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Chemotherapy in advanced ovarian cancer Angiolo Gadducci Department of Gynecology and Obstetrics, Unit of Gynecologic O

Mediterranean School of Oncology Highlights in the management of ovarian cancer . Chemotherapy in advanced ovarian cancer Angiolo Gadducci Department of Gynecology and Obstetrics, Unit of Gynecologic Oncology, University of Pisa Rome October 5-6 2007.

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Chemotherapy in advanced ovarian cancer Angiolo Gadducci Department of Gynecology and Obstetrics, Unit of Gynecologic O

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  1. Mediterranean School of Oncology Highlights in the management of ovarian cancer Chemotherapy in advanced ovarian cancer Angiolo Gadducci Department of Gynecology and Obstetrics, Unit of Gynecologic Oncology, University of Pisa Rome October 5-6 2007

  2. Integrated therapies in ovarian cancer (OC) • Early stage: Surgery Adjuvant therapy • Advanced stage: Surgery: Primary cytoreduction Interval surgery Second-look Chemotherapy Consolidation/manteinance therapy Recurrent disease: Chemotherapy Surgery

  3. Advanced Ovarian Cancer Trialist Group • Subjects: 8139 patients (6408 deaths) included in 45 trials. • Conclusions in term of survival • Platinum based treatment was better than non-platinum regimens (RR= 0.93; 95% CI, 0.83-1.05) • Platinum in combination was better single agent platinum when used as the same doses (RR= 0.85; 95% CI, 0.72-1.00) • CDDP and CBDCA were equally effective RR= 1.05; 95% CI, 0.94-1.18) (B.M.J., 1991)

  4. Chemotherapy for advanced OC 49 trials involving 8763 women HR for survival (95% CI) Platinum combination chemotherapy versus single non-platinum 0.93 (0.83-1.05) CDDP + non-platinum regimen versus non-platinum regimen 0.88 (0.79-0.98) Platinum combination versus single platinum 0.91 (0.79-1.05) CDDP versus CBDCA 1.02 (0.93-1.12) Advanced Ovarian Cancer Trialists Group 2000

  5. Ovarian Cancer Meta-Analysis Project PAC vs PC pathologic response 6-y survivalrate PAC 27% 31% PC 21% 25% p value 0.01 <0.02 (1991)

  6. Impact of DOX on survival in advanced OC • The addition of DOX improves survival (RR= 0.85; 95% CI = • 0.76-0.95, p=0.003) and the size of this benefit is of a similar • magnitudo to that of platinum • Overview of the data from: • Advanced Ovarian Cancer Trialist Group • Ovarian Cancer Metanalysis Project A’Hern and Gore, 1995

  7. ICON 2: randomised trial of CBDCA versus CAP (CTX, DOX, and CDDP) Patient population: 1526 patients from 132 centres in nine countries. CBDCACAP 360/ 760368/766 Deaths Median survival33 months33 months 2-year survival60% 60% HR= 1.00 (95% CI 0.86-1.16) p=0.98 International Collaborative Ovarian Neoplasm Group Lancet 1998

  8. Using the expected survival to explain differences between the results of randomized trials: a case in advanced OC Buyse et al, 2003 • A prognostic model for survival obtained in the meta-analysis included residual disease, age, grade and FIGO stage. • A proportional hazard model, fitted the meta-analysis data, was used to construct the expected survival curve for each treatment arm of the ICON 2 trial. • Expected survival curves were compared with observed survival curves in the ICON 2 trials.

  9. The addition of DOX to platinum-based regimen in OC • When this model was applied to the ICON 2 data, there was no difference between the observed and expected curves in the CAP arm. • In contrast, the observed survival curve for CBDCA was superior to the expected survival curve. Buyse et al, 2003

  10. The addition of DOX to platinum-based regimen in OC • The difference between the survivals in ICON 2 and in the meta-analysis may be related to the better results achieved with CBDCA alone at an optimally tolerated dose compared with PC at a CDDP dose of 50-60 mg/m2. Buyse et al, 2003

  11. Retrospective analysis of 33 published Trials using CDDP in advanced OC . Conclusions Relationship between dose-intensity (mg/m2/w) of CDDP, response rate,and survival Bias: analysis performed on trials not designed to assess value of the dose-intensity concept Levin et al, 1989

