describing adjuvant managment of high risk early endometrial cancers

1. Optimizing the Adjuvant Treatment of
Early Stage High Risk Endometrial
Carcinoma
Dr. Ashutosh Mukherji
Professor and Head
Department of Radiation Oncology,
Mahamana Pandit Madanmohan Malviya Cancer Centre
And Homi Bhabha Cancer Hospital,
(A Unit of Tata Memorial Centre), Varanasi

2. WHAT DO WE DISCUSS
• What is early stage high risk disease
• What is the expected survival and prognosis
• Treatment Recommendations and Review of
literature
• Take home message
2

3. 3
Staging Of
Endometrial Cancer
(FIGO 2009)

4. 4
ESMO-ESTRO Risk
Grouping for
Endometrial
Carcinoma (2016)

5. What is early stage high risk Endometrial
cancer
• Most recurrences in patients with early stage disease occurred in
whom tumors exhibited multiple high-risk features.
• Investigators from the GOG (Gynecologic Oncology Group) and
PORTEC (Post Operative Radiation Therapy in Endometrial
Carcinoma) defined “high intermediate risk” subgroups—about 1/3
of their intermediate risk patients—that had relatively high rates of
recurrence
• These patients appeared to benefit from post-operative radiation.
5
Creutzberg CL et al. PORTEC Study Group. post operative RT in endometrial carcinoma.
Lancet 2000;355:1404–11.
Keys HM et al. Gynecologic Oncology Group study. Gynecol Oncol 2004;92:744–51.

6. • Using the National Cancer Database (NCDB), Li et al tried to refine
the definition of high intermediate risk by analyzing outcomes of
30,986 patients who met either the PORTEC or GOG high
intermediate risk criteria.
• found no significant benefit from adjuvant radiation therapy for
5920 relatively favorable cancers that were deemed high
intermediate risk solely by PORTEC
• Molecular markers promise to yield powerful, independent
information about the biology of endometrial cancers, their
potential to spread, and their response to various treatments.
6
Li. Int J Gynecolo Oncol 2019.

7. High Risk Early stage EC – Risk factors
• Multiple factors have been identified for high risk of recurrence in
apparent early-stage disease:
– histological subtype,
– grade 3 histology,
– myometrial invasion ≥50%,
– Lympho-vascular space invasion (LVSI),
– lymph node metastases
– tumour diameter >2 cm.
• This high-intermediate risk group is defined by
1. any age with 3 of the above risk factors,
2. age ≥ 50 years with 2 of the above risk factors, and
3. age ≥ 70 years with at least one of the above risk factors
7
Keys HM et al. Gynecologic Oncology Group study. Gynecol Oncol 2004;92:744–51.

8. Expected Survival And Prognosis
• In case Early Stage disease:
– Endometrial tumours have a 5-year survival of 83% compared with
62% for clear-cell and 53% for papillary carcinomas.
– LVSI is present in 25% of cases.
– Five-year overall survival is 64% and 88% with or without LVSI,
respectively.
– 5-year survival was 89.6% and 77.6% for stage IA and IB.
8

9. Treatment Recommendations
• The optimal adjuvant treatment of intermediate risk endometrial cancer is
still to be defined. External beam radiation (EBRT) has been shown to
reduce the rate of locoregional recurrence in intermediate risk
endometrial cancer.
• But 3 large randomised studies (PORTEC-1, GOG 99 and ASTEC MRC-NCIC
CTG EN.5) failed to demonstrate that radiation improves overall or
disease-specific survival.
• In Norwegian trial, the subgroup with grade 3 tumors with deep (>50%)
myometrial invasion showed improved local control and survival after
EBRT (18% versus 27% cancer-related deaths).
• A randomised clinical trial (PORTEC-2) comparing vaginal brachytherapy
(VBT) and EBRT in intermediate risk patients showed that the both were
equally effective but that the quality of life was better in the VBT arm.
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10. 10

11. 11
Comparison of high-
intermediate (HIR)
risk groups in stage I
endometrial cancer
in PORTEC and GOG-
99 trials, and risk
reduction with RT

