Intraperitoneal chemotherapy: where are we going? A. Gadducci Pisa

Transcription

1 Intraperitoneal chemotherapy: where are we going? A. Gadducci Pisa

2 Intraperitoneal Chemotherapy (IP) in advanced ovarian cancer (EOC): Rationale The spread of disease is often limited to the peritoneal cavity Dose-response relationship of platinum analogues Platinum analogues can be administered intraperitoneally without local toxicity The peritoneal cavity has a pharmacokinetic advantage specific

3 Drugs used for IP chemotherapy of EOC peritoneal /plasma AUC ratio CDDP 12 CBDCA 17 Etoposide 65 Mitoxantrone 1408 Paclitaxel > 1000 Docetaxel Topotecan Gembitabine 791

4 IP chemotherapy in advanced EOC Salvage treatment for pts with persistent minimal RD after 1 st- line systemic chemotherapy Consolidation treatment for pts in pcr 1 st- line chemotherapy for pts with minimal RD after initial cytoreductive surgery

5 IP CDDP + IV CTX vs IV CDDP + IV CTX in stage III (RD <2 cm) EOC 654 evaluable patients Median S RR p (months) (95% CI) IP CDDP 100 mg/m ( ) 0.02 IV CTX 600 mg/m 2 vs IV CDDP 100 mg/m IV CTX 600 mg/m 2 Alberts 1996

6 IP CDDP + IV TAX vs IV CDDP + IV TAX in stage III (RD <1 cm) advanced EOC 523 evaluable pts Median PFS median S CBDCA AUC9 IV x 2 cycles 28 months 63 months TAX IV + CDDP IP x 6 cicli 135 mg/m mg/m 2 versus TAX IV + CDDP IV x 6 cycles 22 months 52 months 135 mg/m 2 75 mg/m 2 p=0.01 p= 0.05 Markman M 2001

7 IP CDDP + IV TAX vs IV CDDP + IV TAX in stage III (RD <1 cm) advanced EOC The experimental arm differed in many ways from the standard arm The first 2 courses of CBDCA were given at a high dose (AUC 9) and doses of CDDP were different in the two arms Toxicity was very high The authors concluded that this IP CT could not be recommended as standard of care Markman M 2001

8 IP CDDP + IV CTX + IV EPIDOX vs IV CDDP + IV CTX + IV EPIDOX in stage II-IV (RD <2 cm) EOC 113 evaluable patients Median PFS (months) median OS months IP CDDP 50 mg/m IV CTX 600 mg/m 2 IV EPIDOX 60 mg/m2 IV CDDP 50 mg/m IV CTX 600 mg/m 2 IV EPIDOX 60 mg/m2 p= Gadducci for GONO 2000

9 IP vs IV CDDP in combination with IV CTX + EPIDX in optimally cytoreduced advanced EOC pts: a randomized GONO trial GONO, 2000

10 IP vs IV CDDP in combination with IV CTX + EPIDX in optimally cytoreduced advanced EOC pts: a randomized GONO trial GONO, 2000

11 Phase III randomized study of IV TAX + IV CDDP vs IV TAX + IP CDDP + IP TAX in optimal stage III EOC: (GOG 172) 415 elegible pts (RD <1 cm) randomized to: TAX IV 135 mg/m 2 d1 + CDDP IV 75 mg/m 2 d2 TAX IV 135 mg/m 2 d1 + CDDP IP 100 mg/m 2 d2 + TAX IP 60 mg/m 2 d8 every 21 days x 6 cycles Armstrong 2006

12 Phase III randomized study of IV TAX + IV CDDP vs IV TAX + IP CDDP + IP TAX in optimal stage III EOC: (GOG 172) IV arm IP arm Median PFS (months) p= 0.05 Median OS (months) p= 0.03 Grade 3-4 pain, fatigue, and haematological gastrointestinal and neurological toxic effects were more common in the IP arm (p < or = 0.001) Armstrong 2006

