1. Management of Endometrial Cancer in 2008 Marcus E. Randall, MD, FACR Chair and Professor Markey Foundation Endowed Chair Department of Radiation Medicine University of Kentucky Medical Center

2. Endometrial Carcinoma Classification of Disease Categories – Locoregional disease Low-risk disease: stage IA grades 1-2 Intermediate-risk disease: all other stage I, stage II High-risk disease: stage III and IVA – Disseminated disease: stage IVB or recurrent

3. EARLY STAGE ENDOMETRIAL CANCER: INTERMEDIATE RISK DOES EVERYONE NEED RT?

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

5. GOG # 99 392 evaluable patients 58.5% IB, 32.1% IC, only 9.4% stage II(occult) 82.3% inner and middle third invasion, only 17.6% outer third invasion 81.6% grade 1 and 2, only 18.4% grade 3

6. GOG # 99 Recurrence Pattern Surgery Surgery+EBRT Vagina, by randomization 13/172 (7.6%) 2/179 (1.1%) Vagina, by treatment 15/172 (8.7%) 1/179 (0.6%) received Total pelvic failure, by 20/172 (12%) 3/179 (1.7%) randomization Total pelvic failure, by 22/172 (13%) 1/179 (0.6%) treatment received

7. GOG # 99 Surgery Surgery +EBRT Alive (4 years) 86% 92% Dead of disease 15/202 (7.4%) 8/190 (4.2%) Intercurrent deaths 18/202 (8.9%) 14/190 (7.4%) Conclusion: The use of adjuvant RT, in women with intermediate risk endometrial cancer, decreases the risk of recurrences but has an inappreciable effect on overall survival

8. PROBLEMS WITH GOG # 99 The number of events was smaller than expected and approximately 50% of deaths were due to intercurrent disease. Therefore, the study was insufficiently powered to demonstrate a statistically significant survival difference. The patient population was largely composed of low risk patients.

9. GOG # 99 Recognized during study that patient population being accrued was mostly low risk. Therefore, “low intermediate” and “high intermediate” risk groups were defined based on GOG #33 data base.

10. “HIGH INTERMEDIATE RISK” Moderately-poorly differentiated tumor and Presence of LVSI and Outer 1/3 myometrial invasion Age >50 with any 2 risk factors above Age >70 with any 1 risk factor Others considered “low intermediate risk.”

11. 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. Keys et al. Gynecol Oncol 2004; 92:744- 751.

13. Trial design for ASTEC/EN.5 Surgery High risk pathology and no macroscopic disease RANDOMIZE No external beam RTExternal beam RT Primary endpoint: Overall survival Secondary endpoint: Recurrence-free survival 905 cases 453 cases 452 cases 2% EBRT, 51% Brachytherapy 98% EBRT, 52% Brachytherapy EN.5: July 1996- ASTEC: July 1998- Analyzed by ITT principle 71% ATH BSO 29% ATH BSO PLN

14. HR=1.01, 95%CI=0.71-1.42. P=0.98 5y-OS: EBRT 84%, no EBRT 84% HR=0.53, 95%CI=0.29-0.97. P=0.038 5y-RFS: EBRT 4%, no EBRT 7% Outcomes of ASTEC/EN.5 Overall survival Isolated vaginal or pelvic initial recurrence

15. JGOG2033 ： Randomized phase III trial of pelvic RT versus cisplatin-based chemotherapy in patients with intermediate risk endometrial carcinoma S. Sagae, N. Susumu, Y. Udagawa, K. Niwa, R. Kudo, S. Nozawa, for the Japan Gynecologic Oncology Group (ASCO 2005)

