Capecitabine and Timing of Radiotherapy During Preoperative Chemoradiation for Rectal Cancer

摘要

Background Capecitabine is effective in treating colorectal cancer and is increasingly being investigated for use in preoperative chemoradiation of rectal cancer. Since capecitabine and its metabolites have a plasma half-life of 0.5–1 hour, the relative timing of capecitabine and radiotherapy may affect clinical outcomes. We retrospectively investigated whether the timing of radiotherapy affects rates of acute toxicity, pathologic response, and relapse in rectal cancer patients receiving capecitabine. Methods Between June 2001 and July 2004, 111 rectal cancer patients were treated with preoperative radiotherapy and concurrent capecitabine given twice daily, in the early morning and at night. Of these, 44 received at least 70% of their radiation treatments before 12 PM (AM group), and 47 received at least 70% of their radiation treatments after 12 PM (PM group). Results There were no significant differences between the AM vs. PM groups in rates of grade ≥ 2 acute gastrointestinal toxicity (61% vs. 47%) or skin toxicity (23% vs. 26%) or grades ≥ 1 hand-foot syndrome (27% vs. 15%). Although the PM group had numerically higher rates of pathologic complete response (28% vs. 16%) and tumor downstaging (57% vs. 39%), differences in these outcomes and in sphincter preservation were not significant. Rates of 2-year local control, distant control, and disease-free survival were nearly identical in the two groups. Conclusions No significant differences were seen in the rates of acute toxicity, pathologic response, and relapse between patients in the AM and PM groups. The timing of radiotherapy does not appear to be critical in patients with rectal cancer receiving concurrent capecitabine. Capecitabine is an oral prodrug that preferentially generates 5-fluorouracil (5-FU) in tumor tissue through a threestep enzymatic cascade. 1 , 2 After passing through the intestinal tract unmetabolized, capecitabine undergoes conversion to 5′-deoxy-5-fluorocytidine (5′-DFCR) by carboxylesterase in hepatic tissue. Cytidine deaminase, an enzyme that resides in both healthy and tumor tissues, converts 5′-DFCR to 5′-deoxyfluorouridine (5′-DFUR). The latter is converted to 5-FU by thymidine phosphorylase preferentially in tumor tissue, thereby decreasing the effect of 5-FU on healthy cells. The pharmacokinetics of capecitabine can vary somewhat between patients due to interpatient variation variation in metabolic enzyme levels; time to peak plasma concentration of capecitabine is reported at between 1 and 2 hours, and its plasma half-life is between 0.5 and 0.8 hours. 3 – 7 The 5′-DFCR and 5′-DFUR metabolites have plasma half-life values of 0.8–1.0 and 0.6–0.75 hours, respectively. 3 – 7 Elimination of capecitabine and its derivatives occurs rapidly, primarily in the urine. 3 , 4 Large randomized trials in metastatic colorectal cancer have shown that capecitabine treatment leads to a superior response rate and safety profile, as well as at least equivalent time to disease progression and overall survival, compared to 5-FU and leucovorin. 8 – 10 A randomized phase III trial in stage III colon cancer patients revealed that adjuvant therapy with capecitabine yielded improved relapse-free survival, at least equivalent disease-free survival, and fewer adverse events compared to bolus 5-FU and leucovorin. 11 A number of studies investigating concurrent capecitabine and radiation therapy in rectal cancer have indicated encouraging rates of pathologic complete response, tumor downstaging, and sphincter preservation, as well as a favorable safety profile. 12 – 16 A matched-pair comparison showed no significant differences in grade 3 or 4 toxicity, pathologic response, sphincter preservation, or relapse rates in rectal cancer patients treated with preoperative radiotherapy with concurrent capecitabine vs. concurrent protracted infusional 5-FU. 17 Two other retrospective studies in rectal cancer have also shown similar outcomes with capecitabine and 5-FU together with radiotherapy. 18 , 19 The National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial is currently comparing preoperative chemoradiation therapy with capecitabine vs. protracted infusional 5-FU, both with and without oxaliplatin. 20 Given the short plasma half-life of capecitabine and its metabolites, it is possible that the interval between capecitabine administration and radiation therapy affects the degree of capecitabine radiosensitization. Capecitabine is typically administered once in the early morning and once in the late evening. Patients that are treated with a longer interval between capecitabine and radiotherapy may have diminished tumor responses compared to those treated with a shorter interv