Oxaliplatin

Abstract

Oxaliplatin is a platinum compound that inhibits DNA synthesis, primarily by causing intrastrand cross-links in DNA. Oxaliplatin has a broad spectrum of antineoplastic activity and has demonstrated a lack of cross-resistance with other platinum compounds. In patients with metastatic colorectal cancer, intravenous oxaliplatin has been trialled as a monotherapy and in combination with other agents. The highest response rates were achieved when oxaliplatin was used in combination with fluorouracil/folinic acid (leucovorin; calcium folinate), typically ≥50% in the first-line setting and 13 to 45% as a second-line therapy. First-line triple therapy with oxaliplatin and fluorouracil/folinic acid achieved significantly higher response rates and longer median progression-free survival than fluorouracil/folinic acid therapy alone. However, no significant difference in the median duration of overall survival was found. This may be a consequence of the subsequent use of oxaliplatin and/or surgery after disease progression in patients who relapsed after fluorouracil/folinic acid therapy alone. Neoadjuvant therapy with oxaliplatin/fluorouracil/folinic acid has proven beneficial in enabling surgical removal of previously unresectable liver metastases. In 2 studies, surgery with curative intent was performed in 16 and 51% of patients with initially unresectable liver metastases following oxaliplatin/fluorouracil/folinic acid therapy; the 5-year survival rates were 40 and 50%, respectively. In patients with advanced ovarian cancer, first-line therapy with oxaliplatin/cyclophosphamide achieved an objective response rate which did not differ significantly from that of cisplatin/cyclophosphamide (33 vs 42%). In addition, oxaliplatin has shown efficacy in patients with platinum-pretreated ovarian cancer and achieved objective response rates similar to paclitaxel in this setting (16 vs 17%). Promising results have also been found with oxaliplatin in patients with non-Hodgkin’s lymphoma, breast cancer, mesothelioma and non-small cell lung cancer. Reversible, cumulative, peripheral sensory neuropathy is the principle dose-limiting factor of oxaliplatin therapy. Haematological and gastrointestinal toxicities occur frequently but are generally mild to moderate in intensity. Conclusion: Oxaliplatin in combination with fluorouracil/folinic acid is an effective treatment option for patients with metastatic colorectal cancer, both as a first-line therapy and in patients refractory to previous chemotherapy. Although preliminary results failed to show any overall survival advantage of this regimen over fluorouracil/folinic acid alone, this may be a consequence of trial design and requires further examination. Additional clinical investigation of oxaliplatin in patients with other cancers is warranted given the promising results achieved in early trials, most notably in patients with platinum-pretreated ovarian cancer. Oxaliplatin is a diaminocyclohexane (DACH) carrier ligand-based platinum compound that inhibits DNA synthesis. The major cytotoxic lesions are intrastrand platinum-DNA adducts, formed by cross-linking between activated platinum species and specific base sequences. In addition, apoptosis may also contribute to the mechanism of action of this drug. Oxaliplatin has shown in vitro antiproliferative activity against several human tumour cell lines and against tumour isolates from patients. Moreover, greater cytotoxic activity than cisplatin or carboplatin has been reported for oxaliplatin against some drug-resistant cancer cell lines. Oxaliplatin has shown similar antitumour activity to cisplatin in vivo in a number of murine tumours, including colon carcinoma, melanoma, P388 and L40 AkR leukaemia models. Superior antineoplastic efficacy to cisplatin has been reported in murine tumour models of mammary carcinoma, sarcoma, L1210 leukaemia and LGC lymphoma, and efficacy is retained in some cisplatin-resistant strains. Additive or synergistic effects of a number of oxaliplatin-based combinations have been reported in human colon cancer cell lines and in several in vivo tumour models, most notably oxaliplatin and fluorouracil. Oxaliplatin undergoes rapid nonenzymatic biotransformation to form a variety of reactive platinum intermediates and these species bind rapidly and extensively to plasma proteins and erythrocytes. Maximum plasma concentrations (C_max) of platinum and area under the concentration-time curve values of 