Review Article

Complications of Pelvic Radiation in Patients Treated for

Gynecologic Malignancies
Akila N. Viswanathan, MD, MPH1; Larissa J. Lee, MD1; Jairam R. Eswara, MD2; Neil S. Horowitz, MD3;
Panagiotis A. Konstantinopoulos, MD4; Kristina L. Mirabeau-Beale, MD5; Brent S. Rose, MD5; Arvind G. von Keudell, MD6;
and Jennifer Y. Wo, MD7

Radiation therapy is a critical treatment modality in the management of patients with gynecologic tumors. New highly conformal
external-beam and brachytherapy techniques have led to important reductions in recurrence and patient morbidity and mortality.
However, patients who receive pelvic radiation for gynecologic malignancies may experience a unique constellation of toxicity
because of the anatomic locations, combination with concurrent chemotherapy and/or surgery, as well as potential surgical interven-
tions. Although side effects are often categorized into acute versus late toxicities, several late toxicities represent continuation and
evolution of the same pathologic process. Comorbidities and radiation dose can significantly increase the risk of morbidity. Current
understanding of the incidence of various morbidities in patients treated with current radiation techniques for gynecologic malignan-
cies, the impact of chemotherapy and surgery, treatment options for those effects, and future areas of research are highlighted. Can-
cer 2014;120:3870-83. VC 2014 American Cancer Society.

KEYWORDS: radiation, morbidity, toxicity, gynecologic cancer.

INTRODUCTION
Approximately 94,890 women will be diagnosed with gynecologic cancer in the United States in 2014.1 Although multi-
modality therapy may be curative, morbidity because of treatment presents a significant concern to patients, health care
providers, and society. In this article, we highlight novel techniques for treating radiation-related morbidities as well as the
role of surgical and medical management.

Gastrointestinal Complications of Pelvic Radiation

Incidence of gastrointestinal complications
One prospective trial demonstrated that approximately 30% of postoperative patients with endometrial cancer who
received radiation therapy (RT) experienced acute diarrhea, which persisted in approximately 10% of patients up to 5
years after treatment.2 Late toxicities are less common, and significant gastrointestinal (GI) symptoms (Common Termi-
nology Criteria for Adverse Events [CTCAE] grade 3) range from 3% to 8% of patients who receive postoperative treat-
ment to the pelvis3,4 and up to 20% of patients with locally advanced and unresectable tumors who require external-beam
RT (EBRT) with both dose escalation and brachytherapy.5 Most recently, the use of image-guided and high-dose-rate
(HDR) brachytherapy has significantly reduced overall long-term complication rates from 22.7% to 2.6%.6,7
A validated preradiation biomarker-assessment tool to determine the risk of future enteritis is not available. Recent
genome-wide association studies (GWAS) have analyzed single-nucleotide polymorphisms (SNPs) and identified those
that may be associated with GI toxicity, including 1 region of chromosome 11q14.3 associated with rectal bleeding in
prostate cancer.8 Others have analyzed serum and fecal markers in an attempt to intervene early with treatment but have
reported no conclusive findings.

Corresponding author: Akila N. Viswanathan, MD, MPH, Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, 75
Francis Street, ASB 1, L2, Boston, MA 02115; Fax: (617) 278-6988; aviswanathan@lroc.harvard.edu
1
Department of Radiation Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts; 2Division of Urology, Washington
University School of Medicine, St. Louis, Missouri; 3Division of Gynecologic Oncology, Brigham and Women’s Hospital, Boston, Massachusetts; 4Department of
Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; 5Harvard Radiation Oncology Residency Program, Boston, Massachusetts; 6Harvard Ortho-
pedic Combined Residency Program, Boston, Massachusetts; 7Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.

We thank Barbara Silver and Remi Nout, MD for reviewing the article.

DOI: 10.1002/cncr.28849, Received: March 28, 2014; Revised: April 30, 2014; Accepted: May 1, 2014, Published online July 23, 2014 in Wiley Online Library
(wileyonlinelibrary.com)

3870 Cancer December 15, 2014

 Morbidity From Pelvic Radiation/Viswanathan et al

Diagnosis of GI complications
For common symptoms like acute diarrhea, mucus, tenes-
mus, pain, or hemorrhoids controlled with medication,
radiologic or invasive diagnostic tests such as endoscopy
are not recommended (see Table 1). If symptoms progress,
a computed tomography (CT) scan may be obtained;
radiographically, the small bowel within the irradiated pel-
vis can become thickened, which can easily be appreciated
on CT scans (Fig. 1). All patients who present with persis-
tent, symptomatic rectal bleeding should be evaluated by
flexible sigmoidoscopy or colonoscopy to rule out disease
recurrence or an occult primary tumor. For patients with
chronic radiation proctitis, endoscopic findings can
include rectal pallor, telangiectasias (which are friable and
prone to bleeding especially if the patient is on anti-coagu-
lants), and possibly strictures, fistulae, or regions of ulcera-
tion (Fig. 2). Biopsies also should be avoided unless a new
malignant process is suspected. Interventions such as
argon-laser coagulation should be used judiciously to avoid
exacerbation of bowel injury (see Table 2).
Patient-related and treatment-related factors
associated with GI toxicity
Prior abdominal or pelvic surgery has been associated
with an increased risk of developing small bowel obstruc-
tions in patients who receive >50 Gray (Gy) of RT to the
pelvis and can lead to adhesions, which limit intestinal
displacement. In addition, patients with coexisting
comorbidities, including prior pelvic inflammatory dis-
ease, vascular disease because of diabetes or arteriosclero-
sis, collagen vascular disease, a smoking history, or
inflammatory bowel disease, may be at greater risk for
developing acute and long-term radiation side effects.5
Improvements in radiation technique to reduce GI
complications
Effective strategies to minimize or prevent GI toxicity
include multiple RT fields to avoid significant dose inho-
mogeneity, the use of a “belly board” with the patient in
the prone position, and treatment with the patient’s blad-
der full to optimize physical displacement of the small
bowel. Treatment planning with intensity-modulated RT
(IMRT) optimization may further decrease the risk of GI
toxicity. IMRT is a highly conformal, advanced type of
radiation that uses multiple beams to conform to the tu-
mor and minimize surrounding normal-tissue dose; it
requires complex treatment planning, which entails signif-
icantly more time than 3-dimensional (3D) conformal
RT (3D-CRT) radiation planning. Adaptive IMRT
(image-guided radiation, IGRT) with adjustments during
treatment may further reduce dose to normal tissues. Fig-
ure 3 depicts a 3D-CRT “belly board” 4-field plan

