Dr. Qian Shi presents LBA1.
In view of these findings, investigators in the IDEA collaboration reached a clinical consensus to recommend a risk-based approach to selecting adjuvant chemotherapy for stage III colon cancer. The consensus recommends 3 months of adjuvant chemotherapy for patients with low-risk disease, defined as T1-3N1 tumors, which includes approximately 60% of stage III patients. For high-risk patients, defined as patients with T4 or N2 tumors, decisions on use of the shorter course should be based on an individual assessment of tolerability, risk, and choice of regimen.
Findings of the IDEA collaboration were presented during the June 4 Plenary Session by Qian Shi, PhD, of the Mayo Clinic Cancer Center. Dr. Shi dedicated her presentation to the memory of Daniel J. Sargent, PhD, the leader and creator of the IDEA collaboration, who died last year. The audience acknowledged Dr. Sargent with a sustained burst of applause.
The rationale for the collaboration was to determine whether the standard 6 months of oxaliplatin-based chemotherapy (FOLFOX or CAPOX) is necessary. Oxaliplatin is associated with cumulative, dose-dependent toxicity, and a shorter duration of treatment would be of benefit if no efficacy were lost. The aim of the international collaboration, which pooled data from six phase III trials conducted in 12 countries and included more than 12,000 patients, was to determine the noninferiority of 3 versus 6 months of treatment.
In each trial, patients were randomly assigned to 3 or 6 months of treatment. Five of the six trials allowed investigator’s choice of FOLFOX or CAPOX.
The primary endpoint was DFS, defined as the earliest date of relapse, secondary colorectal primary tumor, or death due to all causes. To demonstrate noninferiority, the investigators reached consensus that a 12% relative risk increase in DFS in the 3-month arm compared with the 6-month arm was acceptable. This required a noninferiority margin of 1.12 for the DFS hazard ratio (HR).
Patient characteristics were well balanced at baseline in the 3- and 6-month treatment arms. Compliance was worse in the 6-month arm than the 3-month arm, regardless of the regimen (90% vs. 71%, respectively, for FOLFOX; 86% vs. 65%, respectively, for CAPOX). Dr. Shi noted that patient characteristics varied across the six studies; notably, two studies enrolled a higher percentage of patients with stage T4 disease, and the percentage of patients who received CAPOX varied from 0% to 75% across the studies.
Dr. Cathy Eng discusses LBA1.
The estimated 3-year DFS in the 3-month arm was lower than that in the 6-month arm by 0.9% (HR 1.07, 95% CI [1.00, 1.15]). As noted above, to demonstrate noninferiority, the upper limit of the CI had to be 1.12 or less, so noninferiority was not established.
When high- and low-risk groups were analyzed, 3 months of treatment was noninferior to 6 months of treatment for low-risk patients. For high-risk patients, however, 3 months of treatment was clearly inferior to 6 months. Dr. Shi noted that this subgroup analysis by risk groups defined by combined T and N stages was not prespecified.
The IDEA collaborative advises that clinicians consider the tradeoff between loss of DFS benefit and reduced neurotoxicity in clinical decision-making regarding treatment duration. Although 3-year DFS is a validated surrogate endpoint for OS, Dr. Shi said, longer-term data are needed to show the robustness of these results.
Discussant Cathy Eng, MD, FACP, of The University of Texas MD Anderson Cancer Center, said the IDEA collaboration highlights some of the pitfalls of pooled analyses of heterogeneous independent trials. The analysis of 3-month versus 6-month data did not meet its preplanned primary endpoint of noninferiority for DFS. The combined subgroup comparison of low-risk versus high-risk disease was an unplanned post-hoc analysis.
“Six months of oxaliplatin-based chemotherapy for stage III colon cancer remains the standard of care,” Dr. Eng said. “In reality for practicing physicians, however, few patients are able to receive all 6 months of oxaliplatin-based chemotherapy due to treatment-related serious adverse events. The final duration of therapy is always a continuous matter of discussion between the physician and the patient, based on toxicities of therapy.”
She commended the investigators for allowing their individual data to be pooled for the common objective of reducing toxicity for patients.
–Tim Donald, ELS