IDEA Collaboration Affects Choice of Chemotherapy Regimen, Treatment Duration in Stage III Colon Cancer

Daniel H. Ahn, DO

Although findings from the International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration in 2018 failed to demonstrate the noninferiority of 3 months of adjuvant chemotherapy vs 6 months for patients with stage III colon cancer, clinically relevant data in subgroup analyses have influenced practice prescribing patterns, according to a retrospective analysis.¹

Findings, which were published in the Journal of the National Comprehensive Cancer Network and included 399 patients, reflected a significant trend toward prescribing 3 months of chemotherapy of either CAPOX (capecitabine and oxaliplatin) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) compared with 6 months after the IDEA data were presented (P<.001). Additionally, investigators reported that the rate of CAPOX prescribing rose from 14% before the June 2017 presentation of the IDEA abstract to 48% after the presentation (P<.001). In terms of 3 months of CAPOX vs 6 months of FOLFOX, the use of the 3-month regimen also steadily increased over time (adjusted OR, 1.28; 95% CI, 1.20-1.37; P<.001).¹

Additional findings from the analysis showed that before the presentation of the IDEA abstract, only 5.6% of patients were prescribed 3 months of chemotherapy compared with 94.4% who received a 6-month regimen. Moreover, the likelihood of prescribing a 3-month regimen increased over the study period (adjusted OR, 1.19; 95% CI, 1.14-1.26; P < .001). The rate of FOLFOX prescription declined from 86.0% to 52.0% following the publication of the abstract.¹

“Even though [the IDEA collaboration] suggested that certain patients may have noninferior outcomes from a shortened duration of chemotherapy, because the overall results of the study didn’t apply to all patients, we were curious to see how prescribing patterns would change,” Daniel H. Ahn, DO, an internist and oncologist at Mayo Clinic in Phoenix, Arizona, said in an interview with OncLive®. “Not only did providers adopt 3 months of adjuvant chemotherapy for most patients, we also saw changes in regimen prescribing patterns. Some of that early adoption may be the fact that these are providers at academic institutions that were more familiar with the nuanced data from the IDEA collaboration. That may have led to a more rapid adoption of CAPOX compared with FOLFOX.”

IDEA was a prospective, preplanned, pooled analysis of 6 randomized phase 3 trials that were conducted during the same period to examine the noninferiority of adjuvant therapy with either FOLFOX or CAPOX given for 3 months vs 6 months in patients with stage III colon cancer. The international collaboration included data from 12,834 patients enrolled in the CALGB/SWOG (NCT01150045), IDEA France (2009-010384-16), SCOT (NCT00749450), ACHIEVE (UMIN000008543), TOSCA (2007-000354-31), and HORG (NCT01308086) trials. The primary end point of the 6 studies was disease-free survival (DFS).²

Previously published findings from IDEA showed that at a median follow-up of 41.8 months 3 months of chemotherapy was not found to be noninferior to 6 months in terms of DFS (HR, 1.07; 95% CI, 1.00-1.15). However, noninferiority of the 3-month regimen was observed among patients who received CAPOX (HR, 0.95; 95% CI, 0.85-1.06) but not in those who were treated with FOLFOX (HR, 1.16; 95% CI, 1.06-1.26). Additionally, in an exploratory analysis of the combined regimens, patients with T1, T2, or T3 and N1 disease experienced a 3-year DFS rate of 83.1% vs 83.3% with 3 months of therapy compared with 6 months, respectively, showing the noninferiority of the shorter treatment duration in this subgroup of patients (HR, 1.01; 95% CI, 0.90-1.12).²

As expected, shortening the duration of chemotherapy was found to be associated with significantly lower rates of adverse effects (AEs), no matter which regimen was selected. For patients who received FOLFOX, the rates of grade 1, 2, and 3/4 AEs were 30.7%, 31.6%, and 37.6%, respectively, for those who received 3 months of treatment (n = 3870) compared with 11.0%, 32.1%, and 56.9%, respectively, for those who had a treatment duration of 6 months (n = 3893; P < .001). Among those treated with CAPOX, the rates of grade 1, 2, and 3/4 AEs were 35.0%, 40.8%, and 24.2%, respectively, for those who received 3 months of treatment (n = 2554) compared with 14.6%, 48.5%, and 36.9%, respectively, in the 6-month group (n = 2517; P < .001).²

