Cetuximab Adds No Benefit to Adjuvant Chemotherapy in Stage III Colon Cancer

Abstract & Commentary

By Gary Shapiro, MD, Director of Medical Oncology, Cancer Center of Western Wisconsin. Dr. Shapiro reports no financial relationships relevant to this field of study.

Synopsis: This randomized Phase 3 clinical trial found that adding cetuximab to standard mFOLFOX6 adjuvant chemotherapy did not improve either overall survival or disease-free survival in patients with resected stage III colon cancer, including those with wild-type KRAS tumors.

Source: Alberts SR, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer. JAMA 2012;13:1383-1393.

In this North Central Cancer Treatment Group (NCCTG) study (N0147), 2686 patients with lymph node positive (stage III) colon cancer were randomized to receive 12 biweekly cycles of postoperative mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) chemotherapy with or without cetuximab. The N0147 trial began in 2004 before KRAS testing was widely available. Once it was found that patients whose colon cancer had mutations in exon 2 of the KRAS gene were refractory to cetuximab, the study was modified and powered to assess the effect of cetuximab only in patients with normal (wild-type) KRAS tumors. The trial was stopped early, after a planned interim analysis showed that adjuvant cetuximab had no benefit over the mFOLFOX6 regimen.

In patients with wild-type KRAS, the 3-year disease-free survival for those treated with mFOLFOX6 alone was 74.6% compared to 71.5% in those who also received cetuximab (hazard ratio [HR], 1.21; 95% confidence interval [CI], 0.98-1.49; P = 0.08). It was 67.1% vs 65.0% (HR, 1.12; 95%CI, 0.86-1.46; P = 0.38) in patients with mutated KRAS. Similarly, both time-to-recurrence and overall survival were not significantly different between the two treatment groups. There was no evidence that cetuximab benefited any particular subgroup of patients (stratified by age, gender, race, histologic grade, T stage, N stage, obstruction/perforation). On the other hand, patients aged 70 years or older with wild-type KRAS treated with mFOLFOX6 alone had significantly better overall 3-year survival (86.2% vs 72.5%) than those who also received cetuximab (HR 2.00; 95% CI, 1.05-3.78; P = 0.03).

Regardless of age, toxicity (> grade 3) was significantly higher in those treated with cetuximab in addition to mFOLFOX6 (51.1% vs 73.3%). Those aged 70 years or older who received cetuximab experienced more toxicity (81%) than their younger counterparts (72%). This was primarily due to increased rates of diarrhea, dyspnea, nausea, fatigue, infection, neutropenia, and mucositis in the older aged patients. Younger patients had higher rates of acne/rash than older patients (21.7% vs 10.4%, P = 0.002).

Commentary

Although studies have clearly demonstrated the efficacy of adding cetuximab to FOLFOX in treating metastatic colon cancer,1 the N0147 trial failed to show a similar benefit in the adjuvant setting. This study's authors conclude that cetuximab did not work as they had expected because the "molecular characteristics of micrometastases appear to differ from established metastases." The lack of response to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, may be due to a transient loss of EGFR dependence and may well apply to other agents directed against EGFR.

In an accompanying JAMA editorial, Segal and Saltz note that many clinicians and patients extrapolated the positive results from the metastatic studies to the adjuvant setting choosing regimens with cetuximab because they "apparently could not afford to wait for the data." In addition to their well-taken warning against such "off study" practices, they conclude that it should also not be assumed that agents that are ineffective in macrometastatic setting will not be active in the adjuvant setting.2

The N0147 authors devote much of their discussion to the group of patients 70 years of age or older who received cetuximab and had worse outcomes than those who received mFOLFOX6 alone (in contrast to the younger group that simply showed no added benefit with cetuximab). Though these findings should remind us about the potential pitfalls in caring for older patients with cancer, it is important not to generalize them to all older individuals or to all chemotherapy regimens. Clinical studies have established the efficacy and safety of adjuvant chemotherapy and palliative cetuximab in elderly colon cancer patients, but they often lack sophisticated geriatric assessments that help determine risk and benefit in this heterogeneous group.3,4 Older adults are under-represented in clinical trials5 and new tools6 are on the horizon to control for frailty and other geriatric factors that may confound study results.

Thus, in addition to the headline "Adjuvant Cetuximab Does Not Improve Survival in Stage III Colon Cancer," the take home message from N0147 is a reminder to us all about the importance of data. In this era of evidence-based medicine, we should remember that clinical trials have been the cornerstone of oncology care since its inception, and now is not the time to stray from that path.

References

1. Bokemeyer C, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009;27:663-671.

2. Segal NH, Saltz LB. Antitumor activity in metastatic disease does not predict efficacy in the adjuvant setting. JAMA 2012;13:1431-1432.

3. Goldberg RM, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006;24:4085-4091.

4. Jehn CF. Cetuximab-based therapy in elderly comorbid patients with metastatic colorectal cancer. Br J Cancer 2010;106:274-278.

5. Lewis JH, et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 2003;21:1383-1389.

6. Shapiro GR. A simple tool for predicting chemotherapy toxicity in older adults. Clin Oncol Alert 2012;.