PRIMARY TREATMENT OF EARLY STAGE EPITHELIAL OVARIAN CANCER THE ...

PRIMARY TREATMENT OF EARLY STAGE EPITHELIAL OVARIAN CANCER: THE EUROPEAN EXPERIENCE Sergio Pecorelli Gynecologic Oncology Spedali Civili, University of Brescia (Italy) European Institute of Oncology, Milan Presented at Korean Society of Gynecologic Oncology and Colposcopy JEJU ISLAND, KOREA May 3, 2002 Clinical Background • Early stage ovarian cancer: uncommon yet sufficiently lethal disease – 35% of all ovarian cancer – high risk: 25-30% lethal Is early disease really “early”? Incidence of occult metastatic sites in presumed early ovarian carcinoma. Peritoneal washings Omentum Diaphragm 20% 6% 15% Peritoneal biopsies Pelvic nodes Paraortic nodes 13% 8% 14% Modif. from Trimbos JB, Int J Gynecol Cancer, 10(S1):8-11, 2000 European Guidelines of Staging of Ovarian Cancer (EGSOC) 1. 2. 3. 4. 5. 6. Peritoneal washings Careful inspection and palpation of all peritoneal surfaces Biopsy of any lesion suspect for tumor metastasis TAH-BSO * Infracolic omentectomy Biopsy or resection of any adhesion adjacent to the primary tumor 7. Blind biopsies (2) of bladder peritoneum and cul de sac 8. Blind biopsies (3) of right and left paracolic gutter 9. Blind biopsies (2) or smear of the right hemidiaphragm 10. Blind biopsies (2) of the pelvic side wall peritoneum at the side of the primary tumor (ovarian fossa) 11. Lymphnode sampling along external and common iliac arteries and veins 12. Lymphnode sampling along the aorta and the vena cava including the area between the inferior mesenteric artery and the left renal vein * MSO is permitted in young women with stage Ia disease wanting to retain their fertility OPEN ISSUES IN SURGERY OF EARLY OVARIAN CANCER  The staging procedure in case of conservative surgery  Lymphadenectomy  The need and the timing for radical surgery (conservative surgery)  Adjuvant Therapy  The optimal follow-up Surgery: the role of lymphadenectomy • Accrual: • Patients randomised: – LY – SA 1992-1999 218 105 113 • Patients evaluable: – LY – SA Multicentric Italian Study 192 92 100 Pattern of relapses LY No relapse Relapses Endo Retro Retro+Endo Distant Unknown 73 (79%) 19 (21%) 11 1 2 2 3 SA 79 (79%) 21 (21%) 14 3 1 0 3 Multicentric Italian Study Disease-free survival Multicentric Italian Study Overall Survival Multicentric Italian Study LYMPHADENECTOMY • No proof of its value for survival • Attention should be paid at ovarian vessels in order not to jeopardize fertility potentials OPEN ISSUES IN SURGERY OF EARLY OVARIAN CANCER  The staging procedure in case of conservative surgery  Lymphadenectomy  The need and the timing for radical surgery (conservative surgery)  Adjuvant Therapy  The optimal follow-up Chemotherapy: the evidences 1990 GOG • Iai-Ibi G1-G2 – 5yrs PFS Melphalan 98% NS NFT* 91% 32P • Ic, G3 – 5yrs PFS Melphalan 80% NS 80% *NFT= No further treatment Chemotherapy: the evidences 1992 Norwegian Radium Hospital • Stage I – 5yrs PFS DDP 82% NS 32P 79% CONCLUSIONS – High number of bowel complication in 32P – DDP treatment of choice Chemotherapy: the evidences GICOG Study (Italian Cooperative Group) • Stage Iai Ibi G2G3 DDP – 5yrs PFS 83% NFT 65% p=0.09 32P • Stage IC – 5yrs PFS DDP 85% 65% p<0.01 Chemotherapy: the evidences • GICOG all data: Disease free survival p=0.001 Chemotherapy: the evidences GICOG Study (Italian Cooperative Group) • Stage Iai Ibi G2G3 DDP – 5 yrs Survival – 10 yrs Survival 85% 73% NFT 83% 71% p=0.94 32P • Stage IC – 5 yrs Survival – 10 yrs Survival DDP 83% 80% 76% 70% p=0.16 Chemotherapy: the evidences • GICOG Stage IC : survival p=0.164 Early Stage Ovarian Cancer GICOG trial Factors to be considered for interpretation of trial results • Platinum dosage (50 mg/m2): too low • Statistical power: too small Chemotherapy: the evidences 1999 GOG #95 • Accrual • Number of patients • Median follow up 1986-1994 205 6 years • Stage IC-IIA – 5yrs PFS – 5yrs Survival * After CP 77% 84% 32P 66% 76% NS* adjusting for stage and histologic grade, the recurrence rate on the cisplatin regimen is 34% lower than the P32 regimen. Estimated RR is 0.659 (95%CI: 0.403-1.078) Implications Based on data before 2000 • Platinum based chemotherapy seemed to improve PFS, but not survival • The optimal schedule and the optimal length of treatment was yet to be defined Implications • To give definitive answers in early stage ovarian cancer large multinational clinical trials were needed to increase the power and reduce accrual time Implications ICON & ACTION Trials to treat soon or to defer treatment at relapse ? Reached accrual: 900 patients About 50% from Italian Centers MRC/Mario Negri/SIAK EORTC ICON1+ACTION Two Parallel Randomised Trials of Adjuvant Chemotherapy in Patients with Early Stage Epithelial Ovarian Cancer ICON1 (International Collaborative Ovarian Neoplasm studies) launched in 08/92 ACTION (EORTC: Adjuvant Clinical Trial In Ovarian Neoplasm) launched in 11/91 MRC/Mario Negri/SIAK Design Early ovarian cancer surgically removed EORTC RANDOMISE Immediate platinumbased chemotherapy Treatment delayed until indicated MRC/Mario Negri/SIAK EORTC Principal Difference in Eligibility Criteria • ICON1: any patient in which the clinician was uncertain whether patient should receive chemotherapy • ACTION: Stages Ia, Ib Grades 2, 3 / Stages Ic, IIa all grades MRC/Mario Negri/SIAK EORTC Patient Accrual Trials ICON1 ACTION Total Number of patients 477 448 925 MRC/Mario EORTC Negri/SIAK Patient Characteristics - Stage Overall Groups Stage I Stage Ia Stage Ib Stage Ic Stage II Stage III Not yet known Total ICON1 13 (3%) 185 (39%) 52 (11%) 189 (40%) 28 (6%) 9 (2%) 1 477 ACTION 0 Deferred 4 (1%) Immediate 9 (2%) 155 (35%) 172 (38%) 37 (8%) 43 (9%) 168 (36%) 46 (10%) 208 (45%) 30 3 (7%) (1%) 1 465 223 (50%) 204 (45%) 31 (7%) 0 2 448 29 (6%) 6 (1%) 2 460 MRC/Mario Negri/SIAK EORTC Patient Characteristics - Differentiation ICON1 Poor Intermediate Well Not yet known Total 124 184 143 (27%) (41%) (32%) 26 477 ACTION 156 229 54 9 448 (35%) (52%) (12%) MRC/Mario EORTC Negri/SIAK Patient Characteristics - Histology ICON1 Serous Mucinous Endometroid Clear cells Undiff. Others Not yet known Total 144 103 103 67 7 26 27 477 (32%) (11%) (11%) (15%) (2%) (6%) ACTION 156 77 120 63 8 16 8 448 (35%) (18%) (27%) (14%) (2%) (4%) MRC/Mario EORTC Negri/SIAK Treatment details - chemotherapy ICON1 Never received CAP Carboplatin Cisplatin Carbo Comb Cisplatin comb Not yet known Total ACTION 13 (6%) 6 (6%) 71 (33%) 11 (5%) 20 (9%) 102 (47%) 7 224 Overall 25 8 241 12 23 115 (6%) (2%) (57%) (3%) (5%) (27%) 41 465 12 8 170 1 3 13 (6%) (4%) (82%) (1%) (1%) (6%) 34 231 MRC/Mario Negri/SIAK 1.0 0.9 0.8 0.7 EORTC Recurrence-free survival HR=0.64, p=0.001 95%CI (0.50, 0.83) Absolute difference at 5-year = 11% (65%76%) 95% CI (5%, 16%) Events Total 98 465 140 460 36 48 60 72 84 96 108 120 P 0.6 e r c e 0.5 n t a g e 0.4 0.3 0.2 0.1 0.0 0 12 24 immediate defer Patients at risk immediate defer 465 460 401 366 324 291 262 238 Months from randomisation 213 193 158 144 120 101 82 62 40 30 13 8 4 1 MRC/Mario EORTC Negri/SIAK Recurrence-free survival 1.0 1.0 ICON1 0.9 0.8 ACTION 0.9 0.8 0.7 0.7 P 0.6 e r c e 0.5 n t a g e 0.4 0.3 P 0.6 e r c e 0.5 n t a g e 0.4 0.3 0.2 0.2 0.1 0.1 immediate EventsTotal 52 241 defer 74 236 0 12 24 36 48 0.0 HR (95% CI)=0.65 (0.46-0.93) p=0.02 60 72 84 96 108 120 0.0 0 immediateEventsTotal 46 224 defer 66 224 12 24 36 HR (95% CI)=0.63 (0.44-0.92) p=0.02 60 72 84 96 108 48 Patients at risk immediate defer 241 236 199 177 157 148 121 114 Months from randomisation 94 91 70 65 51 43 33 22 12 12 7 5 4 1 Patients at risk immediate