The administration of hypotonic intraperitoneal cisplatin during operation as a treatment for the peritoneal dissemination of gastric cancer

Abstract

Gastric cancers with serosal invasion often spread to the peritoneal surface. Beneficial effects of hypotonic intraperitoneal cisplatin against peritoneal dissemination was noted in experimental models. Prophylactic hypotonic intraperitoneal cisplatin during operation should therefore be examined in human gastric cancer. Isotonic intraperitoneal cisplatin was administered immediately after gastrectomy in increasing doses to patients with locally advanced gastric cancer until dose-limiting toxicity (DLT) was observed in 2 or more of 3 patients who were treated at a specific dose level. The osmolarity reduction and dose escalation trial for hypotonic intraperitoneal cisplatin was then performed until DLT was observed in 2 or more of 6 patients. The dose-escalation trial revealed the DLT of isotonic intraperitoneal cisplatin in the form of nausea and vomiting at a dose of 120 mg/m2. Isotonic intraperitoneal cisplatin treatment was recommended at a dose of 100 mg/m2. Because of the possible enhanced toxicity by hypotonic solution, hypotonic intraperitoneal cisplatin at a dose of 70 mg/m2 in one-half normal saline solution was injected, but no serious toxic reaction was observed. Hypotonic intraperitoneal cisplatin at a dose of 70 mg/m2 that had been dissolved in distilled water was then injected. It was accompanied by serious renal toxicity in 2 of 6 patients. Dose escalation was thus terminated, and the trial in an additional 25 patients confirmed that the toxicity of hypotonic intraperitoneal cisplatin at a dose of 70 mg/m2 was tolerable. A pharmacokinetic study to determine the maximum concentration and the area under the curve of concentration versus time of platinum revealed that hypotonic intraperitoneal cisplatin did not appear to increase the maximum concentration or area under the curve of the total and free platinum in the plasma in comparison with the isotonic intraperitoneal cisplatin at the same dose. Hypotonic intraperitoneal cisplatin treatment with distilled water at the time of a gastric resection is well tolerated. Hypotonic intraperitoneal cisplatin does not increase the plasma level of platinum at a dose of 70 mg/m2. Phase II/III studies are still required to clarify the efficacy of hypotonic intraperitoneal cisplatin for the treatment of the peritoneal dissemination in gastric cancer.