ADJUVANT THERAPY IN

EARLY ENDOMETRIAL
CANCER
WHEN TO GO ?
K.S.Reddy
Pondicherry

CANCER INCIDENCE - ESTIMATES

GLOBOCAN, IARC
INDIA

USA

YEAR

AGE
GROUP

CERVIX
UTERI

CORPUS
UTERI

CERVIX
UTERI

CORPUS
UTERI

2012*

AGE < 65

107287

9178

10545

29041

AGE > 65

15557

3147

2421

20604

AGE < 65

115060

9985

10819

30341

AGE > 65

17254

3492

2676

22859

2015*

Accts for 1.1% of all cancers as compared to 7% in USA

Introduction
EC usually diagnosed at early stage (up to 80%
diagnosed as stage I, 13% as stage II)
5-year OS as high as 88% in stage I disease.
Subgroups of patients with early stages have
significantly decreased 5-OS rates, based on
various prognostic factors, such as
Myometrial invasion & grade 3 have a 5-OS of 66%.

Endometrial cancer is often divided into 2 subtypes:

Type I (75% of cases) etiologically related to

unopposed estrogens and occurs mostly in

Hyperplastic Endometrium - Estrogen related.
Younger, Perimenopausal and Heavier patients
Better prognosis
Type II (10% of cases) occurs mostly in
Atrophic Endometrium with 3 atypical
histological subtypes such as clear cell,
papillary serous cancer and poorly differentiated
Associated with high virulence,
advanced stage at diagnosis and poor prognosis.
Unrelated to estrogen stimulation
Occurs in older & thinner women
5

Surgery is the primary treatment of both localized

and advanced disease,
Adequate surgical staging and pathological review
are the prerequisites for any discussion about
individual need for an adjuvant therapy

Staging FIGO 1988

I A: Tumor limited to endometrium
I B: Invasion to < 50% of
myometrium
I C: Invasion to > 50% of
myometrium
II A: Cervical glandular involvement
only
II B: Cervical stromal invasion
III A: Tumor invades serosa and/or
adnexa and/or positive
peritoneal cytology
III B: Vaginal metastases
III C: Metastases to pelvic or para
aortic nodes
IV A: Tumor invasion of bladder
and/or bowel mucosa
IV B: Distant metastases, including
abdominal metastases and/or
inguinal lymph nodes

FIGO 2010

I: Tumor confined to the corpus uteri

I A: No or < half myometrial invasion
I B: Invasion half of myometrium
II: Cervical stromal invasion but not
beyond the uterus
III: Local and/or regional spread
III A: Tumor invades the serosa of the
corpus uteri and/or adnexa
III B: Vaginal and/or parametrial inv
III C: Metastases to pelvic and /or PA LN
C1: Pelvic node involvement
C2: PA LN involvement pelvic
lymph node involvement
IV A: Tumor invades bladder and/or
bowel mucosa,
B: Distant metastases (abd mets/
inguinal LN mets)
Peritoneal Cytology is done, does not affect staging
7

Proposed definition of risk

RISK GROUPS (1)

Low risk:
Grade 12 histology, with invasion through
less than 50% of the myometrium.
Grade 3 without myometrial invasion.
Disease confined to the uterine fundus.
No lympho-vascular space invasion (LVSI)
No evidence of metastases.
8

RISK GROUPS (2)

High-intermediate
Moderately-poorly differentiated tumor
Presence of LVSI
More than 50% myometrial invasion
Age >50 with any 2 risk factors above
Age >70 with any 1 risk factor
No evidence of metastases
All others considered as Low intermediate risk.
9

RISK GROUPS (3)

High risk:
Serosal involvement ( any Grade )
Positive Peritoneal Cytology
IC Gr. 3
Adnexal involvement
Pelvic or Para aortic nodal metastases
(any Grade and MMI)
10

Radiotherapy in high-risk early

endometrial cancer
Complex
Controversial
Confusing

11

PORTEC-1
PORTEC-1 study group (1990-97) aimed to
Determine the impact of pelvic irradiation without
additional brachytherapy on the outcome in patients with
early stage endometrial cancer
The surgical procedure was a simple
total abdominal hysterectomy and bilateral salpingo
oophorectomy (TAH-BSO) without any lymphadenectomy.
714 patients - IBG2, IBG3, ICG1, ICG2
(ICG3 specifically NOT included)
Randomized to NAT vs 46 Gy pelvic RT
No brachytherapy

12

Role of RT in non-formally staged EC?

