. In
comparison, there were 12 recurrences (21%) in 58 patients
treated with combined EBRT and brachytherapy. The authors
concluded that coverage of the entire tumor volume is critical
for optimal outcome.
Brachytherapy should be carefully delivered to ensure
adequate coverage of tumor volume. An interstitial technique,
ideally with three-dimensional (3D) imaging for treatment plan-
ning, is required for tumors >5 mm in depth.92,152 Extensive
tumors, or deeply infiltrating tumors with nondistinct margins,
may be poor candidates for brachytherapy. In such cases, boost-
ing tumors with conformal techniques or intensity-modulated
radiation therapy (IMRT) may be preferred and may yield better
outcomes than suboptimal brachytherapy.114 The tumor volume
should receive a minimum of 75 to 80 Gy using combined EBRT
and brachytherapy. Fleming et al.153 and Puthawala et al.154 both
report improved outcomes with higher doses of 80 to 100 Gy.
The 5-year survival rate for patients with stage II disease
treated with radiation therapy alone ranges from 35% to 70%
for stage IIA to 35% to 60% for stage IIB.29,153 Pelvic relapse at
10 years has been reported to be 25% by Frank et al.,114 con-
sistent with recent series reporting 5-year pelvic-control rates
ranging from 76% to 84%.131 The likelihood of distant metasta-
sis is higher for stage IIB lesions compared with stage IIA,93,151
with overall reported rates ranging from 22% to 46%.93,95
Stages III and IVA
Patients with more advanced disease generally also receive
EBRT to the pelvis, followed in certain cases by additional dose
to the parametrium. If adequate tumor coverage can be achieved
without undue toxicity, interstitial brachytherapy is employed to
deliver a minimum tumor dose of 75 to 80 Gy. If brachytherapy
is not feasible, due to extensive tumor infiltration of the rectovag-
inal septum or bladder, a shrinking-field technique or IMRT has
been used to deliver additional dose to the primary lesion.155,156
The overall cure rate for patients with stage III disease ranges
from 30% to 50%. Stage IVA carries a worse prognosis. In highly
selected patients with small volume stage IV disease, pelvic
exenteration can yield good long-term control; however, in prac-
tice, EBRT remains the primary treatment.1,4,63,98,99,114,135,157,158
Five-year actuarial survival rates for women with stage III dis-
ease range from 25% to 58%,1,4,159 with local failure rates of 30%
to 75%.93,114,131 Outcomes for stage IV disease are worse, with
survival rates of 0% to 40%.60,98,160 Despite treatment with EBRT
and brachytherapy, only 20% to 30% of patients with stages III
and IV disease achieve local control. Pelvic recurrences occur
more often than distant recurrences.114
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Role of Chemotherapy and Radiation
There are no randomized trials that compare radiation alone
with radiation plus chemotherapy in vaginal cancer, and
many studies of chemoradiation for primary vaginal cancer
are limited by small numbers or inclusion of other cancers,
such as cervical and vulvar carcinomas. However, many cli-
nicians incorporate the use of cisplatin for treatment of vagi-
nal cancers, extrapolating from data demonstrating improved
progression-free and overall survival in cervical cancer when
cisplatin is added to radiation.63,161164
Holleboom et al.165 published a case report documenting the
use of cisplatin with EBRT and brachytherapy in a patient with
advanced stage SCC of the vagina. The patient was free of dis-
ease at 16 months. Evans et al.166 reported the use of radiation
with 5-FU and mitomycin-C (MMC) in seven patients with vaginal
cancer. Four of seven patients were free of disease with follow-up
times ranging from 19 to 39 months. Roberts et al.167 reported
results for seven patients with vaginal cancer treated with con-
current 5-FU, cisplatin, and radiation. Three patients received
interstitial brachytherapy after EBRT, and two patients received
intracavitary brachytherapy after EBRT. Eighty-five percent of
patients achieved a complete response initially. Ultimately, 61%
recurred, with a median time to recurrence of 6 months. There
were three local recurrences and one distant metastasis and the
5-year overall survival rate was 22%. Kirkbride et al.91 reported
on the use of concurrent 5-FU, with or without MMC, in 26 of
153 patients with vaginal carcinoma treated at Princess Margaret
Hospital. Seventy-seven percent of the patients had stage III or IV
disease. Radiation was EBRT followed by interstitial or intracavi-
tary brachytherapy to a total dose of 62 to 74 Gy. The 5-year
survival rate was 50%. Dalrymple et al.168 reported results using
5-FU-based chemotherapy in combination with radiation for
treatment of primary SCC of the vagina. Thirteen of 14 patients
(93%) had stage I or II disease. The median dose of radiation was
63 Gy, achieved using EBRT alone or EBRT with intracavitary
brachytherapy. The 5-year survival rate was 86% for all patients,
and nine patients were free of disease with a median follow-up
time of 100 months, suggesting that good local control can be
achieved despite the use of lower radiation doses. There was a
31% rate of severe bowel complications reported, with two
deaths as a result of bowel obstruction.
