1. Fuerst, Mark L.

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NEW YORK-Six months of adjuvant therapy should be the standard of care for stage III colon cancer, although the treatment regimen matters and can make a difference in terms of duration of therapy, according to two experts who presented at the Great Debates & Updates in Gastrointestinal Malignancies, held March 23-24.

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3-Month Adjuvant Therapy

The duration of adjuvant therapy for stage III colon cancer should be 3 months, argued Alex Grothey, MD, of the Mayo Clinic in Phoenix. "If you are wondering whether to shift to capecitabine/oxaliplatin (CAPOX), which we have done at the Mayo Clinic, you can get away with 3 months of therapy. For 5-fluorouracil (5-FU)/oxaliplatin/leucovorin (FOLFOX), stick with 6 months therapy," said Grothey.


In 2005, 6 months of bolus 5-FU was shown to be equal to standard of care with 6 months of 5-FU/leucovorin (LV). "But there was no formal non-inferiority hypothesis and no appropriate control arm. No hazard ratios were given for comparisons between arms. We truly do not know if 5-FU/LV over 12 months might be best. The oncology community was eager to accept a shorter duration," said Grothey.


Another study in 2005 showed that 12 weeks continuous administration of 5-FU was better than longer duration therapy. This was largely ignored in 2005 as oncologists moved into the era of FOLFOX and CAPOX.


At a presentation at the 2017 ASCO Annual Meeting, the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration, an academic collaboration of clinicians and statisticians, evaluated data from six randomized phase III trials of 12,834 patients with stage III colon cancer, which were more patients than any adjuvant trial in colon cancer.


"A high number of patients were needed to make sure with high confidence that we were not sacrificing efficacy of therapy for decreased toxicity," Grothey said.


The studies compared 3 months or 6 months of FOLFOX or CAPOX. Median follow-up provided reliable data for 2-3 years DFS, but "not so much beyond 3 years DFS," he said, adding that 3 months of therapy was clearly better in toxicity prevention than 6 months.


The primary outcome showed that 3-year DFS at 3 months was 74.6 percent and 3-year DFS at 6 months was 75.5 percent (HR=1.07). "The primary outcome 3-year DFS difference of 0.9 percent would never translate into a difference in OS," noted Grothey.


An analysis by risk groups and regimens showed a large difference in overall prognosis observed between T1-3 N1 (low-risk) and T4 and/or N2 (high-risk) cancers. In the low-risk group, which was about 60 percent of the total patients, the 3-month DFS (83.1%) was non-inferior to the 6-month DFS (83.3%) (HR=1.01). In the high-risk group (40% of patients), the 3-month DFS was 62.7 percent and 6-month DFS was 64.4 percent (HR=1.12).


For those taking CAPOX, the 3-year DFS was non-inferior, he pointed out. "Overall, with CAPOX there is no difference in 3 months versus 6 months in DFS. If you use CAPOX, regardless of the risk group, you can get away with 3 months therapy. For low-risk patients in the adjuvant setting, you can make CAPOX work, as long as you learn to manage toxicity and dose reduction," said Grothey.


"If you use CAPOX in low-risk cancer, you can give it for more than 3 months of therapy. For FOLFOX, you can get away with 6 months duration of therapy even in high-risk patients."


An international effort is underway to change the standard of care to shorter duration of therapy, which would save patients toxicity and health care resources, he said.


6-Month Adjuvant Therapy

Six months of therapy is still the best idea, said Howard Hochster, MD, of the Rutgers Cancer Institute of New Jersey in New Brunswick.


He presented a different view of the IDEA consensus of oncologists and patient advocates. Oxaliplatin-based treatment at 3 months versus 6 months showed a 12 percent relative risk increase, which equals a non-inferiority margin in the 3-year DFS (HR=1.12). "The collaboration needed to recognize that data was collected on an individual patient basis as part of the rationale for non-inferiority," said Hochster.


He argued that primary outcome 3-year DFS difference of 0.9 percent will translate to some survival difference. "The 90 percent confidence interval does not meet the definition of non-inferior. We cannot be 95 percent certain these are equivalent," he noted.


"The primary endpoint was not fulfilled. We cannot accept 3 months equals 6 months for everyone with stage III colon cancer. Some patients will have to go back to 6 months duration."


Looking at the DFS comparison by stage and risk group, he noted "none of these are statistically significant. At best, one subset, those in the T1 3 group, is non-inferior. For T4 or N2 patients, 3 months therapy is definitely not superior and we should not use for those patients."


He added, "we need to use 3 months continuously to be sure patients are getting CAPOX with good intensity."


In conclusion, Hochster noted: "Some patients will not be cured with the shorter course therapy. Capecitabine is not well-tolerated in the U.S., and the effect of CAPOX may be attenuated. Six months of FOLFOX remains the standard of care."


The 300 attendees appeared to agree with Hochster's argument: more than three-quarters of the audience (77%) voted in favor of 6 months adjuvant therapy.


Mark L. Fuerst is a contributing writer.