Oxaliplatin plus fluorouracil (5-FU)/leucovorin or capecitabine (Xeloda) is a standard of care in adjuvant therapy for stage III colorectal cancer. There is ongoing debate about whether any adjuvant therapy is of benefit in patients with stage II disease, and it is not routinely recommended in this patient population. There is also ongoing debate about the role of adjuvant therapy in elderly patients, with some data suggesting that such patients do as well on 5-FU–based therapy as younger patients and do not derive additional benefit from the addition of oxaliplatin to treatment.
A post hoc analysis of outcomes in the MOSAIC trial, reported in Journal of Clinical Oncology by Tournigand and colleagues,1 suggests that there is no benefit in overall or disease-free survival with the addition of oxaliplatin to 5-FU/leucovorin in patients with stage II disease or patients aged 70 to 75 years.
In the MOSAIC study, a pivotal trial for regulatory approval of oxaliplatin in adjuvant therapy, 2,246 patients were randomly assigned to 5-FU/leucovorin with oxaliplatin (FOLFOX4) or without oxaliplatin. The trial included 889 patients with stage II disease, including 451 in the FOLFOX4 group and 448 in the 5-FU/leucovorin group. Of these, 569 were high-risk patients, including 282 in the FOLFOX4 group and 287 in the 5-FU/leucovorin group.
Of a total of 315 patients aged 70 to 75 years, 155 were in the FOLFOX4 group and 160 in the 5-FU/leucovorin group. Of the 155 in the FOLFOX4 group, 96 had stage III disease and 59 had stage II disease (18 low-risk, 41 high-risk). Of the 160 in the 5-FU/leucovorin group, 94 had stage III disease and 66 had stage II disease (22 low-risk, 44 high-risk).
There was no imbalance in baseline characteristics or comorbidities between the stage II or elderly subgroups in the two treatment groups. There was no difference between FOLFOX4 and 5-FU/leucovorin treatment with regard to incidence of serious adverse events in patients with stage II disease; among elderly patients, serious adverse events were significantly more common with FOLFOX4 (P = .018). Median follow-up durations were 63 months for disease-free survival and 80 months for overall survival.
Stage II Disease
For all stage II patients, FOLFOX4 was associated with a nonsignificant 16% reduction in risk for recurrence or death from any cause (disease-free survival hazard ratio [HR] = 0.84, P = .26). The interaction test between treatment and risk was not significant (P = .066). Among low-risk stage II patients, 5-year disease-free survival was 86.0% with FOLFOX4 vs 89.3% with 5-FU/leucovorin, representing a nonsignificant 36% increase in risk with FOLFOX4 (HR = 1.36, P = .305). Among high-risk patients, 5-year disease-free survival rates were 82.3% with FOLFOX4 vs 74.6% with 5-FU/leucovorin, representing a nonsignificant 28% reduction in risk (HR = 0.72, P = .063).
FOLFOX4 was associated with a significant 30% reduction in risk of recurrence (time to recurrence HR = 0.70, P = .045). The interaction test between treatment and risk was not significant (P = .235). FOLFOX4 was not associated with a significantly reduced risk for recurrence in low-risk patients (5-year time to recurrence = 90.8% vs 90.5%, HR = 1.01, P = .972), but was associated with a significant 38% reduction in risk in high-risk patients (5-year time to recurrence = 86.8% vs 78.8%, HR = 0.62, P = .020).
There was no significant difference between FOLFOX4 and 5-FU/leucovorin in overall survival (HR = 1.00, P = .986) and the interaction test between treatment and risk was not significant (P = .343). Six-year overall survival was 90.2% with FOLFOX4 vs 93.0% with 5-FU/leucovorin in low-risk patients, representing a nonsignificant 36% increase in risk of death with FOLFOX4 (HR = 1.36, P = .399), and 85.0% vs 83.3% in high-risk patients, representing a nonsignificant 9% decrease in risk (HR = 0.91, P = .48).
Among elderly patients, 5-year disease-free survival was 69.1% with FOLFOX4 vs 65.8% with 5-FU/leucovorin, representing a nonsignificant 9% decrease in risk for recurrence or death with FOLFOX4 (HR = 0.91, P = .71). Risk of recurrence was nonsignificantly reduced by 32% (5-year time to recurrence = 78.8% vs 69.9%, HR = 0.68, P = .089). Five-year overall survival was 75.8% with FOLFOX4 vs 76.1% with 5-FU/leucovorin, representing a nonsignificant 10% increase in risk of death (HR = 1.10, P = .661). Tests for interaction between treatment and age for disease-free survival, time to recurrence, and overall survival were not significant (P = .418, 0.719, and 0.180, respectively).
As stated by the authors, “[These] results show that patients with low-risk stage II colorectal cancer do not benefit from oxaliplatin; in high-risk stage II patients, oxaliplatin significantly improved time to recurrence without benefit in disease-free survival or overall survival. However, these subgroup analyses should be cautiously considered as exploratory results only. In elderly patients, there was no benefit from oxaliplatin for [time to recurrence], disease-free survival, or overall survival, but the subgroup was small and restricted to patients younger than 76 years. The lack of interaction between treatment and stage or age suggests that the effect of FOLFOX4 compared with 5-FU/leucovorin does not differ according to high vs low risk in stage II patients or according to age.”
The investigators also noted that similarities in survival estimates for high-risk stage II patients and elderly patients are in part explained by the overlap in the subgroups, with 40% of elderly patients having stage II disease and 15% of the stage II patients being older than 70 years.
The authors concluded: “The administration of fluoropyrimidines alone remains the standard option for both elderly and selected low-risk stage II patients. According to the MOSAIC subgroup analyses…, the addition of oxaliplatin to infusional 5-FU/leucovorin has not been shown to be beneficial in low-risk or high-risk stage II patients or for patients between 70 and 75 years. The identification of a patient population for which adjuvant therapy is necessary, safe, and effective continues to be challenging, especially for high-risk stage II patients and for elderly patients.” ■
1. Tournigand C, André T, Bonnetain F, et al: Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: Subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer Trial. J Clin Oncol 30:3353-3360, 2012.
The pendulum continues to swing in the treatment of stage II and III colon cancer. Not 5 years ago, our party line was that essentially all patients should receive 6 months of adjuvant FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin): patients with stage II or III disease, whether rectal or...