A retrospective series from MDACC by Frank et al.114
included nine patients with stage II or IVA SCC of the vagina
treated with radiation therapy and concurrent cisplatin-based
chemoradiation. With a mean follow-up time of 129 months,
improved local control with the use of chemotherapy was
noted, with 44% of patients treated with concurrent chemora-
diation remaining free of disease. Samant et al.169 published a
review of 12 vaginal cancer patients, stage II to IVA, treated
with concurrent weekly cisplatin at a dose of 40 mg/m2 for 5
weeks. Patients received concurrent EBRT to a median dose of
45 Gy, with LDR interstitial or an HDR intracavitary brachy-
therapy boost of median dose 30 Gy. Six patients had stage II
disease, four had stage III disease, and two had stage IVA. Ten
of 12 (83%) patients had SCC; the other 2 had adenocarcinoma.
Overall, treatment was well tolerated, with 92% of patients
completing therapy as prescribed. Two of 10 patients who
received interstitial brachytherapy required surgery for fistula
repair. The 5-year overall survival, progression-free survival,
and locoregional progression-free survival rates were 66%,
75%, and 92%, respectively, supporting use of concurrent
weekly cisplatin therapy. A small series of six patients treated
with chemoradiation at the University of the Ryukyus was
reported by Nashiro et al.170 All patients received EBRT to 50
Gy, followed by either a boost with shrinking fields (n = 4) or
intracavitary brachytherapy (n = 2). Radiation was delivered
with two to three cycles of cisplatin. Two patients had stage II,
one had stage III, and three had stage IVA disease. All six
achieved a complete response, and four of six patients
remained free of disease at follow-up times of 18 to 55 months.
 Chapter 72 Vaginal Cancer 1477

In a retrospective analysis of 71 patients with primary vagi-
nal cancer treated at Dana-Farber Cancer Institute/Brigham
and Womens Hospital from 1972 to 2009, 51 patients were
treated with radiation alone and 20 were treated with chemo-
therapy and radiation.170 Of patients treated with chemo-
sensitization during radiation, 85% of patients received weekly
cisplatin chemotherapy, while the remainder received either
carboplatin or 5-FU. Three-year actuarial overall survival and
disease-free survival was 56% for the radiation alone group,
compared with 79% for the chemoradiation group (P = .01).
Three-year disease-free survival was 43% for the radiation
alone group, compared with 73% for the chemoradiation group
(P = .01). At a median follow-up of 3 years, tumor relapse was
seen in 15% of patients treated with chemoradiation compared
with 45% of patients treated with radiation alone (P = .03).
Ghia et al.172 published a retrospective patterns-of-care
analysis using the SEER database, analyzing data from women
with primary vaginal cancer treated with EBRT or brachyther-
apy between 1991 and 2005. Of the 326 women in the study
cohort, 80.4% had SCC. It was noted that chemoradiation was
used in 7.5% of patients treated before 1999 compared with
36.1% of those treated afterward (P <.001). Cisplatin was the
most frequently utilized agent, accounting for 59% of chemora-
diation treatments. Chemotherapy was significantly less likely
to be used in conjunction with radiation for women over 80
years of age; otherwise, there was no difference for race, stage,
grade, histologic diagnosis, comorbidities, or brachytherapy
use. On multivariate analysis, chemoradiation was not found to
correlate with improved cause-specific or overall survival.