12. Treatment Recommendations
• Platinum-based chemotherapy can be considered in stage I G3 with
adverse risk factors (patient age, LVSI and high tumour volume) and in
patients with stage II–III.
• Japanese multi-centre RCT compared whole-pelvic RT with 3 or more
courses of cyclophosphamide, doxorubicin and cisplatin in patients with
old stages IC–IIIC endometrioid adenocarcinoma. No difference in overall
survival, relapse rate or PFS was observed.
• Two RCTs (NSGO-EC-9501 / EORTC-55991 and MaNGO ILIADE-III)
undertaken to compare sequential chemotherapy and radiotherapy versus
RT alone for PFS in high-risk endometrial cancer patients (stage I–IIA, IIIC,
any histology). Cancer-specific survival significantly favoured (HR 0.55,
95% CI 0.35–0.88; P = 0.01) use of adjuvant chemotherapy plus RT. The
combined modality treatment associated with 36% reduction in risk of
relapse
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13. Treatment Recommendations
• Both PORTEC-1 and PORTEC-2 specifically excluded patients with 1998
FIGO stage 1C and grade 3 endometrial carcinoma (2009 FIGO stage IB,
grade 3) thus, the use of adjuvant brachytherapy alone in the highest
risk subset remains undetermined.
• GOG 249 examined VBT and pacli+carbo chemo (brachy+chemo) versus
pelvic EBRT only in patients with high-risk, uterine-confined
endometrial carcinoma (n=601) and reported significantly increased
nodal recurrence (primarily pelvic) in the brachy+chemo arm versus
the pelvic EBRT arm.
• 3-year recurrence-free survival was 82% for both treatment arms; 3-
year OS was 88% for the brachy+chemo cohort and 91% for the pelvic
EBRT cohort.
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14. Treatment Recommendations
• PORTEC-3 trial initiated to evaluate benefit of chemoRT versus RT alone
for women with high-risk endometrial cancer in overall survival and
failure-free survival.
• The PORTEC-3 trial was powered (80%) to detect a 10% difference in 5-
year overall survival. Median follow-up was 60·2 months (IQR 48·1–73·1)
overall and was 60·0 months (47·8–73·1) in the chemoradiotherapy group
and 60·7 months (48·7–72·9) in the radiotherapy group.
• 5-year Estimated overall survival was 81·8% (95% CI 77·5–86·2) for
patients in the chemoRT group versus 76·7% (72·1–81·6) for patients in
the RT group (HR 0·76, 95% CI 0·54–1·06; p=0·109). 5-year failure-free
survival was 75·5% (70·3–79·9) in the chemoRT group versus 68·6% (63·1–
73·4) in the RT group (HR 0·71, 0·53–0·95; p=0·022).
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15. 15

16. 16

17. 17

18. 18
ESMO Adjuvant Treatment Guidelines in Early
Endometrial Cancers

19. ESMO-ESTRO Adjuvant Treatment Guidelines (2016) in
Early Endometrial Cancers By Risk Groups
19
Intermediate Risk Group
High-Intermediate
Risk Group

20. ESMO-ESTRO Adjuvant Treatment Guidelines (2016) in
Early Endometrial Cancers By Risk Groups
20
High Risk Group

21. Molecular markers in Risk identification and
Prognosis
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22. 22

23. PORTEC-4a: Molecular Profile-based Versus Standard Adjuvant
Radiotherapy in Endometrial Cancer : started 2016
• multicenter, phase III RCT in endometrial cancer with high-intermediate
risk features.
• Aims to investigate the role of an integrated clinicopathological and
molecular risk profile to determine if participants should receive no
adjuvant therapy, vaginal brachytherapy or external beam radiotherapy
based on a favourable, intermediate or unfavourable profile compared to
standard adjuvant vaginal brachytherapy.
• To Measure Vaginal recurrence rates as primary outcomes; 5y-RFS, QOL,
Toxicities, OS as Secondary outcomes
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24. TAKE HOME MESSAGE

25. • Low-risk are stage I, grade 1 or 2 EC of endometrioid histology with
no or superficial myometrial invasion.
• High-risk are non-endometrioid histologies; stage I-II grade 3 EC
with deep myometrial invasion, and stages III-IV.
• All others are intermediate risk EC; this group has further been
refined with other factors to define a high-intermediate risk (HIR)
group.
• Patient age, tumor grade, and LVSI were highly predictive for
locoregional relapse (LRR), distant relapse (DR), OS, and DFS.
• Treatment given (EBRT versus vaginal brachytherapy) is predictive
for LRR and DFS.
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26. • Pelvic RT (EBRT) in stage I endometrial carcinoma provides a highly
significant improvement of local control, but without survival
advantage.
• Most relapses occur in the vagina in high-intermediate risk patients
and use of vaginal brachytherapy alone has been advocated for local
control with fewer side effects than EBRT and better QOL.
• EBRT continues to be indicated for patients with high-risk EC to
maximize pelvic control.
• However, the increased rates of early distant disease spread
determine the inferior outcome for high-risk patients, and effective
systemic therapies are needed to improve their prognosis.
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27. Treatment Recommendations Based on NCCN 2020
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28. • Biomarkers may have a future role in identifying specific subsets of patients
for specific lines of therapy / risk grouping.
• Expression of steroid receptors is associated with higher survival rates and
better treatment response.
• Overexpression of HER-2, p53, Loss of p16 expression or high Ki67 score is
associated with a reduced survival rate
• PORTEC-4a is ongoing to study effect of molecular factors to risk profile and
treat High Intermediate risk EC (HIR-EC); while PORTEC-4 is studying vaginal
relapse rates with 21 Gy VBT vs 15 Gy VBT vs Observation in HIR-EC.
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29. Thank you