  12. Studies designed to explore the dose-response curve of CDDP . High dose arm CDDP dose CDDP Survival intensity total dose advantage Kaye et al.1992double double yes McGuireet al.1992double identical no Colomboet al. 1992double identical no Conte et al. 1996double double no

  13. First Line Chemotherapy: Randomized trials comparing TAX + CBDCA vs CDDP + TAX Author pts median PFS median S n (months) (months) Neijt 2000 208 TAX 175 mg/m2 (3-h) + CBDCA AUC 5 16 32 TAX 175 mg/m2 (3-h) + CDDP 75 mg/m2 16 30 p= ns p=ns Bookman 2003 840 TAX 175 mg/m2 (3-h) + CBDCA AUC 7.5 20.7 56.7 TAX 135 mg/m2 (24-h) + CDDP 75 mg/m2 19.4 48.8 p= ns p=ns Du Bois 2003 798 TAX 185 mg/m2 (3-h) + CBDCA AUC 6 17.2 43.3 TAX 185 mg/m2 (3-h) + CDDP 75 mg/m2 19.1 44.1 p= ns p=ns

  14. Vasey P. Proc ASCO 2001;(abstract and oral presentation 804)

  15. 1.0 .9 .8 .7 Paclitaxel/Carbo .6 Docetaxel/Carbo Proportion progression free .5 .4 .3 .2 .1 0.0 0 6 12 18 24 30 36 Time from randomisation (months) No. of patients PC 537 80 0 319 ar risk:- DC 537 90 0 320 SCOTROC ASCO 2002:Progression Free Survival Vasey P. Proc ASCO 2002;(abstract and oral presentation 804)

  16. 1.0 .9 .8 .7 Paclitaxel/Carbo .6 Docetaxel/Carbo .5 Proportion alive .4 .3 .2 .1 0.0 0 6 12 18 24 30 36 Time from randomisation (months) No. of patients PC 537 183 0 454 ar risk:- DC 537 168 0 449 SCOTROC: Overall Survival Vasey P. Proc ASCO 2002;(abstract and oral presentation 804)

  17. PC vs DCToxicity DCPC Myelosuppression Neurotoxicity Allergy Stomatitis Diarrhea Myalgia/Arthralgia Ozols, ASCO 2001

  18. 1st CT: Phase III randomized study of TAX + CDDP vs CDDP vs TAX in stage III-IV with RD > 1 cm: GOG 132 TAX 135 mg/m2(24-h) +CDDP 75 mg/m2 14.0 26.6 CDDP 100 mg/m2 16.4 30.2 TAX 200 mg/m2 (24-h) 11.2 26.0 Braccio 1+2 versus 3 p< 0.001 p= ns Braccio 1 versus 2 p= ns p =ns 614 evaluable patients median PFS median S (months) (months) Muggia, 2000

  19. First Line Chemotherapy: ICON 3 randomized study 2074 randomized patients Median PFS Median S months months TAX 175 mg/m2 (3-h) + CBDCA AUC 5-6 17.3 36.1 CBDCA AUC 5-6 or 16.1 35.4 CDDP 50 mg/m2 + DOX 50 mg/m2+ CTX 500 mg/m2 p=ns p=ns International Collaborative Ovarian Neoplasm Group 2002

  20. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3 • Statistical bias • Different extent of crossover to the taxane-based treatment in the control arm • The use of CBDCA instead of CDDP in the experimental arm • Type of treatment used in the control arm

  21. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3 • The large effect seen in GOG 111 which maintained at 5-years of follow up excludes the possibility of a type I error. • ICON 3 enrolled 2074 patients and the chance of missing the effect of TAX as large as seen in GOG 111 is only 1%.

  22. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3 Crossover to taxanes OV 10 48% GOG 132 24% ICON 3 30% (on progression) 6% (before progression)

  23. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3 • The experimental arm in ICON 3 differ from that of the other trials, because CBDCA was used instead of CDDP and because TAX was given at the dose of 175 mg/m2 3-h infusion. However, recent randomized studies showed that CBDCA + TAX 3-h infusion can substitute CDDP + TAX 24-h infusion without abrogation of activity

  24. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3 Control arm GOG 111 CTX 750 mg/m2 + CDDP 75mg/m2 OV 10 CTX 750 mg/m2 + CDDP 75 mg/m2 GOG 132 CDDP 100 mg/m2 ICON 3 CDDP 50 mg/m2 + DOX 50 mg/m2 + CTX 500 mg/m2or CBDCA AUC 5-6

  25. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3 • The control PC regimen (GOG 111 and OV 10) may be inferior to the control arm used in ICON 3 (PAC or CBDCA) and GOG 132 (high-dose CDDP) • The addition of CTX to CDDP may increase the hematologic toxicity of the regimen, causing excessive treatment delay and dose reduction. • Although there is no evidence of an improvement in survival with higher platinum dose-intensity, the addition of CTX to CDDP may have induced a dose reduction below the minimum standard.

