Oxaliplatin

Abstract

Oxaliplatin (Eloxatin™) is the only platinum compound to show clinical activity in colorectal cancer. The efficacy of a combination of oxaliplatin with various schedules of fluorouracil (5-FU)/folinic acid (FA) as first- or second-line treatment for advanced metastatic colorectal cancer has been investigated in large phase III trials. FOLFOX4 (an oxaliplatin/5-FU/FA regimen) as first-line therapy (n = 795) was superior to irinotecan/5-FU/FA (IFL). Response rates were 45% vs 31%, and median progression-free survival duration was 8.7 vs 6.9 months. The survival advantage shown by FOLFOX4 over the irinotecan combination (median survival duration 19.5 vs 14.8 months) may be confounded by differences in post-study treatment but equivalent efficacy is supported by another phase III trial of oxaliplatin and irinotecan combinations. As first-line therapy, oxaliplatin added to various 5-FU/FA regimens more than doubled the response rates from 16–22.6% to 48.3–53% and the median duration of progression-free survival was significantly longer with oxaliplatin/ 5-FU/FA than 5-FU/FA alone (7.9–9 versus 5.3–6.2 months, respectively). In disease resistant to irinotecan-based therapies, the oxaliplatin (FOLFOX4) regimen had superior efficacy to 5-FU/FA alone in a pivotal phase III trial (n = 816). Response rates and median durations of progression-free survival were 9.6% vs 0.7% and 5.6 vs 2.6 months, respectively. An oxaliplatin-induced cumulative peripheral sensory neuropathy (evident when total dose reaches ≈800 mg/m²) is dose limiting. The most frequently occurring grade 3 or 4 toxicities in oxaliplatin/5-FU/FA-recipients were neutro-penia (up to 48%) and neurological toxicities (up to 18%). Gastrointestinal effects (diarrhoea [≈12%], nausea, vomiting, or mucositis/stomatitis [up to 6%]) are manageable. Withdrawals from oxaliplatin treatment were due to neuropathy (up to 10%), diarrhoea and/or vomiting (1%) or cutaneous toxicity (1%). Conclusion: As first-line therapy for metastatic colorectal cancer, oxaliplatin with 5-FU/FA consistently improves response rates and progression-free survival compared with various regimens of 5-FU/FA alone. The significant survival advantage shown by oxaliplatin/5-FU/FA (FOLFOX4) compared with first-line therapy with irinotecan/5-FU/FA (IFL) is encouraging but may require further confirmation. Oxaliplatin/5-FU/FA produces a significantly higher response rate and longer progression-free survival than 5-FU/FA in patients failing irinotecan-based therapies, and as such is also a useful second-line treatment. Although cumulative neurotoxicity is dose limiting, oxaliplatin has a manageable tolerability profile. Oxaliplatin as first- or second-line therapy is a valuable addition to the limited, but expanding, armamentarium of cytotoxic agents useful in advanced metastatic colorectal cancer. Oxaliplatin exerts its cytotoxic effect chiefly through the formation of platinated intrastrand DNA adducts, together with a small proportion of interstrand crosslinks. This leads to inhibition of tumoural DNA synthesis and repair, and ultimately to cellular apoptosis. Oxaliplatin is distinguished from other platinum compounds by its possession of a bulky diaminocyclohexane (DACH) moiety, and it is believed that this leads to enhancement of cytotoxicity via differences in patterns of molecular distortion relative to agents such as cisplatin and carboplatin. The antiproliferative activity of oxaliplatin has been shown to be at least as great as cisplatin or carboplatin in a number of different tumour types. Cytotoxicity studies in cell lines including the colonic HT-29 tumour type indicate the relative antiproliferative potencies of five platinum agents to be oxaliplatin = tetraplatin > cisplatin > iproplatin > carboplatin. Additivity and/or synergy has been reported in cellular cultures when oxaliplatin is combined with fluorouracil (5-FU), the topoisomerase I inhibitor SN-38, the thymidylate synthase inhibitor nolatrexed (AG337), or gemcitabine. Activity of oxaliplatin in vitro against hepatic metastases from colorectal primary tumours has also been shown. Moreover, studies have identified potential genetic markers of response to oxaliplatin (e.g. the excision cross complementing gene ERCC1). After administration, oxaliplatin is biotransformed rapidly and nonenzymatically to a number of reactive intermediates; the antitumour activity of the drug resides in free platinum species present in the ultrafilterable fraction of plasma. Elimination