1. Study proposal After 4 A Phase III intergroup trial on adjuvant therapy in radically operated endometrial cancer patients (FIGO stage IC-IIIC) with high risk for micro- metastatic disease NSGO

2. What we know from randomized studies Aalders et al. (1980), GOG-99 (Keys et al. 2003), PORTEC (Creutzberg et al. 2000) ASTEC/EN.5 (Blake et al. 2009) Better loco- regional control but no (or very small) effect on OS. GOG-34 (Morrow et al. 1990) Prematurely terminated GOG-122 (Randall et al. 2006) CT is better than WAR (more advan- ced disease) Maggi et al. 2006 Failed to show superiority JGOG-2033 (Susumi et al. 2008) of either CT or RT RTOG-9708 (Greven et al. 2006) ChemoRT (CMT) is feasible NSGO-EC-9501/EORTC-55991 (Hogberg et al. ASCO 2007) The sequential addition of CT to RT improves PFS Kouppala et al 2008 Failed to show superiority of CT+RT vs RT n=150 PORTEC-3 (ongoing) is CMT better than RT? Thomas Hogberg, Lund Univ Hosp Oct 2009

3. Radical surgery TAH+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) with high risk for micro- metastatic disease Patients with serous, clear cell, or anaplastic carcinomas were eligible regardless of other risk factors ≥ 44 Gy XRT ± optional VBT (39%) CT : intially AP Later AP, TcP, TAP, TEcP n=196 n=186 n=382 May 1996 to January 2007 (VBT 44%) NSGO EC-9501/EORTC-55991 Thomas Hogberg, Lund Univ Hosp Oct 2009

4. NSGO EC-9501/EORTC-55991 PFS progression-freee survival (PFS) Thomas Hogberg, Lund Univ Hosp Oct 2009

5. NSGO EC-9501/EORTC-55991 PFS progression-freee survival (PFS) serous/clear cell ca Thomas Hogberg, Lund Univ Hosp Oct 2009

6. Radical surgery TAH+BSO (+PLA) CT+RT RT Randomization Primary endpoint Progression-free survival (PFS) and overall survival (OS) Surgical stage IIB, IIIA-C endometrioid carcinomas (IIIA with only pos per cytol not eligible 45 Gy XRT (+VBT If st IIB or IIIB) CT : APX3 q 3 weeks n=76 n=80 n=156 October 1998 to July 2007 MANGO ILIADE Thomas Hogberg, Lund Univ Hosp Oct 2009

7. NSGO EC-9501/EORTC-55991/MANGO Pooled data failure-free survival (FFS) endometrioid carcinoma Thomas Hogberg, Lund Univ Hosp Oct 2009

8. Pooled results failure-free survival (FFS) endometrioid carcinoma RandomizationObservedExpectedevents RT n=18750 37.15 RT+CT n=19729 41.85 Totaln=38479 79.00 HR 0.46 (95% CI 0.28-0.74) p=0.001 which translates to an estimated absolute difference in 5- year FFS of 13 % from 71 – 84 % NSGO EC-9501/EORTC-55991/MANGO Thomas Hogberg, Lund Univ Hosp Oct 2009

9. Pooled data cancer-specific survival (CCS) endometrioid carcinoma NSGO EC-9501/EORTC-55991/MANGO Thomas Hogberg, Lund Univ Hosp Oct 2009

10. Pooled results cancer-specific survival (CCS) endometrioid carcinoma RandomizationObservedExpectedevents RT n=18736 27.33 RT+CT n=19721 29.67 Total n=38457 57.00 HR 0.51 (95% CI 0.29-0.91) p=0.02 which translates to an estimated absolute difference in 5-year CSS of 10 % from 77 – 87 % NSGO EC-9501/EORTC-55991/MANGO Thomas Hogberg, Lund Univ Hosp Oct 2009

11. NSGO EC-9501/EORTC-55991 Lokoregional progressions 4.1 % in the RT-arm vs. 1,1 % in the RT+CT-arm – additive effects? Thomas Hogberg, Lund Univ Hosp Oct 2009 The combination of RT + CT is better than RT An additive interaction between RT + CT could explain the difference in the EORTC/NSGO/MANGO-study And the lack of difference in the Italian and Japanese studies

12. Conclusions & questions PORTEC-3 Unless there is something fundamentally wrong with NSGO-9501/EORTC-55991 PORTEC-3 will most probably show that CMT is better than RT When PORTEC-3 is published CMT will probably become standard treatment The question about the contribution of RT will remain unanswered Thomas Hogberg, Lund Univ Hosp Oct 2009

13. Proposition We have a time-frame in which we can resolve the question of the value of addition of radiotherapy to chemotherapy Thomas Hogberg, Lund Univ Hosp Oct 2009

