Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial

Abstract

Objective: To determine whether extending the interval between chemoradiation (CRT) and surgery, and administering additional chemotherapy during the waiting period has an impact on tumor response, CRT-related toxicity and surgical complications in patients with advanced rectal cancer.

Background: Locally advanced rectal cancer is usually treated with preoperative CRT followed by surgery approximately 6 weeks later. The Timing of Rectal Cancer Response to Chemoradiation Consortium designed a prospective, multicenter, Phase II clinical trial to investigate extending the interval between CRT and surgery, and administering additional chemotherapy during the waiting period. Here, we present preliminary results of this trial, reporting the tumor response, CRT-related toxicity and surgical complications.

Methods: Stage II and III rectal cancer patients were treated concurrently with 5-Fluorouracil (FU) and radiation for 5 to 6 weeks. Patients in study group (SG) 1 underwent total mesorectal excision (TME) 6 weeks later. Patients in SG2 with evidence of a clinical response 4 weeks after CRT received 2 cycles of modified FOLFOX-6 (mFOLFOX-6) followed by TME 3 to 5 weeks later. Tumor response, CRT-related toxicity and surgical complications were recorded.

Results: One hundred and forty-four patients were accrued. One hundred and thirty-six (66, SG1; 70, SG2) were evaluated for CRT-related toxicity. One hundred and twenty-seven (60, SG1; 67, SG2) were assessed for tumor response and surgical complications. A similar proportion of patients completed CRT per protocol in both SGs, but the cumulative dose of sensitizing 5-FU and radiation was higher in SG2. CRT-related toxicity was comparable between SGs. Average time from CRT-to-surgery was 6 (SG1) and 11 weeks (SG2). Pathologic complete response (pCR) was 18% (SG1) and 25% (SG2). Postoperative complications were similar between SGs.

Conclusions: Intense neoadjuvant therapy consisting of CRT followed by additional chemotherapy (mFOLFOX-6), and delaying surgery may result in a modest increase in pCR rate without increasing complications in patients undergoing TME for locally advanced rectal cancer.

Trial registration: ClinicalTrials.gov NCT00335816.

Conflict of interest statement

Disclosure:

The authors declare no conflicts of interest associated with this manuscript.

Figures

Figure 1. Treatment schema for the trial

CRT: 5-FU was given at 225 mg/m2/day for 7 days/week in continuous infusion throughout radiation therapy. Radiation therapy was given once a day for 5 days at 1.8 Gy/day for a total of 45 Gy, given in 25 fractions. A minimum boost of 5.4 Gy was required. Surgery was performed following the principles of sharp-mesorectal excision. mFOLFOX-6 chemotherapy: Racemic leucovorin (LV) was given at 200 mg/m2 or 400 mg/m2 in a 2-hour infusion on day 1. Oxaliplatin was given at 85 mg/m2 in a 2-hour infusion concurrent with LV on day 1, followed by bolus 5-FU 400 mg/m2 on day 1 and a 46-hour infusion of 5-FU 2,400 mg/m2 (mFOLFOX-6) with two weeks between cycles. Resting period was defined as the interval between treatments.

Figure 2. Patient attrition

Abbreviations: Dx = diagnosis.