Less may be more for many patients with colon cancer.
Most patients with stage III colon cancer can be treated with a shorter schedule of adjuvant chemotherapy, according to the findings of a large phase 3 trial. Specifically, for patients with low-risk stage III disease, treatment with 3 months of therapy was as effective as treatment for 6 months.
Low-risk disease accounts for about 60% of stage III colon cancers.
The findings were initially presented at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting and were reported by Medscape Medical News at that time. The study has now been published in the the New England Journal of Medicine.
The results are practice changing, commented Richard Schilsky, MD, chief medical officer at ASCO, when the results were presented at the meeting. “I would predict that beginning next week in clinic, patients are going to be prescribed shorter courses of adjuvant chemotherapy if they have a low-risk colon cancer.”
ASCO expert Nancy Baxter, MD, from St. Michael’s Hospital in Toronto, Ontario, Canada, also commented at that time that “less is more.”
“This is a great day for patients throughout the world,” she said. “Now, today, up to 60% of my patients with stage III colon cancer will be able to stop after 3 months of therapy and be able to get on with their lives and have a lower risk of permanent problems, such as numbness of their hands and feet.”
On the basis of this study, the National Comprehensive Cancer Network’s colon cancer guidelines were recently changed to indicate that patients with low-risk stage III colon cancers can be treated with a shorter schedule of adjuvant chemotherapy.
IDEA in Practice
Since 2004, the standard treatment for stage III colon cancer had been 6 months of adjuvant therapy with oxaliplatin plus a fluoropyrimidine. But because oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy would reduce the risk for adverse events and would also lower healthcare expenditures.
Led by Axel Grothey, MD, from the Mayo Clinic Cancer Center in Rochester, Minnesota, the IDEA (International Duration Evaluation of Adjuvant Therapy) collaboration pooled results from six prospective studies that involved 12,834 patients with stage III colon cancer.
The phase 3 trials, which were conducted concurrently, evaluated the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) given for 3 months as opposed to 6 months.
The primary end point was disease-free survival at 3 years. Noninferiority of 3 months of therapy in comparison with 6 months was achieved if the upper limit of the two-sided 95% confidence interval (CI) of the hazard ratio (HR) did not exceed 1.12.
However, after 3263 cases involving either disease recurrence or death were reported in the cohort, noninferiority of 3 months of treatment vs 6 months could not be confirmed in the overall study population (HR, 1.07; 95% CI, 1.00 – 1.15). The 3-year rates of disease-free survival were 74.6% for the 3-month regimen and 75.5% for 6-month regimen.
Noninferiority in Subgroups Only
Noninferiority of a 3-month regimen was observed in the subset of patients treated with the CAPOX regimen (HR, 0.95; 95% CI, 0.85 – 1.06). The 3-year rates of disease-free survival were 75.9% for the 3-month regimen and 74.8% for the 6-month regimen.
Noninferiority was not observed in patients treated with FOLFOX. In this subset, 6 months of adjuvant therapy was superior to 3 months (HR, 1.16; 95% CI, 1.06 – 1.26; P = .001 for superiority of the 6-month therapy). The difference in 3-year disease-free survival for the two groups was 2.4 percentage points for all stages combined (73.6% vs 76.0%).
An exploratory analysis of the combined regimens for patients with low-risk disease (T1, T2, or T3 and N1 tumors) also found that 3-month regimens were noninferior to regimens of 6 months. The 3-year disease-free survival rates were 83.1% and 83.3%, respectively (HR, 1.01; 95% CI, 0.90 – 1.12).
For patients with higher-risk T4 tumors, N2 tumors, or both, the disease-free survival rate seen with 6 months therapy was superior to that of 3 months (64.4% vs 62.7%) for the combined treatments (HR, 1.12; 95% CI, 1.03 – 1.23; P = .01 for superiority).
The 3-month regimen was associated with significantly lower rates of adverse events, regardless of the chemotherapy regimen. This was particularly true for neurotoxicity of grade 2 or higher. Rates were substantially lower in the 3-month therapy group (16.6% with FOLFOX and 14.2% with CAPOX) than in the 6-month therapy group (47.7% with FOLFOX and 44.9% with CAPOX). Rates of occurrence of other events, including diarrhea, neutropenia, thrombocytopenia, nausea, mucositis, fatigue, and the hand-foot syndrome, were also substantially lower with the 3-month regimen.
Better Markers, Less Toxic Treatments
In an accompanying editorial, Schilsky notes that the “conundrum of adjuvant chemotherapy for cancer is that for any individual patient the oncologist cannot readily determine the presence or absence of cancer or its response to treatment.”
He points out that if the tumor never recurs, it remains unclear whether the treatment was effective or unnecessary. “Thus, the most effective use of adjuvant chemotherapy depends primarily on a multidimensional assessment of risk in each patient,” he says.
The results of the current study will help to guide discussions between oncologists and their patients about the complex issues associated with adjuvant therapy. To truly optimize the use of this treatment, Schilsky emphasizes that “we need two things: better markers to assess the risk of recurrence and the likelihood of benefit and more effective, less toxic treatments.
“Until we see improvements in these two 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,” he concludes.
The IDEA study was funded by grants from the Medical Research Council, the National Institute for Health Research, the National Cancer Institute, the Italian Agency for Drugs, the Japanese Foundation for Multidisciplinary Treatment of Cancer, the French Ministry of Health, and the French National Cancer Institute. Dr Grothey and several coauthors have disclosed relationships with industry, which are listed in original article. Dr Baxter has disclosed no relevant financial relationships. Dr Schilsky has received grant support and nonfinancial support from AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Genentech, Merck, and Pfizer outside the submitted work.
N Engl J Med. Published online March 29, 2018. Abstract, Editorial
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