CHICAGO – In patients with high-risk stage II colon cancer, capecitabine plus oxaliplatin (CAPOX) given for 3 months may have efficacy as good as that of 6 months, with considerably less toxicity, as suggested by results of a new analysis by the IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration.
By contrast, 6 months of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) had better efficacy than that of 3 months of FOLFOX, albeit with significantly more toxicity than the shorter duration of treatment, according to IDEA investigator Timothy Iveson, MD, FRCP, of University Hospital Southampton (England) NHS Foundation Trust.
“As oncologists, we have patients in front of us, and we have the ability to choose which chemotherapy regimen we would choose,” Dr. Iveson said in a presentation at the annual meeting of the American Society of Clinical Oncology, “and we now have good data on both the efficacy and also toxicity of the regimens according to duration of treatment, and therefore, that should really allow us to recommend both the chemotherapy regimen and duration of treatment to our patients.”
The findings echo those of the previous study by the collaborative group, presented at ASCO in 2017 and subsequently published in the New England Journal of Medicine, focused on patients with stage III colon cancer. The overall analysis was negative, in that they could not confirm the noninferiority of 3 versus 6 months of adjuvant FOLFOX or CAPOX in the overall population; however, further analysis showed that, specifically for CAPOX, 3 months of treatment delivered the same efficacy as 6 months, especially in the lower-risk subgroup.
Treatment of stage III colon cancer got “more complicated” as a result of that study, said David P. Ryan, MD, of Harvard Medical School, Boston.
That’s in part because the National Comprehensive Cancer Network (NCCN) colon cancer guidelines subsequently divided stage III disease into low and high risk, with different recommendations for each, he said in an oral presentation at the ASCO meeting.
Specifically, the NCCN’s preferred regimens for low-risk stage III disease (T1-3, N1) are now 3 months of CAPOX or 3-6 months of FOLFOX, while for high-risk stage III disease (T4, N1-2; T any, N2), the preferred regimens are 3-6 months of CAPOX or 6 months of FOLFOX.
“The reason for this study is the toxicity of oxaliplatin, particularly neuropathy,” Dr. Ryan said in his remarks from the podium. “It can be substantial and life altering.” The incidence of grade 2 or greater neuropathy was cut from about 45% to 15% by going from 6 to 3 months of treatment, though reporting of the rate of chronic neuropathy would be informative to better qualify these results, he said.
The more recent prospective, preplanned, pooled analysis from the IDEA group focused on the four phase 3 IDEA studies (SCOT, TOSCA, ACHIEVE-2, and HORG), out of six total studies, that enrolled high-risk stage II patients. Their primary analysis included 3,273 patients, of whom 2,019 received CAPOX and 1,254 received FOLFOX.
Rates of grade 2 or greater neuropathy were 36% for 6 months of treatment, but just 13% for 3 months of treatment. However, in the overall analysis, IDEA investigators could not demonstrate the noninferiority of 3 versus 6 months of treatment in terms of efficacy—similar to what was reported in the previously reported analysis of stage III patients.
Results for CAPOX, however, did demonstrate noninferiority, according to Dr. Iveson, with a 5-year disease-free survival (DFS) of 81.7% for 3 months of treatment versus 82.0% for 6 months, an absolute difference of 0.3%, he said in his presentation. By contrast, the 5-year DFS for FOLFOX was 79.2% for 3 months of treatment versus 86.5%, an absolute 7.3% difference in favor of longer treatment duration.
“Therefore, the data strongly suggest noninferiority of 3 months’ CAPOX treatment compared to 6 months, but equally, it suggests inferiority of 3 months FOLFOX compared to 6 months,” Dr. Iveson said.
Whether these findings also change practice remains to be seen.
Dr. Ryan, discussant for the study, agreed that 3 months of CAPOX, but not FOLFOX, is likely sufficient for patients with high-risk stage II disease, with one caveat: “Remember, it is not proven as the primary endpoint,” he told attendees at ASCO.
He said a new era of adjuvant studies is needed to address individual subsets of colon cancer in the adjuvant setting, particularly those defined by different biologies, such as BRAF-mutant, MSI-high, or HER2-amplified.
“I have little enthusiasm to return to the fundamental question posed by IDEA in a new prospective study, given that the magnitude of benefit or difference is so small,” he said.
Dr. Iveson reported disclosures related to Lilly, Servier, BMS, Celgene, Roche, and Bayer.