boxed-textKuebler JP (2007) Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer. J Clin Oncol 25: 2198–2204

Synopsis

Background

The Multicenter International Study of Oxaliplatin/5-Fluorouracil, Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) study reported that the addition of oxaliplatin to a regimen of bolus and continuous-infusion 5-fluorouracil (5-FU) combined with leucovorin (LV)—the FOLFOX4 regimen—improved 3-year disease-free survival (DFS) in comparison with FULV (5-FU and LV administered alone).

Objective

The aim of the study was to determine the advantage of adding oxaliplatin to a weekly Roswell Park regimen of bolus 5-FU and LV (FLOX) as postoperative adjuvant chemotherapy for patients with high-risk colon cancer.

Design

Patients with stage II or III colon cancer who had undergone surgical resection with no evidence of remaining malignant disease were enrolled in this clinical trial between 1 February 2000 and 15 November 2002. Patients were required to have adequate renal, hepatic and hematologic function and no evidence of clinically significant peripheral neuropathy.

Intervention

The FULV regimen consisted of three 8-week cycles of FU and LV therapy for a total of 24 weeks. LV 500 mg/m2 was administered as a weekly 2-hour intravenous infusion for 6 consecutive weeks on days 1, 8, 15, 22, 29 and 36 of the treatment cycle, followed by 2 weeks' rest. 5-FU 500 mg/m2 was given on each of the same days as LV infusion and was administered as an intravenous bolus 1 hour after the initiation of LV infusion. The FLOX regimen consisted of three cycles of therapy over 6 months. FU and LV were administered as for the FULV regimen, but in addition, a 2-hour infusion of oxaliplatin (85 mg/m2) was administered before LV and FU on days 1, 15 and 29 of the treatment cycle.

Outcome measures

DFS was the primary end point; the secondary end point was relapse-free interval.

Results

In total, 2,407 of the 2,492 eligible patients identified were included in analyses. The median follow-up was 42.5 months. Thirteen patients (1%) treated with FULV and 15 patients (1.2%) treated with FLOX died from any cause within 60 days of chemotherapy. Compared with FULV, FLOX was associated with higher rates of bowel wall thickening (P = 0.008), grade 3 or 4 diarrhea (P = 0.003), grade 3 or 4 nausea (P <0.001), grade 3 or 4 vomiting (P <0.001) and grade 3 or 4 neurosensory toxicity (P <0.001). For DFS, the hazard ratio (HR) for FLOX versus FULV during the median follow-up period was 0.80 (95% CI 0.69–0.93)—a relative risk reduction of 20%. Overall 4-year DFS rates were 73.2% for FLOX and 67% for FULV. After adjustment for age and number of positive nodes, the HR for 4-year DFS following FLOX versus FULV was 0.81 (95% CI 0.69–0.94; P = 0.005). At 4 years, the percentage of patients who remained relapse-free was 78.1 for FLOX and 72.9 for FULV (HR 0.80, 95% CI 0.67–0.95).

Conclusion

The authors recommend either FLOX or FOLFOX4 as adjuvant therapy following surgery in patients with stage II and III colon cancer.

Commentary

NSABP C-07 is an important chapter in the developing story of adjuvant therapy of colon cancer. Initial evidence of survival benefit with 5-FU and levamisole presented nearly 20 years ago1 was followed by the replacement of levamisole by LV, the recognition that low-dose LV was as effective as higher doses, and the reduction in treatment duration from 12 to 6 months. Further improvement in DFS with the FOLFOX4 regimen was first shown in the MOSAIC study.2

The NSABP C-07 study of FLOX adds significantly to our knowledge of adjuvant fluoropyrimidine/oxaliplatin combinations. Both NSABP C-07 and MOSAIC recruited over 2,000 patients with stage II or III colon cancer, and the patient characteristics of the two cohorts, including gender and age, were very similar. The only major difference between the study populations was that 40% of patients in MOSAIC had stage II disease compared with 28.5% of patients in NSABP C-07. The two studies also differed in the chemotherapy regimens used. In the MOSAIC study 5-FU was administered as a 48-hour infusion, whereas NSABP C-07 used the bolus 'Roswell Park' regimen, which is known to cause a higher incidence of gastrointestinal toxicity. Although both studies used the same headline dose of oxaliplatin (85 mg/m2), the total planned dose differed (765 mg/m2 in NSABP C-07 and 1,020 mg/m2 in MOSAIC), as did the median dose delivered (677 mg/m2 and 876 mg/m2, respectively).

The highly statistically significant DFS benefit in NSABP C-07 for FLOX compared with FULV was very similar to that seen in the MOSAIC study for FOLFOX4 compared with FULV, with HRs of 0.80 and 0.77, respectively. In both studies this benefit came at the price of significantly increased incidences of neuropathy, myelosuppression and emesis, although the pattern of toxicities differed. There was a higher incidence of severe diarrhea (38% vs 10.8%), but a lower incidence of severe neurotoxicity (8.2% vs 12%) in the NSABP C-07 study than in the MOSAIC study, probably because of the higher cumulative dose of oxaliplatin used in the MOSAIC trial.

The combination of 5-FU with irinotecan has so far been disappointing in the adjuvant setting as reported recently by Saltz et al.3 Oxaliplatin in combination with infusional (MOSAIC) or bolus (NSABP C-07) 5-FU can, therefore, be considered 'gold-standard' adjuvant therapy for colon cancer; the difference between the regimens being mainly their pattern of toxicities. FOLFOX and FLOX will, therefore, be the platforms for addressing outstanding questions, including whether we can use molecular markers in clinical practice to identify which individual patients (especially amongst those with stage II disease) will benefit from more-effective but more-toxic combination therapy. Adjuvant XELOX, with the oral fluoropyrimidine capecitabine replacing 5-FU, is well tolerated.4 If efficacy data show equivalence, it might be possible to improve the tolerability and convenience of adjuvant fluoropyrimidine/oxaliplatin chemotherapy by replacing 5-FU with capecitabine. Given the benefits of adding the anti-VEGF monoclonal antibody bevacizumab to chemotherapy in patients with metastatic disease, results of ongoing adjuvant trials evaluating bevacizumab in combination with capecitabine, FOLFOX and XELOX are eagerly awaited.