Three Months of Oxaliplatin-Based Adjuvant Therapy Noninferior to 6 Months in Stage III Colon Cancer

IN A PROSPECTIVE POOLED ANALYSIS

of 6 phase 3 trials investigating the duration of adjuvant oxaliplatin-based therapy (3 vs 6 months) for patients with stage III colon cancer, noninferiority was not established for the overall cohort, but noninferiority of 3 versus 6 months oxaliplatin-based adjuvant therapy was supported for capecitabine plus oxaliplatin (XELOX). This outcome from the International Duration Evaluation of Adjuvant chemotherapy (IDEA) collaboration was reported in a plenary session at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Since 2004, 6 months of oxaliplatin-based treatment has been the standard of care as adjuvant therapy for stage III colon cancer. Oxaliplatin is associated with cumulative neurotoxicity, so a shorter duration of adjuvant therapy could spare patients toxicity and lead to substantial reductions in health expenditure.

A prospective, preplanned pooled analysis of 6 concurrently conducted randomized phase 3 trials conducted in North America, Europe, and Asia was performed to evaluate the noninferiority of 3 versus 6 months of adjuvant 5-fluorouracil and oxaliplatin (FOLFOX/XELOX).

The primary endpoint was disease-free survival (DFS), defined as time from enrollment to relapse, second colorectal cancer, and death from all causes. Noninferiority was to be declared if the 2-sided 95% confidence interval (CI) for hazard ratio (HR) for DFS (3 vs 6 months) was below 1.12. Noninferiority was examined within regimen and stage subgroups as planned.

The analysis included 12,834 patients from 12 countries, accrued from 2007 to 2015. Axel Grothey, MD, of Mayo Clinic Cancer Center, Rochester, Minnesota, said, “We needed this large number of patients to answer the study question, but at the time this study began in 2007 it was not possible to run one study of that size anywhere in the world. With more than 12,834 patients, this is the largest collaboration of its kind in oncology.”¹

Stage distribution was:

• 13% T1-T2
• 66% T3
• 21% T4
• 28% N2

Forty percent of patients received XELOX. Grade ≥3 neurotoxicity was higher in the 6- than in the 3-month arm (16% vs 3% FOLFOX, 9% vs 3% XELOX, P <.0001).

After a median follow-up of 39 months, 3263 DFS events were observed. Overall, the 3-year DFS rate was 74.6% (3 months) and 75.5% (6 months), with estimated HR for DFS of 1.07 (95% CI, 1.00-1.15).

HRs for 3- versus 6-month DFS were 1.16 (95% CI, 1.06-1.26) and 0.95 (95% CI, 0.85-1.06) for FOLFOX- and XELOX-treated patients, respectively. HRs for 3- vs 6-month DFS were 1.01 (95% CI, 0.90-1.12) in T1-3 N1 and 1.12 (95% CI, 1.03-1.23) for T4 or N2 patients.

A central side effect of oxaliplatin is nerve damage, which can result in permanent numbness, tingling, and pain. The longer a patient receives oxaliplatin, the higher the risk of severe and long-lasting nerve damage. Nerve damage (numbness/tingling of the hands and feet) was substantially less common in patients receiving a 3-month course of chemotherapy versus a 6-month month course (15% vs 45% with FOLFOX and 17% vs 48% with XELOX).

“Many side effects of chemotherapy, such as hair loss, go away over time, but nerve damage is a side effect some patients have to deal with for the rest of their lives,” said Grothey.²

The investigators concluded that, while noninferiority was not established for the overall cohort, noninferiority of 3 versus 6 months of oxaliplatin-based adjuvant therapy was supported for XELOX. Each IDEA trial treated varying proportions of patients with XELOX (0%-75%), so the interaction among regimens likely produced the differential outcomes observed between individual studies.

Certain substages (T1-3 N1) also showed noninferiority for 3 versus 6 months. The data provide a framework for discussions on risks and benefits of individualized approaches to adjuvant therapy.

Grothey said, “Our findings could apply to about 400,000 colon cancer patients worldwide every year. For 60% of these patients, who are at lower risk for cancer recurrence, 3 months of chemotherapy will likely become the new standard of care. Patients with higher-risk colon cancer, however, should discuss these results with their doctor to determine whether a shorter course of therapy would be right for them, taking into account their preference, age, and ability to tolerate chemotherapy.”²

“Aside from nerve damage, longer chemotherapy also means more diarrhea and fatigue, more doctor appointments, blood draws, and time away from work and social interactions,” he added.²

ASCO Expert Nancy Baxter, MD, PhD, of St. Michael’s Hospital in Toronto, Canada, remarked, “This is extremely important work that will affect the lives of many of my patients, and will allow us to provide a more personalized approach to our patients with colon cancer. Though addressing the question, ‘can we give less treatment?’ is of major importance to patients and their doctors, it is rare to see this type of study. Given that these questions are unlikely to be of interest to the pharmaceutical industry, federal support for these trials is critical.”²

She added, “In this case, less is more. We are now able to spare many patients with colon cancer unnecessary side effects of an additional 3 months of chemotherapy without compromising results. The study is an excellent example of how existing treatments can be refined to work even better for patients.”²REFERENCES

1. Shi Q, Sobrero AF, Shields AF, et al. Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration. J Clin Oncol. 2017;35(suppl; abst LBA1).

2. Global study sets new risk-based standard to personalize chemotherapy for colon cancer after surgery [press release]. Chicago, IL: ASCO; June 4, 2017. asco.org/about-asco/press-center/news-releases/global-study-sets-newrisk- based-standard-personalize. Accessed June 30, 2017.

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