13 IP chemotherapy for the initial management of primary EOC To determine if adding a component of the CT regimen into the peritoneal cavity affects OS, PFS, and toxicity for women receiving primary treatment of EOC, the Cochrane Collaboration Group analyzed 8 randomised trial included 1819 women. Two reviewers conducted data extraction independently. The reviewers retrieved data on OS and PFS as well as adverse events and then performed a meta-analysis of outcomes. Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

14 Lead Author Allocation Method Concealment Intention-to- Treat Overall Quality Alberts Adequate (a) Adequate (a) Performed (a) High Armstrong Adequate (a) Adequate (a) Performed (a) High Gadducci Adequate (a) Adequate (a) Adequate (a) High Kirmani Unclear (c) Unclear (c) Unclear (c) Low Markman Adequate (a) Adequate (a) Performed (a) High Polyzos Unclear (c) Unclear (c) Unclear (c) Low Yen Adequate (a) Unclear (c) Adequate (a) High Zylberberg Unclear (c) Unclear (c) Unclear (c) Low Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

15 IP chemotherapy for the initial management of primary EOC Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

16 IP chemotherapy for the initial management of primary EOC Comparison IP component therapy versus iv therapy, Outcome Time to recurrence Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

17 IP chemotherapy for the initial management of primary EOC Comparison IP component therapy versus iv therapy, Outcome Time to death Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

18 IP chemotherapy for the initial management of primary EOC Comparison IP component therapy versus IV therapy, Outcome Adverse effects - GI (G3-4) Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

19 IP chemotherapy for the initial management of primary EOC Comparison IP component therapy versus IV therapy, Outcome Adverse effects - fever (G3-4) Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

20 IP chemotherapy for the initial management of primary EOC Comparison ip component therapy versus iv therapy, Outcome Adverse effects - anaemia (G3-4) Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

21 IP chemotherapy for the initial management of primary EOC Comparison Ip component therapy versus iv therapy, Outcome Adverse effects - thrombocytopenia (G3-4) Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

22 IP chemotherapy for the initial management of primary EOC Comparison ip component therapy versus iv therapy, Outcome Adverse effects - leukopenia (G3-4) Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

23 IP chemotherapy for the initial management of primary EOC Comparison IP component therapy versus IV therapy, Outcome Adverse effects - renal (G3-4) Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

24 IP chemotherapy for the initial management of primary EOC Comparison IP component therapy versus IV therapy, Outcome Adverse effects - neurologic (G3-4) Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

25 IP chemotherapy for the initial management of primary EOC Catheter related complication of IP administration Abdominal pain (G3-4) Blockade infection Alberts 18% - - Armstrong 11.2% 4.1% 19.5% Gadducci 21.7% 8.7% Kirmani - 10% - Markman % Yen 42% (all G) 25.5% 12.8% Jaaback K, Johnson N Cochrane Database Syst Rev. 2006

26 IP chemotherapy for the initial management of primary EOC Women were less likely to die if they received an IP component to the chemotherapy (HR= 0.79; 95% CI: ) and PFS (HR= 0.79; 95% CI: ) was also significantly prolonged. There may be greater serious toxicity with regard to gastrointestinal effects, pain and fever but with the ip than the iv route. Jaaback K, Johnson N Cochrane Database Syst Rev

27 IP chemotherapy for the initial management of primary EOC The results of this meta-analysis should be used as part of this decision making process, taking into consideration the potential for catheter related complications (blockade, leakage, infection, bowel perforation). The importance of prior bowel resection deserves further evaluation, since distal colic resection appear to predispose to catheter complications and to reduce the number of successful cycles delivered. The optimal dose, timing and mechanism of administration cannot be addressed from this meta-analysis Jaaback K, Johnson N Cochrane Database Syst Rev

