Preoperative Chemotherapy for Operable Colon Cancer: Mature Results of an International Randomized Controlled Trial

Abstract

Purpose: Neoadjuvant chemotherapy (NAC) has potential advantages over standard postoperative chemotherapy for locally advanced colon cancer but requires formal evaluation.

Methods: Patients with radiologically staged T3-4, N0-2, M0 colon cancer were randomly allocated (2:1) to 6 weeks oxaliplatin-fluoropyrimidine preoperatively plus 18 postoperatively (NAC group) or 24 weeks postoperatively (control group). Patients with RAS-wildtype tumors could also be randomly assigned 1:1 to receive panitumumab or not during NAC. The primary end point 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.

Results: Of 699 patients allocated to NAC, 674 (96%) started and 606 (87%) completed NAC. In total, 686 of 699 (98.1%) NAC patients and 351 of 354 (99.2%) control patients underwent surgery. Thirty patients (4.3%) allocated to NAC developed obstructive symptoms requiring expedited surgery, but there were fewer serious postoperative complications with NAC than with control. NAC produced marked T and N downstaging and histologic tumor regression (all P < .001). Resection was more often histopathologically complete: 94% (648/686) versus 89% (311/351), P < .001. Fewer NAC than control patients had residual or recurrent disease within 2 years (16.9% [118/699] v 21.5% [76/354]; rate ratio, 0.72 [95% CI, 0.54 to 0.98]; P = .037). Tumor regression correlated strongly with freedom from recurrence. Panitumumab did not enhance the benefit from NAC. Little benefit from NAC was seen in mismatch repair-deficient tumors.

Conclusion: 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 down-staging, fewer incomplete resections, and better 2-year disease control. Histologic regression after NAC is a strong predictor of lower postoperative recurrence risk so 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.

Trial registration: ClinicalTrials.gov NCT00647530.

FIG 1.

CONSORT diagram showing flow of patients through the FOxTROT trial. FOxTROT, Fluorouracil, Oxaliplatin, and Targeted Receptor preoperative therapy.

FIG 2.

(A) Tumor regression grade by treatment allocation in the NAC group, and recurrence after surgery by regression grade in (B) NAC and (C) control groups. NAC, neoadjuvant chemotherapy; RR, rate ratio.

FIG 3.

Risk of (A) recurrence or persistent disease, (B) death from colon cancer, and (C) death from any cause: NAC v control. NAC, neoadjuvant chemotherapy; RR, rate ratio.

FIG 4.

(A) Regresssion grade by MMR status in preoperative chemotherapy group and (B and C) recurrence or residual disease by treatment allocation for patients with pMMR or unknown MMR status^a tumors and for dMMR tumors. ^aSeventy-six of five hundred fifty-three (14%) had unknown MMR status. dMMR, MMR-deficient; MMR, mismatch repair; pMMR, MMR-proficient; RR, rate ratio.