Outcomes
Overall survival rates by stage, based on reports from smaller
series, are shown in Table 72.4. The NCDB report by Creasman
et al.,4 which focused on 4,885 women diagnosed with vaginal

Clinical Radiation Oncology

TABLE 72.4 OUTCOMES FOR VAGINAL CANCER BY TREATMENT MODALITY
Series (Reference) Outcome Stage I (%) Stage II (%) Stage III (%) Stage IV (%) Treatment
Dixit (19851989) et al. (138) 2 yr DSS 100 70 19 0 EBRT and/or BT
Fine et al. (19631991) (160) 5 yr OS 42 68 58 0 EBRT and/or BT
Kucera et al. (19751984) (137) 5 yr OS 81 44 35 32, 0b EBRT and/or BT
Perez et al. (19531991) (63) PC 85 66, 56a 65 27 EBRT and/or BT
10 yr DFS 80 55%, 35%a 38 0
de Crevoisier et al. (19702001) (172) 5 yr PC 79 62 EBRT and/or BT
Lee et al. (19641990) (143) 5 yr PC 87 88, 68a 80 67 EBRT and/or BT
5 yr CSS 94 80, 39%a 79 62
Frank et al. (19702000) (114) 5 yr PC 86 84 71 EBRT+BT (n = 119), EBRT
5 yr DSS 85 78 58 (n = 63)
Chyle et al. (19531991) (60) 10 yr PC 84 75 60 40 EBRT+BT (n = 121), EBRT (n =
10 yr OS 55 51 37 40 95), BT (n = 26), transvaginal
cone (n = 2)
Stryker et al. (19761994) (173) 5 yr DSS 78 63 33 50 EBRT+BT (n = 25), EBRT (n = 7),
BT (n = 2)
Lian et al. (19862006) (174) 5 yr DSS 90 87 32 26 EBRT+BT (n = 28), EBRT (n =
17), BT (n = 4), S+RT (n = 6)
Tran et al. (19592005) (131) 5 yr PC 83 76 62 30 EBRT+BT (n = 43), EBRT (n =
5 yr DSS 92 68 44 13 22), BT (n = 10)
Mock et al. (19861999) (83) 5 yr DSS 92 57 59 0 EBRT+BT (n = 55), EBRT (n = 5),
BT (n = 26)
Urbanski et al. (19651988) (135) 5 yr DFS 73 54 23 0 EBRT+BT (n = 77), BT (n = 11),
EBRT (n = 15)
Beriwal et al. (20002006) (175) 2 yr crude LC 100 100 100 EBRT+HDR BT
Creasman et al. (19851994) (4) 5 yr OS 73 58 36 RT and/or S
Kirkbride et al. (19741989) (91) 5 yr DSS 72 70 53 42 RT and/or S
Rubin et al. (19581980) (99) 5 y OS 75 48 54 0 RT and/or S
Stock et al. (19621992) (98) 5 y LC 72 62 0 21 RT and/or S
5 y DFS 67 53 0 15
Shah et al. (19902004) (1) 5 yr DSS 84 75 57 RT and/or S
Hellman et al. (19561996) (176) 5 yr DSS 75 36 36 20, 0b RT and/or S
Surgical Outcomes
Ball and Berman (89) 5 yr OS 84 63 S
Creasman et al. (19851994) (4) 5 yr OS 90 70 S
Davis et al. (19601987) (95) 5 yr OS 85 49 S
Rubin et al. (19581980) (99) 5 yr OS 80 33 S
Tjalma et al. (132) 5 yr OS 91 S
Hellman et al. (19561996) (176) 5 yr DSS 75 36 36 20, 0b RT and/or S
Chemoradiation Outcomes
Miyamoto et al. (19722009) (170) 3 yr OS 79% St I, n = 18; St II, n = 19, St III, n = 8, St IVA, n = 6 RT+cis, 5-FU or carboplatin
Dalrymple et al. (19861996) (168) NED n = 9(FU 74168 mo); St I, n = 1; St II, n = 10, St III, n = 1 RT+5-FU, cis/5-FU or MMC
DOD n = 1 (12 mo); DID
n = 4 (46109 mo)
Samant et al. (19992004) (169) 5 yr OS 66% St II, n = 6; St III, n = 4; St IVA, n = 2 RT+cis
Nashiro et al. (20022005) (177) DOD n = 1(25 mo); NED St II, n = 2; St III, n = 1; St IVA, n = 3 RT+cis or cis/5-FU
n = 4 (FU 1954 mo);
AWD n = 1 (FU 19 mo)
DSS, disease-specific survival; OS, overall survival; PC, pelvic control; DFS, disease-free survival; CSS, cause-specific survival; LC, local control; BT, brachytherapy; EBRT, external-
beam radiation; HDR, high-dose rate; S, surgery; NED, no evidence of disease; DOD, died of disease; DID, died of intercurrent disease; St, stage; 5-FU, 5-fluorouracil; cis, cisplatin;
MMC, mitomycin C; AWD, alive with disease.
a
Outcomes for stages IIA, IIB, respectively.
b
Outcomes for stages IVA, IVB, respectively.

