FOxTROT: randomised phase 2/3 study of neoadjuvant chemotherapy (CT) ± an anti-EGFR monoclonal antibody for locally advanced, operable colon cancer


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Dion Morton1, Gina Brown2, David Ferry3, Richard Gray4, Laura Magill4, Phil Quirke5, Matt Seymour5, Bryan Warren6
1The Queen Elizabeth Hospital, Birmingham, United Kingdom,2The Royal Marsden Hospital, London & Surrey, United Kingdom,3New Cross Hospital, Wolverhampton, United Kingdom,4The University of Birmingham, Birmingham, United Kingdom,5University of Leeds, Leeds, United Kingdom,6The John Radcliffe Hospital, Oxford, United Kingdom

Background

Preoperative CT and radiotherapy are surprisingly more effective than postoperative treatment in rectal and other cancers. This may be because micrometastases are more readily eradicated by neoadjuvant CT than CT given after the delay and immunological stress of surgery. Or, shrinking the tumour before surgery may reduce the risk of incomplete surgical excision and tumour cell shedding during surgery. Neoadjuvant CT has become feasible in colon cancer now that response rates exceed 50% and radiological staging is more accurate. Pre-operative CT also provides a unique opportunity to identify tumour markers predictive of response to CT and anti-EGFR therapy.

Method

The FOxTROT pilot (Fluoropyrimidine, Oxaliplatin and Targeted Receptor pre-Operative Therapy) has randomised 142 patients with radiologically staged T4 or “T3 bad” (extramural depth ?5mm), M0, resectable colon cancer 2:1 to receive the first 6 weeks of OxMdG  (oxaliplatin 85 mg/m2, l-folinic acid 175mg, 5-FU 400 mg/m2 bolus then 2400 mg/m2 by 46h infusion) CT pre-operatively or all 24 weeks post-operatively. KRAS wildtype patients are randomised 1:1 to receive an anti-EGFR monoclonal antibody, panitumumab (6 mg/kg; 2-weekly) with the first 6 weeks of CT or control.

Results

Pre-operative KRAS testing and chemotherapy is feasible with acceptable toxicity and perioperative morbidity. Preoperative radiological staging has high specificity for high-risk tumours with all tumours in the control arm being T3 and above. Significant histological downstaging was seen in the neoadjuvant arm including T stage (p<0.02), apical node involvement (p<0.01) and regression grading (p<0.02). Three cases of complete pathological response have been identified.

Conclusion

Neoadjuvant chemotherapy for high risk colon cancer is feasible. The FOXTROT phase III trial is proceeding with target 900 patients, integrated molecular marker studies and primary outcomes of 2-year recurrence for pre-operative CT and pathological down-staging for panitumumab.