OXALIPLATIN - A REVIEW OF PRECLINICAL AND CLINICAL-STUDIES

Of the new generation platinum compounds that have been evaluated, tho se with the 1,2-diaminocyclohexane carrier ligand - including oxalipla tin - have been focused upon in recent years. Molecular biology studie s and the National Cancer Institute in vitro cytotoxic screening showe d that diaminocyclohexane platinums such as oxaliplatin belong to a di stinct cytotoxic family, differing from cisplatin and carboplatin, wit h specific intracellular target(s), mechanism(s) of action and/or mech anism(s) of resistance. In phase I trials, the dose-limiting toxicity of oxaliplatin was characterized by transient acute dysesthesias and c umulative distal neurotoxicity, which was reversible within a few mont hs after treatment discontinuation. Moreover, oxaliplatin did not disp lay any, auditory, renal and hematologic dose-limiting toxicity at the recommended dose of 130 mg/m(2) q three weeks or 85 mg/m(2) q two wee ks given as a two-hour i.v. infusion. Clinical phase II experiences on the antitumoral activity of oxaliplatin have been conducted in hundre ds of patients with advanced colorectal cancers (ACRC). Single agent a ctivity reported as objective response rate in ACRC patients is 10% an d 20% overall in ACRC patients with 5-fluorouracil (5-FU) pretreated/r efractory and previously untreated ACRC, respectively. Synergistic cyt otoxic effects in preclinical studies with thymidylate synthase inhibi tors, cisplatin/carboplatin and topoisomerase I inhibitors, and the ab sence of hematologic dose-limiting toxicity have made oxaliplatin an a ttractive compound for combinations. Phase II trials combining oxalipl atin with 5-FU and folinic acid ACRC patients previously treated/refra ctory to 5-FU showed overall response rates ranging from 21% to 58%, a nd survivals ranging from 12 to 17 months. In patients with previously untreated ACRC, combinations of oxaliplatin with 5-FU and folinic aci d showed response rates ranging from 34% to 67% and median survivals r anging from 15 to 19 months. Two randomized trials totaling 620 previo usly untreated patients with ACRC, comparing 5-FU and folinic acid to the same regimen with oxaliplatin, have shown a 34% overall response r ate in the oxaliplatin group versus 12% in the 5-FU/folinic acid group for the first trial; and 51.2% vs. 22.6% in the second one. These sta tistically significant differences were confirmed in time to progressi on advantage for the oxaliplatin arm (8.7 vs. 6.1 months, and 8.7 vs. 6.1 months, respectively). A small but consistent number of histologic al complete responses have been reported in patients with advanced col orectal cancer treated with the combination of oxaliplatin with 5-FU/f olinic acid, and secondary metastasectomy is increasingly done by onco logists familiar with the combination. Based on preclinical and clinic al reports showing additive or synergistic effects between oxaliplatin and several anticancer drugs including cisplatin, irinotecan, topotec an, and paclitaxel, clinical trials of combinations with other compoun ds have been performed or are still ongoing in tumor types in which ox aliplatin alone showed antitumoral activity such as ovarian, non-small -cell lung, breast cancer and non-Hodgkin lymphoma. Its single agent a nd combination therapy data in ovarian cancer confirm its non-cross re sistance with cisplatin/carboplatin. While the role of oxaliplatin in medical oncology is yet to be fully defined, it appears to be an impor tant new anticancer agent.