Human pharmacokinetic study of heated intraperitoneal oxaliplatin in increasingly hypotonic solutions after complete resection of peritoneal carcinomatosis.
OBJECTIVE
We studied the pharmacokinetics of heated intraoperative intraperitoneal (i.p.) oxaliplatin (LOHP) solution and its safety profile in increasingly hypotonic solutions. This is the first clinical study of i.p. chemohyperthermia with hypotonic solutions.


METHODS
Patients with peritoneal carcinomatosis (PC) underwent complete cytoreductive surgery followed by intraoperative i.p. chemohyperthermia (IPCH) with successive dextrose solutions of 300, 200, 150 and 100 mosm/l. LOHP (460 mg/m(2)) was administered in 2 liters of solution/m(2) at an i.p. temperature of 42-44 degrees C for 30 min. IPCH was performed using an open procedure (skin pulled upwards) with a continuous closed circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of LOHP. i.p. plasma and tissue samples were analyzed by means of atomic absorption spectrophotometry. Sixteen consecutive patients with PC of either gastrointestinal or peritoneal origin were treated. The safety of the procedure was studied.


RESULTS
Pharmacokinetics: The mean duration of the entire procedure was 7.7 +/- 2.6 h. Half the LOHP dose was absorbed within 30 min at all dose levels. Absorption was not higher with hypotonic solutions than with isotonic solutions. The area under the curve of LOHP in plasma did not increase with decreasing osmolarity of the i.p. solutions. Intratumoral LOHP penetration was high; it was similar to that at the peritoneal surface, and about 18 times higher than that in nonbathed tissues. LOHP penetration was not significantly increased by using hypotonic solutions.


RESULTS
There was a very high incidence of unexplained postoperative peritoneal bleeding (50%) and unusually severe thrombocytopenia in the 150 and 100 mosm/l groups.


CONCLUSIONS
Contrary to experimental studies, this clinical study showed no increase in tumoral or systemic penetration of LOHP with i.p. hypotonic solutions (200, 150 or 100 mosm/l) during IPCH. A high incidence of i.p. hemorrhage and thrombocytopenia was observed.
Elias
D
D
Department of Surgical Oncology, Institut Gustave Roussy, Villejuif, France. elias@igr.fr
El Otmany
A
A
Bonnay
M
M
Paci
A
A
Ducreux
M
M
Antoun
S
S
Lasser
P
P
Laurent
S
S
Bourget
P
P
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D002277:Carcinoma / Q000188:drug therapy* / Q000601:surgery; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D007038:Hypotonic Solutions; D007430:Intraoperative Care; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000601:surgery; D013054:Spectrophotometry, Atomic
D000970:Antineoplastic Agents; D007038:Hypotonic Solutions; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil