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 : 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

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 times greater concentration IP than when given IV

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

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

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

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)

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

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

DAY 0 - Dexamethasone 20 mg PO DAY 1 - Paclitaxel 135 mg/m 2 IV (3 hours) : 6 시간 전 Dexamethasone 20 mg PO (or 30 분 전 Dexamethasone 10~20 mg IV) : 30~60 분 전 Ranitidine 50 mg IV Diphenhydramine 50 mg IV

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/m 2 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

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/m 2 IP in 2L saline 30 분전 Dexamethasone 10mg IV 30~60 분 전 Ranitidine 50mg IV Diphenhydramine 50mg IV

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 2 nd -look laparotomy - 8 weeks after the last cycle negative : complete response positive : microscopic or grossly visible

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

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

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

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

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

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

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

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

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

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

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

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