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Current Standard of Care in the management of Ovarian cancer

Current Standard of Care in the management of Ovarian cancer. Cyclophosphamide and Cisplatin compared with Paclitaxel and Cisplatin in Patients with Stage III and Stage IV Ovarian Cancer GOG111. William P. Mc Guire et al. The New England Journal of Medicine, vol 334. January 4, 1996.

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Current Standard of Care in the management of Ovarian cancer

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  1. Current Standard of Care in the management of Ovarian cancer

  2. Cyclophosphamide and Cisplatin compared with Paclitaxel and Cisplatin in Patients with Stage III and Stage IV Ovarian CancerGOG111 William P. Mc Guire et al. The New England Journal of Medicine, vol 334. January 4, 1996

  3. Randomized Intergroup trial of Paclitaxel and Cisplatin vs Cyclophosphamide and Cisplatin in women with advanced epithelial ovarian cancer. Three year results.OV 10 M. Piccart et al. JNCI Vol 92, Nº 9, May 3, 2000

  4. CARBOPLATIN-PACLITAXEL

  5. GOLD STANDARD REGIMEN • Ozols R.: Sem in Oncology, Vol 9, Nº 1, Suppl 1 ( February), 2002. “Currently, the standard chemotherapy for patients with ovarian cancer consists of a combination of a taxane( primarily Paclitaxel) together with Carboplatin” • Piccart MJ.:EJC 36 ( 2000) 10-12. “We will soon learn whether Carboplatin-Paclitaxel is the new gold standard regimen for all patients. • Covens A. : Gynecologic Oncology 85, 71-80 (2002) “Intravenous Carboplatin plus Paclitaxel is the recommended postoperative chemotherapy regimen for newly diagnosed stage II-IV epithelial ovarian cancer”

  6. Advanced Ovarian Cancer 2002 Treatment • Paclitaxel + Carboplatin (TC) • Accepted standard • “Control Arm” of all recent randomized trials • No other regimen shown to outperform it • How we can improve the benefit? : • Median TTP: 15-18 mos • Median OS: <3 yrs

  7. Basis of failure? Strategic approaches Improve efficacy of primary chemotherapy Maintenance regimens Improving Outcomes Quality/quantity of primary response inadequate Relapse following response Goal: Improve Overall Survival

  8. Improve Efficacyof Primary Chemotherapy • Add: • New cytotoxics • New “non-cytotoxics” • Substitute: • new agent for paclitaxel or platinum • Resistance modulation: • Add modulating agent • Increase dose/exposure: Systemic or Regional

  9. Trials: Adding New Cytotoxics • Epirubicin (2): • AGO/GINECO (ASCO 2001) • NSGO/NCIC CTG/EORTC GCG (ASCO 2002) • Topotecan (2): • NCIC CTG/EORTC GCG/ GEICO • GOG/ICON • Gemcitabine (2): • GOG/ICON • AGO/NSGO/GINECO • Liposomal doxorubicin (1): • GOG/ICON

  10. THERAPEUTIC INDEX Statement: “ Chemotherapy with a palliative intention should be characterised by a good THERAPEUTIC INDEX“. (A. Seidman) Anti-tumoural effectiveness of the agent (RO) TI = Toxicity Severity of the agent (Tox. Sev.) Example 1: RO = 40% Tox. Sev.=10% = 4 Example 2: RO = 55% Tox. Sev.= 30% = 1.8

  11. THERAPEUTIC INDEX DC PC Neutropenia: RO = 65% G4+fever Tox. Sev.=10% = 6.5 Neutropenia: RO = 62% G4+fever Tox. Sev.=2% = 31 Neutropenia: RO = 65% G 4>7 d. Tox. Sev.= 12% Neutropenia: RO = 62% G 4>7 d. Tox. Sev.= 1% = 62 = 5.4 Neurosensorial: RO = 65% G3 Tox. Sev.=2% Neurosensorial: RO = 62% G3 Tox. Sev.=8% = 32.5 = 8 Neuromotor: RO = 65% G3 Tox. Sev.=1% Neuromotor: RO = 62% G3 Tox. Sev.=3% = 65 = 21

  12. Phase 3 Randomized Trial of 12 Versus 3 Months of Single Agent Paclitaxel in Patients with Advanced Ovarian Cancer who Attained a Clinically-Defined Complete Response to Platinum/Paclitaxel-Based ChemotherapyM. Markman.33rd Annual Meeting. Society of Gynecologic Oncologists. Miami 2002(Abst 1)