TABLE 1. Acute Toxicities of Pelvic Radiation

Toxicity Symptoms Diagnosis Treatment

GI (0-6 mo)
Enteritis Diarrhea, tenesmus, If severe, CT; consider Early changes (frequent loose stools, not watery): encourage
mucus C. diff testing oral fluids, psyllium, low fiber diet; for diarrhea (<4 episodes/
d), imodium, check electrolytes, consider IV fluids; for
diarrhea (4-8 episodes/d), lomotil, 1-2 3 weekly IV fluids; for
diarrhea (refractory), DTO drops, regular IV fluids, consider
hospitalization
Proctitis Rectal bleeding Sigmoidoscopy or Topical hydrocortisone/pramozine; steroid enemas, butyrate
anoscopy enemas, sucralfate enemas
Hemorrhoids Physical examination with Aquaphor/lidocaine topically (mixed 1:1); oral pain regimen if
visual inspection severe
GU (0-6 mo)
Cystitis Dysuria, frequency, Assess for UTI Antibiotics if infectious source; pyridium/ibuprofen if
urgency non-infectious; consider anticholinergic agents for
obstructive symptoms
Hematologic
Anemia Hematocrit <30 mg/dL Consider transfusion of packed erythrocytes
Neutropenia ANC <500/lL Infection risk precautions
Thrombocytopenia Platelets <40 mg/lL Consider holding radiation; transfuse platelets if count
<10 3 103/lL
Dermatologic (0-6 mo)
Dermatitis Pruritis, tenderness Moisturizing creams, Sitz bath, Domeboro soaks, antibiotics,
antifungal agents
Desquamation Pain, wound drainage Nonadherent hydrogel (Xeroform), or silver nylon dressing pads

Abbreviations; ANC, absolute neutrophil count; C. diff, Clostridium difficile; CT, computed tomography; DTO, diluted tincture of opium; GI, gastrointestinal; GU,
genitourinary; IV, intravenous; UTI, urinary tract infection.

Cancer December 15, 2014 3871

Review Article
compared with an IMRT plan. A recently published
randomized study evaluated the toxicity and clinical out-
comes of 44 patients with locally advanced cervical cancer
who received either whole-pelvis RT or IMRT at a dose of
50.4 Gy in 28 fractions administered with concurrent cis-
platin 40 mg/m2 followed by HDR intracavitary RT.
Compared with 3D-CRT, IMRT was associated with sig-
nificantly fewer grade 2 acute GI toxicities (63.6% vs
31.8%; P 5 .034) and grade 3 acute GI toxicities
(27.3% vs 4.5%; P 5 .47). In addition, IMRT was associ-
ated with less chronic GI toxicity (50% vs 13.6%;
P 5 .011). Dosimetric comparison between the 2 groups
demonstrated significantly less dose to the rectum and
small bowel, which likely accounted for these important
clinical differences.9
Total prescribed RT dose; daily fraction size; treat-
ment duration; and volume of small bowel, large bowel,
and rectum within the RT field all have been associated
with the risk of GI toxicity. Brachytherapy, that is, internal
radiation administered after the completion of external
radiation for patients with locally advanced cervical cancer,
Figure 1. Acute radiation enteritis manifests as diffuse thick-
ening, hyperemia, and hyper-enhancement (red arrows) of
the small bowel wall in the pelvis on computerized tomogra-
phy imaging.
Figure 2. (Left) Rectal proctitis and (Right) ulceration are shown (courtesy of Dr. John Saltzman).
3872
is required for curative management. New techniques
involving the use of 3D imaging with either CT or mag-
netic resonance imaging (MRI) (Fig. 4) allow for the place-
ment of dose away from critical surrounding normal tissues
in patients who receive HDR brachytherapy (Fig. 4). A CT
and MR contouring-atlas was recently published.10,11 It is
noteworthy that studies have demonstrated a significant
reduction in toxicity when using these techniques.6,7,12
Treatment of Common GI Toxicities
Acute radiation enteritis. The management of acute radi-
ation enteritis is mainly supportive. Patients who develop
diarrhea may be treated with fiber products (psyllium)
and probiotics, although the published studies to date
have yielded mixed results.13-17 Frequent use of antidiar-
rheal agents, such as loperamide or diphenoxylate and at-
ropine, starting with 1 tablet a day before the
development of diarrhea and increasing as needed, may be
indicated. Fluid status and electrolytes also should be
monitored carefully, because intravenous hydration may
also be required if patients are unable to adequately main-
tain fluid intake. Aggressive management during treat-
ment is important to reduce the risk of chronic
enteropathy. Sucralfate has been tested in randomized tri-
als and has demonstrated no benefit for either acute or late
symptom prevention when administered either immedi-
ately after RT18-21 or after argon plasma coagulation.22
Chronic radiation enteritis. Chronic radiation enteritis is
optimally managed by a multidisciplinary team, including
a radiation oncologist, gastroenterologist, medical oncolo-
gist, surgeon, nutritionist, and dedicated nursing staff.
Patients who develop malabsorption should be referred to
a gastroenterologist, and vitamin B12 levels should be
monitored and supplemented if necessary. Cholestyr-
amine may be useful in treating bile salt malabsorption.
Cancer December 15, 2014
 Morbidity From Pelvic Radiation/Viswanathan et al

