Oxaliplatin (cis-[(1R,2R)]-1,2-cyclohexanediamine-N,N´ oxalato (2-)-O,O´] platinum, Eloxatin) is a novel antineoplastic platinum derivative with a 1,2-diaminocyclohexane (DACH) carrier ligand. Although its precise mechanism of action is unknown, platinum compounds in general are thought to exert their cytotoxic effects through the formation of DNA adducts that block both DNA replication and transcription, resulting in cell death in actively dividing cells as well as the induction of apoptosis.[2,3] Oxaliplatin(Drug information on oxaliplatin) is often more potent than cisplatin(Drug information on cisplatin) (Platinol) in vitro, requiring fewer DNA adducts to achieve an equal level of cytotoxicity, and shows the same or greater efficacy against many tumor cell lines in preclinical studies, including some that are resistant to cisplatin and carboplatin(Drug information on carboplatin) (Paraplatin).[4-6]
Based on provocative responses seen in patients with metastatic colorectal cancer, oxaliplatin has been approved for use with the fluoropyrimidines in the treatment of metastatic colorectal cancer in Asia, Latin America, and Europe. Studies with oxaliplatin have also demonstrated its broad efficacy in several solid tumors and yielded encouraging preclinical data on combination therapy with novel agents (eg, thymidylate synthase inhibitors, epidermal growth factor-receptor antagonists, microtubule interactive agents).
Novel drug combinations with oxaliplatin that have entered the clinic may be grouped as follows:
Combinations with topoisomerase inhibitors
Combinations with novel thymidylate synthase inhibitors
Combinations with DNA interactive agents
Combinations with microtubule interactive agents
Other novel combinations
Many of the above combinations have been described in detail by other investigators in this supplement. Because oxaliplatin is a new drug, several approaches that have the potential for clinical application are being tested; however, data supporting these applications are still predominantly preclinical.
In vitro and in vivo studies of oxaliplatin have shown its additive or synergistic cytotoxic properties with the fluoropyrimidines (fluorouracil [5-FU]), thymidylate synthase inhibitors (AG337, raltitrexed [Tomudex]), nucleoside analogs (gemcitabine [Gemzar]), topoisomerase I inhibitors (topotecan, irinotecan [Camptosar], and SN-38), microtubule binding agents (paclitaxel [Taxol]), and DNA modifying/alkylating agents (cisplatin and cyclophosphamide(Drug information on cyclophosphamide) [Cytoxan, Neosar]).[7-13]
Although oxaliplatin demonstrates additive/synergistic activity in combination with many standard anticancer agents in preclinical models, some combinations do not show increased in vivo activity and are sometimes associated with increased toxicity. More extensive synergy studies with irinotecan(Drug information on irinotecan)/SN-38 and oxaliplatin in HT-29 colon carcinoma cell lines and GRI mouse mammary and other human tumor models suggest that there is increased stabilization of DNA adducts in cells exposed to topoisomerase I inhibitors after exposure to platinum. There are increased DNA topoisomerase I cleavable complexes that result in increased inhibition of DNA elongation and S-phase arrest.[8,9]
Other combinations include increased platinum-DNA adducts with hyperthermia exposure to cultured SW 1573 cells, potentiation of platinum-DNA adducts and cellular cytotoxicity when combined with antisense oligonucleotides against XPA (or CSB), and potentiation of oxaliplatin cytotoxicity by ZD1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor.
The efficacy of oxaliplatin monotherapy in patients with advanced colorectal cancer has been evaluated in several studies, and objective response rates achieved with oxaliplatin as first-line therapy averaged 18% while those of oxaliplatin as second-line therapy averaged 10%.[18-21] Furthermore, this single-agent response rate is comparable to that achieved with irinotecan alone in patients with colorectal cancer. Nevertheless, single-agent use of oxaliplatin is not currently recommended as standard therapy except in some European countries for patients with dihydropyrimidine dehydrogenase deficiency, which is associated with an increased risk for severe or lethal 5-FU toxicity, or in patients with 5-FU-related cardiotoxicity.
Combinations With 5-FU and Leucovorin
Given the relatively high response rates reported with oxaliplatin in colorectal cancer, an obvious choice was to study combinations with 5-FU and leucovorin in a front-line setting. These trials have been reviewed elsewhere in this supplement; however, in summary, the response rates varied from 25% to 67% depending on the delivery schedules of 5-FU/leucovorin. The major toxicities of oxaliplatin/5-FU/leucovorin combination therapy were diarrhea, stomatitis, peripheral sensory neuropathy, and nausea and vomiting. Multiple reviews of these trials have been published, and confirmatory data from randomized trials of oxaliplatin (with or without 5-FU/leucovorin) in the United States are awaited.
The next obvious point of investigation is the combination of oxaliplatin with 5-FU, with or without irinotecan. Several tumor models (eg, HT-29 colon carcinoma, GRI mouse mammary tumor) have shown that the combination of irinotecan and oxaliplatin has synergistic activity. At the molecular level, there is increased stabilization of adducts in cells exposed to the topoisomerase I inhibitor after exposure to platinum. There are increased DNA topoisomerase I cleavable complexes that result in prolonged inhibition of DNA elongation and S-phase arrest.[8,9]
Scheduling for Optimal Efficacy: The observed preclinical synergy and the potential for nonoverlapping toxicities in the combination has stimulated several clinical studies. Various irinotecan combinations delivered on a number of schedules, eg, every 3 weeks, weekly, or every 2 weeks, have been studied (Table 1).[24-27] Wasserman et al investigated the every-3-week schedule of irinotecan and oxaliplatin delivery. The maximum tolerated dose (recommended phase II dose) of irinotecan was 200 mg/m2 with oxaliplatin administered at a dose of 85 mg/m2. Toxicities included neuropathy and gastrointestinal events. No pharmacokinetic interactions between the two drugs were noted, and 7 of 24 patients had partial responses.
In a subsequent study, Goldwassser and colleagues described an every-2-week schedule of irinotecan administered with oxaliplatin. The maximum tolerated dose of the combination was irinotecan at 175 mg/m2 and oxaliplatin at 85 mg/m2. There was a slightly higher incidence of myelosuppressive events in this study compared with those described in the Wasserman study; however, the regimen was well tolerated overall, and significant responses were reported.
Rothenberg and collaborators have reported on the combination of irinotecan and oxaliplatin using an every-2-week schedule. The maximum tolerated dose has not yet been reached at 200 mg/m2 of irinotecan and 85 mg/m2 oxaliplatin (Mace Rothenberg, personal communication).
Other studies of irinotecan in the United States include one of a weekly schedule that is currently underway at Memorial Sloan-Kettering Cancer Center. Additional phase I and II studies have reported on the tolerability of this combination and also on the synergistic responses.[28,29] The toxicity of the triple combination of irinotecan, oxaliplatin, and 5-FU, with or without leucovorin, is predominantly dictated by the dose schedule of 5-FU/leucovorin.
The bulk of published studies indicate that it is feasible and safe to combine these three drugs [30-33]; however, there are examples of combinations that are very toxic and that do not significantly increase the activity of irinotecan and oxaliplatin. Gil-Delgado et al published a study of the triplet combination, which incorporated a modified de Gramont schedule (leucovorin at 200 mg/m2 followed by a 400 mg/m2 bolus of 5-FU plus continuous intravenous 5-FU at 600 mg/m2) in combination with irinotecan and oxaliplatin. The triplet was very toxicmore than 50% of patients presented with grade 3/4 diarrhea, and 1 of the 10 patients enrolled developed septic shock.