  13. Rationale: • High response rate, high relapse rate (70-80% following attainment of a clinical CR) • Currently, no evidence for curative potential of any second-line management strategy • Protracted treatment program of Paclitaxel, a cycle-specific agent, previously shown to be safe and of possible clinical utility (non-randomized experience)

  14. Eligibility criteria: • Histologically confirmed ovarian, fallopian tube or primary peritoneal cancers • Exploratory laparotomy with attempt maximal cytoreduction, FIGO stages 3 or 4 • Treatment with a platinum/paclitaxel regimen (minimum 5, maximum 6 courses) • Registration > 21 days and < 56 days following last course of chemotherapy

  15. Eligibility Criteria (cont): • Attained a clinically-defined complete response (no disease of PE, CT scan abdomen/pelvis, CA-125 antigen < 35; no symptoms) • Standard laboratory criteria WNL • Any persistent peripheral neuropathy < grade 2 in severity

  16. Treatment Regimens: • ARM 1: Paclitaxel 175 mg/m2 IV over 3 hours q 28 days x 3 courses • ARM 2: Paclitaxel 175 mg/m2 IV over 3 hours q 28 days x 12 courses

  17. Toxicity: 3-courses12-courses Neutropenia (G4) 9% 4% Myalgias (G2-3) 4% 5% Peripheral neuropathy G2 14% 18% G3 1% 5%

  18. PFS Event Rate V. “At Risk” Months3-courses12-courses 0-3 4% 2% > 3-6 11% 4% >6-9 14% 7% >9-12 18% 6% >12-15 0%8% >15-18 6%10% >18-21 10%15%

  19. Implications of the Study for Patient Management • Consolidation therapy with 12 courses of single agent Paclitaxel should not be considered a required component of “standard of care” in the absence of data demonstrating a statistically significant favorable impact of this management strategy on overall survival

  20. Implications of the Study for Patient Management • Women with advanced ovarian cancer, who attain a complete clinical response to front-line chemotherapy, should be informed of the results of this study. An individual patient will need to decide whether continuation of treatment with single agent Paclitaxel, with its associated toxicity and required time/effort, is an appropriate strategy for her.

  21. Maintenance Chemotherapy:AFTER SIX carboplatin + Paclitaxel or cisplatin + Paclitaxel q.21 x 6 courses CR + PR AFTER SIX 3 AFTER SIX 2 AFTER SIX 1 macro-PR micro-PR CR MAINTENANCE (arm A) (paclitaxel 60 mg/m2 weekly) OBSERVATION (arm A) (intensive follow-up) MAINTENANCE (Phase II) (paclitaxel 60 mg/m2 weekly for 21 weeks) up to PD or excessive toxicity VS VS Any kind of 2nd line-CT (arm B) (topotecan-anthracyclines-gemcitabine etc.) MAINTENANCE (arm B) (paclitaxel 175 mg/m2 in 3hrs q. 3 wks for 6 courses) up to PD or excessive toxicity

  22. AFTER SIX: Toxicity TOXICITYAFTER SIX 1 AFTER SIX 2 AFTER SIX 3 169 courses 342 courses 288 courses G2 G3 G4 G2 G3 G4 G2 G3 G4 Leukopenia 9 1 - 4 - - 3 - - Neutropenia 8 8 - 3 - - 3 2 - Anemia 4 - - 1 - - 5 - - Myalgia 3 - - - - - - - - Neuropathy 6 3 - 11 - - 11 4 - NO OTHER TOXICITY  G 2

  23. Maintenance Chemotherapy: AFTER SIX Conclusions: • Maintenance Paclitaxel, both as 3-weekly and weekly administration, is well tolerated. • Patient compliance is good. • This multicenter trial will contribute to clarify the role of maintenance Paclitaxel in patients who achieve a response after induction chemotherapy with CbT.

