"Optimal regimens and ideal patients remain undefined"
- Neoadjuvant chemotherapy did not improve disease-free survival compared with upfront surgery in patients with locally advanced colon cancer in a randomized trial.
- However, neoadjuvant chemotherapy did result in tumor downstaging and a reduced need for adjuvant chemotherapy.
- Exploratory analyses suggested survival results varied by mismatch repair status, but these findings must be interpreted with caution.
The use of neoadjuvant chemotherapy failed to improve disease-free survival (DFS) over upfront surgery in patients with locally advanced colon cancer, a phase III randomized trial showed.
Among 248 patients, the DFS rate at 3 years was 87% for those who underwent upfront surgery versus 83% for those who received neoadjuvant chemotherapy (P=0.36), reported Lars Henrik Jensen, MD, PhD, of University Hospital of Southern Denmark in Vejle, and colleagues.
However, neoadjuvant chemotherapy did result in tumor downstaging, as well as a reduced need for adjuvant chemotherapy compared with upfront surgery (59% vs 73%, P=0.02), they wrote in JAMA Surgery.
While the study was negative, it, along with other phase III trials, supports neoadjuvant chemotherapy's "potential role in individualized management of locally advanced colon cancer," Jensen and team noted.
With the FOxTROT and OPTICAL trials, the NeoCol trial was the third phase III randomized study that did not demonstrate a DFS benefit with neoadjuvant chemotherapy in colon cancer. However, neoadjuvant oxaliplatin and fluoropyrimidine resulted in significant tumor downstaging in the two earlier trials, as well as a 28% reduction in recurrence at 2 years in FOxTROT, and a potential improvement in overall survival (OS) in OPTICAL.
In a commentary accompanying the study, Matthew F. Kalady, MD, of the Ohio State University in Columbus, and colleagues pointed out that, despite the negative DFS results, "neoadjuvant therapy likely still has a role, but the optimal regimens and ideal patients remain undefined."
"Future progress in locally advanced colon cancer will hinge on integrating tumor biology into decision-making," they wrote, adding that "the goal should be to deliberately align systemic therapy, precision diagnostics, and surgical quality, so that colon cancer is managed as an anatomically and biologically defined disease requiring individualized treatment pathways."
NeoCol was conducted from October 2013 through November 2020 at nine hospitals in Denmark, Norway, and Sweden among adults with histologically confirmed, locally advanced colon cancer and an Eastern Cooperative Oncology Group performance status of 0 to 1. Median age was 66, and 55% were men.
Patients in the upfront surgery arm underwent surgery followed by up to 8 cycles of adjuvant chemotherapy, consisting of capecitabine on days 1 through 14, plus oxaliplatin on day 1, every 3 weeks, or capecitabine monotherapy, based on postoperative risk stratification and age.
Patients in the neoadjuvant chemotherapy arm received 3 cycles of the capecitabine-oxaliplatin regimen, followed by surgery. Postoperatively, they received an additional 5 or fewer cycles of capecitabine-oxaliplatin or capecitabine monotherapy if adjuvant chemotherapy was indicated.
OS was comparable between the groups, with 5-year OS rates of 85% in the upfront surgery group and 87% in the neoadjuvant chemotherapy group (P=0.83). At 10 years, OS rates were 75% and 81%, respectively (P=0.36).
When stratified by age at a median of 66.3 years, DFS and OS analyses showed no significant difference between the treatment arms.
Exploratory analyses suggested survival results varied by mismatch repair status. In patients with mismatch repair-deficient tumors (dMMR), 3-year DFS rates were numerically higher in the upfront surgery group versus the neoadjuvant chemotherapy group (95% vs 79%, P=0.09). For patients with mismatch repair-proficient tumors (pMMR), DFS was similar between groups, but 10-year OS rates were numerically higher in the neoadjuvant chemotherapy group (81% vs 71%, P=0.19).
"These subgroup analyses were not prespecified and the study was not powered for them, so findings must be interpreted with caution," Jensen and team wrote. "Nevertheless, together with observations from other trials, the results raise the hypothesis that pMMR tumors may derive benefit from neoadjuvant chemotherapy, whereas dMMR tumors appear less likely to do so."
Diarrhea, including colitis, was the most frequent grade 3-4 adverse event during treatment (14% of patients in the upfront surgery group and 13% in the neoadjuvant chemotherapy group). Sensory neuropathy was observed in both groups (11% and 7%, respectively), while nausea was more frequent in the neoadjuvant chemotherapy group (7% vs 4% in the upfront surgery group).
During follow-up, sensory and motor neuropathy persisted in 5% and 3% of patients in the upfront surgery group compared with 2% and 1% in the neoadjuvant chemotherapy group.
Overall, there were no differences in quality of life between the two groups.
Disclosures
Jensen reported trial monitoring from the Danish Good Clinical Practice units, and relationships with Merck, Bristol Myers Squibb, Incyte, Roche, and Pfizer.
Co-authors reported relationships with Bristol Myers Squibb, AstraZeneca, Servier, Pierre Fabre, Pharmacosmos, Reponex, Repoceuticals, Intuitive Surgery, and Merck.
The editorialists had no disclosures.
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