Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial

Abstract

Background: Adding modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) after chemoradiotherapy and lengthening the chemoradiotherapy-to-surgery interval is associated with an increase in the proportion of rectal cancer patients with a pathological complete response.

Objective: The purpose of this study was to analyze disease-free and overall survival.

Design: This was a nonrandomized phase II trial.

Settings: The study was conducted at multiple institutions.

Patients: Four sequential study groups with stage II or III rectal cancer were included.

Intervention: All of the patients received 50 Gy of radiation with concurrent continuous infusion of fluorouracil for 5 weeks. Patients in each group received 0, 2, 4, or 6 cycles of modified FOLFOX6 after chemoradiation and before total mesorectal excision. Patients were recommended to receive adjuvant chemotherapy after surgery to complete a total of 8 cycles of modified FOLFOX6.

Main outcome measures: The trial was powered to detect differences in pathological complete response, which was reported previously. Disease-free and overall survival are the main outcomes for the current study.

Results: Of 259 patients, 211 had a complete follow-up. Median follow-up was 59 months (range, 9-125 mo). The mean number of total chemotherapy cycles differed among the 4 groups (p = 0.002), because one third of patients in the group assigned to no preoperative FOLFOX did not receive any adjuvant chemotherapy. Disease-free survival was significantly associated with study group, ypTNM stage, and pathological complete response (p = 0.004, <0.001, and 0.001). A secondary analysis including only patients who received ≥1 cycle of FOLFOX still showed differences in survival between study groups (p = 0.03).

Limitations: The trial was not randomized and was not powered to show differences in survival. Survival data were not available for 19% of the patients.

Conclusions: Adding modified FOLFOX6 after chemoradiotherapy and before total mesorectal excision increases compliance with systemic chemotherapy and disease-free survival in patients with locally advanced rectal cancer. Neoadjuvant consolidation chemotherapy may have benefits beyond increasing pathological complete response rates. See Video Abstract at http://links.lww.com/DCR/A739.

Figures

FIGURE 1.

Inclusion and exclusion of patients.

FIGURE 2.

Kaplan-Meier curves of disease-free (DFS) and overall survival (OS) are shown, with numbers of subjects at risk indicated. a, b) DFS and OS in relation to ypTNM stage. c, d) DFS and OS in relation to pathological complete response (pCR).

FIGURE 3.

a, b) Kaplan-Meier curves of disease-free survival (DFS) and overall survival (OS) are shown in different study groups (SGs), with numbers of subjects at risk indicated. SG1, CRT + TME; SG2, CRT + mFOLFOX6 (two cycles) + TME; SG3, CRT + mFOLFOX6 (four cycles) + TME; SG4, CRT + mFOLFOX6 (six cycles) + TME. CRT, chemoradiotherapy; TME, total mesorectal excision.

FIGURE 4.

Kaplan-Meier curves of disease-free survival, with numbers of subjects at risk shown in different study groups (SGs) for patients who received at least 1 chemotherapy cycle, either as consolidation chemotherapy after chemoradiotherapy (CRT), as adjuvant chemotherapy after total mesorectal excision (TME), or both. SG1, CRT + TME + ≥1 cycle of adjuvant chemotherapy; SG2, CRT + mFOLFOX6 (two cycles) + TME +/− adjuvant chemotherapy; SG3, CRT + mFOLFOX6 (four cycles) + TME +/− adjuvant chemotherapy; SG4, CRT + mFOLFOX6 (six cycles) + TME +/− adjuvant chemotherapy.