Molecular classification is an emerging topic in endometrial carcinoma… which has led to few updates in the risk stratification and treatment of endometrial carcinoma

1. Adjuvant treatment in high risk
endometrial carcinoma with
chemo radiation
Presenter- Dr. Komal Mittal
DNB resident at Action Cancer Hospital, New
Delhi
Moderator- Dr. Manoj Kumar Sharma
Senior Consultant at Action Cancer Hospital,
New Delhi

2. INTRODUCTION
● The majority of women with endometrial cancer are diagnosed with early-stage
disease and have a favourable prognosis. Approximately 15 to 20% have an
unfavourable prognosis with the high risk of distant metastasis.
● The primary treatment of endometrial cancer is surgery (total abdominal or
laparoscopic hysterectomy, and bilateral salpingo-oophorectomy + pelvic
lymphadenectomy)
● Adjuvant treatment is indicated based on clinico-pathological factors, such as
age, grade, histological type, depth of myometrial invasion, and presence of
lymphovascular space invasion.
● Based on these factors, it is classified as low, intermediate, high- intermediate
and high-risk groups, each having distinct prognosis and indications for
adjuvant treatment.

3. REVISED ENDOMETRIAL CANCER SURGICAL STAGING SYSTEM:
INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS 2009
Stage I
IA grades 1-
3
Tumor limited to the endometrium or invasion to <50% of the myometrium (includes
endocervical glandular involvement)
IB grades 1-
3
Invasion to ≥50% of the myometrium (includes endocervical glandular involvement)
Stage II
II grades 1-3 Cervical stromal invasion
Stage III
IIIA grades
1-3
Tumor invades uterine serosa or adnexa (positive cytology has to be reported
separately without changing the stage)
IIIB grades
1-3
Tumor involving the vagina and/or parametria

4. IIIC grades
1-3
Pelvic or para-aortic lymph nodal involvement
IIIC1 grades
1-3
Pelvic nodal involvement only
IIIC2 grades
1-3
Para-aortic nodal involvement with or without pelvic nodal involvement
Stage IV
IVA grades
1-3
Invasion of bladder, bowel mucosa, or both
IVB grades
1-3
Distant metastases, including intra-abdominal spread or inguinal lymph nodes

5. Risk Stratification according to ESMO-ESGO-ESTRO consensus conference on
endometrial cancer
Risk stratification Factors
Low-risk Grade <3, <50% myometrial invasion
Intermediate risk - Grade <3, =>50% myometrial invasion
- Grade 3, <50% myometrial invasion
High intermediate risk IR with age >60/ LVSI+ *
High-risk Grade 3, >50% myometrial invasion**
*High intermediate:
● ESMO/ESTRO : Grade 1-2 with LVSI+
● GOG : Age >70 + 1/3 risk factor, age >50 + 2/3 risk factors, any age + 3/3 risk factors
** High Risk:
Endometrioid carcinoma of stage IB grade 3, or stage II-III any grade, along with non-
endometrioid carcinomas of stage I-III (serous, clear cell and uterine carcinonasarcoma)

6. In recent years, it is clear that traditional classification lacks reproducibility and yields heterogeneous molecular
groups, therefore, The Cancer Genome Atlas (TCGA) is based upon the combination of somatic mutational
burden and somatic copy number alterations. This approach results into four distinct molecular groups.
1. DNA polymerase epsilon (POLE)- ultra mutated (POLEmut)
2. Hypermutated microsatellite-unstable
3. Somatic copy number high -TP53 mutated
4. Somatic copy number low- (PI3K) and WNT signal abnormalities

7. ESMO guidelines 2022
Risk stratification

8. ESMO guidelines 2022

9. ESMO guidelines 2022

10. PORTEC-1
- Randomised 715, patients of stage I, grade 1-3,
endometrioid EC into two arms.
- EBRT versus observation as adjuvant approach.
- EBRT arm received 46Gy in 23 #
- 5-year locoregional recurrence was reduced to 4% in
the EBRT arm from 14% in the observation alarm
- 5-year overall survival benefit was 85% versus 81% NS.
- The benefit was at the cost of complications which
increased to 25% from 6% in the EBRT arm from
observation arm.
Conclusion:
EBRT should be considered in high-intermediate and high-risk EC and could be avoided in low and
intermediate risk EC.