defer 224 224 202 189 167 143 141 124 Months from randomisation 119 102 88 79 69 58 49 40 28 18 6 3 MRC/Mario Negri/SIAK 1.0 0.9 0.8 0.7 EORTC Overall Survival HR = 0.68, p=0.01 95%CI (0.51, 0.92) S 0.6 u r v 0.5 i v a l 0.4 0.3 0.2 0.1 0.0 0 Patients at risk immediate defer 465 460 429 405 356 342 294 283 12 24 36 48 60 72 84 Months from randomisation 239 226 178 171 135 120 93 73 96 108 120 immediate defer Events 75 105 Total 465 460 Absolute difference at 5-year = 7% (75%82%) 95%CI (2%, 11%) 41 33 13 8 4 1 MRC/Mario Negri/SIAK Overall Survival 1.0 0.9 0.8 0.7 0.6 S u r v 0.5 i v a l 0.4 0.3 0.2 0.1 0.0 0 Patients at risk immediate 241 defer 236 219 203 179 170 135 135 12 24 36 EventsTotal immediate 42 241 defer 60 236 1.0 EORTC ICON1 ACTION 0.9 0.8 0.7 0.6 S u r v 0.5 i v a l 0.4 0.3 0.2 0.1 HR (95% CI)=0.68 (0.46-1) p=0.05 96 108 120 Events otal T immediate 33 224 defer 45 224 0 12 24 36 48 0.0 HR (95% CI)=0.69 (0.44-1.08) p=0.10 60 72 84 96 108 120 48 60 72 84 Months from randomisation 104 104 76 77 55 51 37 27 Patients at risk 12 12 7 5 4 1 immediate 224 defer 224 210 202 177 172 159 148 Months from randomisation 135 122 102 94 80 69 56 46 29 21 6 3 0 0 MRC/Mario Negri/SIAK EORTC Conclusions • Adjuvant CT in these patients improves – recurrence-free survival by 11% (65% to 76%) at 5 years – overall survival by 7% (75% to 82%) at 5 years • No statistical evidence that the effect of adjuvant chemotherapy is smaller or greater in the subgroups grade, cell type, age and stage MRC/Mario Negri/SIAK EORTC Differences between Action and Icon1 • no stage definitions for eligibility in Icon1 (stage II-III) • no grading recommendations in Icon1 • no staging recommendations in Icon1 • no information on staging performance in Ic • other „rules‟ for chemotherapy regimen in Icon1 • no subdivision of stage Ic in Icon1 Differences between Icon1 and Action % S (%) 100 90 80 70 60 50 0 1 2 3 4 5 6 7 8 Action Icon yrs Observation arms for survival in Action and Icon-1 100 90 80 70 60 50 40 30 20 10 0 IA IB IC II(A-C) III(A-C) Logrank: p=0.0001 0 1 2 3 4 5 6 7 8 years Overall survival by stage in Icon-1 EORTC Action trial • • • • IA/IB grade 2/3 all stages IC/IIA all clear cell carcinomas adjuvant vs no adjuvant chemotherapy following surgery (4 courses platinum containing CT) • when recurrence in observation arm, treatment with same CT as in adjuvant setting Disease free survival by treatment EORTC Action trial 100 90 % 80 70 60 50 0 1 2 3 4 5 6 7 Chemo Obs E 45 66 N 224 224 8 9 10 years Overall logrank test: p=0.0153 Overall Wilcoxon test: p=0.0034 E=events N=number of patients Overall survival by treatment EORTC Action trial 100 90 80 Chemo Obs % 70 60 50 0 1 2 3 4 5 6 7 8 9 10 E 33 45 N 224 224 years Overall logrank test: p=0.1037 Overall Wilcoxon test: p=0.0347 E=events N=number of patients Multivariate analysis of prognostic factors EORTC Action trial • STAGING: S and DFS HR 2.05 and 1.99 (p=0.027 / p=0.008) • GRADE: S and DFS HR 1.62 and 1.96 (p=0.04 / p=0.001) • CELL TYPE: S HR 1.72 (p=0.03) EORTC STAGING DATA Staging categories 1. Optimal Complete staging (EGSOC); lymphnode sampling instead of radical lymphadenectomy Modified Everything between 1. and 3. Minimal 4. + washings + omentectomy Inadequate Careful inspection and palpation of all peritoneal surfaces and biopsies of suspect lesions 2. 3. 