TABLE 2. Late Toxicities of Pelvic Radiation

Toxicity Symptoms Diagnosis Treatment

GI (>6 mo)
Enteritis Urgency, fecal leakage, CT with or without EGD/ Diarrhea: psyllium, probiotics, low fiber diet; fecal
diarrhea; malabsorption colonoscopy; leakage: physical therapy for perineal
malabsorption: fecal fat, strengthening; malabsorption: vitamin B12,
breath test cholestyramine, parenteral nutrition,
gastroenterology evaluation
Proctitis Rectal bleeding, tenesmus, Bleeding, sigmoidoscopy Sulcrafate enema, steroids enema, argon laser
pain coagulation, hyperbaric oxygen
Fistula Malodorous discharge, fecal Surgical evaluation for resection vs. colostomy
incontinence
Stricture Pain, constipation, thin-caliber Surgical evaluation for resection, lysis of adhesions
stools vs. colostomy
Obstruction Nausea, pain, persistent ileus, Bowel rest; refractory: surgical evaluation for
adhesions resection vs. colostomy
GU
Fistula Discharge, incontinence, Cystoscopy, biopsy to Surgical repair, ileal conduit
urethral edema evaluate for recurrent
disease
Contracture Frequency, pain Urodynamics Cystectomy with ileal conduit or bladder
augmentation in severe cases
Cystitis Bleeding Cystoscopy Hyperbaric oxygen
Strictures Pain, hesitancy Retrograde urethrogram Surgical dilation (urethral); stent placement (ureteral),
urethroplasty or ureteroplasty
Gynecologic
Vaginal stenosis Bleeding with dilator use, Physical examination with Vaginal dilator; evaluation by sexual function clinic
and/or pain with assessment of narrowing/
intercourse length
Menopause Hot flashes Oral contraceptive, serotonin reuptake inhibitors,
natural products
Vaginal dryness Vaginal estrogen (caution in using for patients with
ER-positive adenocarcinoma)
Dermatologic
Telangiectasia -------
Fibrosis -------
Ulceration Pain Biopsy to exclude recurrent Hyperbaric oxygen
disease
Necrosis Severe pain, infection, Biopsy to exclude recurrent Hydrogen peroxide douching, metronidazole,
odorous disease hyperbaric oxygen
Bone (>3 mo)
Osteopenia DEXA Bisphosphonates; vitamin D and calcium
Insufficiency fracture Pain, inability to ambulate X-ray, CT, PET, MRI Pain management, weight-bear as tolerated,
physical therapy as recommended by orthopedics
Avascular necrosis Pain, disability X-ray, bone scan, CT, MRI Surgical repair (total hip replacement)

Abbreviations: CT, computed tomography; DEXA, dual-energy x-ray absorptiometry; EGD, esophagogastroduodenoscopy; ER, estrogen receptor; GI, gastroin-
testinal; GU, genitourinary; MRI, magnetic resonance imaging.

Figure 3. (A) Sagittal and (B) axial views of 3-dimensional conformal plans are compared with (C) an intensity-modulated radio-
therapy plan for postoperative endometrial cancer. These images demonstrate bowel sparing with the intensity-modulated radio-
therapy plan.

Cancer December 15, 2014 3873

Review Article
Figure 4. MR axial and sagittal (top) and CT (bottom) brachytherapy images for cervical cancer showing the optimized maximal
dose to the tumor while minimizing the dose to the bladder, rectum, and sigmoid.
For patients who develop chronic diarrhea, antidiarrheal
agents like loperamide may be helpful. Surgical resection
may be required in up to 30% of patients because of per-
sistent ileus, intestinal fistulization, or adhesions.23
After radiation, fibrosis and progressive obliterative
vasculitis may occur, resulting in the need for surgical inter-
vention. Extensive, dense interloop and pelvic bowel adhe-
sions may present as a small bowel obstruction, large bowel
stricture, or severe enteritis. Although preventive and non-
surgical management techniques are preferred, patients
who are refractory to these interventions require operative
management. The goals of operative management of irradi-
ated bowel are manifold. These include operating early,
minimizing dissection of adhesions to avoid bowel injury,
resecting rather than bypassing bowel to preserve as much
functional bowel as possible and avoid blind loop syn-
drome, and creating an anastomosis with unirradiated or
healthy-appearing irradiated bowel. If there is concern
regarding the vitality of an anastomosis, then there should
be a low threshold for proximal diversion. In addition, if
sufficient omentum is available, then creating an omental
J-flap to cover a denuded pelvis may prevent additional
adhesions and future obstructions. Because malnutrition is
often an important component of chronic radiation enteri-
3874
tis, perioperative nutritional support with parenteral nutri-
tion leads to improved outcomes.24
Acute radiation proctitis. Numerous anti-inflammatory
agents,21,25 intestinal protectants,26 intestinal antimotility
agents,27 and probiotics28 have been studied as preventa-
tive strategies; however, to date, none of these agents have
demonstrated the ability to definitively mitigate radiation
toxicity. The treatment of acute radiation proctitis is
mainly supportive and includes antidiarrheals and intrave-
nous hydration as needed. Several studies have also sug-
gested a potential benefit with short-chain fatty acid
butyrate enemas, which may aid in accelerating the heal-
ing process of acute radiation damage.29,30
Late radiation proctitis. If rectal bleeding does not cause
symptoms, then treatment is not always necessary, because
most cases will resolve spontaneously. For patients with
severe bleeding, antiplatelet or anticoagulation therapy
should be discontinued if possible. Stool softeners may
aid in minimizing damage to friable rectal tissue with the
passage of stool. Treatment with a 4-week course of met-
ronidazole also has been effective, possibly because of the
treatment of anaerobic bacteria, which may contribute to
hypoxia or immunomodulatory effects.31 For severe rectal
Cancer December 15, 2014

