Chemotherapy in Ovarian Cancer. Dr R Jones Consultant Medical Oncologist South Wales Gynaecological Oncology Group

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1 Chemotherapy in Ovarian Cancer Dr R Jones Consultant Medical Oncologist South Wales Gynaecological Oncology Group

2 Adjuvant chemotherapy for early stage EOC Fewer than 30% women present with FIGO stage I/II disease These patients have 5 yr survival ranging from 68 90% Surgery is mainstay of treatment Does use of adjuvant chemotherapy prolong recurrence-free survival and improve overall survival in patients with early stage epithelial ovarian cancer?

3 Adjuvant chemotherapy for early stage EOC Trial Patients Intervention 5 yr survival Statistics Comments ICON , 93% FIGO I Carbo/CAP vs.delayed Rx OS 79% vs. 70% HR=0.66 CI p=0.03 Improved 5yr OS ACTION , Ia/b G2-3 Ic-IIa IIa G1-3 All clear cell Platinum based regimen vs. delayed Rx OS 85% vs. 78% HR=0.69 CI p=0.1 Improved 5yr OS and RFS Trope et al I G2-3 Carbo vs. delayed Rx OS 86% vs. 85% Log rank test p=0.43 No difference in OS or DFS Young et al FIGO I Melphalan vs. delayed Rx OS 94% vs. 98% Log rank test p=0.43 No difference in OS or DFS Bolis et al IA-IB, IB, G2-3 Cisplatin vs. delayed Rx OS 88% vs. 82% HR=1.20 CI p=0.71 No difference in OS or DFS

4 Adjuvant chemotherapy for early stage EOC Cochrane review of above trials concluded: Benefit of adjuvant platinum based chemotherapy in prolonging survival (HR 0.71; 95% CI ) 0.93) and PFS (HR 0.67; 95% CI ) 0.84) Subgroup analysis: patients who are optimally surgically staged may have little to gain from adjuvant chemotherapy Appears safe to withhold adjuvant chemotherapy from optimally staged early EOC with well differentiated tumours

5 Chemotherapy for advanced ovarian cancer AOCTG meta-analyses analyses (1998): Included 37 trials, 5667 patients & 4664 deaths No good evidence of any difference between cisplatin and carboplatin either as single agent or combination ICON 2 (1998): Compared cyclophosphamide,, doxorubicin and cisplatin vs. carboplatin Survival curves showed no evidence of a difference between carboplatin and CAP (HR=1.0, p=0.98) Single agent carboplatin safe, effective and appropriate as standard of care in AOC

6 Paclitaxel era. GOG pts, FIGO III/IV, residual disease >1cm Improved PFS and OS with taxol combination Mc Guire et al, NEJM. 1996; 334(1):1-6. Piccart et al, JNCI. 2000; 92(9); OV pts, FIGO IIb/c, III/IV Optimal or sub-optimal debulking Improved PFS and OS

7 Paclitaxel era. GOG pts, FIGO III/IV residual disease > 1cm No diffence in OS between 3 treatment regimens ICON pts, all FIGO stages No difference in OS or PFS between regimens Muggia et al. JCO. 2000:18(1); ICON group. Lancet. 2002: 360;

8 Paclitaxel era..? Potential explanation for discrepancy between 4 main trials: Second-line therapy and treatment crossovers Cyclophosphamide/cisplatinum combination not best alternative as standard arm ICON 3 trial 20% pts FIGO stage I/II and extent of surgery was not defined

9 Paclitaxel - NICE recommendations 2003

10 Paclitaxel the future Dose-dense weekly paclitaxel in combination with carboplatin Recent Japanese study demonstrated improved survival compared to 3 weekly regimen in FIGO II-IV IV EOC, FTC or PPC

