A Pilot Phase II Trial of Intravenous Paclitaxel and Intraperitoneal Carboplatin/Taxol Followed by Radiation in Patients With Advanced Stage Uterine Serous Carcinoma

TREATMENT PLAN 5.1 Dosing Guidelines 5.1.1 Chemotherapy Paclitaxel is available commercially. Paclitaxel 135mg/m2 will be given over 1 hour in 250-500 ml of 5% dextrose or normal saline. Premedication for prevention of anaphylactic reactions with anti-histamines and/or steroids should be administered as per standard practice. Paclitaxel should be given first given the risk of immediate drug sensitivity reaction. Following on Day 8 of the cycle, paclitaxel will be given IP at 60mg/m2. After infusion the patient will be asked to change position at 15-minute intervals for two hours to ensure adequate intra-abdominal distribution. No attempt will be made to retrieve the infusate, however if a large amount of ascites is present, ascites may be drained by paracentesis or accessed port prior to instillation of drug.

Carboplatin is available commercially. Carboplatin should be reconstituted in 500-1000cc of normal saline warmed to 37 °C (when feasible) and infused through a peritoneal catheter as rapidly as possible. It is preferred that an additional 1000 ml of warm saline is infused after IP Carboplatin, or 500ml of warmed normal saline infused before and after IP Carboplatin to help with drug dispersion throughout the peritoneal cavity, for a total volume of approximately two liters. After infusion the patient will be asked to change position at 15-minute intervals for two hours to ensure adequate intra-abdominal distribution. No attempt will be made to retrieve the infusate, however if a large amount of ascites is present, ascites may be drained by paracentesis or accessed port prior to instillation of drug. Carboplatin at an AUC of 6.0 will be administered intraperitoneally (if there is a prior history of radiotherapy, AUC of 5 would be used). AUC based dosing as described by Calvert et al. will be according to the following formula: Dose (mg) = AUC x (GFR + 25).

The initial GOG trial using combination paclitaxel and carboplatin therapy was performed on patients with optimally debulked ovarian epithelial carcinoma.40 At that time, the carboplatin dose was an AUC of 7.5. Since then, multiple large cooperative trials have been performed using AUCs of 6.0 and even 5.0. The lower dosage of carboplatin does not appear to compromise the efficacy of the drugs, and is associated with less toxicity.41-43 Where AUC is as stated above and GFR is the calculated renal function according to the method of Cockcroft and Gault: GFR (ml/min) = 0.85 x {(140-age)/Scr)} x {wt(kg)/72}.

Where Scr is the serum creatinine level. Investigators will use GFR of 125ml/min as cutoff as per NCI guidelines.

Following 6 cycles of IV/IP chemotherapy, a CT of chest, abdomen and pelvis should be obtained for disease surveillance prior to proceeding with radiotherapy (See section 5.4). If clinically indicated, the primary oncologist may have the option to proceed with the CT imaging after 3 cycles of chemotherapy.