Clinical Investigation
Preoperative Capecitabine and Pelvic Radiation in Locally Advanced Rectal Cancer—Is it Equivalent to 5-FU Infusion Plus Leucovorin and Radiotherapy?

Presented at the 89th Annual Meeting of the American Radium Society, May 5–9, 2007, Amsterdam, The Netherlands.
https://doi.org/10.1016/j.ijrobp.2009.03.048Get rights and content

Purpose

The aim of this retrospective case-matching study was to compare the treatment outcomes and acute toxicity of preoperative radiotherapy (RT) with capecitabine vs. preoperative RT with intermittent 5-fluorouracil (5-FU) infusion, leucovorin, and mitomycin C in rectal cancer.

Methods and Materials

We matched 34 patients who were treated with preoperative concurrent capecitabine and 50 Gy of RT by their clinical T stage (T3 or T4) and the tumor location (≤7 cm or >7 cm from the anal verge) with another 68 patients who were treated with preoperative intermittent 5-FU infusion, leucovorin, mitomycin C, and 50 Gy of RT for a comparison of the pathologic tumor response, local control, distant failure, and survival rates.

Results

The pathologic complete response rate was 21% with capecitabine and 18% with 5-FU and leucovorin (p = 0.72). The rate of T downstaging after chemoradiation was 59% for both groups. The rate of sphincter-sparing resection was 38% after capecitabine plus RT and 43% after 5-FU plus RT (p = 0.67). At 3 years, there was no significant difference in the local control rate (93% for capecitabine and 92% for 5-FU and leucovorin), relapse-free rate (74% for capecitabine and 73% for 5-FU and leucovorin), or disease-specific survival rate (86% for capecitabine and 77% for 5-FU and leucovorin). The acute toxicity profile was comparable, with little Grade 3 and 4 toxicity.

Conclusions

When administered with concurrent preoperative RT, both capecitabine and intermittent 5-FU infusion with leucovorin modulation provided comparable pathologic tumor response, local control, relapse-free survival, and disease-specific survival rates in rectal cancer.

Introduction

Preoperative chemoradiotherapy has become the standard of care for patients with locally advanced rectal cancers after a randomized trial by the German Rectal Cancer Study Group showed that preoperative chemoradiotherapy, when compared with postoperative chemoradiotherapy, provided a similar overall survival rate but a lower rate of local recurrence and toxicity for patients with locally advanced rectal cancer (1). Currently, 5-fluorouracil (5-FU) is the most commonly administered concurrent chemotherapy with pelvic radiotherapy (RT). Many Phase II and Phase III trials used intermittent bolus injection of 5-FU, with or without leucovorin modulation during the first and fifth weeks of RT 2, 3, 4. In the German rectal cancer study, an intermittent 5-FU infusion was given over a period of 96 hours concurrently during the first and fifth weeks of RT (1). Other investigators have extended the duration of chemotherapy to a protracted infusion of 5-FU throughout the entire 5 weeks of RT 5, 6, 7. In a randomized study on postoperative chemotherapy and pelvic RT for Stage II and Stage III rectal cancer, O'Connell et al.(8) have shown that patients who received concurrent RT with protracted 5-FU infusion had an improved time to relapse and survival when compared with patients who received bolus 5-FU and pelvic RT. However, protracted 5-FU infusion requires an indwelling venous catheter throughout the 5 weeks of therapy, which is associated with increased morbidity (infection and thrombosis) and patient discomfort.

Capecitabine is an orally administered fluoropyrimidine carbamate, which is preferentially converted to active 5-FU through a three-step enzymatic pathway in the liver and in the tumor cells 9, 10. When administered on a twice-daily schedule, it may mimic the pharmacokinetics of a protracted 5-FU infusion. Capecitabine has been shown in two randomized trials to be at least equivalent in efficacy to bolus 5-FU and leucovorin in the treatment of metastatic colorectal cancers 11, 12. It was associated with a higher rate of tumor response and less toxicity but equivalent survival when compared with bolus 5-FU and leucovorin. Several Phase II trials had used capecitabine and preoperative RT for locally advanced rectal cancers and showed that this treatment combination was well tolerated by patients and the rate of pathologic response was comparable to that of preoperative 5-FU, leucovorin, and RT 13, 14, 15, 16. However, there is no randomized trial that has directly compared RT with capecitabine vs. RT with 5-FU infusion or bolus 5-FU with leucovorin modulation.

This study was undertaken to compare the outcome of preoperative capecitabine plus RT vs. intermittent 5-FU infusion with leucovorin modulation plus RT in locally advanced rectal cancers. Patients were matched by their clinical T stage and the tumor location. The goal of the study was to demonstrate noninferiority in the pathologic response, local control, and survival rates between the two treatments.

Section snippets

Patent population

In 2003 we initiated a Phase II study using preoperative concurrent oral capecitabine and pelvic radiation followed by resection for locally advanced rectal cancer. This study was approved by the University of Calgary Conjoint Health Research Ethics Board (Calgary, Alberta, Canada). We enrolled 34 patients in this protocol. These 34 patients were matched with 68 patients who were previously treated in another Phase II study with preoperative 5-FU infusion, leucovorin, mitomycin C, and pelvic RT

Results

The pretreatment characteristics of both patient cohorts are given in Table 1. Of the patients, 76% had a low rectal cancer (<7 cm from the anal verge). Twenty-four percent of the patients had a T4 tumor, and seventy-six percent had a T3 tumor. There were no significant differences in the gender, age, performance status, and degree of tumor mobility between the two groups. The only exception was the clinical lymph node status. More patients with positive lymph node disease had been enrolled in

Discussion

In this retrospective matched-pair comparison, we have found comparable outcome between preoperative radiation plus oral capecitabine and preoperative radiation plus intermittent 5-FU infusion with leucovorin modulation and mitomycin C in locally advanced rectal cancers. There was no significant difference in the tumor response as measured by the rates of pathologic complete response and T downstaging. The 3-year local control, relapse-free survival, and disease-specific survival rates were

Conclusions

Preoperative capecitabine plus RT appears to be equal in efficacy to preoperative 5-FU infusion with leucovorin modulation, mitomycin C, and RT in locally advanced rectal cancer. Their acute hematologic and nonhematologic toxicity profiles are comparable. Although the risk of venous catheter–related toxicity associated with protracted 5-FU infusion is low, 2% to 3% (20), patient comfort and treatment tolerability without such a venous catheter is an important factor to consider in advocating

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Conflict of interest: none.

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