14. Primary endpoint Overall survival (OS) Radical surgery TAH+BSO±LA CTx4 CTx2 RT Randomization Main inclusion criteria a. Endometrioid carcinoma b. Stage 1C grade 3 c. Stage IIA grade 3 and MI≥50%, IIB d. Stage IIIA-C Radical surgery, LA recommended but optional Main exclusion criteria Serous or clear cell carcinoma IIIA with only pos fluid cytology CT : Paclitaxel 175 mg/m 2, carboplatin AUC 5-6 (calculated) q 3 weeks N=1000 Proposed study Thomas Hogberg, Lund Univ Hosp Oct 2009

15. After 4 Informed consent and registration after surgery before CT. All patients are followed If there is extensive neurotoxicity the patient will not be randomized but will be treated with RT If severely detoriated general condition protocol therapy is stopped These patients will then not be drop-outs after randomization Negative consequence of ”after 4” randomization. The therapy will only evaluated in a subgroup with better general condition who tolerate 4 cycles of CT Thomas Hogberg, Lund Univ Hosp Oct 2009

16. End-points Primary: To compare overall survival (OS) of patients treated with either 2 more courses of CT versus sequential RT after 4 courses of CT Secondary: 1. Cause-specific survival (CSS) (time to death of endometrial carcinoma or of treatment complications), progression-free survival (PFS) (time to relapse of endometrial carcinoma or death all causes), failure-free survival (FFS); (time to relapse or death of endometrial carcinoma or of treatment complications, with deaths unrelated to endometrial carcinoma censored) 2. Toxicity 3. Patterns of progression 4.Quality of life evaluated by EORTC QLQ‑30 5.Fraction of registered patients that could be randomized and reasons for non-randomization. Survival for non-randomized patients Thomas Hogberg, Lund Univ Hosp Oct 2009

17. Inclusion criteria Histologically confirmed endometrial carcinoma with no macroscopic remaining tumor after primary surgery (systematic lymph node exploration optional), with one of the following postoperative FIGO 1988 stage and grade: FIGO 1988 stage IC grade 3. FIGO 1988 stage IIA MI≥50 %, IIB. FIGO 1988 stage IIIA*, IIIB, IIIC all grades. Thomas Hogberg, Lund Univ Hosp Oct 2009 *IIIA only because of positive peritoneal lavage fluid is included if there is also grade 3 and MI≥50 %

18. Inclusion criteria According to the new proposed FIGO staging Stage IB grade 3. Stage II all grades. Stage IIIA, IIIB, IIIC1, and IIIC2 all grades Thomas Hogberg, Lund Univ Hosp Oct 2009

19. Exclusion criteria Any postoperative residual macroscopic tumor Clear cell, serous, squamous carcinoma or small cell carcinoma with neuroendocrine differentiation Preoperative irradiation Previous or concurrent malignant disease except for curatively treated carcinoma in situ of the cervix or basal cellosquamous carcinoma of the skin Active infection or other serious underlying medical condition, which might prevent the patient from receiving treatment or to be followed Uncontrolled or potentially active site of pelvic infection (e.g. fistula or abscesses) Inadequate bone marrow, liver, or kidney function Previous extensive abdominal surgery or other condition that might give a substantial increase in the risk for complications from RT or CT Whatever reasons which interferes with an adequate follow-up. Longer interval than 3 weeks between last CT and randomization Thomas Hogberg, Lund Univ Hosp Oct 2009

20. Surgical procedure Hysterectomy with bilateral salpingo-oophorectomy and extirpation of macroscopic palpable suspicious lymph nodes must be done. Pelvic and paraaortic lymph node exploration is recom- mended but is not mandatory. Stratification depending on lymph node exploration Thomas Hogberg, Lund Univ Hosp Oct 2009

21. Chemotherapy Adjuvant CT should start as soon as possible or within 2 weeks after registration. Registration after the start of CT is not allowed. Schedule for CT Paclitaxel 175 mg/m2 i.v./3 hours. Carboplatin AUC 5-6 i.v. infusion over 30-60 minutes. Both drugs are given on the same day and the treatment is to be repeated every 3‑weeks for four cycles to all patients. Patients who are randomized to further CT will receive two more cycles, i.e. 6 in all. The minimum allowed starting dose of carboplatin is AUC 5. Calculated GFR. Thomas Hogberg, Lund Univ Hosp Oct 2009