4. Disease free survival by staging performance Opt=optimal; Mod=modified; Min=minimal; Inad=inadequate 100 90 Opt Mod Min Inad % 80 70 60 50 E 28 32 32 19 N 151 138 114 43 0 1 2 3 4 5 6 7 8 years E=events N=number of patients Overall Logrank test: p=0.0277 Overall Wilcoxon test: p=0.0223 Overall survival by staging performance Opt=optimal; Mod=modified; Min=minimal; Inad=inadequate % 100 90 80 Opt Mod Min Inad % 70 60 50 0 1 2 3 4 5 6 7 8 E 18 19 25 16 N 151 138 114 43 years E=events N=number of patients Overall Logrank test: p=0.0151 Overall Wilcoxon test: p=0.0511 Overall survival by staging performance EORTC Action trial, OBSERVATION ARM 100 90 80 70 60 50 0 1 2 3 4 5 6 7 8 optimal not-optimal % E 8 37 N 75 147 years Overall Logrank test: p=0.0272 Overall Wilcoxon test: p=0.0472 E=events N=number of patients Overall survival by staging performance EORTC Action trial, CHEMOTHERAPY ARM 100 90 80 70 60 50 0 1 2 3 4 5 6 7 8 optimal not-optimal % E 10 23 N 76 148 years Overall Logrank test: p=0.8750 Overall Wilcoxon test: p=0.5995 E=events N=number of patients Disease free survival by staging performance EORTC Action trial Optimally staged Optimally staged 100 Not optimally staged Not optimally staged 100 % % 90 Chem o Obs 90 Chem o Obs 80 80 70 70 60 50 E 13 15 0 1 N 76 75 2 3 4 5 6 7 8 60 50 E 32 51 0 1 N 148 147 2 3 4 5 6 7 8 years years Overall logrank test: p=0.7319 Overall Wilcoxon test: p=0.9757 Overall logrank test: p=0.0086 Overall Wilcoxon test: p=0.0007 E=events N=number of patients Overall survival by staging performance EORTC Action trial Optimally staged 100 Not optimally staged 100 % 90 % Chem o 90 Obs 80 Chem o 70 80 Obs 70 60 50 E 10 8 0 1 N 76 75 2 3 4 5 6 7 8 60 50 E 23 37 0 1 N 148 147 2 3 4 5 6 7 8 years years Overall logrank test: p=0.6535 Overall Wilcoxon test: p=0.7033 Overall logrank test: p=0.0329 Overall Wilcoxon test: p=0.0062 E=events N=number of patients Preliminary conclusions (Action Trial) • Significant CT effect on DFS (11% at 5 yrs); trend of CT-effect on S • Prognostic significance of – grade – cell type – surgical staging • Indication of decreased effect of CT in optimally staged, really early stage patients Believers of figures and statistical proof only (P) • CT improves S and DFS, so everybody has to have CT • Staging is a prognostic factor and the better the staging, the better the prognosis, so everybody has to have optimal staging Includers of circumstantial evidence in clinical decision making (C) • CT may correct for poor staging, so all poorly staged patients have to get CT • CT does not work in optimally staged patients, so omit CT in patients that had optimal surgery What shall we do with the poorly staged patient? • P group: reoperate and give CT • C group 1: CT and no reoperation • C group 2: reoperate for optimal staging state and no CT Final Conclusions (1) • European experience contributed to: – establish the indications for conservative treatment (Italian experience) – potentially clarify the role of lymphadenectomy (Italian experience) – indicate the superiority of platinum chemotherapy over 32P in prolonging DFS but not in S in high risk patients (Italian, Norwegian and GOG experience) – set up large scale multinational trials for assessing the impact of chemotherapy on survival of Early Ovarian Cancer patients (ICON1 and ACTION) Final Conclusions (2) • ICON1 and ACTION trials demonstrated that adjuvant systemic chemotherapy (platinum-based) improves not only DFS (by 11%) but also S (by 7%) at 5 years. • Unfortunately both trials failed to identify any impact of CT in the different risk subgroups (by age, substage, grade and cell type). • ACTION trial only demonstrated the outmost importance of proper staging in the clinical management of these patients. • Based on ACTION results, the role of chemotherapy in “really” early stage ovarian cancer patients remains questionable. • Modify staging (new prognostic factors)? • Modify adjuvant therapeutic approach? PRIMARY TREATMENT OF EARLY STAGE EPITHELIAL OVARIAN CANCER: THE EUROPEAN EXPERIENCE Sergio Pecorelli Giuseppe Favalli Franco Odicino Gynecologic Oncology Spedali Civili, University of Brescia (Italy) Korean Society of Gynecologic Oncology and Colposcopy JEJU ISLAND, KOREA May 3, 2002