0.83 to 1.21 mg/L and 11.9 to 13.6 mg/L · h, respectively, have been reported in the pharmacologically active ultrafilterable plasma fraction following a 2-hour infusion of oxaliplatin 130 mg/m². Steadystate plasma ultrafiltrate platinum concentrations were achieved during the first cycle of treatment with oxaliplatin 130 mg/m², and accumulation was not reported after single or multiple dosing. Platinum C_max was dependent on the time of peak oxaliplatin infusion during a chronomodulated treatment regimen. Ultrafilterable platinum C_max was significantly lower after peak delivery at 0100 hours compared with values at 0700 or 1600 hours. Oxaliplatin-derived platinum has a volume of distribution from plasma ultra-filtrate of 582 to 812L and a clearance range of 9.3 to 10.1 L/h. Excretion of oxaliplatin biotransformation products is principally by the renal route. Exposure to plasma platinum was increased in patients with moderate renal impairment compared with that in individuals with normal renal function. However, further deterioration of renal function was not reported and the toxicity of oxaliplatin was not increased in patients with renal impairment. Reported pharmacokinetic interactions of oxaliplatin with fluorouracil or raltitrexed are inconsistent. There were no pharmacokinetic interactions between oxaliplatin and irinotecan or topotecan. The majority of clinical trials have focused on the efficacy of oxaliplatin in metastatic colorectal cancer and, more recently, in patients with advanced ovarian cancer. Preliminary studies have also looked at oxaliplatin in the treatment of several other cancers including non-Hodgkin’s lymphoma, non-small cell lung cancer, mesothelioma and breast cancer. While oxaliplatin monotherapy has been investigated in some trials, the drug has been most widely used in combination with fluorouracil/folinic acid (leucovorin; calcium folinate). There is some evidence to suggest that chronomodulated delivery of these agents achieves a higher response rate than standard fixed-rate infusion; however, whether this translates into a survival benefit is unclear. Metastatic Colorectal Cancer In patients with metastatic colorectal cancer, the addition of oxaliplatin to first-line fluorouracil/folinic acid therapy significantly increased the objective response rate compared with fluorouracil/folinic acid therapy alone in 2 large randomised trials: the objective response rates were 53 vs 16% (p < 0.001) and 50.7 vs 22.3% (p < 0.001) in patients receiving fluorouracil/folinic acid with or without oxaliplatin, respectively. Median progression-free survival was also significantly longer for patients receiving oxaliplatin in both trials (≈9 vs 6 months), but there was no significant difference in the median duration of overall survival. This could be due to the fact that second-line oxaliplatin and/or irinotecan and/or surgery was allowed in patients initially randomised to receive only fluorouracil/folinic acid therapy. In patients relapsing after fluorouracil-based therapy, oxaliplatin combined with fluorouracil/folinic acid produced objective response rates typically between 13 and 45%. Median progression-free survival typically ranged between 5 and 10 months and the median duration of survival was between 9 and 17 months. Initial reports indicate that oxaliplatin may also be effectively combined with irinotecan (second-line objective response rates of 28 to 44%) and raltitrexed (first-line objective response rate of 62%) in patients with metastatic colorectal cancer. These combinations have also been examined in combination with fluorouracil-based therapy. As a monotherapy, oxaliplatin produced response rates of 20 and 24% as a first-line therapy and ≈10% as a second-line therapy in patients refractory to, or progressing after, fluorouracil-based therapy. Chemotherapy with oxaliplatin/fluorouracil/folinic acid is useful in reducing metastases, such that a proportion of patients with previously unresectable disease can undergo surgery with curative intent. In 2 separate studies (n = 330 and 151), surgery with curative intent was performed in 16 and 51% of patients with initially unresectable liver metastases following oxaliplatin/fluorouracil/folinic acid therapy (complete resection was achieved in 87 and 75% of these patients); the 5-year survival rates were 40 and 50%. The latter, retrospective analysis included only patients with metastases confined to the liver; this study also reported 5-year