22. Radiotherapy External radiotherapy (preliminary) The dose, fractionation and radiation technique is a matter of departmental preference, but at least CT-based computer-aided 3- dimensional dose planning and 4‑field technique is recommended. The advised prescribed dose to the target volume should be at least 44 Gy specified according to ICRU or NACP. If other fractionations than 2.0 Gy 5 times per week are used, the dose should be converted to a 2 Gy equivalent dose according to the linear quadratic formula Brachytherapy Vaginal brachytherapy should be added for patients with FIGO 1988 stage IIB (proposed new FIGO stage II) Thomas Hogberg, Lund Univ Hosp Oct 2009

23. Statistical issues We suppose that a 10 % increase in OS from about 65-70 % to 75-80 % would be regarded as convincing evidence to accept the addition of RT Significance level and power are usually set to 5% and 80%. In this case it is very important not to miss a difference if it exists; thus it is suggested power is set to 90 % Thomas Hogberg, Lund Univ Hosp Oct 2009

24. Statistical issues About 1000 patients would be needed and 266 events need to be observed Thomas Hogberg, Lund Univ Hosp Oct 2009 Suppose a trial propulation with somewhat more advanced cases than in NSGO/EORTC/MANGO-study with 65 % 5 year survival in the control group, recruitment period 3 years, and 3 additional years for observation; power 0.9 and significance level 0.05, two sided test Survival experimental armN 70 % 4002 75 % 968 80 % 414

25. With 50 participating departments each depart- ment would have to randomize 7 patients/year for 3 years Possible collaborations: ?????.... Statistical issues Thomas Hogberg, Lund Univ Hosp Oct 2009

26. 1. Study group 2. Institution 3. Stage FIGO 1988 stage I-IIA FIGO 1988 stage IIB, IIIA, IIIC According to the new proposed FIGO staging FIGO stage IB FIGO stage II-IIIC2 4. Lymph node exploration Yes No Stratification Thomas Hogberg, Lund Univ Hosp Oct 2009

27. We have to get used to doing big randomized trials also in endometrial cancer Thomas Hogberg, Lund Univ Hosp Oct 2009

28. These guys are eagerly waiting for results from clinical trials in endometrial cancer!

29. CONTACT INFORMATION Thomas Hogberg Dept Cancer Epidemiology Lund University Hospital 221 85 Lund Sweden thomas.hogberg@med.lu.se NSGO DATA CENTER J.B. Winsløws Vej 9, DK-5000 Odense C, Denmark Phone: + 45 6550 4346 Fax: + 45 6550 4348 gandersen@health.sdu.dk Thomas Hogberg, Lund Univ Hosp Oct 2009

30. Problem This is a disease with generally good prognosis OS 8 yr PORTEC ~75% OS 5 yr GOG-122 ~50% OS 5 yr Susumo ~90% OS 5 yr Maggi ~70% NSGO/EORTC-5591 ~80 AZTEC/EN.5 ~85% PORTEC recorded ~15% mortality rate at 8 years related to intercurrent causes (~10% at 5- years) (which is more than in AZTEC and NSGO ~5%) Thomas Hogberg, Lund Univ Hosp Oct 2009

31. Example Suppose we have 30 % 5-year mortality in a risk group of endometrial cancer ~20 % would be cancer related and ~10 % unrelated to cancer Suppose that we have an adjuvant therapy that prevents 50 % of the cancer related deaths The effect on OS will be a change from 70 % to 80 % (10 % absolute difference). Thomas Hogberg, Lund Univ Hosp Oct 2009

32. Eligibility:include IBG3+LVSI (as in PORTEC3)? include serous pap./clear cell types? Stratification: Center, LA? Design: Two-arm trial (RT+CT vs CT)? three-arm (CTRT+CT vs CT+RT vs CT)? VBT:To allow or not to allow? Decision before randomization Statistics: To be re-evaluated according with trial design, strata at randomization POSSIBLE COLLABORATIONS: GEICO, AGO-Austria?, KGOG NSGO-MITO Proposals - Issues Thomas Hogberg, Lund Univ Hosp Oct 2009

33. Baseline within 14 days prior to enrolment During RTBefore each course (up to –3 days) Between courses Day 14±2 End of T he ra py During Follow-up at 3, 6, 12, 18… months up to 5 years Determination of FIGO stageX-- Informed consentX-- Performance status WHOXXX--XX HeightX-- WeightX--X Physical + gynecologic examination X-- XX CTC v2.0 scale toxicityXXX--XX Blood counts a XDepartmental praxis XXX until rec ove ry -- Calculation b (or measurement) of GFR X--X Chemistry c XDepartmental praxis X S-creatinine within 7 days --X until rec ove ry -- CT chest and abdomenX d -- Yearly ECGX EORTC QLQ ‑ 30 XXeXe XX Thomas Hogberg, Lund Univ Hosp Oct 2009