PORTEC - 1
(Creutzberg CL et al, J Clin Oncol 2004, Scholten IJROBP 2005)

10 yr LR failure rate: S 14%, S+RT 5% (p < 0.001)

73% of LRFs were isolated vaginal
Subgroup Analysis of risk factors
Risk factors age 60, Gr 3, 50% myometrial inv.
If at least 2 of 3 risk factors present
10 yr. LRF rate: S- 23.1%, S+RT 4.6%
Late toxicity - 5 yr. actuarial rates
All grades: S 4%, S+RT 26% (p < 0.0001)
Grade 1:
S - 4%, S+RT 17%
Grade 3-4:
S+RT 3%
13

FIFTEEN-YEAR
RADIOTHERAPY
OUTCOMES OF
THE RANDOMIZED
PORTEC-1 TRIAL
CREUTZBERG et al.
IJROBP 81(4), 2011

14

Radiation therapy
Pelvic EBRT was administered with a target volume
that included the parametrial tissues, the proximal two
thirds of the vagina, and lymphatic drainage regions
along the internal iliac vessels up to the promontory.
The superior field border was at the L5S1 disc.
The total dose was 46 Gy in 2-Gy daily fractions.
The PORTEC trial was done before three dimensional
conformal treatment planning techniques had been
introduced. Radiation was delivered by
AP-PA opposed fields(30%), three-field (18%) or
four-field techniques (52%)
Calculation of the dose distribution on the central axis
and specification at isocenter or midplane
15

Role of RT in surgically staged EC

GOG # 99 (2004)

16

GOG # 99 (2004)
Complete surgical staging including pelvic and
para-aortic node sampling
Surgical stage IB, IC, IIA (occult) and IIB (occult)
All histologic types except serous papillary and
clear cell
Randomized to pelvic RT vs. no further therapy

17

GOG 99 (2004) at 4 years

(Keys, et al Gynecol Oncol 2004)
No RT arm (N = 202)WPRT arm (N = 190)

Vaginal Rec.

Pelvic Rec.

Distant Rec.

Over all survival

EBRT

No RT

EBRT

EBRT

No RT

EBRT

No RT

2(1.1%)

13(6.4%) 1(0.5%)

13(6.4%)

92%

86%

No RT

5(2.5%) 10(5.3%)

Statistically
significant

Statistically not
significant

18

GOG #99: CONCLUSION

Adjunctive RT in early stage intermediate risk
endometrial carcinoma decreases the risk of
recurrence, but should be limited to patients
whose risk factors fit a high intermediate risk
definition.
Use of adjunctive RT in women with
intermediate risk EC decreases the risk of
recurrences but has an inappreciable effect on
overall survival
Keys et al. Gynecol Oncol 2004; 92:744-751.
19

Patterns of failure in early endometrial cancer

undergoing surgery only implications for
treatment
The majority of pelvic failures in both PORTEC and
GOG 99 were isolated vaginal
Are non-radiated isolated vaginal failures curable?
Predictors of vaginal relapse
Gr 3 histology, LVSI+
(Mariani, Gyn Oncol 2005)

Can adjuvant vaginal brachytherapy address potential

vaginal failures, and improve the therapeutic index?
20

Two important phase III randomized trials

reported in 2007-2008

21

22

Trial design for ASTEC/EN.5

71% TAH BSO
29% TAH BSO PLN

Surgery

High risk pathology and no macroscopic disease

905 cases

RANDOMIZE
453 cases

No external beam RT
(51% Brachytherapy)

452 cases

External beam RT
(52% Brachytherapy)

Primary endpoint: Overall survival

Secondary endpoint: Recurrence-free survival
23

Outcomes of ASTEC/EN.5

24

Outcomes of ASTEC/EN.5
EBRT: N-452
OBSERVATION: N-453
Vag. Rec.