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12 ICON 8 Trial Schema

13 Neo-adjuvant vs. primary surgery Current practice is primary surgical cytoreduction followed by systemic chemotherapy unless unfeasible: Disease bulk, comorbidities,, poor PS Alternative approach is giving primary chemotherapy followed by surgery in responding patients Advantages of neo-adjuvant approach: Avoid surgery in women with aggressive disease, increase number of pts who obtain optimal debulking and surgery may be less complicated However increasing number of chemotherapeutic cycles beyond 3 has a potential negative impact on survival Bristow RE, Chi DS. Gynecol Oncol 2006; 103:1070

14 Neo-adjuvant vs. primary surgery Preliminary data from EORTC GCG / NCIC CTG: No significant difference in PFS or OS between primary and interval-debulking surgery group (12 and 30 months, F/U 4.8 yrs) IDS group had significant reduction in postoperative deaths, postoperative fever, haemorrhage and blood clots Multivariate analysis suggested strongest independent prognostic factor for OS was obtaining optimal debulking But caveat to study, pts with disease less than FIGO IIIC or small IIIC ovarian cancers were not well represented Vergote I, Trope CG, Amant F et al. Proceedings of 12 th Biennial Meeting of the International Gynecologic Cancer Society, Bangkok 2008

15 CHORUS trial Chemotherapy or Upfront Surgery

16 Intraperitoneal Chemotherapy

17 IP Chemotherapy GOG 172 trial 429 patients with optimally debulked FIGO III EOC: Randomised to IV paclitaxel (135mg/m 2 /24 hrs D1), followed by IV cisplatin (75mg/m 2 D2) IV paclitaxel (135mg/m 2 /24 hrs D1),IP cisplatin (100mg/m 2 D2) and IP paclitaxel (60mg/m 2 D8) Only 42% pts in IP group completed 6 cycles

18 IP Chemotherapy GOG 172 trial Median F/U 48 months IP group associated with improved median PFS (23.8 vs months) and overall survival (65.6 vs months)

19 IP Chemotherapy GOG 172 trial IP therapy was associated with significantly more toxicity: Catheter-related related complications Haematological toxicity (neutropenia( and thrombocytopenia) GI events and abdominal pain metabolic abnormalities neuropathy

20 Relapsed EOC Choice of chemotherapy regimen in relapsed EOC depends on response to first-line therapy: Platinum-sensitive relapses > 12months Partially platinum-sensitive relapses between 6 12 months Platinum-resistant relapses < 6 months Platinum-refractory NICE Technology Appraisal 91

21 Platinum Refractory/Resistant disease Agent Pegylated liposomal doxorubicin Topotecan Paclitaxel Oral Etoposide Gemcitabine Oxaliplatin Vinorelbine No of patients Response Rate 18% 17% 22% 31% 18% 23% 23% Gore ME, In ASCO Education Book ASCO, pp

22 Platinum-sensitive and partially platinum-sensitive disease Combination therapy appears to offer greater benefit in this setting Increased response to platinum re- challenge as time to recurrence increases > 12 months RR 30 60% 6-12 months RR 25 30%

23 Platinum-sensitive and partially platinum-sensitive disease ICON IV/AGO-OVAR OVAR pts with treatment-free interval at least months Benefit of paclitaxel-platinum platinum regimen with improved PFS and OS Higher rate of G2-4 4 neurological toxicity and alopecia but lower myelosuppression Parmar MK, Ledermann JA, Colombo N et al. Lancet. 2003; 361:2099

24 Platinum-sensitive and partially platinum-sensitive disease CALYPSO trial 974 pts, stratified by therapy-free interval PLD and carboplatin vs. carboplatin/taxol taxol Results showed PLD-carboplatin was not inferior in terms of PFS and was associated with an decreased risk of recurrence Overall survival data immature at present Toxicity more severe with taxol regimen with hypersensitivity reactions, alopecia and neuropathy Pujane-Lauraine E et al. J Clin Oncol. 2009;27(15S):Abstract LBA5509

25 Platinum-sensitive and partially platinum-sensitive disease - CONCLUSIONS Platinum-based combination superior to platinum monotherapy Need to consider: Drug activity Toxicity profile Quality of life Nature of prior drug toxicity Patient preference Clinical trials: ICON 6, MORAb

26 ICON VI

27 MORAb trial