bleeding that is refractory to medical management,
patients may be referred for consideration of endoscopic
therapy with argon-plasma coagulation. In cases of
chronic rectal bleeding, hyperbaric oxygen has been effec-
tive in reducing chronic pelvic radiation toxicity that was
refractory to all other therapy. Hyperbaric oxygen is gen-
erally safe and well tolerated, but the limited number of
available treatment facilities, prolonged treatments, and
expensive treatment costs may be prohibitive.
Genitourinary Complications of Pelvic Radiation
Pelvic radiation for gynecologic malignancy may result in
both upper and lower tract genitourinary (GU) complica-
tions, which are dose-dependent and related to RT mo-
dality. Low-grade (grade 1-2) acute GU toxicity is
relatively common during EBRT, with an incidence of
17% to 40% in the definitive treatment of cervical cancer
with concurrent chemoradiotherapy.5 The incidence of
low-grade GU toxicity was similar at 43% in the Gyneco-
logic Oncology Group (GOG) GOG-99 study of postop-
erative RT for endometrial cancer.3 Severe urinary tract
toxicity is relatively rare during treatment (range, 2%-
5%). The Postoperative Radiation Therapy in Endome-
trial Cancer (PORTEC-2) trial demonstrated that urinary
frequency was more common after vaginal brachytherapy
than EBRT for endometrial cancer (an increase of 6% vs.
1% over baseline).2
Patient-related and treatment-related risk factors
for GU toxicity
Treatment-related factors that influence the risk of GU
toxicity include cumulative radiation dose, treatment vol-
ume, radiation modality (EBRT, brachytherapy, or both),
and prior pelvic surgery.32 The use of anticoagulation also
may lead to higher rates of post-treatment bleeding. In
patients who undergo radical hysterectomy, adjuvant
radiation may cause higher rates of bladder dysfunction,
hydroureteronephrosis, stress incontinence, and radiation
cystitis.33 Tobacco use has also been associated with fistula
formation in patients with stage IVA cervical cancer and
bladder involvement at diagnosis.34 The use of concurrent
chemotherapy reportedly does not increase the risk of late
GU complications in patients with cervical cancer.5
Treatment of common GU toxicities
Patients with dysuria, urgency, or frequency should have a
urinalysis and urine culture to assess for infection. After
infection has been excluded, treatment options for dysuria
include ibuprofen or phenazopyridine (Pyridium). Urinary
urgency is effectively managed with anticholinergics like
oxybutynin (Ditropan). Other agents, such as tolderodine
Cancer December 15, 2014
Morbidity From Pelvic Radiation/Viswanathan et al
(Detrol) and trospium (Sanctura), have similar efficacy but
lower rates of confusion, dry eyes, dry mouth, and consti-
pation compared with oxybutynin. If oral agents fail, then
cystoscopic injection of botulinum toxin A into the detru-
sor muscle reportedly is effective.35 Injections typically
give 6 to 9 months of relief and may be repeated.
Late GU effects
Several large institutional series reported grade 1 and 2 late
bladder complications in 28% to 45% of patients after de-
finitive RT for cervical cancer, whereas severe bladder dys-
function was relatively uncommon.5 Parkin et al noted a
26% incidence of severe urgency, frequency, and inconti-
nence after RT for cervical cancer. Urodynamics performed
before and after treatment revealed no differences in post-
void residual or maximum flow rate, although there were
decreases in maximum bladder capacity and bladder com-
pliance.36,37 In a series of 141 patients with cervical cancer
who received MR-guided brachytherapy, the rate of grade
1 and 2 late complications was 16%, and the rate of grade
3 and 4 late complications requiring cystectomy was
1.4%.7 In that study, the estimated dose to the 2-cc bladder
volume that resulted in a 10% risk of grade 2, 3, and 4
complications was 101 Gy.
In contrast, GU complications after postoperative RT
for endometrial cancer are less common, probably related
to the use of a single radiation modality (EBRT or brachy-
therapy) and a relatively moderate delivered dose. Low-
grade toxicity (grade 1-2) has been reported in 11% to
16% of patients in prospective trials, whereas grade 3 and 4
toxicity is rare.3,38 In patients with medically inoperable en-
dometrial cancer who receive HDR brachytherapy, the
reported major complications rate is 6%.39,40
The reported rates of major urologic complications
(grades 3-4) after RT for cervical cancer range from 1.3% to
14.5% at 3 years and most commonly include ureteral stric-
ture and hemorrhagic cystitis (Fig. 5). Hemorrhagic cystitis
may be treated with laser fulguration of ectatic vessels, intra-
vesical alum or formalin, or hyperbaric oxygen.41,42
Ureteral strictures have been noted in 5% of patients
after preoperative RT and in 2.5% of patients after defini-
tive RT alone for cervical cancer.5 Strictures of the ureter