Pelvic Rec.

Distant Rec.

Over all
survival

EBRT OBSE EBRT OBSE EBRT OBSE EBRT OBSE

7
17
6
12
34
31
(1.5%) (3.8%) (1.3%) (2.6%) (7.5%) (6.8%)

25

84%

84%

ASTEC/EN.5 CONCLUSION
Overall morbidity (which included documented
postsurgical complications) was greater in the
radiation therapy study arm (60% vs 26%).
No differences in recurrence-free, diseasespecific, or overall survival (hazard ratio 1.01;
P = 0.98)
Although it was not a primary end point of the
study (Not randomized to receive or not)
Vault brachytherapy
Decreased the risk of isolated recurrence in the vagina
(hazard ratio: 0.53; P = .038).
This reduction in local recurrence did not influence survival.
26

 EBRT alone is not indicated in the treatment

of women with early-stage endometrial
cancer at intermediate risk of relapse
Further refinement of which subgroups of
women might benefit from treatment would
require an individual patient data metaanalysis.

27

28

PORTEC 2 (2008)
Vaginal brachytherapy versus external beam
pelvic radiotherapy for high-intermediate risk
endometrial cancer: Results of the randomized
PORTEC-2 trial
R. A. Nout, H. Putter, I. M. Joergenliemk-Schulz, J. J. Jobsen, L. C. Lutgens,
E. M. van der Steen-Banasik, J. W. Mens, A. Slot, V. T. Smit and C. L.
Creutzberg
Leiden University Medical Center, Leiden, Netherlands; University Medical
Center Utrecht, Utrecht, Netherlands; Medisch Spectrum Twente,
Enschede, Netherlands; MAASTricht Radiation Oncology Clinic, Maastricht,
Netherlands; Radiotherapy Institute Arnhem, Arnhem, Netherlands; Daniel
den Hoed Cancer Center, Rotterdam, Netherlands

29

PORTEC 2 Design
TAH / BSO no LND
Eligibility:
High intermediate risk group
-age>60+ IC G1-2 or IB G3
-stage IIa
N=427 pts

EBRT
N=214

Brachytherapy
N=213

Primary endpoint: rate of vaginal relapse

Secondary endpoints: OS, QOL
30

PORTEC 2 Trial Results

Median F/U 36 months

EBRT
Vaginal relapse:
1.9%
Loco reg. relapse: 2.5%
Distant relapse:
5.7%
Pelvic relapse:
0.6%
No deaths:
20 pts
DFS:
89%
OS:
90%

BT
0.9%
4%
6.3%
3.5%
20 pts
89%
90%
31

P
(p = 0.97)
(p = 0.15)
(p = 0.37)
(p = 0.03)

PORTEC 2 Toxicity Results

QOL Diarrhea
Impairment in:
daily activities
Decreased social:
functioning
G1-2 GI toxicity:
G1-2 GU toxicity:
Skin toxicity:

EBRT
~30%
~30%

BT
~10%
~13%

P
(p = 0.001)
(p = 0.03)

~20%

~10%

(p=0.001)

54%
27%
20%

13%
22%
2%

(p = 0.001)
(p=0.1)
(p = 0.001)
32

PORTEC 2 Conclusions
VBT as effective as EBRT for intermediate high
risk EC. Despite the slightly but significantly
increased pelvic failure rate in the VBT arm.
OS and RFS were similar.
QOL significantly better with brachytherapy
VBT should be the treatment of choice for
patients with high-intermediate risk EC.
Remaining question:

Treat at recurrence or treat upfront?

33

GOG # 99 vs PORTEC-2
GOG # 99
(2004)
EBRT in early stage
intermediate risk
endometrial carcinoma
decreases the risk of
recurrence, but should be
limited to patients whose
risk factors fit a
high intermediate risk
definition.

PORTEC-2
(2008)

Brachytherapy should be
the treatment of choice
for patients with
high intermediate risk
endometrial carcinoma.