of unbound platinum from the ultrafiltrate is triphasic, and consists of two short phases with half-lives of 0.43 (t½α) and 16.8 (t½β) hours. The long terminal phase has a half-life (t½)gg of 391 hours. Steady-state ultrafiltrate drug concentrations are attained during the first cycle of treatment with oxaliplatin, and inter- and intrapatient variabilities in ultrafilterable platinum exposure are low. Plasma protein binding of oxaliplatin is extensive and rapid, and exceeded 90% 5 days after a 2-hour infusion of 130 mg/m². Excretion of the biotransformation products of oxaliplatin is predominantly renal, with 54% of platinum eliminated in the urine 5 days after a single 2-hour infusion. Renal clearance ranges from 10–17 L/h and correlates with the glomerular filtration rate. The pharmacokinetic disposition of oxaliplatin is broadly similar after hepatic arterial or intravenous infusion. In a small sample of patients, mild or moderate renal impairment did not alter C_max, and although platinum exposure increased with increasing renal dysfunction, incidence or severity of toxicities did not. Despite conflicting evidence for the effects of oxaliplatin on the pharmacokinetics of 5-FU, standardised dosage regimens for using the two drugs in combination have been developed. There is no evidence of pharmacokinetic interactions between oxaliplatin and either irinotecan or topotecan. Data pertaining to the thymidylate synthase inhibitor raltitrexed are conflicting. The potential efficacy of oxaliplatin in combination with fluorouracil (5-FU)/ folinic acid (FA) has been investigated in numerous phase II and several large, randomised, multicentre, phase III clinical studies in either previously untreated (first-line therapy) or treated patients (second-line therapy). In combination, the dosage of oxaliplatin is typically 85–100 mg/m² per 2-week cycle and that of 5-FU/FA regimen has many variations. These include 1- or 2-day bolus or infusion (chronomodulated or continuous fixed rate), or both bolus and infusion schedules of 5-FU. FOLFOX4, an established and commonly used regimen in phase III clinical trials of oxaliplatin, consists of a 2-week cycle of oxaliplatin 85 mg/m² (day 1), and FA 200 mg/m² with a 5-FU 400 mg/m² bolus and 600 mg/m² infusion (on days 1 and 2). Oxaliplatin/5-FU/FA as First-Line Therapy: As first-line treatment compared with 5-FU/FA alone, combination regimens of oxaliplatin with 5-FU/FA had significantly greater objective response rates and progression-free survival durations. Response rates more than doubled when oxaliplatin was added to each of two different 5-FU/FA regimens (the de Gramont regimen [bolus and infusion], 50.7% vs 22.3%, and a chronomodulated schedule, 53% to 16%). Response rates were also significantly increased when oxaliplatin, in combination with an infusion schedule of 5-FU/FA, was compared with a bolus regimen of 5-FU/FA alone (the Mayo schedule). The median duration of progression-free survival was significantly longer with oxaliplatin combinations with 5-FU/FA than comparator regimens (7.9–9 months versus 5.3–6.2 months, respectively). An oxaliplatin-containing regimen (FOLFOX4) as first-line therapy was superior to the current US first-line therapy for metastatic colorectal cancer (irinotecan 125 mg/m² plus FA 200 mg/m² and 5-FU 500 mg/m² weekly for 4 weeks of a 6-week cycle [IFL or Saltz regimen]). In a recent large clinical trial (n = 795 evaluable patients) response rates were 45% versus 31%, respectively. The median duration of progression-free survival was 8.7 months versus 6.9 months, respectively. This FOLFOX regimen also showed a survival advantage over the irinotecan combination, (19.5 vs 14.8 months). Interpretation of survival results may be confounded by post-study treatment, as different proportions of patients received second treatment regimens on disease progression. The conclusion that the activity of these treatments in patients with metastatic colorectal cancer could be considered at least equivalent is supported by the similar response rates of another FOLFOX regimen and an irinotecan regimen (FOLFIRI) that were the initial regimens used in a trial of sequential therapies. No significant survival advantages in oxaliplatin treatment groups were observed in three other major comparative phase III studies, although post-study chemotherapy may have diluted the results of the first major comparative study of oxaliplatin with 5-FU/ FA compared with 5-FU/FA alone. Oxaliplatin/5-FU/FA as Second-Line