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Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer

Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer. 부산백병원 산부인과 R2 서영진. BACKGROUND. Ovarian cancer - leading cause of the death in USA Standard chemotherapy for the initial Tx - combination of a platinum analogue with paclitaxel - with modern surgical intervention

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Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer

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  1. Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer 부산백병원 산부인과 R2 서영진

  2. BACKGROUND • Ovarian cancer - leading cause of the death in USA • Standard chemotherapy for the initial Tx - combination of a platinum analogue with paclitaxel - with modern surgical intervention : attain clinical remission  however, relapse and die of the disease • The rationale for intraperitoneal CTx - the peritoneum receives sustained exposure to high concentrations of antitumor agents while normal tissues are relatively spared

  3. Theory of IP approach • High IP concentration of drug • Longer half-life of drug in abdominal cavity than with IV administration • Prolonged systemic exposure • IP chemotherapy not effective in bulky disease; should be targeted at women with no residual or minimal residual disease • Chemotherapeutic agents with higher molecular weight had longer half-lives • Platinums/ taxanes have 10-20 times greater concentration IP than when given IV

  4. Intraperitoneal(IP) chemoTx - high cost, toxicity, cilnicians’ lack of familiarity with peritoneal administration, cathrter-placement technique

  5. Development of IP CTx • 1950’s: First use of intraperitoneal chemotherapy for malignant ascites • 1968: Long-term peritoneal access device • 1978: Demonstration of slow peritoneal clearance of some drugs • 1984: Feasibility of intermittent large volume intraperitoneal therapy • 1996: First report of a survival benefit for IP vs. IV chemotherapy in advanced ovarian cancer

  6. IV paclitaxel + IV cisplatin (6 cycle) VS. IV paclitaxel + IP cisplatin / IP paclitaxel (6 cycle)

  7. METHODS (patient) • Stage III epithelial ovarian or peritoneal carcinoma - no residual mass (<1.0cm) after surgery - GOG performance status of 0 to 2 - normal CBC, adequate renal & hepatic function • At registration - decide the 2nd-look laparotomy at the completion of chemotherapy • Before each Tx - PEx, Hx, CBC, chemistry, CA125 (every 3 months for 24 months and then every 6 months)

  8. Quality-of-life assessment (FACT-O) - at registration before cycle 4 3 to 6 weeks after cycle 6 12 months after the completion of therapy

  9. METHODS (treatment plan) • IV group - day 1: IV paclitaxel 135 mg/m2 day 2: IV cisplatin 75 mg/m2 • IP group - day 1 : IV paclitaxel 135 mg/m2 day 2 : IP cisplatin 100 mg/m2 day 8 : IP paclitaxel 60 mg/m2 • Standard premedication - hydration & antiemetics before cisplatin - reconstituted IP agent with 2 liter warmed N/S

  10. DAY 0 - Dexamethasone 20 mg PO • DAY 1 - Paclitaxel 135 mg/m2 IV (3 hours) : 6시간 전 Dexamethasone 20 mg PO (or 30분 전 Dexamethasone 10~20 mg IV) : 30~60분 전 Ranitidine 50 mg IV Diphenhydramine 50 mg IV

  11. DAY 2 - Palonosetron 250 mcg IV Dexamethasone 12 mg IV/PO Aprepitant 135 mg PO - hydration before cisplatin : N/S 1000ml (350ml/hr) : output > 100mg/hr - cisplatin 75mg/m2 IP in 2L saline : need a bed,lie flat, slight head elevation : ascites should be drained - hydration after cisplatin : N/S 350ml/hr x 5 hrs

  12. DAY 3 - Dexamethasone 12 mg PO Aprepiant 80 mg PO in AM • DAY 4 - Dexamethasone 12 mg PO Aprepiant 80 mg PO in AM • DAY 8 - Paclitaxel 60mg/m2 IP in 2L saline 30분전 Dexamethasone 10mg IV 30~60분 전 Ranitidine 50mg IV Diphenhydramine 50mg IV

  13. Before the treatment - ANC > 1,500 PLT > 100,000 Cr < 2.0 Ccr < 50 hepatic toxicity, peripheral neuropathy → if not, cycle delay, dose reduction, G-CSF • 2nd-look laparotomy - 8 weeks after the last cycle negative : complete response positive : microscopic or grossly visible

  14. Dose of IP CTx - grade 2 abd. pain, neuropathy • If grade 3 abd. pain , recurrent grade 2 abd. pain complication s involving the IP catheter - IV CTx for the remaining cycle • Cisplatin-related complication - carboplatin substituted for cisplatin

  15. METHODS (statistical analysis) • Overall survival - survival was measured up to the date of death or, for living patients, the date of last contact • Progression-free survival - until progression, death, or the date of last contact

  16. RESULTS (patients) • March 1998 ~ January 2001 • IV group : 215 patients IP group : 214 patients • Ineligible patients (14 patients) - IV group (5), IP group (9) - stage > III second primary cancer nonepithelial cell type other primary cancer inadequate surgery low malignant potential

  17. RESULTS (toxicity) • Intolerable toxic effects related cisplatin - drug was switched to IV carboplatin • Primary reason for discontinuation of IP CTx - catheter-related complications • All treatment-related deaths were attributed infection

  18. RESULTS (pathologic responses at second-look laparotomy) • Laparotomy was not mandatory • IV group - 102 patients : 41% complete pathological responses • IP group - 100 patients : 57% complete pathological responses

  19. RESULTS (survival) • The median duration of follow-up - IV group : 48.2 months IP group : 52.6 months • Median progression-free survival - IV group : 18.3 months IP group : 23.8 months • Median overall survival - IV group : 49.7 months IP group : 65.6 months

  20. Mean FACT-O quality-of-life score - IP group reported lower scores than IV group - but, no significant differences between the groups 1 year after tretment

  21. DISCUSSION • IP CTx significantly improved progression-free survival and overall survival - IP CTx had a 25% reduction in the risk of death • In a previous GOG study - doubling dose of IV cisplatin & cyclophosphamide - increasing dose density or intensity  limitation

  22. Toxic events - IP group > IV group - may be attributed to the higher cisplatin • Paclitaxel - persists in the peritoneum for 1 week - peritoneal clearance is very slow - peritoneal clearance is altered when drug is given after IP cisplatin - increase toxicity

  23. IP CTx toxic effects - catheter-related : substantial portion - catheter type & the timing of catheter replacement were not specified - standardization of the device : improve the success of IP CT

  24. Conclusion - IP CTX has a clinical advantage in the ovarian ca - but, toxicity ↑ & quality of life ↓ - Use of IP CTx in patients with advanced ovarian cancer

  25. CONSENSUS: 2005 • The toxicities, inconvenience and cost of IP therapy are justified by the improved survival seen with this treatment • New, targeted therapies are likely to be more effective in patients who have an excellent response to chemotherapy • While we work to improve the tolerability and toxicities of IP therapy, it remains the most effective means of treating ovarian cancer today

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