Combined-Modality Therapy for Rectal Cancer Using Irinotecan

The standard adjuvant treatment for patients with T3 and/or N1/2 rectal cancer is pelvic radiation plus concurrent fluorouracil(Drug information on fluorouracil) (5-FU)-based chemotherapy. Several newer chemotherapeutic regimens have been developed for the treatment of patients with metastatic disease and are now being combined with pelvic radiation therapy. This review will focus on the results of irinotecan(Drug information on irinotecan) (CPT-11, Camptosar)-based regimens in combination with radiation therapy in patients with rectal cancer.

Adjuvant Therapy With 5-FU-Based Regimens: Postoperative Therapy

Published results of randomized trials from the Gastrointestinal Tumor Study Group (GITSG)[1,2] and the Mayo/NCCTG (North Central Cancer Treatment Group, trial 79-47-51)[3] revealed significant improvements in local control and/or survival with postoperative radiation plus bolus 5-FU with or without semustine (methyl-CCNU) in patients with rectal cancer. Based on these findings, the National Cancer Institute Consensus Conference concluded in 1990 that combined-modality therapy with 5-FU-based regimens was the standard postoperative adjuvant treatment for patients with T3 and/or N1/2 rectal cancer.[4] While radiation therapy decreases local recurrence rates by half, the addition of 5-FU-based chemotherapy further decreases local recurrence rates to approximately 10% to 12%, and is responsible for increasing overall 5-year survival rates by approximately 10% to 15% above those achieved with surgery alone. Data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-02 randomized trial revealed that, although postoperative 5-FU-based chemotherapy alone decreased the local recurrence rate to 13%, the combination of chemotherapy plus radiation significantly decreased the local recurrence rate to 8%.[5]

Based on the positive results reported in the Mayo/NCCTG 86-47-51 trial that used continuous infusion 5-FU, the postoperative Intergroup trial INT 0144 was designed. The primary end point of this trial was to determine whether there was a benefit of continuous infusion 5-FU throughout the entire chemotherapy course (six cycles) as compared with continuous infusion only during the combined-modality segment (two cycles) and bolus 5-FU during the remaining four cycles. The control arm was bolus 5-FU/leucovorin/levamisole (Ergamisol). The trial closed to accrual in 2000 and the results are pending.

Until the results of INT 0144 are available, the choice of a postoperative adjuvant regimen in the nonprotocol setting remains controversial. If 5-FU alone is used, then it is probably best administered by continuous infusion. Otherwise, published data on 5-FU-based regimens indicate that they are probably equally effective; the choice of a regimen should be based on factors such as acute toxicity profiles and patient compliance.

Adjuvant Therapy With 5-FU-Based Regimens: Preoperative Therapy

Given the advantage of chemotherapy in the postoperative setting, several phase I/II preoperative combined-modality treatment programs have been developed. Most have used 5-FU-based chemotherapy. Retrospective data suggest that preoperative combined-modality therapy increases pathologic down-staging compared with preoperative radiation alone[6] and is associated with a lower incidence of acute toxicity compared with postoperative combined-modality therapy.[7]

Preoperative therapy may also increase sphincter preservation. Seven series examining this issue have been reported. The studies were carried out in patients with clinically resectable rectal cancer whose surgeons had determined prospectively (based on a clinical office exam before beginning preoperative therapy) that they required abdominoperineal resection. All of the studied regimens used conventional radiation doses and techniques—three with radiation therapy alone[8-10] and four as combined-modality therapy.[11-14]

Results showed that the incidence of sphincter preservation after preoperative therapy was only 23% in the NSABP R-03 series[11] and 44% in the Lyon series[10]; however, approximately 70% of patients in the remaining five series had sphincter preservation. In the four series reporting functional outcome, the majority of patients (approximately 75%) had good to excellent sphincter outcome.