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Three months of chemotherapy may be sufficient for stage III colon cancer
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CHICAGO — Patients with stage III colon cancer who stopped chemotherapy after 3 months had similar DFS at 3 years as those who continued chemotherapy for 6 months, according to a prospective analysis of six clinical trials presented during the plenary session of the ASCO Annual Meeting.
“Nothing has really changed for the treatment of stage III colon cancer since 2004 when 6 months of oxaliplatin-based chemotherapy — FOLFOX or CAPOX — became standard of care with curative intent for patients,” Axel Grothey, MD, oncologist at Mayo Clinic in Rochester, Minnesota, said during his presentation. “The problem is long durations of therapy are associated with long-term toxicities that are debilitating for many patients — nerve damage that causes numbness, tingling and pain that can persist for the rest of a patient’s life. Shorter duration of treatment without compromising efficacy would really benefit patients and health care resources.”
Grothey and colleagues pooled data from six studies conducted in North America, Europe and Asia to determine whether 3 months of chemotherapy demonstrated comparable efficacy to 6 months. Researchers also evaluated potential differences with FOLFOX chemotherapy (5-fluorouracil and oxaliplatin) compared with CAPOX (capecitabine and oxaliplatin).
Beginning in 2007, researchers followed 12,834 patients (13% T1-3; 66% T3; 21% T4) from 12 countries for a median of 39 months.
DFS — defined as time from enrollment to relapse, second cancer and death of all causes — served as the primary endpoint.
For all patients combined, the rate of 3-year DFS appeared comparable with 3 months and 6 months of chemotherapy (74.6% vs. 75.5%; HR = 1.07; 95% CI, 1-1.15).
However, the type of chemotherapy affected the difference. Three months of treatment yielded a slightly higher 3-year DFS with CAPOX (75.9% vs. 74.8%; HR = 0.95; 95% CI, 0.85-1.06) and slightly lower 3-year DFS with FOLFOX (73.6% vs. 76%; HR = 1.16; 95% CI, 1.06-1.26).
In the subset of patients with lower-risk colon cancer (60% of study participants) — defined as cancer spread to one to three lymph nodes and not completely through the bowel wall — DFS at 3 years appeared almost identical for those who received 3 months and 6 months of treatment (83.1% vs. 83.3%; HR = 1.01; 95% CI, 0.9-1.12).
“For 60% of these patients who have lower risk for cancer recurrence, 3 months of chemotherapy will likely become the new standard of care,” Grothey said. “Patients with higher-risk colon cancer, however, should discuss these results with their doctor to see if a shorter course of therapy would be right for them, taking into account their preference, age and ability to tolerate chemotherapy.”
The rate of grade 2 or worse nerve damage differed depending on the type of chemotherapy regimen received, but was consistently higher for people who received 6 months vs. 3 months of chemotherapy (FOLFOX, 45% vs. 15%; CAPOX, 48% vs. 17%).
Nerve damage — a key side effect of oxaliplatin — occurred less frequently in patients receiving a 3-month course of chemotherapy with both FOLFOX (15% vs. 45%) and CAPOX (17% vs. 48%).
“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,” Grothey said.
It is important for physicians to keep in mind that the debilitating nature of neuropathy can persist for years after chemotherapy treatments are completed, according to Richard L. Schilsky, MD, FASCO, senior vice president and chief medical officer of ASCO, who was not involved in the study.
“This is not one of those side effects from chemotherapy that patients experience only while they are getting the treatment,” Schilsky said. “It is also related to the cumulative dose of the oxaliplatin chemotherapy. The less of this chemotherapy you give, the less likely patients are to develop this neuropathy and the less likely it will be long lasting.
“This represents another step on the road toward increasing personalization of cancer treatment based upon risk assessment,” Schilsky added. “Not every patient needs or benefits from adjuvant chemotherapy, and the duration of therapy is arbitrarily determined based upon the results of large, prospective trials. Beginning next week, I’m sure patients will be prescribed shorter courses of adjuvant chemotherapy if they have low-risk colon cancer.”– by Chuck Gormley
Reference:
Shi Q, et al. Abstract LBA1. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Disclosure: Medical Research Council, National Institute for Health Research, NCI, Italian Agency for Drugs, Japanese Foundation for Multidisciplinary Treatment of Cancer, French Ministry of Health, and French National Cancer Institute funded the study. Please see the abstract for a list of relevant financial disclosures.
Perspective
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Cathy Eng, MD, FACP
Based on the information provided in the IDEA (International Duration Evaluation of Adjuvant chemotherapy) pooled analysis, 3 months of adjuvant oxaliplatin-based chemotherapy is not noninferior to 6 months for DFS. CAPOX appears noninferior for low-risk patients, but that is largely based upon one trial — the SCOT trial — with incomplete capture of serious adverse events. Furthermore, CAPOX is not a regimen for all patients. Six months of adjuvant oxaliplatin-based chemotherapy for patients with stage III colon cancer remains the standard of care. In reality, few patients were able to receive all 6 months of oxaliplatin-based therapy due to treatment-related serious adverse events, notably neuropathy. The final determination surrounding oxaliplatin-based therapy should be continuous discussion between the physician and the patient based upon existing toxicities of this therapy.
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Nancy Baxter, MD, FRCSC, FACS, PhD
This is practice-changing work that shows for most people with stage III colon cancer, 3 months of treatment provides all the benefits of 6 months of treatment with fewer risks — less is more. The researchers brought data together from six large, randomized trials that included almost 13,000 patients from 12 countries — comparing 6 months to 3 months of treatment — and found that more treatment had no benefit for most patients with lower-risk disease. Six months of treatment did, however, have more side effects, some of which will be permanent.
Now, up to 60% of my patients with stage III colon cancer will be able to stop after 3 months of therapy and move on with their lives with a lower risk for permanent problems, such as numbness in their hands and feet. Proving we can give less treatment with the same benefit is a major advance for our patients and our health care systems, but this type of work can only be done with federal funding. The pharmaceutical industry is not interested in giving less treatment. This study is a great example of how NIH funding can have a major and immediate impact on the lives of patients with cancer.
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Patrick Boland, MD
This is a very important study, and it definitely is practice changing. This pooled study analysis represented an enormous undertaking, reflecting more than 13,000 patients enrolled worldwide in six different studies. Still, as we try to understand the nuances of these data, we only have seen the results of half of those studies.In the end, this was a “negative” study. It aimed to show that 6 months and 3 months of chemotherapy following surgery in stage III colon cancer were equivalent, but it failed to show that. However, when you look at the difference between 3 months and 6 months and risk for recurrence, it is a tiny difference — less than 1% — for the average patient. For this reason, we can conclude that many of our patients with stage III colon cancer can safely be treated with 3 months of adjuvant therapy instead of 6 months. This is wonderful, as one of the major potential long-term side effects is neuropathy, which can be substantially limited with an abridged course of oxaliplatin.
There are many nuances to these data and lingering uncertainty surrounding possible differences between the treatment regimens. At this point, it appears some patients with higher-risk stage III disease will still get a significant benefit from 6 months instead of 3 months, specifically those with more invasive tumors (T4) and those with more than three involved lymph nodes (N2). So, treatment will still come down to an individualized decision and a long discussion between physicians and patients, looking at specific risks and benefits.
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