booksmedicos.org
1478 Section III Clinical Radiation Oncology Part J Gynecologic
cancer between 1985 and 1994, found 5-year survival rates
of 96% for stage 0, 73% for stage I, 58% for stage II, and 36%
for stages III and IV, with 85% of invasive cases being SCC.
The more recent study by Shah et al.1 analyzed records from
the SEER database of 2,149 women diagnosed with primary
vaginal cancer between 1990 and 2004. The risk of mortality is
noted to have decreased over time, with a 17% decrease in the
risk of death for women diagnosed after 2000 relative to those
diagnosed between 1990 and 1994. The authors reported
5-year disease-specific survival rates of 84% for stage I, 75%
for stage II, and 57% for stage III or IV.
Overall rates of locoregional recurrence, by stage, are shown
in Table 72.4. In general, the rate of locoregional recurrence
ranges from 10% to 20% for stage I and 30% to 40% for stage II.
Patients with advanced disease often have persistent disease
despite treatment. In a series by Dixit et al.,138 68% of failures in
stage III patients were due to persistent disease. Most treatment
failures occur within 5 years, with a median time to recurrence
of 6 to 12 months,114,178 and local recurrence is the most com-
mon pattern of treatment failure in the majority of published
series. Extravaginal recurrences in the pelvic lymph nodes are
less common. The reported rates of distant metastasis vary,
ranging from 7% to 33%, and usually occur later in the course
of disease, with approximately half of all distant metastases
presenting at the time of local recurrence.92,93,104,138
Clear Cell Adenocarcinoma
Epidemiology
Clear cell adenocarcinoma of the vagina was first reported in
1971 by Herbst et al.179 who documented six cases of primary
vaginal clear cell carcinoma in patients 15 to 22 years of age:
five of the six had been exposed to the synthetic estrogen DES in
utero during the first trimester. This was the first report suggest-
ing in utero exposure to DES, prescribed during the mid-1940s
to 1960s for high-risk pregnancies, could result in an increased
risk of clear cell adenocarcinoma. DES-related clear cell adeno-
carcinoma presents at a young age, with studies documenting
median age at presentation to be within the second or third
decade of life.179,180 Studies suggest that there is a bimodal distri-
bution for clear cell adenocarcinoma of the vagina, with the first
peak among young women with a mean age of 26, most of whom
were exposed to DES in utero, and a second peak among women
with a mean age of 71 years, born prior to 1950 and thus not
exposed to DES.179,181
The majority of patients present with stage I or II dis-
ease.179,182 In 45% to 95% of cases, clear cell adenocarcinoma of
the vagina is associated with vaginal adenosis, most commonly
tuboendometrial in morphology, although three patterns of ade-
nosis have been described: endocervical, tuboendometrial, and
embryonic.35,183,184 Grossly, clear cell adenocarcinoma has pol-
ypoid morphology and presents most commonly on the anterior
vaginal wall.
Risk Factors
The risk of developing clear cell adenocarcinoma in DES-
exposed women is estimated to be 1 in 1,000,182 suggesting
that there are multiple factors contributing to pathogenesis.
Additional factors associated with increased risk include DES
exposure prior to the 12th week of pregnancy, a maternal his-
tory of prior miscarriage, birth in autumn, and prematurity.185
Vaginal adenosis, defined as the abnormal presence of glan-
dular epithelium in the vagina, is believed to be a precursor
lesion to clear cell adenocarcinoma of the vagina and, there-
fore, is a common histologic abnormality in women who have
been exposed to DES in utero, presenting in up to 95% of such
women.183,186 However, it is not strictly confined to this popula-
tion.187 Grossly, vaginal adenosis appears as red, velvety,
grape-like clusters in the vagina. Glandular columnar epithe-
lium of mllerian type either appears beneath the squamous
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epithelium or replaces it, undergoing progressive squamous
metaplasia.188
Histology
Clear cell adenocarcinoma of the vagina is most often located
in the upper third of the anterior vagina and can vary greatly
in size. These cancers can also arise in the cervix. Grossly,
they exhibit exophytic growth and are superficially invasive.189
Microscopically, they are composed of vacuolated, glycogen-
rich cells, hence the term clear cell carcinoma. The most com-
mon histologic pattern is tubulocystic, although solid, papillary,
and mixed cell patterns have also been described.114,190 Cells
are cuboidal or columnar in shape, with large, atypical protrud-
ing nuclei, rimmed by a small amount of vacuolated cytoplasm.