may be managed by endoscopic procedures, such as dila-
tion or stent placement, but they often require ureteral
reimplantation or ileal ureteral substitution. The classical
teaching is that a ureteral stricture represents recurrent
cancer until proven otherwise; imaging with CT or MRI
is recommended. Patients who have bladder involvement
at diagnosis are at risk of developing a vesicovaginal fistula
after definitive RT.34 Moore and colleagues reported that
3875
Review Article
Figure 5. This image shows cystitis as observed during cys-
toscopy (courtesy of Dr. Graeme Steele).
the diagnosis of vesicovaginal fistula followed the diagno-
sis of stage IVA cervical cancer by 2.9 months.34 Fistulae
should first undergo biopsy to rule out recurrence of
malignancy. Small vesicovaginal fistulae may be managed
with simple fulguration and catheter drainage, but they
may require open surgical repair and, occasionally, uri-
nary diversion. Ureteroarterial fistulae are rarely encoun-
tered and have a 10% acute mortality rate.43 They should
be treated with endovascular stent placement or, if this
fails, open surgical repair.
Sexual Function After Pelvic Radiation
The most common gynecologic complications of pelvic
radiation are ovarian failure in premenopausal patients and
vaginal stenosis (VS) in any female patient who receives
vaginal radiation. VS is defined as narrowing or shortening
of the vaginal canal that may interfere with physical exami-
nation or sexual function. The incidence ranges from 20%
to 88% of patients.44,46-49 Other series have demonstrated
that patients who undergo surgery and receive HDR vagi-
nal brachytherapy alone have an incidence of VS from as
low as 2.5%,49 with the lowest rates reported in those who
receive low-dose-per-fraction regimens,50 to as high as 54%
with tandem/ovoid treatments. Vaginal telangiectasia and
pallor of the vaginal mucosa may be observed on follow-up
examination. Sexual dysfunction can occur in about half of
women who receive treatment for gynecologic malignancies
with radiation.51 Uterine distension is limited because of
fibrosis after pelvic radiation. Consequently, the delivery
of a full-term infant is not feasible after the uterus is
treated with the pelvic radiation dose required for primary
gynecologic malignancies.52
Time course of sexual dysfunction
Patients who receive radiation to the pelvis for locally
advanced cervical cancer will have their ovaries irradiated
3876
and, thus, will undergo menopause, typically within the
first 6 months after treatment.53 Temporally, VS is most
likely to occur within the first year of treatment but has
been observed in as short a time as 26 days and as far out
as 5.5 years from definitive therapy.44,45 The distal vaginal
mucosa has less radiation tolerance than the mucosa in the
upper region, and vaginal shortening may begin during
the course of RT.54 One randomized trial demonstrated
higher rates of VS with higher vaginal brachytherapy
doses.55 In terms of quality of life,56 a systematic review
concluded that survivors of gynecologic cancer experience
a broad range of sexual concerns after diagnosis and treat-
ment.57 In a study of patients with cervical cancer, com-
pared with 6-year to 10-year survivors, those who were 2
to 5 years out from diagnosis had more sexual worry and
body-image concerns. Notably, women who received
radiation and also underwent surgery experienced more
symptoms (P 5 .001), worse body image (P 5 .029), and
more sexual worry (P 5 .004) than women who under-
went surgery alone.58
Patient-related and treatment-related factors
associated with sexual dysfunction
Risk factors for VS include higher radiation dose, age
older than 50 years,44,49 lack of compliance with dilator
use, and concomitant chemoradiation therapy.49 Radia-
tion doses >80 Gy have been associated with a 10% to
15% increased risk of grade 2 vaginal toxicity, including
VS.59 Several studies have demonstrated that VS can have
a negative effect on patient sexual satisfaction because of
vaginal dryness, vaginal shortness, tightness, and
dyspareunia.
Treatment of sexual dysfunction
Menopausal symptoms, such as hot flashes and mood
changes, may be treated with supplemental oral progester-
one and/or estrogen or with serotonin-specific reuptake
inhibitors. The most commonly used intervention to pre-
vent VS is the use of vaginal dilators. In addition to dila-
tors, other treatments for stenosis include topical
estrogens and benzydamine, hyperbaric oxygen, and sur-
gical reconstruction, although these are based on small,
single-institution experiences.60
Vaginal necrosis (Fig. 6) may result from high doses
of radiation, especially in patients who have undergone
reirradiation. Patients who receive HDR, particularly
those treated with interstitial brachytherapy to the distal
vagina, may be at greater risk for vaginal necrosis.61
Hydrogen peroxide douching with a dilution of at least
Cancer December 15, 2014