Therapy: An oxaliplatin/5-FU/FA combination (FOLFOX4) had superior efficacy to 5-FU/FA alone in a phase III study in patients (n = 816 evaluable) with disease resistant to irinotecan-based therapy. Response rates and median durations of progression-free survival were 9.6% vs 0.7% and 5.6 vs 2.6 months, respectively). Response rates in small noncomparative trials of various established oxaliplatin/5-FU/FA regimens in disease resistant to or progressive with irinotecan-based therapies ranged from 4% to 21%. In a smaller randomised study in disease which was progressive during or within 6 months of a 5-FU-based treatment regimen, the 2-weekly FOLFOX4 regimen of oxaliplatin with 5-FU/FA had a similar response rate and median duration of progression-free survival when compared to irinotecan 180 mg/m² plus the same 5-FU/FA regimen, or a combination of oxaliplatin 85 mg/m² and irinotecan 200 mg/m² once every 3 weeks. In small noncomparative studies in patients with progressive disease during treatment with 5-FU and other chemotherapies, response rates ranged from 7% to 46% and, where stated, progression-free survival durations were 4.4–6 months and median survival durations were 7–17 months. These trials employed a wide range of treatment regimens, which varied with respect to dose, frequency and 5-FU infusion duration. In Liver Metastases: An adequate response to palliative chemotherapy in advanced colorectal cancer with initially unresectable liver metastases may permit resection of the metastases and prolong survival. Following treatment in two separate studies with oxaliplatin combined with 5-FU/FA and subsequent liver resection, the 5-year survival rate of patients who also had extrahepatic disease was 40%, and for patients with liver-only metastases was 50% (a retrospective analysis). Oxaliplatin combination regimens administered by hepatic arterial infusion for hepatic metastases and coadministered with intravenous chemotherapy to reduce extrahepatic relapses have shown activity in previously untreated or treated patients. Oxaliplatin in Combination With Other Agents: In a well controlled study, oxaliplatin (85 mg/m²/day for 3 days per 6-week cycle or 1 day per 3-week cycle) administered with irinotecan (80 mg/m² weekly per 6-week cycle or 200 mg/m² on 1 day per 3-week cycle) as first-line treatment for metastatic colorectal cancer had a similar response rate to the current standard treatment (irinotecan with 5-FU/FA) [51% vs 48%]. Second-line therapy with the oxaliplatin and irinotecan combination gave response rates of 15.2–28% (comparative trials) and 31–37% (noncomparative trials). The four-drug combination (oxaliplatin, irinotecan, 5-FU and FA), with encouraging preliminary results as first-line treatment (response rates 58.2% and 63.6%), is now the focus of a phase III study. In previously treated patients, the response rate was 41.7%, and in mixed populations, response rates were 54.7–71.4%. For oxaliplatin combinations with other agents, response rates were 31–55% (first-line) and 15% (second-line) with capecitabine (a 5-FU prodrug), and 42–54% (first-line) and 16–33% (second-line) with raltitrexed. Tolerability of oxaliplatin in combination with 5-FU/FA is generally predictable, and in line with the toxicity profile of each component of the combination. The incidence of grade 3 or 4 toxicities occurring with oxaliplatin monotherapy as first- or second-line therapy include neurotoxicity (up to 31%), nausea and/or vomiting (8–17%), diarrhoea (0–10%), mucositis (3%), thrombocytopenia (0–8%) and neutropenia (0–5%). Alopecia or myelosuppression are uncommon, and nephrotoxicity or ototoxicity are not associated with oxaliplatin. Toxicities associated with 5-FU therapy, biomodulated with FA, include mucositis, diarrhoea, plantar-palmar erythema (hand-foot syndrome) and myelosuppression. The principal dose-limiting toxicity occurring with oxaliplatin therapy is neurotoxicity which presents as an acute, early-onset, cold-induced dysesthaesia and a late-onset, cumulative peripheral sensory neuropathy. The acute syndrome occurs in up to 85% or more of patients. Cumulative neurotoxicity occurs in 10–15% of patients when the total dose of oxaliplatin reaches approximately 800 mg/m². Functional impairment of movements requiring fine sensory-motor coordination is generally reversible on discontinuation of oxaliplatin with >80% of patients recovering within 3 or 4 months. In comparative trials of oxaliplatin in combination with 5-FU/FA, the incidence of