16. Trial design for JGOG 2033 Surgery >1/2 myometrial invasion, no residual tumor FIGO stage IB, IC, IIA, IIB, IIIA, IIIB, IIIC RANDOMIZE Pelvic Radiation Therapy (PRT) Chemotherapy (CAP) Primary endpoint: Overall Survival Secondary endpoints: PFS, incidence of toxicity 475 cases 238 cases 237 cases Enrollment: Jan 1994 - Dec 2000 Analyzed on ITT principle ATH BSO+ PLN (95.3%) PRT:45-50Gy, PAN (5.7%), Brachytherapy (3.1%) Cyclophosphamide 333 mg/m2 Doxorubicin 40 mg/m2 Cisplatin 50 mg/m2 Every 4 weeks for 3 or more courses 193 cases 192 cases (Median follow up: 60.2M)

17. Entry 475 Randomization Pelvic Radiation Therapy (PRT): 238 Chemotherapy (CAP): 237 Subsequently eligible = 193 7 did not receive PRT (18 ineligible) 27 excluded due to non-endometrioid histology Subsequently eligible = 192 4 did not receive CAP (23 ineligible) 22 excluded due to non-endometrioid histology Flow chart of patients

18. Treatment Comparison PRT CAP Chemo Completed Tx 98.9% 97.3% Median No. of courses 3 ( 3-7 ) Median duration of Tx 5.1 wks 11.4 wks Stopped Tx due to toxicity 1.6% 4.8%

19. Adverse Effects Toxicity PRT (n=193) CAP (n=192) Grade0-2 190 (98.4%) 181(95.3%) 3-4 3 ( 1.6%) 9 (4.7%) (chi-square test for Grade 3-4 frequency, p=0.077) Tx-related death 0 (0%) 0 (0%)

20. JGOG #2033: Treatment Outcomes

22. 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. Hogberg 1, P. Rosenberg 1, G. Kristensen 1, CF de Oliviera 2, R dePont Christensen 1 B Sorbe 1, C Lundgren 1, H Andersson 1, T Salmi 1, NS Reed 2. 1 Nordic Society of Gynecologic Oncology, Odense, Denmark, 2 Europ Org for Research and Treatment of Cancer, Brussels, Belgium. NSGOEORTC

23. NSGO EC-9501/EORTC-55991 Radical surgery ATH+BSO (+PLA) RT+CT RT CT+RT OR Randomization Primary endpoint Progression-free survival (PFS) Surgical stage I, II, IIIA ( positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only) Patients with serous, clear cell, or anaplastic carcinomas were eligible regardless of other risk factors 44 Gy XRT ± optional brachytherapy (BT:39%) CT : intially AP Later AP, TP, TAP, TEP 196 cases 186 cases 382 cases May 1996 to January 2007 (BT:44%)

24. HR 0.65 (CI 0.40-1.06) p=0.08; estimated difference in 5-yr OS 8% from 74 % to 82 % CT not completedCT completed RT (n=196)RT + CT (n=186) NSGO EC-9501/EORTC-55991 Overall survival depending on randomization Thomas Hogberg, NSGO - 18

25. HR 0.51 (CI 0.29-0.91) p=0.02; estimated difference in 5-yr CSS 10 % from 78 % to 88 % CT not completedCT completed RT (n=196)RT + CT (n=186) NSGO EC-9501/EORTC-55991 Cancer-specific survival depending on randomization Thomas Hogberg, NSGO - 19

26. NSGO EC-9501/EORTC-55991 Conclusion Despite that 27 % of the patients randomized to RT+CT received no or only part of the prescribed CT, RT+CT was better than RT alone as adjuvant therapy for patients with early endometrial cancer at high risk for micrometastases. Thomas Hogberg, NSGO - 25 NSGO EORTC

27. EARLY DISEASE: CONCLUSIONS 1.Patients with low risk disease probably do not need RT. They can be observed and RT used for salvage of local recurrences (must not immediately treat locally recurrent patients with systemic therapy on the theory they are “incurable.”

28. CONCLUSIONS 2.Adjuvant RT (of some sort) plays an important role in improving local control and possibly survival in most other patients with high intermediate risk endometrial carcinoma. 3. The increasing reliance on up-front surgical therapy and staging, including LN assessment, has raised new questions about the use of and appropriate extent of post-operative RT.