34

Cost of therapy
IVBT less costly than external
beam RT
Patient convenience
Ancillary costs
Time to recovery
Time away from home/employment
35

NSGO

EORTC

A randomized phase-III study on adjuvant

treatment with radiation (RT) chemotherapy
(CT) in early stage high-risk endometrial cancer
(NSGO-EC-9501/EORTC 55991)
On behalf of NSGO and EORTC
T. Hogberg1, P. Rosenberg1, G. Kristensen1, CF de Oliviera2, R de Pont
Christensen1 B Sorbe1, C Lundgren1, H Andersson1, T Salmi1, NS Reed2.
1
Nordic Society of Gynecologic Oncology, Odense, Denmark, 2Europ Org for
Research and Treatment of Cancer, Brussels, Belgium.
Eur J Cancer. 2010 September ; 46(13): 24222431.
36
doi:10.1016/j.ejca.2010.06.002.

NSGO EC-9501/EORTC-55991
RT

May 1996 to January 2007

Randomization
382 cases

Radical surgery

TAH+BSO
TAH+BSO
(+PLA)
(+PLA)

196 cases

RT+CT
(BT:44%)
(BT:44%) 186 cases

OR

Surgical stage I, II,

IIIA ( positive peritoneal fluid cytology
only), or IIIC (positive pelvic lymph
nodes only)
Endometrioid Type 61%
Serous, clear cell, or anaplastic
carcinomas (39%) were eligible
regardless of other risk factors

44
44 Gy
Gy XRT
XRT
optional
optional
brachytherapy
brachytherapy
(BT:39%)
(BT:39%)

CT+RT

Primary endpoint

Progression-free
Progression-free survival
survival (PFS)
(PFS)
37

 Pelvic RT was given according to departmental

guidelines (44 Gy). RT was given before CT in
the RT-CT arm.
Optional vaginal brachytherapy had to be
decided before randomization.
CT consisted of four courses of
o Doxorubicin/epirubicin 50 mg/m2 and cisplatin
50 mg/m2 every four weeks.
o Amendment in Aug 2004 (291 patients
included) allowed alternative CT regimens,
including:
o Paclitaxel 175 mg/m2+epirubicin 60 mg/m2 or
o Doxorubicin 40 mg/m2+carboplatin AUC 5 ; or
o Paclitaxel 175 mg/m2+carboplatin AUC 5-6
every three weeks.
38

NSGO EC-9501/EORTC-55991
Results
Cancer-specific overall survival improved in radiation/
chemotherapy group (10% at 5 y. from 78 % to 88 %).
Combined modality improved progression-free but also
cancer specific overall survival
No difference of overall survival by randomization between
combined modality and radiation alone
RT+CT was better than RT alone.
The next question is if RT+CT better than CT alone
39

Rationale for combining chemotherapy and external beam

radiation in patients with high-risk endometrial cancerRTOG 9708 study (2004)
Combined-modality treatment may be the optimal
approach to minimize the risk of pelvic and distant
recurrence.
Feasibility of this approach was tested by the RTOG 9708
study that treated patients with
Grade 2 or 3 endometrial adenocarcinoma with either
>50%MI, Cervical stromal invasion, or
Pelvic-confined extrauterine disease
with concurrent chemoradiation
(Cisplatin 50 mg/m2 on days 1 and28) followed by adjuvant
chemotherapy 4 cycles of cisplatin and paclitaxel given at
4-week intervals).
40

 Toxicity was acceptable and 98% of patients

were able to complete the planned treatment
regimen.
Overall survival and disease-free survival
rates at 4 years were 85% and 81%,
respectively.
The pelvic recurrence rate was only 2% at 4
years.
Greven K et al, Preliminary analysis of RTOG 9708: Adjuvant postoperative
radiotherapy combined with cisplatin/paclitaxel chemotherapy after
surgery for patients with high-risk endometrial cancer.
Int J Radiat Oncol Biol Phys. 2004;59:168-173.
41

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47

Key Question #1:

Which patients with endometrioid endometrial cancer
require no additional therapy after hysterectomy?