  24. CONSOLIDATION CHEMOTHERAPY IN OVARIAN CANCER

  25. ASCO 2002 OVARIAN CANCER SUMMARY • Paclitaxel plus Carboplatin still gold standard • Addition of a third agent still experimental • Modulation of chemoresistance ineffective • IP chemotherapy promising but not yet accepted (acceptable?) • Prolonged Paclitaxel maintenance feasible and active (to be considered outside of Clinical Trials) • Weekly Paclitaxel  Carboplatin a reasonable option

  26. GOG 182 Control Arm (8 x 21-day cycles) I Paclitaxel 175 mg/m2 - 3h Carboplatin AUC = 6.0

  27. GOG 182 Triplets (8 x 21-day cycles) II Paclitaxel 175 mg/m2 - 3h Carboplatin AUC = 5.0 Gemcitabine 800 mg/m2 d1,8 III Paclitaxel 175 mg/m2 - 3h Carboplatin AUC = 5.0 Doxil 30 mg/m2 (every other cycle)

  28. GOG 182 Sequential Doublets (8 x 21-day cycles) IV Carboplatin AUC = 6.0 x 4 cycles Topotecan 1.5 mg/m2 d1-3 Paclitaxel 175 mg/m2 - 3h x 4 cycles Carboplatin AUC = 6.0 V Carboplatin AUC = 6.0 x 4 cycles Gemcitabine 1000 mg/m2 d1,8 Paclitaxel 175 mg/m2 - 3h Carboplatin AUC = 6.0

  29. Carboplatin and Paclitaxel as initial second-line therapy for recurrent Epithelial ovarian carcinoma

  30. Retrospective analysis of Carboplatin and Paclitaxel as initial second-line therapy for recurrent epithelial ovarian carcinoma: Application Toward a Dynamic disease state model of ovarian cancer Dizon DS. JCO, Vol 20, No5, 2002:pp1238-1247

  31. RATIONALE • The majority of ovarian cancer patients with complete response to first-line platinum-based chemotherapy eventually develop disease • Carboplatin/Paclitaxel is often used to treat patients with platinum-sensitive recurrent disease ( more information on duration of response and survival is needed)

  32. OBJECTIVES • Determine response and survival in patients treated with Carboplatin/Paclitaxel at initial relapse of ovarian cancer following first-line platinum-based chemotherapy ( retrospective analysis of patients treated at Memorial Sloan-Kettering Cancer Center) • Evaluate toxicity in these patients

  33. Eligibility Requirements • Complete response to first-line platinum-based chemotherapy. • Initial response duration > 6 months • Treatment with Carboplatin/Paclitaxel at the time of first recurrence Treatment • Carboplatin AUC 5-6 IV. • Paclitaxel 135-188mg/m² iv q 3w or 60-80mg/m² IV weekly.

  34. Results • 84 cases were evaluable for analysis of survival end points, and 66 were assessable for response • ORR: 70% • Median PFS: 13.8 months • 3-year survival: 72% • Toxicity was limited, and no deaths from treatment were observed

  35. Response Rates to Carboplatin and Paclitaxel Assessable* Measurable No. of Patients % No. of Patients % Total 66 58 Complete response 28 42.4 22 37.9 Partial response 18 27.3 17 29.3 Stable disease 11 16.7 10 17.2 Progressive disease 9 13.6 9 15.5 *Assessable patients consist of both patients with measurable disease (M) and those monitored solely on the basis of their CA-125 (A).

  36. Outcome Data With Selected Agents in Patients With Platinum-Sensitive Ovarian Cancer Drug No. Of Patients* Complete Overal Median Median ResponseRate (%) Response Rate(%) PFI ( m) Survival (m) Platinum 57 35.1 64.9 12 27+ +Paclitaxel Carboplatin 25 70 90 9 10+ +Paclitaxel Topotecan 46 4.3 33 9.6 20.2+ Topotecan v 111 9 28.8 5.8 17.8 Liposomal 109 7.3 28.,4 7 27 Doxorubicin Etoposide 41 14.6 34.1 6.3+ 16.5+ Gemcitabine 7 0 14 2.8 6.2 Paclitaxel 32 25 40.6 5.4 18.7

  37. Investigator´s conclusions • This analysis suggests for the first time that initial second-line Carboplatin-Paclitaxel can have a meaningful impact on response and survival of patients with platinum-sensitive disease. • Based on the disease-state model, we consider ovarian cancer a chronic illness that needs to be managed with a sequence of chemotherapies. • Further implications of this model are that many patients will remain platinum sensitive even after initial second-line Carboplatin/Paclitaxel, and survival may be further extended by treatment of those recurrences.

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