28 A meta-analysis of the efficacy of IP CT for the front-line treatment of EOC Trials IP CT HR 95% CI Hess HR for PFS: HR for OS: Fung-Kee-Fung HR for OS: Elit HR for PFS: HR for OS:

29 International Consensus Conference on ip CT in EOC pts in Innsbruck, Austria, February, 2006 Due to specific problems/complications, this treatment cannot be the new standard although it should be proposed as a valid alternative. IP CT should be reserved to pts with FIGO stage III-IV EOC with pleural effusion only, who have been debulked and who have RD < 1cm. Retroperitoneal N+:not usually considered contraindication for IP therapy This treatment should be administered only in referral centres experienced with the management of typical side-effects and complications Marth C, Walker JL, Barakat RR, Casado A, Gadducci A, Miller B, Odicino F, Pujade-Lauraine E, Sehouli J, Tropé C, Wenzel L, Zeimet AG

30 EOC: can IP CT be regarded as new standard? Reasons why GOG-172 experimental arm cannot be regarded as a new standard The benefit for OS was weak (p= 0.03), and the advantage for PFS was of bordeline significance (p= 0.05) The survival curves differ only after 15 months In IP arm a higher dose of CDDP was administered and TAX was administered both on day 1 and day 8 The control arm with TAX/CDDP had a lower survival than the standard arms of other randomized trials in the same population Vergote, 2008

31 EOC: can IP CT be regarded as new standard? Reasons why GOG-172 experimental arm cannot be regarded as a new standard The number of IP vs retroperitoneal relapse was similar in both arms IP CT resulted in significantly greater toxicities QoL was worse during the first year after IP CT than after IV CT Only 42% of pts could receive of IP CT Vergote, 2008

32 Dose-dense TAX once a week in combination with CBDCA every 3 weeks for advanced EOC: a phase 3 randomised trial 631 stage II-IV EOC pts RANDOM TAX 180 mg/m 2 3-h iv + CBDCA AUC 6 d1 TAX 80 mg/m 2 1-h iv d 1, 8, 15 + x 6 cycles every 3 weeks CBDCA AUC6 d1 every 3 weeks Median PFS 95% CI HR 95% CI p dose-dense arm 28.0 months conventional arm 17.2 months y-OS HR 95% CI p dose-dense arm 72.1% conventional arm 65.1% Toxicity higher with dose-dense than with conventional regimen Katsumata, 2009

33 EOC: can IP CT be regarded as new standard? Pts population of GOG 172 was similar to those of GOG 158, and to the pts collectives with RD < 1cm of the trials AGO-OVAR In these 4 trials: longer OS with IV CBDCA/TAX than with GOG 172 control arm: 57.4, 59.5, 57.0, and 56.5 mos, respectively, vs 49.7 mos Du Bois, 2006

34 EOC: can IP CT be regarded as new standard? IP CT (GOG 172) showed an intolerable toxicity profile with low compliance CBDCA/TAX : more favourable toxicity profile and better QoL compared with CDDP/TAX (GOG 158 and AGO-OVAR 3). In both studies CBDCA/TAX showed a nonsignificant trend for better outcome in optimally debulked pts. Any new regimen should be compared with the standard IV CBDCA/TAX Du Bois, 2006

35 Conclusions: IP CT for EOC: overview and perspective. Strenght of the data The peritoneal route of spread for EOC coupled with the pharmacologic advantage for ip platinums and taxanes suggest that IP administration should result in superior therapeutic outcomes The data are consistent across studies IP therapy: a 20% reduction in risk of recurrence and a 20%-25% reduction in the risk of death Improvement in median OS =from 8-16 months ( clinically meaningful)

36 Conclusion: IP CT for EOC: overview and perspective. Weakness of the data Trials were not pure tests of IP therapy. No trial evaluated CT given exclusively by the IP route. Each trial compared IP/IV CT vs IV CT Control arms did not represent the standard of care. IP therapy could not be given as planned due to toxicities Substantial concerns about QoL and technical difficulties continue to limit the adoption of Ip CT as standard of care

