1. Adjuvant treatment for endometrial cancer Ameri A Associate Professor of Radiation Oncology Shahid Beheshti University of Medical Sciences Dec-6-2012 Pars Hospital, Tehran-IRAN

2. Survival rate and stage Staged according to the 2010 FIGO staging system (from Obstet Gynecol 2010; 116:1141). IAIBIIIIIAIIIBIIIC1IIIC2IVAIVB 5Y Overall Survival(%) 89.677.673.556.336.257492221 Most common sites of recurrence after surgery alone Pelvic cavityEarly Stage Paraaorta and abdominal cavity Distant sites (liver and Lung)Late stage

3. Adjuvant treatment types Local – Pelvic & Paraaorta (External beam Radiotherapy) – Vaginal (Brachy-therapy) Peritoneal directed (Peritoneal installation, Whole Abdominal RT) Systemic (Chemotherapy, targeted therapy)

4. Postsurgical Risk Stratification For Recurrence And Selection Of Adjuvant Treatment Individual patient characteristics – Age >65 years More deeply invasion, HG Advanced Stage Stage by stage lower survival – Race Asian women has better prognosis (younger ) Black women has poorer prognosis (higher rate of HG & non endometrioid histology, HER2 overexpression 5 Years OS For Stage I, II <40 years 96% >80 years 54%

5. Postsurgical Risk Stratification For Recurrence And Selection Of Adjuvant Treatment Individual patient characteristics Surgical staging Extension beyond uterus LN involvement (pelvic and paraaortic) Peritoneal washing ( no Approved role has been ignored in new staging)

6. Postsurgical Risk Stratification For Recurrence And Selection Of Adjuvant Treatment Individual patient characteristics Surgical staging Main Pathologic Factors – Grade ( III vs. I & II) – Depth of invasion (particularly for High Grade) – Extension beyond the Fundus (e.g. lower uterine segment, cervix)

7. Postsurgical Risk Stratification For Recurrence And Selection Of Adjuvant Treatment Individual patient characteristics Surgical staging Main Pathologic Factors Other pathologic factors – Histologic type (Serous, Clear cell, Carcinosarcoma, Mucinous) – Involvement of lymphovascular spaces – Large tumor? (>2 cm in diameter)

8. Risk stratification for adjuvant treatment Low Risk – Comprehensively staged & – Endometrioid Histology & – Confined to the endometrium – No lower segment involvement (Lower segment involvement in Stage IA G1 or 2 surgically staged patient without other risk factors considered as low risk) NCCN perspective also add – Age<60, – No lymphovascular invasion, – No large tumor size

9. Risk stratification for adjuvant treatment Low Risk Intermediate risk (Myometrial or cervical stroma involvement) Low Intermediate High Intermediate – Any age and 3 poor prognostic factor – 50-69 with 2 poor prognostic factor – >70 with 1 poor prognostic factor Based on: Age Lymphovascular invasion Outer 1/3 myometrial invasion Grade 2 or 3

10. Risk stratification for adjuvant treatment Low Risk Intermediate risk High risk – Gross involvement of the cervix – Stage III or IV disease, regardless of grade – Papillary serous or clear cell uterine tumors

11. Low risk patients Very low risk of Distant and peritoneal spread – No systemic treatment indicated – No peritoneal directed treatment indicated Low risk of pelvic nodal involvement – No evidence to support benefit of external beam radiotherapy Pelvic external RT should particularly be avoided, since it would only expose these women to toxicity without benefit

12. Intermediate risk Studies are not conclusive Different definition Different inclusion criteria Chang in staging definition Inappropriate end point Different modality used

13. Retrospective series report or Radiotherapy in early stage

14. RCTs of Adjuvant Radiotherapy in intermediate risk TrialNoStageSurgery typeRandomizationMedian F/U OSVaginal & Or pelvic relapse rate Aalders J,1980 540Clinical ITAH -BSO VBT Vs VBT+ Pelvic RT 3-10 y89 Vs 9 1% at 5 Y(P= NS) 6.9 Vs 1.9 at 5Y P< 0.01 Keys H,2004(GOG) 392 IB, IC, Occult II TAH-BSO Lymphadenectomy Observation Vs 50.4 to Pelvis 69 mo86 Vs 92% at 4Y (P=0.55) 12 Vs 3% At 2Y P=0.007 Blake P,2009 ASTEC 906 IA, IB, IC, IIA TAH-BSO +_ Lymphadenectomy Brachytherapy( 5 0% ) Vs Brachy+ 40-46 to Pelvic 58mo84 Vs 84% at 5 y 6.1 Vs 3.2% P=0.02 Nout R, 2009 PORTEC2 427High intermediate risk Not availablePelvic RT Vs VBT45 mo84.4 Vs 79.6% at 5 Y P=0.57 Vaginal 0.9 Vs 2% at 3Y P=0.97 Pelvic 0.7 Vs 3.6% P=0.03 Nout R, 2011 PORTEC 714IBG2-3, IC G1-2 TAH -BSO Obsevation Vs 46 Gy to Pelvis 13.3 y60 Vs 52% at 15 y (P=0.14) 5.8 Vs 15.5% at 15Y P<0.001

