The integration of paclitaxel and new platinum compounds in the treatment of advanced ovarian cancer

Abstract

There has been a steady improvement in the survival of patients with advanced ovarian cancer. This has been the result of a more skilled surgical approach to these patients and the development of more effective chemotherapy with a better integration of both modalities in first-line treatment. The current optimal chemotherapeutic approach consists of a platinum compound together with paclitaxel. This recommendation is based upon level I evidence of two large randomized trials which established that the combination of paclitaxel-cisplatin was superior to cyclophosphamide-cisplatin. The long-term follow-up of one of these studies continues to show a significant difference in survival at 5 years. Neurotoxicity has been problematic with these regimens, in particular when paclitaxel was given with the higher dosed shorter infusion schedule, as was done in the European-Canadian Intergroup study. Several approaches to reduce this toxicity have been studied. Among these are the use of different paclitaxel infusion schedules, and the application of less neurotoxic platinum compounds. Weekly paclitaxel has a different toxicity profile than the higher dosed three-weekly schedules, with less neutropenia, alopecia, arthralgia and neurotoxicity. Four platinum compounds are currently marketed: cisplatin, carboplatin, oxaliplatin, and nedaplatin. Of these only cisplatin, carboplatin, and nedaplatin have been approved for the treatment of patients with ovarian cancer (nedaplatin only in Japan). The equivalence of carboplatin and cisplatin has been suggested from trials without a taxoid. Three randomized studies of paclitaxel-carboplatin vs. paclitaxel-cisplatin concluded that paclitaxel-carboplatin is the preferred regimen in terms of (less) toxicity and, where studied, in terms of quality of life. So far, no difference in response rates or progression-free survival has been shown. More mature data on overall survival are awaited. Oxaliplatin (a diaminocyclohexane platinum compound) is of interest because it is only partially cross-resistant with cis- or carboplatin and devoid of severe bone marrow suppression, nephrotoxicity, or ototoxicity. Its dose-limiting toxicity is an unusual form of sensory neuropathy, which is cumulative and, contrary to cisplatin's neurotoxicity, generally reversible. Combinations with other active standard agents, as well as platinum compounds and/or taxoids, are feasible and have shown interesting activity. Similar to carboplatin and oxaliplatin, nedaplatin (cis-diammineglycolatoplatinum) can be given without hydration; its dose-limiting toxicity is myelosuppression, in particular thrombocytopenia. Although activity has been shown, no data from randomized comparative trials are available to allow a judgement on its potential advantages.

Oxaliplatin for the treatment of ovarian cancer

“…Oxaliplatin produces the same type of interand intrastrand crosslinks as cisplatin but DACH--platinum adducts are bulkier and more hydrophobic than cisplatin/ carboplatin adducts. Therefore, oxaliplatin may be more effective in DNA replication impairment and its antitumor activity is only partially cross-resistant with cisplatin and carboplatin [8]. Moreover, in cancer cell lines and in clinical studies, oxaliplatin has demonstrated to be superadditive and/or synergistic with cisplatin and carboplatin [15][16][17][18].…”

“…Although its mechanism of action is similar to that of the classic platinum compounds [7], oxaliplatin is only partially cross-resistant with cisplatin and carboplatin and had been demonstrated to be synergistic with these platinum agents in in vitro and in vivo models [8]. Moreover, oxaliplatin is featured by favorable side-effect profile compared to cisplatin and neurotoxicity, usually reversible, and is considered the dose-limiting toxicity [8]. Indeed, oxaliplatin could be considered for the treatment of patients who experienced hypersensitivity reactions to platinum, especially in heavily pretreated population [9].…”

A systematic review of platinum and taxane resistance from bench to clinic: An inverse relationship

“…The pooled response rate for each cohort described was the combined complete and partial response rates of each study based on the published response rate, assuming a standardised measure of response was used in the study. Patients recruited earlier than 1995 were assumed to be taxane naïve as platinum/paclitaxel combination therapy was only adopted as first-line therapy for ovarian cancer after several successful trials in 1996 showed the superiority of this regimen compared to the then standard therapy of cisplatin/cyclophosphamide 17,18 . This group of patients were analysed separately as there is the possibility that this group may have received prior paclitaxel salvage therapy.…”

Clinical application of oxaliplatin in epithelial ovarian cancer

“…Severe toxicity included neutropenia (21% of patients), febrile neutropenia (7%), and reversible grade 2 or higher neurosensory toxicity (21%). The oxaliplatin plus paclitaxel combination showed high antitumor activity and safe toxicity profile as a firstline adjuvant treatment for advanced ovarian cancer (46) . If this were confirmed in a large randomized trial, it would be sure that the passion will be reignited to make oxaliplatin the limelight in ovarian cancer treatment.…”