Figure 6. Lower vaginal necrosis is shown (courtesy of Dr.
Beth Erickson).
1:10 with saline, oral metronidazole, and hyperbaric oxy-
gen may be considered.
Hematologic Toxicity of Pelvic Radiation
Patient-related and treatment-related factors
associated with hematologic toxicity
Higher doses of radiation may lead to chronic myelosup-
pressive effects and poor tolerance to subsequent chemo-
therapy by damaging the bone marrow (BM)
microenvironment.62 Large prospective studies have dem-
onstrated that the rate of grade 3 hematologic toxicity
with cisplatin-based pelvic chemoradiotherapy is approxi-
mately 20% to 25%. Extended-field RT leads to the irra-
diation of a larger proportion of the total BM and a
correspondingly higher rate of hematologic toxicity.63
Hematologic toxicity predisposes patients to infection,
hospitalization, and requirements for transfusions and
growth factors. Hematologic toxicity can also lead to
delayed or missed chemotherapy cycles and treatment
breaks, which potentially may compromise disease con-
trol. Furthermore, some patients with advanced disease
may benefit from intensified treatment,64 and hemato-
logic toxicity is a major barrier to the use of intensified
regimens, with up to 72% of patients experiencing grade
3 acute toxicity.
One important advantage of IMRT over conven-
tional technology is that IMRT results in less BM irradia-
tion, leading to lower rates of acute hematologic toxicity.65
Dose-volume parameters of pelvic BM irradiation are
Cancer December 15, 2014
Morbidity From Pelvic Radiation/Viswanathan et al
associated with hematologic toxicity.66 Other studies of
pelvic radiotherapy have validated this relation.67,68
Treatment approaches for limiting hematologic
toxicity
Sparing functional BM subregions instead of the entire
BM is one investigational approach to limiting hemato-
logic toxicity. Functional imaging with positron emission
tomography (PET), single positron emission CT
(SPECT), and/or specialized MRI sequences has been
proposed as a means to identify active BM subregions.69-
71
Irradiation of BM subregions with higher fluorodeoxy-
glucose (18F-FDG)-PET activity was associated with he-
matologic toxicity, whereas irradiation of subregions with
lower FDG activity was not.71
Management of acute hematologic toxicity
Weekly blood counts are routinely obtained. Chemother-
apy is typically held when the neutrophil count decreases
below 1500/lL. RT is typically held when the neutrophil
count approaches 500/lL to 1000/lL. Lymphopenia
rarely leads to adverse events, and no specific management
recommendations are made based on the lymphocyte
count. Platelet counts typically are monitored weekly, and
chemotherapy is held when counts fall below 100,000/
lL. Radiation therapy is typically continued until the
counts fall below 40,000/lL. Despite uncertainty, the
standard recommendation for patients with cervical can-
cer is to transfuse to maintain a hemoglobin level above
10 mg/dL for patient quality of life and treatment toler-
ance in addition to the potential impact on outcomes.
Bone Complications From Pelvic Radiation
Although uncommon, important sequelae of radiation to
bone, such as pathologic fractures, osteoradionecrosis, and
second malignancies,72 are associated with a decrease in
quality of life73 and increase in mortality.74,75 The factors
that influence bone toxicity include radiation dose (>50
Gy)76 as well as patient factors, such as age, menopausal sta-
tus, presence of underlying bone weakness (such as osteope-
nia or osteoporosis), corticosteroid use, cigarette smoking,
and vascular integrity. In addition, other risk factors have
been identified for sustaining a pelvic insufficiency fracture
(PIF), such as low body mass index, prior fractures, reirra-
diation, and prior hormone-replacement therapy.77,78
The reported incidence of PIF in women with gyne-
cologic tumors who receive RT ranges from 10% to
29%.77,79-81 The published 5-year cumulative rate of PIF
ranges from 5.1 to 45%.80-83 Greater than 60% of
patients present with multiple fractures involving the sac-
rum, acetabulum, or pubic bone; up to 50% of fractures
3877
Review Article
Figure 7. Avascular necrosis of the femoral head in a 50-year-
old 13 years after chemoradiation for cervical cancer. The
patient presented with 4 months of progressive right hip pain,
and had a right femoral head/acetabulum pathologic fracture
identified on (Left) x-ray and (Right) computed tomography.
are bilateral, 10% to 20% occur in the pubic bone, and
5% occur in the acetabulum.84 Grigsby et al85 investi-
gated 207 patients who received RT for gynecologic
malignancies and observed an incidence of femoral neck
fractures (FNFs) of 4.8%, with a 5-year cumulative rate of
11%. Avascular necrosis of the femoral head may occur in
conjunction with pelvic fractures because of generalized
bone weakness (Fig. 7).
Diagnosis of bone complications
The diagnosis of radiation-induced PIF (Fig. 8) or FNF is
often delayed, because the clinical presentation and radio-
graphic findings can mimic metastatic lesions, hip osteoar-
thritis, and spinal or lumbar stenosis. Common clinical
features are usually nonspecific and include severe back,
hip, and leg pain. Radiographic findings are usually equiv-
ocal and, in most patients, CT imaging is necessary.86,87
In the absence of radiographic evidence and an equivocal
CT, MRI may aid in the diagnosis by depicting high sig-
nal intensity on T2-weighted images, representing BM
edema, and a fracture line observed on T1-weighted
images.81,88,89 Bone scintigraphy is sensitive for detecting
PIF. A common feature is an H-shaped pattern of
increased radionuclide uptake occurring across the sacrum,
representing symmetric sacral ala fractures.88
Treatment of bone complications
A 4-level instability classification system with subcategori-
zation has been proposed to guide the management of PIF
based on the ability of the bony and ligamentous pelvic
structures to withstand physiologic loads without displace-
ment. The amount of instability indicates operative versus
nonoperative treatment measures.90 The classification rec-
ommends nonoperative treatment for stable type I frac-
3878
tures, nonoperative or minimally invasive surgical fixation
for type 2 fractures, and surgical stabilization for type 3 and
4 fracture patterns. Nonoperative treatment measures usu-
ally consist of a combination of nonsteroidal anti-
inflammatory and pain medication and slow progression
from bed rest to full mobilization with full weight-bearing
on the affected side. A prolonged course of physical therapy
ranging from 6 months to 12 months is often required. If
the pain persists longer than 8 weeks, then repeat imaging
of the pelvis is indicated to evaluate for fracture healing and
new onset of instability.91 For incomplete and isolated sac-
ral ala fractures, sacroplasty may be considered.
Unlike PIF, FNF usually requires surgical interven-
tion within 24 to 48 hours. FNF in irradiated bone has
been initially treated with hemiarthroplasty, but pub-
lished data demonstrate that 50% of patients developed
protrusio acetabuli.92 Therefore, the current treatment of
choice is a total hip replacement with increased stabiliza-
tion of the acetabulum because of a higher incidence of os-
teolysis.93 Overall, PIF and FNF are complex and require
a multidisciplinary team approach, including the radia-
tion oncologist, gynecologist, radiologist, orthopedic sur-
geon, physiatrist, and physical therapist, to successfully
manage the pathologic disease process.
Dermatologic Toxicity of Pelvic Radiation
Patient-related and treatment-related factors for
dermatologic toxicity
The risk of skin toxicity as well as its onset, severity, and
duration are strongly affected by clinical and treatment-
related factors. Vascular disease, smoking, and poor nutri-
tion may impair acute and long-term recovery of the der-
mis and subcutaneous tissues. Compromised wound
healing after surgery may lead to delays both in the initia-
tion of RT and during the actual treatment. A robust,
radiation-induced skin reaction may occur in a patient
with a high body mass index because of the presence of
skin folds and may be compounded by concurrent fungal
or bacterial infection. IMRT also may have an advantage
in reducing acute skin toxicity in the treatment of vulvar
cancer by lowering the radiation dose within the skin and
subcutaneous tissues, particularly within the groin (Fig.
9).94 For cases in which the distal vagina or vulva is not
within the target volume, specific radiation techniques
may be used to avoid flashing the skin of the perineum,
perianal region, and gluteal fold.
Acute dermatologic effects of pelvic RT
Currently, the Radiation Therapy Oncology Group
(RTOG)/European Organisation for Research and Treat-
ment of Cancer skin toxicity score is widely used in
Cancer December 15, 2014
 Morbidity From Pelvic Radiation/Viswanathan et al