Clinical Presentation
Patients with clear cell adenocarcinoma most often present
with abnormal vaginal bleeding,179 which is found in 50% to
75% of cases. Cytology is not reliable, revealing abnormality in
only 33% of cases; therefore, careful assessment of the entire
vaginal vault to assess for submucosal irregularity is recom-
mended, in addition to four-quadrant cytologic assessment.191
Abnormal discharge, urinary symptoms, and lower gastroin-
testinal complaints can also be noted, particularly in advanced
cases. The differential diagnosis of vaginal adenocarcinoma is
often challenging, because it must be distinguished from metas-
tases from distant sites.
Prognostic Factors
For clear cell adenocarcinoma, prognostic variables associated
with worse survival include advanced stage, nontubulocystic
pattern of histology, size >3 cm, and depth of invasion >3 mm.189
A study of 21 women with clear cell carcinoma of the vagina and
cervix reported overexpression of wild-type p53 to be associated
with a more favorable prognosis.192 Primary adenocarcinoma of
the vagina not associated with DES exposure is extremely rare.
In a review of 26 such cases by Frank et al.,193 5-year overall
survival was 34%, significantly worse than for patients with SCC.
Treatment Options
The optimal management of clear cell adenocarcinoma is
unclear. There are several published series on DES-related clear
cell adenocarcinomas114,189,194197 using conventional treatments
similar to those used for squamous cell carcinoma of the vagina
for stage I or II disease, including surgery with radical hyster-
ectomy, vaginectomy, and lymphadenectomy with construc-
tion of a neovagina, or definitive radiation with consideration
of radiosensitizing concurrent chemotherapy.170,198 There has
been an emphasis on preservation of ovarian and vaginal func-
tion, likely due to the earlier age at diagnosis in DES-exposed
patients. According to data from the U.S. Registry for Research
on Hormonal Transplacental Carcinogenesis, approximately
half of all vaginal clear cell adenocarcinoma cases were treated
with radical surgery alone as primary therapy.199
Wharton et al.200 reported on the use of intracavitary or trans-
vaginal irradiation for early-stage disease, with excellent tumor
control and preservation of ovarian function. Herbst et al.201
reported on 142 cases of stage I clear cell adenocarcinoma. For
the 117 patients treated with radical surgery, there was an 8%
risk of recurrence and 87% overall survival. For patients treated
with radiation, there was a 36% risk of recurrence. The authors
acknowledge that it is difficult to compare surgery to radiation,
as radiation was most likely used in patients with larger lesions
less amenable to resection.
A series by Senekjian et al.195 reported on 219 cases of stage I
clear cell vaginal adenocarcinoma. Forty-three patients received
local therapy alone, consisting of vaginectomy, local excision, or
local irradiation with or without excision, and the rest had con-
ventional radical surgery. At 10 years, the actuarial survival rates
were equivalent (88% vs. 90%) for patients who had received

local therapy only and those treated conventionally, respectively.
However, the actuarial recurrence rate was significantly higher
(40% vs. 13%) with local excision alone. Patients who received
local irradiation, with or without local excision, had decreased
local recurrence compared with those treated with excision alone
(P <.03).
A subsequent series by Senekjian et al.118 reviewed 76 cases
of stage II clear cell adenocarcinoma. The 10-year overall sur-
vival rate was 65%. The 5-year survival rates were 80% for
patients treated with surgery, 87% for patients treated with
radiation, and 85% for patients treated with both. The authors
advocate treatment with combination EBRT and brachyther-
apy for stage II disease, with surgery reserved for smaller,
more easily resectable lesions in the upper vagina. The use of
pelvic exenteration for primary and recurrent lesions has been
reported by Senekjian et al.196 Survival outcomes were compa-
rable to those of patients treated with other modalities. Thus,
to minimize morbidity and preserve quality of life, exenterative
approaches are advocated only for patients with disease recur-
rence after radiation. The 5-year survival rate after pelvic
relapse is reported to be 40% by Herbst et al.194
Most recurrences occur within 3 years of therapy, although
recurrences occurring 10 to 20 years after treatment have been
reported.202 Most recurrences are local or locoregional, with
approximately one-third detected at distant sites, most commonly
in the lungs or extrapelvic lymph nodes, although there have been
rare cases of central nervous system metastases manifesting
years after treatment.203 The 10-year actuarial survival rate for
clear cell adenocarcinoma of the vagina is 79%. For stages I and
II disease, survival rates are 90% and 80%, respectively.
