Clinical investigation
Rectum
Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: A matched-pair analysis

Presented in part at the Forty-Seventh Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), October 16–20, 2005, Denver, CO.
https://doi.org/10.1016/j.ijrobp.2006.07.1374Get rights and content

Purpose: To retrospectively compare the acute toxicity, pathologic response, relapse rates, and survival in rectal cancer patients treated with preoperative radiotherapy (RT) and either concurrent capecitabine or concurrent protracted infusion 5-fluorouracil (5-FU).

Methods: Between June 2001 and February 2004, 89 patients with nonmetastatic rectal adenocarcinoma were treated with preoperative RT and concurrent capecitabine, followed by mesorectal excision. These patients were individually matched by clinical T and N stage (as determined by endoscopic ultrasound and CT scans) with 89 control patients treated with preoperative RT and concurrent protracted infusion 5-FU between September 1997 and August 2002.

Results: In each group, 5 patients (6%) had Grade 3–4 toxicity during chemoradiotherapy. The pathologic complete response rate was 21% with capecitabine and 12% with protracted infusion 5-FU (p = 0.19). Of the 89 patients in the capecitabine group and 89 in the 5-FU group, 46 (52%) and 55 (62%), respectively, had downstaging of the T stage after chemoradiotherapy (p = 0.20). The estimated 3-year local control (p = 0.15), distant control (p = 0.86), and overall survival (p = 0.12) rate was 94.4%, 86.3%, and 89.8% for patients treated with capecitabine and 98.6%, 86.6%, and 96.4% for patients treated with protracted infusion 5-FU, respectively.

Conclusion: Preoperative concurrent capecitabine and concurrent protracted infusion 5-FU were both well tolerated, with similar, low rates of Grade 3–4 acute toxicity. No significant differences were seen in the pathologic response, local and distant recurrence, or overall survival among patients treated with preoperative RT and concurrent capecitabine compared with those treated with RT and concurrent protracted infusion 5-FU.

Introduction

Preoperative chemoradiotherapy now serves as the standard of care for patients with locally advanced rectal cancer. The German Intergroup trial showed that patients treated with preoperative chemoradiotherapy had lower rates of local recurrence and acute and late toxicity, and similar rates of overall survival, compared with patients treated with postoperative chemoradiotherapy (1). In the German trial, concurrent chemotherapy consisted of continuous infusion 5-fluorouracil (5-FU) during the first and fifth weeks of radiotherapy (RT) (1).

Randomized trials have evaluated different methods of administering 5-FU during chemoradiotherapy for rectal cancer. In the Gastrointestinal Intergroup trial, patients treated with postoperative RT with concurrent protracted venous infusion 5-FU had significantly greater rates of overall survival and relapse-free survival compared with patients treated with postoperative RT with concurrent bolus 5-FU (2). On the basis of the results of this trial, protracted infusion 5-FU was accepted as the standard regimen for concurrent chemoradiotherapy for rectal cancer at many institutions. However, in the Intergroup 0144 trial, no significant differences were seen in overall survival and relapse-free survival among three regimens of 5-FU–based postoperative therapy: (1) RT and concurrent infusion 5-FU, with infusion 5-FU before and after chemoradiotherapy; (2) RT and concurrent protracted infusion 5-FU, with bolus 5-FU before and after chemoradiotherapy; and (3) RT and concurrent bolus 5-FU/leucovorin, with bolus 5-FU, leucovorin, and levamisole before and after chemoradiotherapy (3). The results from the Intergroup 0144 trial implied that RT with concurrent protracted infusion 5-FU was comparable to RT with concurrent biochemically modulated 5-FU.

Capecitabine, an orally administered fluoropyrimidine, can serve as an alternative to 5-FU for the treatment of colorectal cancer. Capecitabine is preferentially converted to 5-FU in tumor tissue through a three-step enzymatic pathway (4). Two large randomized trials compared capecitabine with 5-FU and leucovorin in patients with metastatic colorectal cancer (5, 6). An integrated analysis of these trials showed that capecitabine was associated with a superior response rate, equivalent survival, and a more favorable safety profile than 5-FU and leucovorin (7). A recently published randomized trial on colon cancer showed that adjuvant therapy with capecitabine yielded at least equivalent disease-free survival as bolus 5-FU and leucovorin (8). Capecitabine was also associated with greater relapse-free survival and fewer adverse events than bolus 5-FU and leucovorin (8). A number of Phase I and II trials have evaluated preoperative RT with concurrent capecitabine for rectal cancer (9, 10, 11, 12, 13). Capecitabine was well-tolerated with RT in these trials and yielded pathologic complete response rates of 10–24% (9, 10, 11, 12, 13).

Using clinical T and N stage as determined by endorectal ultrasound and CT scans, we individually matched 89 patients treated with preoperative RT and capecitabine with 89 patients treated with preoperative RT and protracted infusion 5-FU. The goal of this study was to compare the acute toxicity, pathologic response, relapse rates, and survival in rectal cancer patients treated with preoperative RT and concurrent capecitabine with those of patients treated with preoperative RT and concurrent protracted infusion 5-FU.

Section snippets

Matching procedure

Between June 2001 and February 2004, 89 patients with newly diagnosed rectal cancer (located at ≤12 cm from the anal verge), no evidence of distant metastasis, and no previous history of pelvic RT, were treated with preoperative RT and concurrent capecitabine, followed by mesorectal excision. These patients were individually matched by clinical T and N stage with 89 patients with newly diagnosed rectal cancer and no evidence of distant metastasis, who were treated with preoperative RT and

Patient characteristics

The patient and tumor characteristics are shown in Table 1. No significant differences were found between the two groups for age, gender, race, circumferential extent of tumor, distance from the anal verge, biopsy pathologic features, or biopsy grade.

Acute toxicity

The worst grades of acute toxicity during chemoradiotherapy in each group are shown in Table 2. Patients treated with capecitabine had a greater rate of hand-foot syndrome (22% vs. 3%, p < 0.01), but these were all Grade 1 or 2. Patients treated

Discussion

This retrospective, matched-pair analysis suggests that preoperative RT with concurrent capecitabine yields comparable outcomes to those of preoperative RT with protracted infusion 5-FU. No significant differences were found in the pathologic complete response, downstaging, and sphincter preservation rates between rectal cancer patients treated with preoperative RT and capecitabine and those treated with preoperative RT and protracted infusion 5-FU. Also, no significant differences were found

Conclusion

No significant differences were found in the rates of Grade 3–4 acute toxicity, pathologic response, relapse, and survival in rectal cancer patients treated with preoperative RT and concurrent capecitabine compared with those treated with preoperative RT and protracted infusion 5-FU. Capecitabine may serve as an acceptable alternative to protracted infusion 5-FU for preoperative chemoradiotherapy of rectal cancer. Longer follow-up and the NSABP R-04 trial will help address this issue more

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