Figure 8. (A) Sacral insufficiency fracture 2 years after treatment. An axial computed tomography (CT) scan demonstrates a lin-
ear lucency that extends to the anterior cortex, with a mild associated cortical step-off and ill-defined sclerosis adjacent to the
lucency. This region was mildly avid on fluorodeoxyglucose positron emission tomography (FDG-PET). (B) A pubic symphyseal
fracture 1.5 years after treatment. The FDG-PET image reveals the hypermetabolic focus indicative of partial healing in the region
of the fracture. (C) Axial CT slices reveal the fracture lucency with adjacent sclerosis. Both patients required conservative meas-
ures, including pain medication and weight-bearing as tolerated.

Figure 9. Shown are (A) intensity-modulated radiotherapy (IMRT) versus (B) 3-dimensional conformal radiotherapy treatment
plans for a patient with vulvar carcinoma. The IMRT plan depicts femoral head sparing.

clinical practice and research. Grade 1 reactions include
folliculitis, faint or dull erythema, epilation, dry desqua-
mation, or decreased sweating. At a dose of 40 Gy, grade
2 reactions are typically observed, defined as tender and
edematous erythema with patchy, moist desquamation in
skin folds and associated pain. Grade 1 and 2 skin reac-
tions are common in gynecologic RT, with an incidence
of 10% to 50% in prospective randomized trials of cervi-
cal and endometrial cancer3,95 and 85% to 100% in the
treatment of vulvar cancer.94,96,97 Grade 3 skin reactions
are associated with confluent moist desquamation when
doses exceed 50 to 60 Gy with bolus placement. Grade 4
skin reactions include skin ulceration, hemorrhage, and
necrosis. Severe skin reactions are rare (range, 1%-5%) in
the treatment of endometrial and cervical cancer,3,95,98
whereas patients with vulvar cancer are at significantly
higher risk (range, 24%-53%) of moist desquamation and
wound complication.96,97 Acute skin reactions typically
peak within 1 or 2 weeks after treatment, with a relatively
rapid healing time of 3 to 4 weeks. IMRT may decrease
the risk of vulvar skin toxicity, and 1 series reported no
grade 3 groin skin desquamation.94
Treatment of dermatologic toxicities
An acute skin reaction is generally apparent after 2 or 3
weeks of pelvic EBRT with conventional dose fractiona-
tion. With a 4-field beam arrangement, mild erythema is
most commonly observed in the vulva, perineum, and
the inguinal and gluteal folds. Mild skin reactions, such
as erythema, may be treated with topical moisturizers
without added perfumes or metals like zinc or silver,
which can irritate the skin or enhance the reaction.
Moisturizing creams may prevent the onset and severity
of erythema, although this warrants further study. Daily
use of a sitz bath with the addition of sodium bicarbon-
ate, Epsom salts, or Domeboro soaks may provide symp-
tomatic relief. Gentle cleaning with a mild, unperfumed
soap is advised for folliculitis.
In patients with vulvar cancer, skin overgrowth of
Candida is common and may be identified by white