15. Vaginal Brachytherapy Vs pelvic RT PORTEC2 Study Stage I & IIA with high risk features High risk definition (1)age ≥60 and stage IC, grade 1/2, (2)age ≥60 and stage IB, grade 3, (3)any age and stage IIA, grade 1/2, or grade 3 with <50 percent myometrial invasion. Randomization EXRT 46 GY/ 23F Vaginal Brachy therapy 21Gy/3 F HDR or 30Gy LDR Primary end point Vaginal Recurrence Rate not inferior The Lancet, Vol 375, issue 9717, P816 - 823, 6 March 2010

16. PORTEC-2 Estimated 5 years OS Estimated 5 years DFS Vaginal Recurrence Rate Pelvic recurrence rate Locoregional Rcurrence rate Grade 1, 2 GI toxicity VBT84.8%82.7%1.8%1.5%5.1%12.6% EBRT79.6%78.1%1.6%0.5%2.1%53.8% P value0.570.74 0.30.17 No difference between EBRT and VBT regarding different end points New Techniques of EBRT may reduce side effects Because of low toxicity and vaginal control some recommend VBT for Low intermediate risk Combination of EBRT and VBT should be avoided except for patient with cervical stromal invasion

17. Adjuvant Radiotherapy in intermediate risk Available date show RT improved local control No impact of adjuvant RT on survival Late toxicity of RT may affect Quality of life Decision should be made based on assessment of risk and benefit Vaginal brachytherapy is preferred modality for most patients because of lower toxicity Combination of brachy therapy and EBRT has no apparent benefit for completely staged patients except for patients with cervical stromal invasion Risk assessment is the main stay for post op RT

18. Low Intermediate risk – No conclusive study to support RT RT is less effective compared to high intermediate group (PORTEC study. Lancet 2000:355:1404, GOG Study. Gynecol Oncol 2004; 92:744) No conclusion can be made Completely staged Low intermediate risk (Age <60, Grade 1 histology, No invasion of the outer one-third of the myometrium, Negative nodes after pelvic and paraaortic lymphadenectomy) Some recommend VBT extrapolating form high intermediate risk patient because of low toxicity

19. High intermediate risk Diverse clinical data Most institution recommended post op RT to improve local control in organ confined high risk patients Optimal RT approach is controversial Pelvic RT recommended for patient at risk for LN and pelvic recurrence » (Cervical involvement limited to uterus) Combination of EBRT and VBT should be avoided exception is – Cervical stromal involvement – Vaginal involvement

20. Future studies for intermediate risk patients PORTEC3 Pelvic irradiation with and without chemotherapy GOG02499 Pelvic RT Vs VBT and chemotherapy

21. High risk Stage III, IV and some stage II 35% will develop distant failure Recurrence in abdominal and pelvic cavity mandate WAPRT or peritoneal installation of P32 Abdominal directed RT has been traditional treatment due to results of several old studies Interest has shifted to use chemotherapy in high risk patients due to result of GOG122 (WART Vs chemotherapy)

22. Studies in advanced stage

23. High risk GOG122 392 stage III & IV Residual disease <2 cm Surgery LN sampling not mandatory Randomization WART 30 Gy/15f then Pelvic and paraaortic RT 15 Gy/8 f Cisplatin 50mg/m2 and Doxorubicin 60mg/m2 Q3W up to 7 cycle OS PFS

24. High risk GOG122 5Years PFS5 Years OS Pelvic Recurrence Rate RT %384213 Chemotherapy %505318 Most recurrences in abdomen and pelvic Sub analysis showed RT is useful specially for LN+ and Cervical Involvement Concept of volume-directed RT developed after this study and are used in multiple GOG studies

25. High Risk Chemotherapy are recommended Tumor-directed radiotherapy is mandatory Chemotherapy and radiotherapy consequent has not been defined EXBRT or VBT or both depend on tumor residual and risk assessment and individualized patient and disease decision

26. High risk Future study GOG 258 (ChRt then Chemotherapy Vs Chemotherapy)