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Combined-Modality Therapy for Rectal Cancer Using Irinotecan

Combined-Modality Therapy for Rectal Cancer Using Irinotecan

ABSTRACT: Preoperative or postoperative pelvic radiation plus concurrent fluorouracil-based chemotherapy is standard adjuvant treatment for patients with T3 and/or N1/2 rectal cancer. Newer chemotherapeutic regimens have been developed for the treatment of patients with metastatic disease. Irinotecan (CPT-11, Camptosar)-based regimens have improved survival in patients with metastatic disease and are being actively investigated in combination with pelvic radiation therapy for patients with rectal cancer. [ONCOLOGY 16(Suppl5):35-38, 2002]

The standard adjuvant treatment for patients with T3
and/or N1/2 rectal cancer is pelvic radiation plus concurrent 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 (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.

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