37 Conclusion: IP CT for EOC: overview and perspective. Procedure such as aggressive upper abdomen surgery, radical pelvic surgery and bowel resection are commonly required to achieve an optimal cytoreduction A pelvic retroperitoneal approach (often including recto-sigmoid resection) is able to achieve a complete cytoreduction is acceptable morbidity in almost all pts with a frozen pelvis

38 Conclusion: IP CT for EOC: overview and perspective. Recto-sigmoidal surgery can be associated with a gross contamination of the operative field, postoperative infections, fistulas, and leaks at anastomotic sites, and in this case the catheter for IP treatment should not be inserted during primary surgery.

39 Conclusion: IP CT for EOC: overview and perspective. Toxicity profile similar for pts who receive ip CT after optimal primary cytoreduction or after NACT + IDS Le 2011 Limited data regarding long-term complications following ip CT Chan (2011) reported the case of a patient who developed bowel obstruction due to peritoneal fibrosis attributed to prior ip CT Surgical exploration revealed an obliterated peritoneal cavity with multiple sclerotic adhesions encasing the small bowel and no evidence of ovarian cancer recurrence

40 Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) R A N D O M I Z E 1:1:1 BEV 15 mg/kg GOG-0218: Schema Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Arm I (CP) II (CP + BEV) Stratification variables: GOG performance status (PS) Stage/debulking status Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 BEV 15 mg/kg III (CP + BEV BEV) Cytotoxic (6 cycles) Maintenance (16 cycles) 15 months 40

41 Proportion surviving progression free GOG-0218: Investigator-Assessed PFS Patients with event, n (%) Arm I CP (n=625) 423 (67.7) Median PFS, months 10.3 Arm II CP + BEV (n=625) 418 (66.9) 11.2 Arm III CP + BEV BEV (n=623) 360 (57.8) Stratified analysis HR (95% CI) One-sided p-value (log rank) ( ) a ( ) < a CP (Arm I) + BEV (Arm II) + BEV BEV maintenance (Arm III) Months since randomization a p-value boundary =

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45 Conclusion: IP CT for EOC: overview and perspective. Iv TAX/ CBDCA should be still considered as the standard of care Ip CT should be used only in the context of properly designed clinical trials. The addition of BEV (concurrent and maintenance) to iv TAX/ CBDCA could represent a new standard It s unclear which group of pts will really benefit from IP CT, and which is the optimal drug, dose and combination The future trials must : I) either assess IP CT vs standard CT ii) to address the issue of route of administration for equivalent dosages and schedules of the same drugs.

46 Conclusion: IP CT for EOC: overview and perspective. Future trials should investigate ip regimens less toxic than those used in the GOG trials, and which could be combined with molecular targeted therapies. The GOG 252 phase III trial is currently comparing bevacizumab + TAX and ip CDDP or CBDCA versus BEV + iv TAX + CBDCA (Burger 2011)

47 GOG 252 REGIMEN I: TAX 175 mg/m2 IV (3 h day 1) + CBDCA AUC 6 IV (day 1) for 6 cycles + concurrent BEV 15 mg/kg IV (cycles 2 6) followed by maintenance BEV 15 mg/kg IV (cycles 7 22) REGIMEN II: TAX 175 mg/m2 IV (3 h day 1) + CBDCA AUC 6 IP (day 1) for 6 cycles + concurrent BEV 15 mg/kg IV (cycles 2 6) followed by maintenance BEV 15 mg/kg IV (cycles 7 22) REGIMEN III: TAX 135 mg/m2 IV (3 h on day 1) + CDDP 75 mg/m2 IP (day 2) + TAX 60 mg/m2 IP (day 8) for 6 cycles + concurrent BEV 15 mg/kg IV (cycles 2 6) followed by maintenance BEV 15 mg/kg IV (cycles 7 22)