“In stage III colon cancer, the recommendation prior to the IDEA collaboration was for 6 months of FOLFOX,” Ahn said. “The challenges with giving 6 months of adjuvant chemotherapy are mainly from the toxicity perspective. We know that increased duration of chemotherapy can lead to AEs, including permanent effects [such as] peripheral neuropathy, cytopenias, and liver and kidney dysfunction. The premise of the study was to see whether we could potentially shorten the duration of adjuvant chemotherapy without compromising patient outcomes.”

The most recent analysis included patient data from all 3 sites and health systems of Mayo Clinic as well as Emory University in Atlanta, Georgia. To be included, patients must have received a diagnosis of stage III colon cancer on or after January 1, 2016, have received oxaliplatin within the health system, and have received their first dose of chemotherapy between January 1, 2016, and January 31, 2021.¹

The median age of the overall population was 60.7 years (range, 50.9-68.3). Patient characteristics were comparable between patients who subsequently received 3 months of chemotherapy (n = 126) vs those who were treated with 6 months of chemotherapy (n = 273). Most patients in both groups were female (50.8% vs 50.9%), White (70.6% vs 86.1%), had an ECOG performance status of 0 (63.5% vs 61.2%), had stage T3 disease (66.7% vs 63.0%), had stage N1 disease (84.1% vs 54.4%), and were mismatch repair proficient/microsatellite instability–low/microsatellite stable (81.0% vs 79.1%). Notably, more patients were considered high-risk in the 6-month group compared with the 3-month group, at 60.4% vs 25.4%, respectively.¹

A subgroup analysis revealed that there were no major differences in the adoption of CAPOX vs FOLFOX in any of the cohorts. In terms of 3 months of therapy vs 6 months, there were also no significant differences except in Black vs White patients, where 3 months of chemotherapy was adopted earlier for Black patients (adjusted OR, 1.55; 95% CI, 1.17-2.05) than in White patients (adjusted OR, 1.19; 95% CI, 1.13-1.26; P=.034 for interaction).1

Black patients also saw quicker adoption of the 3-month regimen of CAPOX (adjusted OR, 1.63; 95% CI, 1.18-2.25) compared with White patients (adjusted OR, 1.30; 95% CI, 1.21-1.40; P=.034 for interaction). There was no major difference in choice of chemotherapy and duration in any of the other subgroups examined, including age, gender, or, notably, risk group. The uptake of 3 months of CAPOX was similar among those with low-risk (adjusted OR, 1.27; 95% CI, 1.17-1.37) and high-risk cancer (adjusted OR, 1.31; 95% CI, 1.16-1.47).¹

Ahn recognized that the study was limited by it examining only patients treated at academic centers, its timing providing only 5 years of data after the IDEA collaboration. Additionally, he noted the effect of the COVID-19 pandemic might have influenced providers to choose CAPOX over FOLFOX and/or 3 months of treatment over 6 months to minimize exposure to the virus. A follow-up study examining patient outcomes is underway, and Ahn noted that studies evaluating the role of circulating tumor DNA in guiding adjuvant chemotherapy are also planned. “[The findings from this analysis] may not be necessarily applicable to patients who are treated in the community. However, the findings from any study are not necessarily applicable to all patients. This is a decision that needs to be made on a patient-by-patient case with [input from] the provider and the patient,” he concluded.

References

1. Ou FS, Walden DJ, Larson JJ, et al. Changes in prescribing patterns in stage III colon cancer. J Natl Compr Canc Netw. 2023;21(8):841-850.e4. doi:10.6004/jnccn.2023.7028
2. Grothey A, Sobrero AF, Shields AF, et al. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018;378(13):1177-1188. doi:10.1056/NEJMoa1713709