Six weeks of neoadjuvant oxaliplatin-fluoropyrimidine chemotherapy for operable colon cancer can be delivered safely, without increasing perioperative morbidity. When given preoperatively, this chemotherapy regimen resulted in marked histopathologic downstaging, fewer incomplete resections, and providing better 2-year disease control. In FOxTROT study, patients with radiologically staged T3-4, N0-2, M0 colon cancer were randomly allocated to 6 weeks of neoadjuvant oxaliplatin-fluoropyrimidine plus 18 weeks of adjuvant treatment or 24 weeks given postoperatively. The results are published by Laura Magill of the University of Birmingham Clinical Trials Unit in Birmingham, UK and the FOxTROT Collaborative Group investigators on 19 January 2023 in the Journal of Clinical Oncology.  

The authors wrote in the background that despite adjuvant chemotherapy, 20-30% of patients with colorectal cancer develop recurrent disease that is usually incurable. Neoadjuvant chemotherapy has substantially improved outcomes in other gastrointestinal cancers and has potential advantages over adjuvant chemotherapy in colon cancer. Shrinking tumours before surgery may reduce the risk of incomplete resection and tumour cell-shedding during surgery. Neoadjuvant chemotherapy can start many weeks earlier than adjuvant chemotherapy, so could be more effective in eradicating micrometastases, particularly as surgery induces growth factor activity, potentially stimulating tumour proliferation before adjuvant chemotherapy is started. Response to neoadjuvant chemotherapy, unlike adjuvant chemotherapy, is observable, so could potentially guide subsequent treatment decisions. However, there are potential disadvantages of neoadjuvant chemotherapy that have delayed its evaluation in colon cancer.

The FOxTROT is a randomised study that assessed the benefits and risks of advancing part of standard adjuvant chemotherapy into the neoadjuvant setting. A short duration of 6 weeks of neoadjuvant chemotherapy was selected to minimise the risk of on-treatment progression or residual toxicity. The planned total duration of chemotherapy was equal in both arms, allowing evaluation of sequencing rather than duration. An internal safety and feasibility pilot was included.

Patients with radiologically staged T3-4, N0-2, M0 colon cancer were randomly allocated (2:1) to 6 weeks of oxaliplatin-fluoropyrimidine given preoperatively plus 18 weeks given postoperatively (neoadjuvant chemotherapy group) or 24 weeks given postoperatively (control group). Patients with RAS-wildtype tumours could also be randomly assigned 1:1 to receive panitumumab or not during neoadjuvant chemotherapy. The primary endpoint was residual disease or recurrence within 2 years. Secondary outcomes included surgical morbidity, histopathologic stage, regression grade, completeness of resection, and cause-specific mortality. Log-rank analyses were by intention-to-treat.

Of 699 patients allocated to neoadjuvant chemotherapy, 674 (96%) started and 606 (87%) completed it. In total, 686 of 699 patients (98.1%) in the neoadjuvant chemotherapy group and 351 of 354 patients (99.2%) in the control group underwent surgery. A total, 30 patients (4.3%) allocated to neoadjuvant chemotherapy developed obstructive symptoms requiring expedited surgery, but there were fewer serious postoperative complications with neoadjuvant chemotherapy than with control.

Neoadjuvant chemotherapy produced marked T and N downstaging and histologic tumour regression (all p < 0.001). Resection was more often histopathologically complete in case of neoadjuvant chemotherapy, 94% versus 89% (p < 0.001). Fewer patients in the neoadjuvant chemotherapy than in the control group had residual or recurrent disease within 2 years, 16.9% versus 21.5% (rate ratio 0.72, 95% confidence interval 0.54 to 0.98; p = 0.037). Tumour regression correlated strongly with freedom from recurrence. Panitumumab did not enhance the benefit from neoadjuvant chemotherapy. Little benefit from neoadjuvant chemotherapy was seen in mismatch repair–deficient tumours.

The authors commented that FOxTROT is the first phase III study evaluating neoadjuvant chemotherapy in operable colon cancer. It showed that a short course of 6 weeks of neoadjuvant chemotherapy can be delivered safely and produced substantial tumour 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 neoadjuvant than adjuvant chemotherapy. Chemotherapy side effects were similar whether given before or after surgery, and surgical complications were less in the neoadjuvant chemotherapy group.

In an accompanied editorial article, drs Julien Taieb and Mehdi Karoui of the Georges Pompidou European Hospital, Université Paris Cité, SIRIC CARPEM in Paris, France wrote that the question now for the gastrointestinal oncology community is if neoadjuvant chemotherapy is going to be a new standard for patients with locally advanced colon cancer. The answer according to the editorialists is not a standard, but an option.

Despite some limitations, FOxTROT remains an important research effort. The results convince that neoadjuvant chemotherapy is feasible and safe and certainly not detrimental for patients. This opens a new avenue for neoadjuvant treatments in patients with resectable colon cancer. In particular, the FOxTROT results suggest that neoadjuvant chemotherapy may be effective in T4 tumours and in patients older than 70 years. These observations should be confirmed by new studies such as the ongoing FOxTROT 2 study testing neoadjuvant chemotherapy in frail and elderly patients.

Furthermore, specific molecular subgroups such as MSI, BRAFV600E-mutated, or RAS-mutated colon cancer are now treated differently in the metastatic setting, and new treatment options are under development for KRAS G12C-, G12D-, and G12V-mutated as for HER2-amplified colon cancer. The first neoadjuvant treatments with targeted agents have been tested using immune checkpoint inhibitors in MSI colon cancer with impressive results. Although the magnitude of efficacy seems more limited for other molecular treatments in colon cancer with specific molecular alterations, the neoadjuvant setting seems a promising way for therapeutic optimisation in the future and neoadjuvant pilot studies for all these molecular subgroups are ongoing or will start in the near future.  

FOxTROT study was funded by Cancer Research UK. Additional support was provided by the Birmingham and Leeds ECMC network, the RCS Eng and Rosetrees Trust, and the Swedish Cancer Society. Panitumumab was provided free of charge by Amgen, who also supported RAS testing and additional CT scans.