Cancer December 15, 2014 3879

Review Article
plaques over the skin. Daily treatment with fluconazole
for the remainder of the treatment course may provide sig-
nificant symptomatic relief and promote healing. The
patient should also be encouraged to wear loose-fitting
and cotton clothing and to avoid temperature extremes.
In the setting of pruritis, 1% hydrocortisone cream may
be helpful. Patients may develop skin warmth in the irra-
diated region without the presence of cellulitis; however,
caution must be exerted with frequent skin checks to
ensure that the area of redness is not rapidly progressing.
For patients with desquamation, the application of
silver clear nylon,99 nonadherent or hydrogel dressings,
which have been used extensively for first-degree burns,
creates a moist environment that stimulates wound heal-
ing. Vaseline gauze impregnated with antibiotics may also
provide topical relief and prevent secondary infection,
although the routine use of antibiotics has not been sys-
tematically studied. A treatment break should be consid-
ered to allow for skin healing as well as pain medications,
such as nonsteroidal anti-inflammatory drugs or narcotics
for symptom control. In the setting of a severe wound
reaction, a wound-care referral may be considered.
Late dermatologic effects
The late effects of gynecologic RT may include hyperpig-
mentation or hypopigmentation, telangiectasia, textural
changes (xerosis and hyperkeratosis), or thinning of the
skin because of atrophy, with a reported incidence of 0%
for cervical cancer (grade 3) and up to 20% in patients
with vulvar cancer (grade 2).100,101 In the months after
RT, folliculitis is common because of regrowth of
occluded hair follicles, sweat glands, and sebaceous glands
and may be relieved with warm compresses or occasionally
may require antibiotics. Subcutaneous fibrosis with asso-
ciated woody thickening of the skin may also be observed,
although tissue retraction and pain are less common.
Recurrent episodes of cellulitis, specifically erysipelas, are
reported in 1% to 16% of patients who have vulvar can-
cer, and the greatest risk is reported after inguinal lymph
node dissection and postoperative RT.102 Patients who
receive cumulative vulvar doses in excess of 60 to 70 Gy or
an interstitial brachytherapy boost may be at higher risk
for severe complications.103,104 Twice daily use of a 1:10
diluted hydrogen peroxide douche can prevent the forma-
tion of necrotic tissue, particularly in previously irradiated
patients. Additional assessment tools for chronic skin tox-
icity are needed to describe the degree of skin reaction and
pain and the impact on quality of life.
Surgical Implications of Radiation-Induced
Toxicity
After radiation, subsequent postsurgical wound healing
may be compromised. Prior RT can complicate not only
3880
abdominal wounds created to address intra-abdominal
chronic radiation complications but also the surgical man-
agement of recurrent vulvar malignancies. Wound infec-
tion, dehiscence, and delayed wound healing are common
and require prolonged management. This poor healing is
likely because of poor vascularity or impaired regeneration
capacity after radiation. In addition, repeat radical vulvar
excisions often do not heal well and may require transpo-
sition, rotational, or advancement flaps. These flaps can
be cutaneous or myocutaneous in nature.105 For late
wound breakdown, ulceration, or necrosis, hyperbaric ox-
ygen should be considered.106,107
Chemotherapy Implications of Radiation-
Induced Toxicity
Although data on late toxicity are sparse and, thus, are
insufficient for drawing firm conclusions, data from a
meta-analysis108,109 and from individual studies (such as
cervical cancer trial RTOG 900198) suggest that there
may be no significant differences in the types or gravity of
late effects between concurrent chemoradiation and RT
alone.108,109 Specifically, only a small number of women
across all trials (range, 1%-3%) experienced serious late
toxicities (mainly late rectal, bladder, intestinal, and vagi-
nal toxicities). Chemotherapy after pelvic RT is routinely
administered in endometrial cancer, and this approach
has been well studied in this disease.110,112 In those stud-
ies, increased hematologic toxicities were observed in
patients who were receiving chemotherapy who had previ-
ously received radiation to the pelvis, although adminis-
tration of platinum-based chemotherapy after pelvic RT
was feasible. Growth factor support should be strongly
considered for chemotherapy administered after pelvic
RT. Modification and/or slow escalation of the doses of
chemotherapy administered after pelvic RT should be
considered, and this strategy has been used in the ongoing
GOG 258 endometrial trial (4 cycles of carboplatin at an
area under the concentration time curve [AUC] of 5 and
escalated to an AUC of 6 if tolerated and paclitaxel
175 mg/m2 every 3 weeks with granulocyte-colony–
stimulating factor support). Administration of sequential
chemotherapy and RT as sandwich therapy (i.e., chemo-
therapy, followed by pelvic RT, followed by further chem-
otherapy) demonstrated the completion of all planned
cycles of postradiation chemotherapy in approximately
75% of patients.113,114 The administration of future
chemotherapy for metastases may be more difficult,
depending on the tolerance of prior chemoradiotherapy.
Conclusions
Administering standard pelvic radiation results in the
potential for toxicities. IMRT may reduce this risk in some
Cancer December 15, 2014

instances. Major morbidities are relatively rare. Comorbid-
ities play an important role in the risk of radiation-induced
toxicities. Both during and after RT, careful management
and long-term monitoring of patients who are treated for
gynecologic malignancies are necessary. Future diagnostic
testing may assist in determining which patients have the
greatest risk for toxicity and will benefit most from frequent
monitoring and early intervention.
FUNDING SUPPORT
Dr. Viswanathan receives funding from the National Institutes of
Health (grant R21 CA 167800).
CONFLICTS OF INTEREST DISCLOSURES
The authors made no disclosures.
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