Oxaliplatin As Part of Adjuvant Therapy for Colon Cancer: More Complicated Than Once Thought

The ability of adjuvant fluorouracil-based therapy to significantly enhance survival in patients with stage III colon cancer was initially reported in 1990 and confirmed in 1995. Such an improved outcome, however, was not observed when fluorouracil or fluorouracil and leucovorin were administered to patients with stage II disease. Although the efficacy of adjuvant therapy for all patients with stage II colon cancer remains an area of controversy, a retrospective subset analysis suggested that those individuals who have stage II disease with clinical characteristics that are predictive for a higher likelihood of recurrence (ie, T4 lesions, bowel obstruction, tumor perforation) might benefit from adjuvant treatment. The definition of high risk was subsequently expanded to include patients in whom fewer than 10 to 12 lymph nodes had been examined in the resected specimens because of presumed artifactual downstaging as a result of an inadequate pathologic evaluation. Although patients with high-risk stage II colon cancer are generally treated with adjuvant chemotherapy, the value of this practice has never been validated through a prospective randomized trial. A recent analysis of 42,032 Medicare beneficiaries with stage II or III colon cancer used the SEER-Medicare database to determine whether patients had received or had not received adjuvant fluorouracil-based chemotherapy. Although this study demonstrated the expected survival benefit for patients with stage III disease, it revealed no improvement in outcome for patients with stage II cancer, regardless of whether they had been classified as being at standard or at high risk for recurrence. Multiple new cytotoxic (irinotecan and oxaliplatin) and targeted (bevacizumab, cetuximab, panitumumab) forms of therapy have been introduced into the management of patients with metastatic colon cancer during the last 15 years. Each of these, when combined with fluorouracil-based therapy, provided a better outcome than that observed with fluorouracil-based therapy alone. On the basis of these encouraging results, it was anticipated that the integration of these new compounds into adjuvant treatment programs would improve the outcomes achieved with fluorouracil-based treatment alone. Surprisingly, multiple randomized trials failed to show that the inclusion of irinotecan, bevacizumab, or cetuximab into fluorouracilbased adjuvant therapy in patients with predominantly stage III disease improved outcome. The one drug that represented an exception to this unexpected observation was oxaliplatin. Oxaliplatin, a third-generation platinum compound, is thought to act by distorting DNA into adducts in a manner similar to that of other platinum molecules. However, oxaliplatin seems to be marginally active at best when used as a single agent in the treatment of colon cancer and seems to provide therapeutic benefit only when administered together with a fluoropyrimidine. Its proposed secondary mechanism of action of reducing thymidylate synthase expression may explain its strong synergy with fluorouracil. The administration of oxaliplatin is associated with a cumulative sensory neuropathy that is usually but not always reversible. Preliminary data suggest that the concomitant administration of intravenous calcium and magnesium may reduce the severity of the neurotoxicity. Oxaliplatin was combined with infusional fluorouracil and leucovorin (FOLFOX) and found to be more effective than fluorouracil and leucovorin alone in treating patients with metastatic colon cancer. The addition of oxaliplatin to fluorouracil and leucovorin as adjuvant therapy for patients with stage II and III colon cancer has been assessed in two large, randomized trials, both of which were carefully designed and meticulously analyzed. In the first of these— the Multicenter International Study of Oxaliplatin/5-Fluorouracil/ Leucovorin in the Adjuvant Treatment of Colon Cancer (the MOSAIC trial)—2,246 patients with stage II (n 899) or stage III (n 1,347) disease were randomly assigned to receive 6 months of either FOLFOX or 48-hour infusions of fluorouracil and leucovorin. Patients were stratified by depth of tumor penetration, number of involved lymph nodes, and the presence or absence of bowel obstruction or tumor perforation. The initial results were published in 2004 and showed that after a median follow-up time of 37.9 months, 79% of the patients who received FOLFOX remained disease-free versus 74% of those allocated to fluorouracil and leucovorin (hazard ratio [HR], 0.77; P .002). In the second of these studies, the C-07 trial, which was conducted by the NSABP (National Surgical Adjuvant Breast and Bowel Project), 2,407 eligible patients with stage II (n 696) or stage III (n 1,711) disease were randomly assigned to receive 6 months of either oxaliplatin combined with weekly bolus fluorouracil and leucovorin (FLOX) or weekly bolus fluorouracil and leucovorin alone. Patients were stratified by the number of involved lymph nodes. The initial results were published in 2007 and showed that after a median follow-up time of 42.5 months, 74% of the patients who received FLOX remained disease-free versus 70% of those given weekly bolus fluorouracil and leucovorin (HR, 0.80; P .005). The initial published data from both the MOSAIC trial and the C-07 trial were too immature to allow estimates of the effect of the addition of oxaliplatin on overall survival or on subsets of patients with stage II versus stage III disease. Nonetheless, the presentations JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 27 SEPTEMBER 2