Other Adenocarcinomas
Most adenocarcinomas found in the vagina represent meta-
static deposits from other sites. Vaginal metastases from adeno-
carcinoma of the breast, or other gynecological primary sites,
and from renal cell carcinomas have been described.204206
Primary nonclear cell adenocarcinoma of the vagina is
extremely rare and occurs predominantly in postmenopausal
women. Histologic variants include endometrioid, mucinous,
mesonephric, and papillary serous adenocarcinoma. Vaginal
endometrioid adenocarcinoma is the most common nonclear
cell subtype and presents most often in women with a history
of endometriosis. Only a few case reports or series have been
published in detail about endometrioid adenocarcinoma of the
vagina.207217 In one series of 18 cases of primary vaginal endo-
metrioid adenocarcinoma, 10 cases arose from the apex.207
Fourteen of 18 cases had vaginal endometriosis, important
in indicating a primary vaginal tumor rather than secondary
spread from the endothelium. Median age at presentation was
57, with a range from 45 to 81 years. There have been case
reports of mucinous adenocarcinoma of the vagina,218220 with
at least one arising from a focus of endocervicosis.221
On gross examination, endometrioid adenocarcinomas can
be polypoid, papillary, rough, granular, fungating, exophytic,
or flat, and most arise from the superior aspect of the vagina.
Microscopically, tumors display a predominant component of
typical endometrioid carcinoma, with tubular glands lined by
columnar cells that have moderate amounts of eosinophilic
cytoplasm and large elongated nuclei. Only a few cases of
mucinous adenocarcinoma have been described,205,218220
including rare cases arising in neovaginas222 or arising from
endocervicosis.221 Mesonephric adenocarcinoma arises from
the mesonephric duct remnants situated in the lateral vaginal
wall.223,224 Primary papillary serous adenocarcinoma of the
vagina has rarely been reported.225
Melanoma
Melanomas arising from the vaginal mucosa are rare, account-
ing for 2.8% to 5% of all vaginal neoplasms,226228 with just over
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Chapter 72 Vaginal Cancer 1479
100 new cases of vaginal melanoma reported each year in the
United States. According to the NCDB report by Creasman
et al.,4 vaginal melanomas comprise 4% of all primary vaginal
cancers. The incidence of vaginal melanoma has remained sta-
ble and is reported to be approximately 0.26 per million.229 Most
reported cases are in white women; one study of 37 women
with primary melanoma of the vagina reported 84% of patients
to be white and only 3% African American.226 According to a
report by Hu et al.230 analyzing SEER data from 1992 to 2005
on 125 cases of vaginal melanoma with known race or ethnic-
ity, there is no significant difference in the incidence rate of vag-
inal melanoma between whites and African American women,
with a white to black ratio of 1.02 after age adjustment. In the
report by Creasman et al.,4 most patients were of advanced age
at presentation, with only 23% of patients diagnosed before the
age of 60; 28% were diagnosed between the ages of 60 and 69,
28% were diagnosed between the ages of 70 and 79, and 22%
Clinical Radiation Oncology
were diagnosed at age 80 or older.
Melanomas arising from the vaginal mucosa are thought to
originate from mucosal melanocytes in regions of melanosis or
from atypical melanocytic hyperplasia. Grossly, melanoma of
the vagina tends to be pigmented and may present as a dark
mass, plaque, or ulceration; multifocal presentation is also
common. The most common appearance is polypoid-nodular.231
The most common location at presentation is the anterior
vaginal wall and lower one-third of the vagina.226,227,232
In a case series of 37 women with primary vaginal melanoma
reported by Frumovitz et al.,226 median tumor size at presenta-
tion was 3 cm (range, 0.4 to 5 cm), with median depth of inva-
sion of 7 mm (range, 1 to 21 mm). Twenty-one percent of patients
presented with multifocal disease; 24 patients (65%) presented
with lesions in the distal third of the vagina or introitus.
Microscopically, tumors may be composed of epithelioid,
spindle, or nevus-like cells and stain frequently positive for
S-100 protein, HMB-45, and melan-A. When S-100 is negative
or only focally positive, tyrosinase and MART-1 are useful
markers. Poorly differentiated tumors may be difficult to dis-
tinguish from carcinomas or sarcomas. Tumor thickness cor-
relates with prognosis and may be measured by the methods
described by Breslow.233
Vaginal melanoma is a highly malignant disease with a pro-
pensity for early hematogenous spread. The most common
presenting symptoms reported have been slight vaginal bleed-
ing and vaginal discharge, which is usually blood-tinged, foul
smelling, or purulent.121 Reid et al.234 reviewed 115 patients
with primary melanoma of the vagina and found depth of inva-
sion and lesion size >3 cm to be negative prognostic factors.
