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Neoadjuvant chemotherapy as a potential treatment option in colon cancer

Presented by
Dr Matthew T. Seymour, National Institute for Health Research Clinical Research Network, England
Medical writer: Muriel Cunningham

Neoadjuvant chemotherapy (NAC) resulted in histologic regression and downstaging and decreased the rate of incomplete resections among patients with operable colon cancer, according to results of the FOxTROT trial presented by Matthew T. Seymour, MD, of the National Institute for Health Research Clinical Research Network, on June 1.

The objectives of FOxTROT were to determine if NAC administration prior to surgery improves disease-free survival among patients with colon cancer. In addition, a substudy evaluated whether adding panitumumab to preoperative NAC for patients whose disease harbored wildtype KRAS would increase NAC anti-tumour activity (Abstract 3504).

Patients with operable, nonobstructed, radiologically staged T3 or T4 (N0-2) colon cancer without metastases were randomly assigned 2:1 to either the NAC group or the control group. Patients in the NAC group received 6 weeks of FOLFOX followed by surgery and then another 18 weeks of FOLFOX, whereas the control group underwent surgery and then received postoperative FOLFOX for 24 weeks.

Patients with wildtype KRAS tumours assigned to the NAC group had the option to be randomly assigned 1:1 to receive panitumumab during 6 weeks of NAC treatment. The protocol allowed for two other options: a total chemotherapy duration of 12 weeks instead of 24 weeks, or treatment with oxaliplatin and capecitabine (OxCap) instead of FOLFOX for patients who were not in the panitumumab substudy. The primary endpoint was 2-year freedom from recurrent or persistent disease. Secondary outcomes included downstaging, tumour regression, R0 resection rate, and perioperative safety.

A total of 1,052 patients were randomly assigned (698 to the NAC group and 354 to the control group). The overall median age was 65, and 64% of patients were male. The baseline characteristics of both treatment arms were well balanced. Surgery was performed in the majority of patients (98% in both groups). In both arms, 28% were to receive OxCap and 6% were to receive 12 weeks of postoperative chemotherapy. A significantly greater proportion of patients in the control group did not receive chemotherapy compared with the NAC group (27% vs. 4%; P < 0.0001) because their tumour was low risk (16%) or they were too ill/declined chemotherapy (11%).

There were no unexpected findings of chemotherapy-associated toxicity. Significantly more patients in the control arm experienced complications that necessitated additional surgery compared with patients receiving NAC (7.1% vs. 4.3%; P = 0.05). Higher numbers of patients in the control group also experienced anastomotic leak or intra-abdominal abscess compared with those in the NAC group (7.4% vs. 4.7%) or a complication prolonging their hospital stay (14.3% vs. 11.6%), but these data did not reach statistical significance.

“Preoperative chemotherapy did not increase surgical morbidity; in fact, there were fewer major surgical complications,” Dr. Seymour said.

The 2-year failure rate improved but was not statistically significant, with rates of 13.6% in the NAC group compared with 17.2% in the control group (HR 0.75, 95% CI [0.55, 1.04]; P = 0.08). The control recurrence rate of 17.2% was much lower than the estimates used when powering the study (25% to 32%). Other outcomes favoured NAC: risk of undergoing surgery without achieving R0, tumour stage/size at surgery, nodal stage at surgery, and tumour regression grade at surgery (all; P < 0.001). Results from a sensitivity analysis indicated that the observed rate of tumour regression was not driven by the addition of panitumumab.

“We feel this approach can be considered a new therapeutic option for locally advanced operable colon cancer,” Dr. Seymour said.

Discussant Jordan Berlin, MD, FASCO, of Vanderbilt University, thought the study results were promising. The safety data from FOxTROT support moving chemotherapy prior to surgery in patients with resectable colon cancer, with positive effects on complication and R1 resection rates, but the tradeoff is that some patients may be over treated.

“This is not practice changing in terms of standard of care, but it gives us a new option when we are thinking about our patients,” Dr. Berlin said.

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