[Renal protection with amifostine during intraoperative peritoneal chemohyperthermia (IPCH) with cisplatin (CDDP) for peritoneal carcinosis. Phase 1 study].

BACKGROUND

An innovative approach to peritoneal neoplasm therapy is based on the surgical exeresis of visceral neoplasms, peritonectomy and lastly perfusion of the abdominal cavity with cytostatic drugs in hypothermia (1PCH). Cisplatin (CDDP) is one of the most frequently used drugs for peritoneal perfusion owing to its excellent synergy with hypothermia, reduced ability to penetrate the peritoneal- plasma barrier and its demonstrated efficacy against the majority of neoplasms causing peritoneal carcinosis. A major restriction is that CDDP causes renal toxicity. In order to minimise the risk of renal damage, the authors studied the use of amifostin to protect the renal system. A phase-1 study was performed to find the dose of amifostin that guarantees effective renal protection without causing hypotension.

METHODS

A total of 67 cytoreductions were performed at our centre associated with abdominal cavity perfusion using cytostatic compounds in hyperthermia (1PCH) with CDDP for peritoneal carcinosis. Among the first 9 patients undergoing IPCH without nephroprotection, Grade 2 (WHO) renal toxicity was observed in 4 cases (44%) and Grade IV-WHO toxicity in one patient (11%) leading to hemodialysis and death. Arnifastin was then administered to 18 patients. The administration protocol was as follows: cytoreduction, im. administration of amifostin 910 mg/m2 in 15 minutes, execution of IPCH. All patients treated using this dose presented hypotension with systolic arterial pressure <70 mmHg and amifostin administration was consequently suspended. Amifostin was then administered to a further 18 patients divided into groups of three. The dose used for the first triplet was 400 mg/m2; we then increased the dose by 50 mg/m2 in each subsequent triplet. The maximum dose tolerated was 50 mg/m2 less than the initial dose that caused systolic pressure to fall below 70 mmHg.

RESULTS

Patients treated with doses = or <500 mg/m2 did not present hypotension and it was therefore possible to administer the entire dose. Patients treated with 600 mg/m2 of amifostin all presented hypotension <70 mg Hg, leading to the suspension of the drug. A new triplet of patients was treated at a dose of 550 mg/m2 and none showed hypotension. Taking 550 mg/m2 as the maximum tolerable dose, a further 22 patients then received amifostin infusion with 550 mg/m2 prior to IPCH. Creatinemia was assayed daily for two weeks and creatinine clearance was measured twice a week to evaluate the efficacy of nephroprotection. None of the patients treated with amifostin during the study died from causes correlated to renal failure: 1 patient died from TEP and 1 from septic shock. No patient treated with a dose of 550 mg/m2 developed arterial hypotension. None of the 18 patients in the dose-finding study presented postoperative creatinemia >1.6 (WHO grade 1 toxicity). In the group of 22 patients treated later, 2 cases (9%) presented creatinemia >1.6 (1.8 and 2.1) for a few days; both had undergone severe debulking and one of the patients subsequently underwent resection and anastomosis of the left renal artery invaded by the neoplasm.

CONCLUSIONS

Some patients undergoing cytoreduction+IPCH without the use of amifostin developed severe renal toxicity; acute renal failure occurred in 1 patient requiring hemodialysis and was the main cause of death. None of the 28 patients treated with amifostin 550 mg/m2 developed hypotension or renal insufficiency; only 2 cases showed a slight transient increase in renal function markers. Amifostin appears to be an effective drug for protecting renal emunctory from the toxic effects of CDDP used in cytoreduction+IPCH in patients with peritoneal carcinosis. The dose of 550 mg/m2 used in this study does not cause hypotension and is recommended for this type of clinical use.