11. Adjuvant treatment in High Risk endometrial carcinoma
Observation vs. radiation
PORTEC 1 Trial GOG 99
No. of patients 715 392
Eligibility FIGO 1988 IB G2-3; IC G1-2 FIGO 1988 Stage IB-IIB
Grade 1-3
Surgery TAH + BSO TAH + BSO + LND
Pelvic RT 46 Gy in 23 # 50.4 Gy in 28 #
Loco-regional recurrence 5 years : 14% vs 4%
(p<0.001)
2 years : 12% vs 3%
(p=0.007)
Overall survival 5 years : 81% vs 85%
(p=0.31)
4 years : 92% vs 86%
(p=0.557)
Complications 6% vs 25% (p<0.001) Higher with pelvic RT
Both PORTEC1 and GOG 99 showed that EBRT provides a highly significant improvement of local
control, though without a survival advantage. Hence, concluded that EBRT would be justified only for
patients at relatively high risk of recurrence.

12. - Randomised 427 patients of stage I-II, grade 1-3, endometrioid EC
of age >60 years into two arms.
- IVRT (7Gy x 3#) vs EBRT (46Gy in 1.8-2Gy/#)
- 5-year vaginal recurrence rates were similar (1.8% for IVRT vs
1.6% for pelvic RT, P = 0.74)
- Pelvic recurrence: higher after IVRT (3.8% vs 0.5% for pelvic RT, P
= .02).
- Long-term follow-up showed no significant difference in 10-year
vaginal recurrence rate, distant metastasis, DFS, or OS.
- VBT had improved QoL.
Conclusion:
VBT was non-inferior to EBRT in preventing vaginal recurrences, with slightly higher pelvic failure rate, but no
impact on RFS or OS, with improved QOL.

13. External beam radiation therapy vs Intravaginal radiation therapy
PORTEC 2 Trial Swedish
No. of patients 427 527
Eligibility FIGO 2009 IB G1-2/IA G3
Age >60
IB, Grade 3, aneuploid
Surgery TAH + BSO TAH + BSO
Treatment IVRT vs EBRT IVRT vs EBRT + IVRT
Dose delivered 7Gyx3# vs 46Gy in 1.8-2Gy/# IVRT: 19.5-23.5Gy at 5mm depth
EBRT 46Gy in 1.8-2Gy/#
Locoregional recurrence Vaginal: 1.9% vs 0.9% p=0.97 Vaginal : 2.7% vs 1.9% p=0.55
Pelvic: 3.5% vs 0.6% p=0.03 Pelvic: 5.3% vs 0.4% p=0.0006
Overall survival 5 years : 85% vs 80% NS 5 years : 90% vs 89% NS

14. - Randomised patients with high-risk early-stage
and advanced stage disease to either pelvic RT
alone or pelvic RT with concurrent followed by
adjuvant chemotherapy.
- 5-year OS was 81.8% for chemoradiation arm
vs 76.7% for RT arm; P = 0.183).
- 5-year failure-free survival rates were 75.5% vs
68.9%, respectively, P = 0.078).

15. - There is a significant improvement in both OS
and FFS with chemoRT versus RT alone for
high-risk endometrial cancer.
- The absolute improvement at 5 years was 5%
for OS and 7% for FFS.
- Most recurrences were at distant sites, with
excellent local and regional control in both
groups.
- Women with serous cancers had worse OS
and FFS than those with other histological
types, and for these women a significant
improvement of OS (absolute improvement
19%) and FFS (absolute improvement 12%)
was found with chemoRT compared with RT
alone.
Conclusion:
PORTEC-3 trial shows improved 5-year OS and FFS with chemoRT compared with RT alone for
women with high-risk endometrial cancer, with the greatest absolute benefit for chemotherapy
seen in women with stage IlI disease or serous cancers, or both.

16. - Patients with p53abn EC have a highly
significant benefit from CTRT.
- There is excellent survival of patients with
POLEmut EC even in those with advanced-
stage and nonendometrioid histologies, with
no differences between adjuvant treatment
received.
- There was a no benefit observed from the
addition of chemotherapy to RT in patients
with MMRd EC suggests a favorable
outcome with EBRT alone in stage I-II
disease.
Conclusion:
It is essential to implement the molecular EC classification in clinical diagnostics and decision-making.
Patients with p53abn EC may be considered for adjuvant treatment including chemotherapy, whereas
adjuvant treatment de-escalation should be considered for those with POLEmut EC; additional studies
are needed especially for MMRd and NSMP EC.

17. Trials of adjuvant Radiotherapy and chemotherapy in high risk endometrial cancer
GOG 122 MANGO/ NSGO PORTEC 3 GOG 249 GOG 258
No. of patients 396 534, NSGO/EORTC
378 and MANGO 156
686 601 736
Eligibility Stage III and IV,
up to 2 cm residual
disease after surgery
NSGO/EORTC
stage I-III and MANGO
stage II-III
Stage I-II high risk
factors, stage III
Stage I-II with high
intermediate or high
risk factors & stage
I-II serous or clear
cell carcinoma
Stage III & IVa
without residual
disease upto 2cm
Randomisation Whole abdominal
irradiation vs 8 x AP
Pelvic RT vs pelvic RT
and 4 x AP or TAP or TC
or TEP
Pelvic RT vs pelvic
RT with 2 x CP f/b 4 x
TC
Pelvic RT vs VBT
and 3 x TC
Pelvic RT with 2 x
CP followed by 4 x
TC vs 6 x TC alone
5- year Overall
survival
42% vs 55% (p<0.01) 75% vs 82% (p=0.07) 76% vs
81%(p=0.034)
Stage III 69% vs 79%
Serous EC 53% vs
71%
87% vs 85% (NS) 70% vs 73% (NS)
5-year
progression,
free survival
38% vs 50% (p<0.01) 69% vs 78% (p=0.02%) 69% vs 77 (p=0.016)
Stage III 58% vs 71%
Serous EC 47% vs
61%
76% vs 76% (NS) 59% vs 58% (NS)

18. PORTEC-4a
PORTEC-4a is the first trial to introduce molecular factors in the adjuvant treatment of
endometrial cancers.

20. This trial will confirm the importance of molecular factors in escalating
or de-escalating adjuvant treatment in high intermediate risk EC .

21. Conclusion
● Adjuvant treatment can be omitted in patients of low-risk EC.
● Patients with intermediate or higher intermediate risk group require
radiation therapy as adjuvant treatment in the form of VBT or EBRT.
● Unfavourable group of patients are at a high risk of locoregional and distant
recurrence, therefore both radiation and chemotherapy is required as
adjuvant treatment in this group.

22. ● There are no data on high-risk endometrial cancer demonstrating a
superiority of chemotherapy over radiation, except GOG 122, which
cannot be considered as a contemporary adjuvant study.
● There was a stage imbalance in GOG 122, there were more stage IIIA
patients in RT arm and more stage IIIC patients in chemotherapy arm.
● GOG 258 compared adjuvant chemotherapy versus chemo radiation, and
PORTEC 3 compared radiation against chemo radiation in patients with
high-risk disease. Patients in both arms did not benefit in terms of distant
metastatic disease-free survival from potentially toxic chemotherapy.

23. As a result radiation remains the standard of care in patients with
high-risk disease.
Chemotherapy can be added with radiation in patients with p53
mutation with myometrial invasion, non-endometrioid with
myometrial invasion, or FIGO stage III & IVA for additional
benefit.

24. THANK YOU
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