Stage was not found to be prognostic for outcome, but only 42
of the 115 patients had this information available. Compared
with women who have SCC, patients with vaginal melanoma
have a significant 1.5-fold increased risk of mortality.1
Treatment Options
Primary vaginal melanoma is uncommon and, as a result,
treatment outcomes for only a small number of patients have
been reported121,226,235238 and it is difficult to make definitive
treatment recommendations. Treatments used in published
series include wide local excision, radical surgery, radiation
and chemotherapy, or a combination of modalities. Overall
prognosis is poor, with historic 5-year survival rates ranging
from 5% to 30% regardless of treatment modality or extent
of surgical resection.234,235,238 There is a high rate of distant
metastases, ranging from 66% to 100%.235,239,240
Regardless of primary treatment, outcomes have been dis-
appointing. Some authors advocate radical surgical resec-
tion.241243 Geisler et al.241 recommend primary pelvic exentera-
tion for vaginal melanomas with >3-mm invasion, reporting a
5-year survival rate of 50% if pelvic nodes are free of disease.
Morrow and DiSaia,243 in their review of gynecologic mela-
noma, recommend radical surgery based on a review of the
1480 Section III Clinical Radiation Oncology Part J Gynecologic
literature revealing 3 of 19 long-term survivors after exentera-
tion with wide local excision. Chung et al.235 reviewed 19 cases
of primary vaginal melanoma treated between 1934 and 1976.
All patients who received wide local excision developed recur-
rence. Five-year survival was only 21%. Miner et al.244 reported
on 35 patients treated at Memorial Sloan-Kettering Cancer
Center from 1977 to 2001. Sixty-nine percent underwent sur-
gery, which was either en bloc removal of the involved pelvic
organs, wide excision, or total vaginectomy, with elective pelvic
lymph node dissection in 74% of cases. Thirty-one percent of
patients received definitive radiation. Primary surgical therapy
was significantly associated with a longer overall survival time
(25 vs. 13 months). Recurrence-free survival was not found to
correlate with surgical extent.
Several series comparing radical surgery and local excision
find equivalent outcomes.121,236,245,246 In general, treatment
modality does not appear to significantly affect survival. Bonner
et al.247 reported on nine cases of vaginal melanoma. Three
patients were treated with wide local excision and six under-
went radical surgery. All nine patients developed locoregional
recurrence. As a result, these authors suggest adding pelvic
radiation therapy to improve local control. The use of wide local
excision followed by postoperative EBRT and brachytherapy
has been proposed. A recently published review by Frumovitz
et al.226 reported that radiation after wide local excision can
reduce local recurrences. However, most patients develop dis-
tant metastases, most commonly in the lungs and liver.
Given the high rates of distant metastases, chemotherapy
has been used, either alone or in conjunction with radia-
tion.226,248 The use of systemic chemotherapy or immunotherapy
has not been shown to improve patient outcomes thus far.248
Frumovitz et al.,226 in their review of 37 women with stage I
melanoma of the vagina treated at MDACC between 1980 and
2009, report very poor prognosis even in this group of patients
with localized disease, with a 5-year overall survival rate of
20%. In that study, 10% of patients received nonsurgical treat-
ment with radiation, chemotherapy, or both. Patients treated
surgically had significantly longer survival times compared with
those treated nonsurgically. Radiation delivered after wide local
excision reduced local recurrence and demonstrated a trend
toward longer survival times, from 16.1 to 29.4 months.
Retrospective data suggest that radiation may improve local
control for vaginal melanoma.121,249 Among the few long-term
survivors reported in the literature are a handful of patients who
were treated with radiation. Harwood and Cummings250
described a complete response in four patients with vaginal mel-
anoma treated with radiation, although two subsequently
relapsed. Rogo et al.,251 in their series of 22 cases of vulvovaginal
melanoma, reported comparable results for surgery and radia-
tion, with eight patients (36%) alive 5 years after treatment. Petru
et al.,249 in their series documenting 14 patients treated for pri-
mary malignant melanoma of the vagina, noted that three of nine
patients treated with radiation, either as primary treatment
(n = 2) or in the postoperative setting (n = 1), survived longer than
5 years. Median overall survival for all patients was 10 months,
with a 5-year disease-free survival rate of 14% and an overall
survival rate of 21%. Typically, vaginal melanoma is treated simi-
larly to vaginal carcinoma, with volumes and doses ranging from
50 Gy for subclinical disease to 75 Gy for gross tumor. Radiation
is offered in the adjuvant setting based on limited data suggesting
an improvement in local control.
