Short Course of CAPOX as Effective as 6-Month Treatment for Advanced Colon Cancer

Axel Grothey, MD

Axel Grothey, MD

Three months of capecitabine (Xeloda) and oxaliplatin (CAPOX) was noninferior for recurrence of death compared with a 6-month course, according to the published findings from IDEA, a pooled analysis of 6 phase III trials.¹

A short course of the combination of capecitabane and oxaliplatin demonstrated noninferiority compared to 6 months of treatment (HR, 0.95; 95% CI, 0.85-1.06) in patients with stage III colon cancer.

However, a 3-month course of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) did not demonstrate noninferiority when compared with 6 months of treatment (HR, 1.16; 95% CI, 1.06-1.26). Investigators found that 6 months of FOLFOX resulted in a higher rate of disease-free survival (DFS), particularly in high-risk patients.

“These data suggest that the choice of treatment regimen, duration of therapy, and characteristics of the patients may be balanced against the substantial risk of increased toxicity of longer oxaliplatin-based therapy, including persistent neurotoxicity,” Axel Grothey, MD, Division of Medical Oncology, Mayo Clinic Rochester, and colleagues wrote.

“For FOLFOX, a therapy duration of 3 months was inferior to a duration of 6 months when all stages and risk groups were combined,” the study authors added.

The IDEA collaboration was a prospectively study of 12,834 patients with stage III colon cancer who were randomly assigned to receive either 3 or 6 months of adjuvant therapy with oxaliplatin and a fluoropyrimidine in 6 phase III trials in 12 countries. Each trial investigated the effect of the duration of adjuvant oxaliplatin-based therapy on DFS. The study period ran from June 2007 through December 2015.

The percentage of patients with N2 tumors, involving ≥4 nodes, varied from 25.2% to 32.5%, and Grothey et al noted that the use of CAPOX or FOLFOX varied greatly. While the CALGB/SWOG trial restricted treatment to FOLFOX and only 10% of the patients in the IDEA France trial received CAPOX, 66.5% of patients in SCOT and 75.1% in ACHIEVE received CAPOX. Overall, about 40% of patients received CAPOX and 60% received FOLFOX.

At the time of the February 2017 data cutoff, the median follow-up ranged from 34.9 months to 61.7 months.

Three months of therapy was noninferior versus 6 months of therapy in patients with N1 tumors, which involved ≤3 nodes (HR, 1.07; 95% CI, 0.97-1.17) and those with N2 tumors, which involved ≥4 nodes (HR, 1.07; 95% CI, 0.96-1.19;P= .91 for interaction).

The long course proved superior in patients with T4 cancers (HR, 1.16; 95% CI, 1.03-1.31) and there was no significant difference in the observed between the courses of therapy between patients with N1 tumors (HR, 1.07; 95% CI, 0.97-1.17) and those with N2 tumors (HR, 1.07; 95% CI, 0.96-1.19;P= .91 for interaction).

Among all the patients with T1, T2, or T3 cancers, the upper boundary of the 2-sided 95% confidence interval for 3 months of therapy was 0.01 higher than the prespecified noninferiority margin (HR, 1.04; 95% CI, 0.96-1.13). The interaction between the duration of therapy and T stage was not significant (P= .14).

Patients with T4 or N2 cancers had a similarly poor 3-year DFS compared with other stages (~60% vs 80%). Therefore, Groethy et al investigated the effect of a shorter duration of therapy among patients at low risk T1, T2, or T3 and N1 cancers (58.7%) and among those with high-risk T4 or N2 disease, or both (41.3%). Among those with low-risk cancers, 3 months of therapy was noninferior to 6 months of therapy (HR, 1.01; 95% CI, 0.9-1.12) with a comparable 3-year DFS (83.1% vs 83.3%).

However, the long course was superior among patients with high-risk cancers (HR, 1.12; 95% CI, 1.03-1.23;P= .01 for superiority). This was the case even though the absolute difference in 3-year DFS was just 1.7 percentage points treatment courses (62.7% vs 64.4%). The interaction between therapy duration and risk group was not significant (P= .11).

As expected, a shorter duration of adjuvant therapy was associated with significantly lower rates of adverse events (AEs) independent of the chemotherapy regimen. With the short course, 37.6% of patients treated with FOLFOX and 24.2% of patients treated with CAPOX experienced grade 3/4 AEs compared with 56.9% and 36.9%, respectively, with the long course.

Grade ≥2 neurotoxicity during active therapy and in the month after cessation of treatment was substantially lower in the 3-month therapy group (FOLFOX, 16.6%; CAPOX, 14.2%) than in the 6-month therapy group (FOLFOX, 47.7%; CAPOX, 44.9%). Rates of diarrhea, neutropenia, thrombocytopenia, nausea, mucositis, fatigue, and hand-foot syndrome were also substantially lower with a shorter treatment duration.

Investigators noted that the incidence of clinically significant peripheral neuropathy was dramatically lower with the 3-month regimen (15% vs 45%).

In an accompanying editorial, Richard L. Schilsky, MD, ASCO senior vice president and chief medical officer, wrote that the challenge of adjuvant chemotherapy is that the treating physician cannot readily determine the presence or absence of cancer or its response to treatment for any individual patient. The IDEA results, he wrote, will help patients and physicians make informed treatment decisions when it comes to weighing the benefits of adjuvant therapy against its risks.²

“To truly optimize the application of adjuvant chemotherapy, we need 2 things: better markers to assess the risk of recurrence and the likelihood of benefit and more effective, less toxic treatments,” he wrote. “Until we see improvements in these 2 important areas, the findings of the IDEA collaboration provide useful information in helping oncologists discuss the duration of adjuvant therapy that best suits the goals, preferences, and tolerances of their patients.”

References:

1. Grothey A, Sobrero AF, Shields AF, et al. Duration of adjuvant chemotherapy for stage III colon cancer [published online March 29, 2018].New Engl J Med. 2018;378:1177-1188. doi: 10.1056/NEJMoa1713709.
2. Schilsky RL. A new IDEA in adjuvant chemotherapy for colon cancer [published online March 29, 2018].New Engl J Med. 2018;378:1242-1244. doi: 10.1056/NEJMe1800419.