DISCUSSION
chemoresistant cancers, tumor, cancers, Tumor, toxicity, obstructive symptoms, colon cancer, tumors, primary cancer
TUMOR, RECURRENCE, CANCERS, TUMOR, CHEMOTHERAPY EFFECTS, EVENT, RECURRENT DISEASE, DISEASE, COLON CANCER, SURGICAL COMPLICATIONS, REGRESSION, REGRESSION, TUMOR STROMAL, TUMORS, PRIMARY CANCER
FOxTROT is, to our knowledge, the first phase III trial evaluating NAC in operable colon cancer. It shows that short-course (6-week) NAC can be delivered safely and produces substantial tumor regression and downstaging, reducing the likelihood of incomplete resection. The primary objective—to detect a reduction in residual or recurrent disease within 2 years—was achieved, with a 28% lower event rate with NAC than AC. Chemotherapy toxicity was similar whether given before or after surgery, and surgical complications were, if anything, less in the NAC group.FOxTROT results indicate that NAC then AC may be superior to conventional postoperative chemotherapy. Current clinical guidelines recommend preoperative chemotherapy as an option only for cT4 colon cancer because of low-quality evidence.Perhaps the first question is whether the observed reduction in 2-year residual or recurrent disease is sufficient to support a change in practice. This primary outcome was chosen because chemotherapy effects on recurrence are concentrated in the first 2 years,FOxTROT was not powered to detect differences in overall recurrence, cancer-specific survival, and overall survival, though the proportional reductions in these longer-term outcomes were of similar magnitude and add to the clinical relevance of the reduction in 2-year recurrence. Longer follow-up of FOxTROT and meta-analysis with more recent studiesAnother question is whether the observed effect might be attributable to less complete compliance in the control than NAC group. FOxTROT was designed to compare the same total quantity of chemotherapy in the two arms; however, 98% allocated to NAC started chemotherapy, whereas 25% of controls did not receive any chemotherapy. Most, predictably, had low-risk tumors of whom only five recurred within 2 years. Had they received chemotherapy, we estimate that one recurrence might have been prevented, which would make no material difference to the study findings. Hence, poor compliance with AC in lower-risk patients cannot account for the overall trial result.The main disadvantage of NAC is that some patients with radiologically misclassified low-risk tumors receive unnecessary chemotherapy. In FOxTROT, 24% of control patients were found to have T3, N0 tumors without additional risk factors. For such patients whose recurrence risk is low, chemotherapy benefits are usually considered insufficient to justify the toxicity.It should also be noted that overtreatment occurs with adjuvant chemotherapy as well as NAC: even for high-risk operable colon cancer, around 10 patients are treated to prevent one recurrence. Regression grade after NAC might be useful in identifying which patients do and do not benefit from chemotherapy. For example, AC may not be needed for those with marked histologic regression after NAC who have a low risk of subsequent recurrence. This would need rigorous evaluation since it is also possible that patients with an excellent response to NAC are those who would benefit most from postoperative AC. Only randomized trials, perhaps incorporating circulating tumor DNA monitoring, can resolve these uncertainties.Interestingly, apparent regression was associated with worse outcomes in control group patients. This may be because appearances similar to those associated with response to NAC are, in untreated patients, instead, indicative of high tumor stromal content, a poor prognostic feature.FOxTROT, when launched in 2008, did not prespecify that lesser benefit was expected in dMMR tumors; however, dMMR has since been reported to predict nonbenefit from adjuvant fluoropyrimidine chemotherapy in colon cancer,We chose a short, 6-week neoadjuvant treatment to reduce the risk of toxicity impairing surgical fitness, and chemoresistant cancers progressing to inoperability. This choice appears justified: NAC was well tolerated, with high completion rates. Surgical morbidity appeared lower rather than higher, which may be due to tumor downsizing after NAC. Despite the fact that one third of NAC patients showed no discernible histologic regression, only 4% developed obstructive symptoms requiring expedited surgery, and all but one who did so were still able to undergo successful primary cancer resection. Therefore, pending randomized trials to explore longer durations, a 6-week NAC treatment remains our recommendation.Over 80 hospitals took part in FOxTROT indicating that the results of this real world trial are generalizable to clinical practice. The median age of patients was 63, somewhat younger than in an unselected colon cancer population, but similar to that in pivotal AC trials. Just 28% (292/1,052) were aged over 70 years, compared with about 50% of incident cases, so they are likely to represent a fitter subset of older patients. However, it is still notable that they benefited at least as much from NAC as the younger patients.In summary, patients with locally advanced but resectable colon cancer, selected using standard CT, may safely undergo 6 weeks of NAC before colon resection and then completion of AC. This does not increase perioperative morbidity, substantial tumor regression is achieved, and disease control is significantly better at 2 years than with the same chemotherapy given entirely postoperatively. NAC, like AC, is of less certain benefit in dMMR than pMMR cancers. Tumor regression after NAC is a strong predictor of lower postoperative recurrence risk and may provide a useful guide for later treatment. Six weeks of NAC should be considered as a treatment option for patients with locally advanced colon cancer.