Sarcoma
Sarcomas represent 3% of all primary vaginal cancers.4 In a
report based on data from the NCDB between 1985 and 1994,4
there were 135 cases of primary vaginal sarcoma, with het-
erogeneous histologies and varying age. Twenty-two percent of
patients were under 14 years of age, with a median age at pre-
sentation of approximately 50 years. In the pediatric popula-
tion, embryonal rhabdomyosarcoma or sarcoma botryoides is
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the most common histology,252 with 90% of cases occurring in
children younger than 5 years of age.253 Vaginal sarcoma most
frequently presents as an asymptomatic vaginal mass.119 In
one series, this was the most frequent symptom, found in 35%
of patients, followed by vaginal, rectal, or bladder pain (26%),
bleeding or serosanguineous discharge from the vagina or rec-
tum (18%), leucorrhea (9%), dyspareunia (7%), or difficulty in
micturition (7%).
Leiomyosarcoma is the most common histology in adults,
representing up to 65% of all vaginal sarcoma cases; however,
overall numbers are very small, with <150 published reports in
the literature.119 Other less common histologies include malig-
nant mixed mllerian tumor (MMT), endometrial stromal sar-
coma, and angiosarcoma.254,255 Vaginal leiomyosarcomas origi-
nate from the smooth muscle of the vaginal wall, but may also
develop from smooth muscle cells in tissues adjacent to the
vagina. Grossly, patients present with a palpable submucosal
nodule, although advanced tumors may demonstrate palpable
necrosis or exophytic polypoid tissue.256 Criteria to distinguish
between benign leiomyoma and leiomyosarcoma include more
than five mitoses per 10 high-power fields, moderate or
marked cytologic atypia, and infiltrating margins.257 Due to
considerable variation in smooth muscle tumors from area to
area, adequate sampling is recommended to achieve an accu-
rate diagnosis. Microscopically, leiomyosarcomas demonstrate
interlacing bundles of spindle-shaped cells, with blunt-ended
nuclei and fibrillar cytoplasm.121,257 Leiomyosarcomas have a
predilection for the posterior vaginal wall, with published
reports suggesting approximately 43% to 45% in the posterior
vagina, 17% to 21% anteriorly, and 34% to 39% laterally.119,258
MMT, also called carcinosarcomas, are highly aggressive,
biphasic neoplasms composed of an epithelial component as
well as a sarcomatous component. The epithelial component in
vaginal MMT is most often SCC.254 The sarcomatous compo-
nent can be composed of fibroblasts and smooth muscle or
include cartilage, striated muscle, bone, and other heterolo-
gous tissues. The metaplastic carcinoma theory suggests that
there is a common cell of origin for MMT, with carcinoma giv-
ing rise to the sarcomatous component via metaplasia.259 The
most common differential diagnosis is sarcomatoid carcinoma.
The spindle and carcinomatous components are positive for
cytokeratin in sarcomatous carcinoma, whereas MMT demon-
strates a sarcomatous component that is positive for vimentin,
with the carcinomatous component positive for cytokeratin.254
The first case of vaginal MMT was described in 1975 by
Davis and Franklin260; since then, only 11 cases have been
reported in the literature, with age ranging from 57 to
74 years.254,261265 At least one case report of MMT of the vagina
detected high-risk HPV in both the carcinomatous and sarco-
matous components, suggesting that some vaginal MMTs may
be related to HPV.261 Fewer than 10 cases of angiosarcoma of
the vagina have been reported in the literature.266,267 A history
of pelvic radiation is a risk factor for pelvic sarcomas, particu-
larly angiosarcoma.255
Prognostic Factors
Review of the literature indicates that vaginal sarcomas
undergo early hematogenous dissemination as well as frequent
local recurrence. Pulmonary metastases are common.119,258
Adverse prognostic factors for vaginal sarcoma include high
histologic grade, stage, size >3 cm, infiltrative pushing borders,
and cytologic atypia.120
Treatment Options
Unfortunately, most sarcomas are diagnosed at an advanced
stage. Despite surgery and the use of adjuvant radiation ther-
apy in select cases, sarcoma patients sustain poor outcomes
due to a high incidence of local recurrence and distant metas-
tasis. Locoregional control is especially important for vaginal
leiomyosarcoma. A series by Peters et al.268 reported on 17