Second-line Therapy with 5-FU/LV

Several Phase II clinical trials evaluated different dosing schedules of oxaliplatin plus infusional 5-FU/LV (FOLFOX) as second-line treatment for patients with metastatic CRC resistant to 5-FU/LV.^22–25 Early trials suggested that a higher dose intensity of oxaliplatin might be associated with a higher response rate without increasing toxicities to an unacceptable level. In 2000, Maindrault-Gœbel et al retrospectively analyzed data from regimens combining oxaliplatin with different schedules of 5-FU and leucovorin (FOLFOX-2,-3,and - 6).They reported that objective responses occurred in a significantly higher percentage of patients treated with high-dose (>85mg/m² for two weeks) than with low- dose (?85mg/m² for two weeks) oxaliplatin (39% versus 19%, respectively; P=0.03).²⁵ They also concluded that a greater proportion of patients treated with high-dose oxaliplatin demonstrated progression-free survival at six months (52% versus 36%;P=0.02) and that improvements in efficacy were not associated with increased neurotoxicity or other toxicities.

A Phase III trial by Rothenberg et al led to the US approval of FOLFOX4 as second-line therapy for metastatic CRC.²⁶ FOLFOX4 was initially approved in Europe in 1999 as first-line treatment in this patient population. A total of 463 North American patients with IFL treatment-resistant metastatic CRC were randomized to receive one of three treatment regimens:

• bolus and infusional 5-FU plus LV (the de Gramont regimen);

• oxaliplatin alone (85mg/m2 intravenously) for 120 minutes, administered on day one of a 14-day treatment cycle); or

• oxaliplatin plus 5-FU/LV (FOLFOX4).

Compared with 5-FU/LV alone, FOLFOX-4 was associated with a significantly higher response rate (9.9% versus 0%; P<0.0001), a longer median TTP (4.6 months versus 2.7 months;P<0.0001),and a greater proportion of patients experiencing relief from tumor-related symptoms (33% versus 12%; P<0.001).Treatment with oxaliplatin monotherapy was similar to that with 5-FU/LV. The incidence of clinically significant toxicities was higher with FOLFOX4 than with 5-FU/LV – including grade 3/4 diarrhea, grade 3/4 hematologic toxicity (neutropenia), and peripheral neuropathy (with either FOLFOX4 or oxaliplatin alone) – but these side-effects did not result in a higher rate of treatment discontinuation or 60-day mortality.The final results, which include data from 821 patients, confirmed the earlier findings with regard to response rate and TTP, but examination of the survival data, which had previously been unavailable, indicated no significant differences between treatment groups with regard to overall survival.²⁷

First-line Therapy of Oxaliplatin in Combination with 5-FU/LV

It is now widely established that FOLFOX4 is effective as first-line treatment for patients with metastatic CRC. In a Phase III study by de Gramont et al, oxaliplatin (85mg/m2 as a two-hour infusion on day one, every two weeks) plus 5-FU/LV (de Gramont regimen) was compared with the de Gramont regimen of 5-FU–LV alone in 420 patients with previously untreated advanced CRC.²⁸ FOLFOX was associated with significantly longer median progression-free survival times (nine versus 6.2 months; P=0.0003) and improved response rates (50.7% versus 22.3%; P=0.0001), although the two treatment groups did not differ significantly with regard to overall survival (16.2 versus 14.7 months; P=0.12). Grade 3/4 neutropenia, diarrhea, and neurosensory toxicity were more frequent with FOLFOX than with 5-FU/LV alone, although measures of quality of life did not differ between the groups. Some studies have suggested that chronomodulated infusion of oxaliplatin and/or 5- FU/LV as first-line therapy in patients with metastatic CRC may reduce toxicity while improving efficacy.^29,30 In addition, there are now a growing number of studies of first-line chronomodulated 5- FU/LV and oxaliplatin that showed that surgical resection of metastatic disease was possible after chemotherapy in a subset of patients (13%) with initially unresectable colorectal metastases, with approximate five-year survival rates of 30%.

Intergroup Trial N9741 was a randomized Phase III trial in the first-line therapy for metastatic CRC with the bolus, weekly IFL regimen as the control arm.³¹ The two experimental arms of this trial included FOLFOX4 and a non-fluoropyrimidine-containing arm of irinotecan and oxaliplatin (IROX).This pivotal study demonstrated that FOLFOX4 had significantly greater clinical efficacy in terms of response rate (45% versus 31%),TTP (8.7 versus 6.9 months; P=0.0001), and median overall survival (19.5 versus 14.8 months; P=0.0001). In addition, when compared with IFL or IROX, FOLFOX4 was associated with a markedly lower incidence of febrile neutropenia and fewer gastrointestinal side-effects in terms of nausea/vomiting, diarrhea, and dehydration. However, peripheral sensory neuropathy and myelosuppression were more common with both FOLFOX4 and IROX when compared with IFL. Based on the results from this large Phase III clinical trial, in Janurary 2004, FOLFOX4 was approved for use in the US as first-line treatment of patients with advanced CRC.

Various Phase I/II clinical studies, conducted mostly in Europe, have been exploring the use of combination therapy with oxaliplatin, irinotecan, and 5-FU/lLV (‘triplet therapy’) as either first-line ^32–34 or second-line treatment ^35,36 in patients with metastatic CRC. The different mechanisms of action and generally divergent dose-limiting toxicities of the various agents form part of the rationale for this combination, and bi-weekly administration is being explored as a means to lower peak drug concentrations and improve tolerance.

Oxaliplatin is also being studied as a component of non-fluoropyrimidine combination therapy. For example, oxaliplatin is being investigated in combination with gemcitabine (GEMOX), which is an agent with minimal activity in CRC.The preliminary results of a Phase II study evaluating this GEMOX regimen in the second-line treatment of 31 patients with advanced CRC has been reported.37 After a median follow-up period of five months, one-year survival was 45.9%, and no grade 4 toxicity was observed. Grade 3 toxicities included febrile neutropenia (19.4%), thrombocytopenia (12.9%), anemia (3.2%), and nausea (3.2%).The combination of pemetrexed–oxaliplatin in patients with previously untreated metastatic colorectal cancer has been reported to be well tolerated and to have clinical activity in advanced CRC.³⁸