Heated intra-operative intraperitoneal oxaliplatin plus irinotecan after complete resection of peritoneal carcinomatosis: pharmacokinetics, tissue distribution and tolerance.
BACKGROUND
The purpose of this study was to report the pharmacokinetics (PK) and tolerance profile of intraoperative intraperitoneal chemo-hyperthermia (IPCH) with oxaliplatin and irinotecan.


METHODS
Thirty-nine patients with peritoneal carcinomatosis (PC) of either gastrointestinal or peritoneal origin underwent complete cytoreductive surgery followed by IPCH with a stable dose of oxaliplatin (460 mg/m(2)), plus one among seven escalating doses of irinotecan (from 300 to 700 mg/m(2)). IPCH was carried out with the abdomen open, for 30 min at 43 degrees C, with 2 l/m(2) of a 5% dextrose instillation in a closed continuous circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of oxaliplatin and irinotecan.


RESULTS
Irinotecan concentration in tumoral tissue increased until 400 mg/m(2) and then remained stable despite dose escalations. It was 16-23 times higher than in non-bathed tissues. Increasing doses of intraperitoneal irinotecan did not modify the PK of intraperitoneal oxaliplatin, and the drug concentration ratio was 17.8 higher in tumoral tissue (bathed) than in non-bathed tissues. The hospital mortality rate was 2.5% and the non-hematological complication rate was 25%. However, grade 3-4 hematological toxicity rate was 58%.


CONCLUSIONS
Intraperitoneal heated oxaliplatin (460 mg/m(2)) plus irinotecan (400 mg/m(2)) presented an advantageous PK profile and was tolerated by patients, despite a high hematological toxicity rate.
Elias
D
D
Department of Surgical Oncology, Institut Gustave Roussy Comprehensive Cancer Center, Villejuif, France.
Matsuhisa
T
T
Sideris
L
L
Liberale
G
G
Drouard-Troalen
L
L
Raynard
B
B
Pocard
M
M
Puizillou
J M
JM
Billard
V
V
Bourget
P
P
Ducreux
M
M
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002277:Carcinoma / Q000188:drug therapy* / Q000601:surgery; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007263:Infusions, Parenteral; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000601:surgery
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002166:Camptothecin