treatment-related deaths was low (1–2%) and due to gastrointestinal, haematological or sepsis-related causes. Withdrawals in the oxaliplatin treatment groups were due to neuropathy (up to 10%), diarrhoea and/or vomiting (1%) or cutaneous toxicity (1%). The incidence of toxicities with the combination treatment varies with the schedule of administration of particularly the 5-FU/FA component (e.g. fixed-rate or chronomodulated infusion, or the bolus and infusion schedule). Treatment schedules that include oxaliplatin with bolus and infused 5-FU/FA have exhibited manageable toxicity. The most frequently occurring grade 3 or 4 toxicities in well controlled trials in patients receiving first- or second-line oxaliplatin/5-FU/FA combination therapy (bolus and infusion) were neutropenia (41.7–48% [febrile 4%] first-line, and 48% second-line), and neuropathy (≈18% first-line and 6% second-line) and gastrointestinal effects (diarrhoea ≈12% [first- or second-line], nausea [≈6% first-line, and 11% second-line], vomiting [3–9%, first- or second-line], and stomatitis/mucositis [5.8% first-line and 3% second-line]). Grade 1 and 2 toxicites occurring in approximately half or more of patients included anaemia, thrombocytopenia, neuropathy, nausea, vomiting and diarrhoea. Bolus administration of 5-FU/FA is generally associated with more myelosuppression, mucositis and diarrhoea, but less hand-foot syndrome than continuous infusion schedules. Oxaliplatin added to chronomodulated infusions of 5-FU/FA have less withdrawals from treatment due to intolerable toxic effects than the fixed-rate infusion schedule (severe gastrointestinal symptoms [3% vs 9%] or sensory neuropathy [24% vs 40%]). Grade 3 or 4 diarrhoea and vomiting occurred with similar incidences in the two groups. Three-weekly oxaliplatin (85 mg/m²) combined with irinotecan (200 mg/m²) in a large phase III clinical study, produced (grade 3 or 4) neutropenia (36% [11% febrile]), gastrointestinal effects (nausea [19%], vomiting [22%], and diarrhoea 27%]), and neuropathy (7%). Similar toxicities were observed in 2-weekly cycles of oxaliplatin 85 mg/m² combined with irinotecan 175 mg/m² (neutropenia [45%], diarrhoea [35%], nausea/vomiting [30%] and alopecia [30%]). Late diarrhoea was the predominant toxicity in patients receiving oxaliplatin (85 mg/m² three times in a 7-week cycle) with irinotecan (80 mg/m² weekly for 6 of 7 weeks) and it occurred significantly more than in the irinotecan/5-FU/FA group (19.4% vs 6.7%). Oxaliplatin compared with irinotecan (both administered with 5-FU/FA in previously untreated patients) had less frequent grade 3 or 4 nausea (6% vs 16%), vomiting (3% vs 14%), diarrhoea (12% vs 28%) and febrile neutropenia (4% vs 15%), and a similar incidence of neutropenia (48% vs 40%). Grade 3 or 4 neurotoxicity (paresthaesias) occurred more often with oxaliplatin-than irinote-can-based therapy (18% vs 3%). In a study of sequential therapies (oxaliplatin or irinotecan combinations), the incidence of grade 3 or 4 toxicities in arm A (FOLFOX followed by FOLFIRI) versus arm B (FOLFIRI followed by FOLFOX) included neurotoxicity (34% vs 0%) and neutropenia (44% vs 25%). However, incidences in arm A and arm B of other toxicities were 1% versus 6% (febrile neutropenia), 3% versus 13% (nausea), 1% versus 10% (stomatitis) and 9% versus 24% (alopecia). Alopecia is more commonly associated with irinotecan or 5-FU than with oxaliplatin, so the potential for alopecia with irinotecan/5-FU/FA is greater than with oxaliplatin/5-FU/FA combinations. Oxaliplatin, in combination with 5-FU and FA, is indicated for first-line (Europe/ Australia/Asia) or second-line (US) therapy of metastatic colorectal cancer. The recommended dosage of oxaliplatin in combination with 5-FU and FA is 85 mg/ m² intravenously once every 2 weeks or 130 mg/m² intravenously once every 3 weeks. Oxaliplatin should be administered as a 2- to 6-hour infusion. Patients should be monitored for neurological toxicity and allergy to platinum compounds. Infusion time should be lengthened to 6 hours in patients who experience acute laryngopharyngeal dysaesthesias. The dosage of oxaliplatin should be reduced or therapy postponed in the event of neurological or haematological toxicity. Gastrointestinal toxicity can be controlled with anti-emetics. Oxaliplatin dosage need not be adjusted in patients with mild or moderate renal impairment. No information is available on dosage adjustment for severe renal impairment and oxaliplatin is contraindicated in these patients.