Intensified adjuvant chemotherapy did not improve disease-free survival (DFS) compared with standard chemotherapy in patients with high-risk stage III colon cancer, the phase III IROCAS trial showed.
The 3-year DFS rate was 65.6% among patients treated with a modified FOLFIRINOX (oxaliplatin, fluorouracil, irinotecan, and leucovorin) regimen versus 66.3% for those who received a modified FOLFOX6 (oxaliplatin, fluorouracil, and leucovorin) regimen (HR 1.07, 95% CI 0.84-1.36, P=0.61), reported Jaafar Bennouna, MD, PhD, of Hôpital Foch in Suresnes, France, at the European Society for Medical Oncology annual congress in Madrid.
While overall survival (OS) data remain immature, 3-year OS rates were 91.2% and 86.7%, respectively (HR 0.85, 95% CI 0.61-1.21, P=0.37).
This study was also published in the Annals of Oncology.
Despite standard adjuvant treatment with oxaliplatin and a fluoropyrimidine, patients with high-risk colon cancer are at high risk of recurrence.
While a previous pooled analysis of six phase III trials showed that 3 months of adjuvant chemotherapy was noninferior to 6 months among patients with low-risk (T1, T2, or T3 and N1) stage III colon cancer, with 3-year DFS rates of 83.1% and 83.3%, respectively, DFS rates were almost 20 percentage points lower among patients with high-risk (T4 and N2) cancers, establishing an unmet need in this subgroup of patients, and providing a strong rationale for intensifying treatment.
But, “we saw no improvement in efficacy” with the intensified regimen in patients with pT4 and/or pN2 stage III colon cancer, Bennouna said. “IROCAS suggests that simply escalating conventional cytotoxic therapy according to pathological risk alone is unlikely to be the way forward. High pathological risk identifies patients who need better outcomes, but does not tell us how to achieve them.”
It is unlikely that inadequate treatment delivery explained the current results, he noted, since the median relative dose intensity of irinotecan in the modified FOLFIRINOX arm was 91.8% and oxaliplatin exposure was comparable between arms.
Invited discussant Jeffrey Meyerhardt, MD, MPH, of Dana-Farber Cancer Institute in Boston, pointed out that “the history of irinotecan with fluoropyrimidines for the past 20 years has continually not shown a benefit, at least with a fluoropyrimidine alone, and we only have very limited data showing a potential marker where irinotecan may benefit in the adjuvant setting.”
He observed that there are several ongoing trials of irinotecan added to adjuvant therapy in colorectal cancer, including CIRCULATE-US and the JANUS Rectal Cancer trial.
“We should — and need to — await ongoing trials, but barring different results, we should accept irinotecan does not add benefit in the adjuvant setting for colon cancer … and until those trials report out, I do not think it is justified to add irinotecan in the adjuvant setting for colon cancer,” Meyerhardt said.
IROCAS was an investigator-initiated trial that included 795 patients with histologically confirmed, completely resected, high-risk stage III colon adenocarcinoma, defined as pT4 and/or pN2 disease, who were enrolled at 93 centers in France, Canada, and Italy. Median age was 59 years, and 40% were women.
“This was truly a high-risk population,” Bennouna noted, as 52.8% of patients had pT4 disease, 72.2% had pN2 disease, and 25.3% had both.
Patients received 12 cycles of modified FOLFIRINOX or modified FOLFOX6 every 2 weeks for 6 months. Median follow-up was 55 months.
The median time from surgery to initiation of adjuvant treatment was 7.1 weeks in both treatment groups.
Temporary discontinuation of at least one study drug occurred in 22.7% and 27% of patients in the modified FOLFIRINOX and FOLFOX6 arms, while permanent discontinuation of at least one study drug occurred in 7.8% and 8.9%, respectively.
Dose modifications were frequent in both treatment groups, with a least one dose reduction of any study drug occurring in 87.2% of patients receiving modified FOLFIRINOX and 86.3% receiving modified FOLFOX6. Treatment delays occurred in 61.5% and 67.9%, respectively.
Grade ≥3 treatment-related adverse events occurred in 62.2% and 62.1% of patients, respectively. Grade ≥3 diarrhea (15.6% vs 3.8%), nausea (6.3% vs 1.3%), vomiting (3.6% vs 1.3%), and fatigue (7.3% vs 1.8%) were more frequent with modified FOLFIRINOX, while grade ≥3 neutropenia was less frequent (18% vs 23.9%).