29. CONCLUSIONS 4. Given early data suggesting that chemotherapy might be effective on an adjuvant basis in high risk early stage disease, the Gynecologic Oncology Group is planning to open a study evaluating chemotherapy with cuff brachytherapy in high risk stage I-II disease.

30. Phase III trial of pelvic radiation therapy versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin chemotherapy in patients with high risk, early stage endometrial cancer: ELIGIBILITY CRITERIA: Surgically staged high-intermediate risk endometrial cancer defined by GOG 99 (age >/= 70 with 1 risk factor, or >/= 50 with 2 risk factors)- using risk criteria of: Grade 2-3 tumor, (+) LVSI, outer 1/3 myometrial invasion + any age with all 3 risk criteria Stage IIb endometrial cancer of any histology Stage I-IIb papillary serous or clear cell cancers Study Chairs: Scott McMeekin, Marc Randall, Carol Aghajanian

31. LOCALLY ADVANCED ENDOMETRIAL CANCER

32. Chemotherapy for Measurable Disease Endometrial Carcinoma GOG Protocol 177: ParameterDox/Tax/Cis Dox/Cis Patients134 129 Response 77 (57%) 44 (34%) Complete Response29 (22%) 9 (7%) Median PFS 8.3 mo. 5.3 mo. Median OS15.3 mo. 12.3 mo. Ref: Fleming et al. JCO 22: 2159-2166, 2004.

33. Whole Abdominal Radiotherapy versus Combination Doxorubicin-Cisplatin Chemotherapy In Advanced Endometrial Carcinoma: A Randomized Phase III Trial Of The Gynecologic Oncology Group Randall ME et al. Journal of Clinical Oncology 24:36-44, 2006.

34. GOG #122: TREATMENT ARMS Whole Abdominal Irradiation (WAI) Doxorubicin and Cisplatin (AP Chemo ) Randomization was balanced within institutions. No other stratification was used.

35. TREATMENT ComparisonWAI AP Chemo Completed Tx 84% 63% Stopped tx due 3% 17% to toxicity Median duration 1.3 mos. 5.1 mos. of treatment Did not receive n=12* n=3* protocol tx (#) * Not assessed for adverse effects but included in analysis of treatment outcomes.

36. ADVERSE TREATMENT EFFECTS Grade 3- 4 ToxicityWAI (%)AP (%) White blood count 4 62 Abs. Neutrophil <1 85 Gastrointestinal 13 20 Hepatic 3 1 Cardiac 0 15 Neurologic <1 7 Tx-related deaths n=4 n=8

37. GOG #122: TREATMENT OUTCOMES

41. SUMMARY: MANAGEMENT OF STAGE III-IV ENDOMETRIAL CARCINOMA 1.Make every effort to have patient surgically staged and maximally debulked. 2.Whole abdominal RT alone is probably no longer an acceptable treatment.

42. MANAGEMENT OF STAGE III-IV ENDOMETRIAL CARCINOMA 3. Combination chemotherapy has a definite place in the management of these patients, Based on GOG #122, this currently represents the treatment of choice, assuming toxicity can be limited or managed. 4.Role of combined chemo-RT is unclear, but early results are promising. Might well be the best treatment.

43. Chemotherapy for Advanced or Measurable Disease Endometrial Carcinoma GOG Protocol 209: Advanced or Recurrent (Measurable) Disease* Regimen I**Doxorubicin 50 mg/m2 d1 Cisplatin 60 mg/m2 d1 Paclitaxel 160 mg/m2/3h d2 Regimen IIPaclitaxel 175 mg/m2/3h Carboplatin AUC 6 d1 *Each regimen given every 3 weeks **Regimen I requires G-CSF.

44. Proposed GOG Study (GOG 704) Chemotherapy alone (6 cycles of Carbo-Taxol) Vs RT Concurrent with weekly cisplatin followed by 4 cycles of Carbo-Tax Study Chairs: Dr. Daniela Matei (Medical Oncology) Dr. Marc Randall (Radiation Oncology) Dr. David Mutch (Gynecologic Oncology)

45. QUESTIONS?