Anthony F. Shields, MD, PhD, discusses pivotal data from the IDEA pooled analysis, consisting of 6 international, noninferiority, phase III colon cancer studies.
Anthony F. Shields, MD, PhD
A 3-month duration of adjuvant chemotherapy has shown evidence of matched efficacy for most patients with stage III advanced colon cancer in comparison with the standard 6 months, according to Anthony F. Shields, MD, PhD, during a presentation at the 2018 International Society of Gastrointestinal Oncology. This finding is based on pivotal data from the IDEA pooled analysis, consisting of 6 international, noninferiority, phase III studies.1
“This study led to a change in the [National Comprehensive Cancer Network (NCCN)] guidelines,” said Shields, professor of medicine and oncology at Wayne State University, associate center director for Clinical Sciences, Karmanos Cancer Institute, and co-author of the IDEA study. “The IDEA data have provided a framework for discussion on risks and benefits of individualized adjuvant therapy approaches [for patients].”
Previously, data from the landmark MOSAIC trial established that the combination therapy of bolus plus continuous-infusion fluorouracil with leucovorin (LV5FU2) would be improved by adding oxaliplatin (FOLFOX4).2Patients with stage III disease who received FOLFOX4 experienced a statistically significant improvement in 5-year disease-free survival (DFS) compared with patients in the LV5FU2 group (73.3% vs 67.4%, respectively; HR, 0.80; 95% CI, 0.68-0.93;P= .003).
“Everything changed in 2007 with the MOSAIC trial,” said Shields. “There was an improvement with the addition of the oxaliplatin. That led to the standard introduction of FOLFOX and subsequent trials showed CAPOX [as beneficial] for patients with stage III disease.”
After the addition of the effective agent oxaliplatin, investigators wanted to see if they could reduce the duration of treatment to lower the rate of neuropathy commonly associated with adjuvant chemotherapy in this setting, said Shields.
The IDEA study enrolled over 12,000 patients to investigate the dose schedule and DFS of physician’s choice of standard of care, adjuvant chemotherapy, including FOLFOX or capecitabine and oxaliplatin (CAPOX). The objective of the study was to reduce the adverse events (AEs) of therapy without giving up anti-cancer efficacy, according to Shields.
Patients with stage III colon cancer were administered FOLFOX (n = 7763) or CAPOX (n = 5071) and randomly assigned to receive 3 or 6 months of therapy.
“We wanted to make sure cutting back to 3 months would not decrease the benefits we got from the MOSAIC trial,” he said.
The efficacy endpoint of the study was not met, with a 3-year DFS of 74.6% with 3 months of chemotherapy versus 75.5% with 6 months (HR, 1.07; 95% CI, 1.00-1.15). However, the shorter regimen was associated with a dramatic reduction in AEs independent of the chemotherapy regimen.
“There was certainly a big difference in the neurotoxicity as we expected,” Shields noted. “Clearly we benefited the patients in terms of the toxicity.”
Neurotoxicity of grade ≥2 AEs was lower in the 3-month chemotherapy arm (16.6% with FOLFOX versus 14.2% with CAPOX) than in the 6-month chemotherapy group (47.7% with FOLFOX and 44.9% with CAPOX). Rates of diarrhea, neutropenia, thrombocytopenia, nausea, mucositis, fatigue, and hand-foot syndrome were also lower with the shorter treatment duration.
“Another thing to note is that when you give patients 3 months of therapy, they are more tolerable of getting higher toxicity,” Shields added. “Patients will put up with [higher intensity] when they know it is a short-term [event].”
According to Shields, some differences were observed between the 2 regimens. For patients who received CAPOX, a therapy duration of 3 months of adjuvant therapy was noninferior to a duration of 6 months. For patients who received FOLFOX, a therapy duration of 3 months was inferior to a duration of 6 months. These findings were independent of disease stage and risk group.
“Overall, CAPOX looked a little bit better in terms of DFS. We did not expect to see that difference,” admitted Shields.
Recurrence risk also showed considerable difference and was a topic of discussion among investigators.
In an exploratory analysis, 3 months of therapy with either regimen was non-inferior to 6 months among patients with T1, T2, or T3 and N1 cancers, with a 3-year DFS of 83.1% versus 83.3%, respectively (HR, 1.01; 95% CI, 0.90-1.12). For patients with higher-risk disease with T4 and/or N2 disease, which accounted for about 40% of the patient population, 6 months of therapy was superior to 3 months. The 3-year DFS was 64.4% versus 62.7% (HR, 1.12; 95% CI, 1.03-1.23;P= .01) between the groups, respectively.
Based on this study, the NCCN guidelines now incorporate the 3-month regimen of adjuvant chemotherapy for patients with stage III colon cancer. The guidelines also reflect that the different risk groups performed differently depending on the regimen used in the trial.
Shields added that factors of age, gender, tumor size, and more will require further evaluation.