Following total abdominal hysterectomy with or without node

dissection, no radiation therapy is a reasonable option for patients with
1) no residual disease in the hysterectomy specimen despite positive
biopsy (Grade: strong recommendation, low-quality evidence)
2) grade 1 or 2 cancers with either no invasion or less than 50%
myometrial invasion, especially when no other high-risk features are
present (Grade: strong recommendation, high-quality evidence).
) Patients with the following pathologic features may be reasonably
treated with or without vaginal brachytherapy
1) grade 3 cancers without myometrial invasion (Grade: strong
recommendation, low-quality evidence)
2) grade 1 or 2 cancers with less than 50%myometrial invasion and
higher risk features such as age greater than 60 and/or lymphovascular
space invasion (Grade: strong recommendation, moderate-quality
evidence).
48

Key Question #2:

Which patients with endometrioid endometrial cancer
should receive vaginal cuff radiation?
Vaginal cuff brachytherapy is as effective as pelvic radiation
therapy at preventing vaginal recurrence for patients with
1) grade 1 or 2 cancers with 50% myometrial invasion or
2) grade 3 tumors with <50% myometrial invasion
(Grade: strong recommendation, moderate-quality evidence).
) Vaginal cuff brachytherapy is preferred to pelvic radiation in
patients with these risk factors particularly in patients who
have had comprehensive nodal assessment
(Grade: strong recommendation, low-quality evidence).

49

Key Question #3A:

Which women with early stage endometrial cancer should
receive postoperative external beam radiation?
Pelvic radiation is an effective means of decreasing pelvic
recurrence for early stage patients but has not been proven
to improve overall survival.
1) Patients with grade 3 cancer with 50% myometrial
invasion or cervical stroma invasion may benefit from pelvic
radiation to reduce the risk of pelvic recurrence
(Grade: strong recommendation, high-quality evidence).
2) Patients with grade1 or 2 tumors with 50% myometrial
invasion may also benefit from pelvic radiation to reduce
pelvic recurrence rates if other risk factors are present such
as age > 60 years and/or LVSI
(Grade: strong recommendation, high-quality evidence).
50

Key Question #3B:

Which women with stage III-IVA endometrial cancer should
receive postoperative external beam radiation?
The use of pelvic radiation has been shown to improve
survival in some settings. The best available evidence at
this time suggests that a reasonable option for adjuvant
treatment of patients with positive nodes, or involved
uterine serosa, ovaries/fallopian tubes, vagina, bladder, or
rectum includes external beam radiation therapy as well as
adjuvant chemotherapy (Grade: strong recommendation,
moderate-quality evidence).
Chemotherapy (Grade: weak recommendation, moderatequality evidence) or Radiation therapy alone (Grade:
weak recommendation, low-quality evidence) may be
considered for some patients based on pathologic risk
factors for pelvic recurrence.
51

Key Question #4:

When should brachytherapy be used in addition to
external beam radiation?
Prospective data is lacking to validate the use of vaginal
brachytherapy after pelvic radiation and retrospective
studies show little conclusive evidence of a benefit, albeit
with small patient numbers.
Use of vaginal brachytherapy in patients also undergoing
pelvic external beam radiation may not generally be
warranted, unless risk factors for vaginal recurrence are
.present
(Grade: weak recommendation, low-quality evidence).

52

Key Question #5:

How should radiation therapy and chemotherapy be
integrated in the management of endometrial cancer?
The best available evidence suggests that concurrent
chemoradiation followed by adjuvant chemotherapy is
indicated for patients with positive nodes or involved uterine
serosa, ovaries/fallopian tubes, vagina, bladder, or rectum
(Grade: strong recommendation, moderate-quality evidence).
Alternative sequencing strategies with external beam
radiation and chemotherapy are also acceptable
(Grade: weak recommendation, low-quality evidence).
Chemotherapy (moderate-quality evidence) or radiation
therapy alone (low-quality evidence) may be considered for
some patients based on pathologic risk factors for pelvic
recurrence.
53

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