survival rates for the total patient population (28%) and for patients achieving complete resection (estimated at 58%). Advanced Ovarian Cancer In patients with advanced ovarian cancer, first-line combination therapy with oxaliplatin/cyclophosphamide showed similar efficacy to cisplatin/cyclophosphamide. No significant differences were reported between the oxaliplatin and cisplatin treatment arms for objective response rate (33 vs 42%), median progression-free survival (13 months) and median overall survival (36 vs 25 months). Oxaliplatin also has shown efficacy as a second-line therapy in patients with platinum-pretreated advanced ovarian cancer, and had similar efficacy to paclitaxel in 1 trial (objective response rates 16 and 17%, respectively). Other Cancers The clinical efficacy of oxaliplatin has been studied in a range of other cancer types including non-Hodgkin’s lymphoma, breast cancer, non-small cell lung cancer, squamous cell carcinoma of head and neck, malignant melanoma, mesothelioma and glioblastoma. In the largest of these trials, combined oxaliplatin/fluorouracil achieved an objective response rate of 25% in 53 patients with advanced breast cancer, and oxaliplatin/raltitrexed achieved a response rate of 26% in 58 patients with mesothelioma. The main toxicities occurring with oxaliplatin can be generally divided into neurological, gastrointestinal and haematological. A cumulative, but generally reversible, peripheral sensory neuropathy is the principle dose-limiting factor. Severe neurotoxicity with functional impairment has been estimated to occur in 10% of patients at a cumulative dose of 780 mg/m² (9 treatment cycles at 85 mg/m² once every 2 weeks or 6 treatment cycles at 130 mg/m² once every 3 weeks), and in 50% of patients at a cumulative dose of 1170 mg/m². Gastrointestinal and haematological toxicities occur frequently but are generally mild to moderate in intensity. Unlike cisplatin, oxaliplatin is not associated with renal or auditory toxicity. The adverse events occurring with oxaliplatin monotherapy increase predictably when used in combination with other chemotherapies. In a large meta-analysis (n = 682), patients receiving oxaliplatin in combination with fluorouracil/folinic acid appeared to have a higher incidence of grade 3 to 4 nausea/vomiting, diarrhoea, haematological events, peripheral neuropathy versus patients receiving oxaliplatin monotherapy. Furthermore, combination therapy with oxaliplatin and fluorouracil/folinic acid was associated with significantly higher rates of nausea/vomiting, diarrhoea and peripheral neuropathy than fluorouracil/folinic acid therapy alone in 2 randomised phase III trials. Chronomodulated delivery of combination oxaliplatin/fluorouracil/folinic acid chemotherapy may improve tolerability. This technique was associated with significantly lower rates of severe mucositis (13 vs 76%; p < 0.0001), peripheral neuropathy (16 vs 31%; p = 0.01), withdrawal because of adverse events (28 vs 51%; p = 0.002) and hospital admissions for severe adverse events (10 vs 31%; p = 0.001) than a fixed rate infusion schedule. Oxaliplatin has also shown acceptable toxicity when used in combination with other chemotherapies including irinotecan, raltitrexed, paclitaxel, cisplatin and cyclophosphamide; however, data are still limited. The tolerability of oxaliplatin compared equally or favourably with paclitaxel, irinotecan and cisplatin in initial comparative studies. Oxaliplatin is available in several countries in Europe, Asia and Latin America for use in combination with fluoropyrimidines as a first-line therapy for metastatic colorectal cancer. It is also available for use in combination with fluoropyrimidines as a second-line therapy for colorectal cancer in some Asian and South American countries. The recommended dosage of oxaliplatin in combination with fluoropyrimidines is 85 mg/m² once every 2 weeks as a first-line therapy and 130 mg/m² once every 3 weeks as a second-line therapy. The dosage should be administered as a 2- to 6-hour intravenous infusion and given before fluoropyrimidine therapy. The dosage should be adjusted according to tolerability; gastrointestinal toxicity may be reduced with prophylactic and/or therapeutic antiemetic therapy. Although oxaliplatin has also been investigated in combination with other agents (such as irinotecan and raltitrexed) and in other indications, formal dosage guidelines are not available for the use of oxaliplatin in these settings.