As reported in the Journal of Clinical Oncology by Morton et al, the European phase III FOxTROT trial has shown that neoadjuvant plus adjuvant oxaliplatin/fluoropyrimidine resulted in a reduced risk of residual disease or disease recurrence vs adjuvant oxaliplatin/fluoropyrimidine in patients with locally advanced colon cancer.
Study Details
In the trial, 1,053 patients with T3–4, N0–2, M0 disease from sites in the United Kingdom (n = 949), Denmark (n = 88), and Sweden (n = 16) were randomly assigned 2:1 between May 2008 and December 2016. They either received oxaliplatin/fluoropyrimidine chemotherapy for 6 weeks preoperatively and 18 weeks postoperatively (neoadjuvant chemotherapy [NAC] group; n = 699) or for 24 weeks postoperatively (control group; n = 354). Patients with RAS wild-type tumors in the NAC group were also randomly assigned to receive panitumumab (n = 137) or no panitumumab (n = 133) during NAC. The primary endpoint was residual disease or recurrence within 2 years in the intent-to-treat population.
Key Findings
A total of 30 patients (4.3%) in the NAC grouped developed obstructive symptoms requiring expedited surgery. However, there tended to be fewer postoperative complications in the NAC vs control group, including anastomotic leaks or abdominal abscesses (4.7% vs 7.4%), emergency reoperation (4.3% vs 7.1%), and complications prolonging hospital stay (11.6% vs 14.3%).
NAC was associated with marked T and N downstaging and histologic tumor regression (all P < .001). R0 resection was achieved in 94% (648 of 686 patients undergoing surgery) of the NAC group vs 89% (311 of 351) in the control group (P < .001).
Rates of residual or recurrent disease within 2 years were 16.9% in the NAC group vs 21.5% in the control group (rate ratio [RR] = 0.72, 95% confidence interval [CI] = 0.54–0.98, P = .037). Risk of recurrence was strongly related to histologic regression: 5-year recurrence rates were 30% for no regression vs 22% for mild, 13% for moderate, 7% for marked, and 0% for complete regression.
Panitumumab did not augment the benefit of NAC in patients with wild-type RAS. Moderate or greater tumor regression was observed in 17% of those receiving panitumumab vs 23% of those not receiving panitumumab. No significant difference in 2-year risk of residual or recurrent disease was observed (18 vs 24 events, RR = 0.67, 95% CI = 0.36–1.23, P = .19).
Little benefit from NAC was observed in mismatch repair–deficient (dMMR) tumors. Moderate or greater tumor regression was observed in 7% of patients (8/115) with dMMR tumors vs 23% (128/553) of those with MMR-proficient (pMMR) tumors (P < .001). Risk of 2-year disease recurrence was not significantly reduced in NAC patients vs control patients with dMMR tumors (RR = 0.86, 95% CI = 0.42–1.76, P = .68), whereas a significant reduction was observed for those with pMMR tumors (RR = 0.69, 95% CI = 0.50–0.97, P = .043).
The investigators concluded, “Six weeks of preoperative oxaliplatin/fluoropyrimidine chemotherapy for operable colon cancer can be delivered safely, without increasing perioperative morbidity. This chemotherapy regimen, when given preoperatively, produces marked histopathologic downstaging, fewer incomplete resections, and better 2-year disease control. Histologic regression after NAC is a strong predictor of lower postoperative recurrence risk, so [it] has potential use as a guide for postoperative therapy. Six weeks of NAC should be considered as a treatment option for locally advanced colon cancer.”
Laura Magill, PhD, of the Institute of Applied Health Research, University of Birmingham, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was funded by Cancer Research UK. For full disclosures of the study authors, visit ascopubs.org.