  26. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3 • The lack of benefit associated to platinum/taxane combination in ICON 3 may be due to the superiority of the control arm in this trial compared to the control arms of the previous trials. • A meta-analysis with individual patient data from the 4 trials revealed a significant benefit for TAX/platinum-based regimen, which was smaller than that originally expected on the basis of GOG 111.

  27. Advanced Ovarian Cancer Current accepted Treatment • Paclitaxel + Carboplatin (TC) • Accepted standard • “Control Arm” of all recent randomized trials • No other regimen shown to outperform it • Median TTP: 15-18 months • Median OS: <36-40 months

  28. Management of Advanced EOCSearch for progress • More active 1st line regimens • Tailored treatments • IP CT • Maintenance/Consolidation therapy • New treatment strategies (IDS, NACT) • Novel (targeted) agents

  29. Control arm selected by institution Carboplatin-paclitaxel x 8 OR Carboplatin x 8 Carboplatin-gemcitabine  Carboplatin-paclitaxel x 4 x 4 Carboplatin-DoxilTM-paclitaxel x 8 Carboplatin-topotecan  Carboplatin-paclitaxel x 4 x 4 Carboplatin-paclitaxel-gemcitabine x 8 Ovarian Cancer III/IV GOG-182 (ICON 5)

  30. GOG 182- ICON 5 Trial Bookman MA, ASCO 2006

  31. Phase II trial of the Northeastern German Society of Gynecological Oncology Study population: 105 pts with stage II-IV EOC. CT regimen CBDCA AUC 5 every 3 weeks x 4 cycles followed by TAX 80 mg/m2/week x 12 cycles No grade 3 or 4 neurotoxicity and/or nausea/vomiting Grade 3-4:thrombocytopenia, 16%; anemia, 3%; leucopenia, 22% After a median follow-up of 10 months (range 1-27), 20 pts died Median OS: not yet reached Median PFS: 19 months (range: 10-23) Oskay-Oezcelik, ASCO Meeting 2007

  32. CBDCA + TAX vs CBDCA + DOXIL in advanced EOC: Preliminary results of phase III MITO-2 trial • RANDOMIZATION • CBDCA AUC 5 + TAX 175 mg/m2 CBDCA AUC 5 + DOXIL 30 mg/m2 every 3 weeks x 6 cycles every 3 weeks x 6 cycles • Preliminary data • Among 137 pts assigned to CBDCA + DOXIL, 87 were not eligible for response assessment by RECIST • Among 50 pts eligible for response assessment, 14 CR and 20 PR were recorded, for a RR of 68% • Among 35 pts with not-target lesions, 9 (26%) CR and 18 (51%) PR were observed Pignata, ASCO Meeting 2007

  33. ASCO 2007Educational SessionRare Subtypes of Ovarian Cancer • Clear Cell Tumors of the Ovary Toru Sugiyama, Iwate University, Japan • Mucinous Ovarian Cancer Martin Gore, Royal Marsden, UK

  34. Progress in the management of EOC • Evidence-based optimal care of EOC should include: - an accurate surgical staging - a debulking surgery (no macroscopic peritoneal RD, systematic LY ) - IP CT • In daily practice, a minority of the pts receive an optimal surgery and NONE is treated with IP CT • Tailored treatments should be developed on the basis of clinico-pathological parameters (histology, tumor grade, stage of disease, RD after surgery) • Education and training of health professionals might have a major impact on survival

  35. Conclusions • Molecular targeted agents able to interfere with fundamental steps in tumor cell re-growth (i. e. neoangiogenesis and growth factor signaling pathways) should be investigated. • CT based on extreme drug resistance (EDR) assay • CT-based on gene-profiling

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