Thymidine phosphorylase and capecitabine: a predictive marker for therapy selection?

Patients with advanced colorectal carcinoma (CRC) currently have seven agents approved by the US Food and Drug Administration available for use in routine clinical practice. Although data on sequence are not definitive, it is likely important that the first treatment chosen be the most effective for an individual patient to allow for maximization of overall outcome. As such, it is important that we have means for selecting the therapy with the best chance of response for an individual. Unfortunately, and despite much effort, clinically useful tests to predict the utility of given treatments for patients with CRC do not exist for any of the available drugs. Fluoropyrimidine therapy remains a foundation piece for most first line treatments for CRC. One potential choice for patients is that between the intravenous fluoropyrimidine, fluorouracil (FU), and the orally available prodrug capecitabine. Capecitabine is transformed to FU in several steps, the last of which is conversion of 5 -deoxy-5-fluorouridine to FU by thymidine phosphorylase (TP). Capecitabine was designed to take advantage of the increased levels of TP observed in tumors as opposed to normal tissues, potentially allowing for selective toxicity in tumors (reviewed by Van Cutsem et al). FU is then either degraded by dihydropyrimidine dehydrogenase (DPD) or anabolized to fluorodeoxyuridylate, whereby thymidylate synthase (TS) is inhibited. Inhibition of TS leads to so-called thymine-less death, through a programmed cell death mechanism. The expression of TP, DPD, and TS is known to vary significantly among a population of colorectal tumors, as well as between primary and metastatic tumors. In practice, the overall efficacy of capecitabine is similar to that of FU, and the toxicity of capecitabine is less than the toxicity of bolus FU, but similar to (or perhaps slightly more than) that seen with infusional FU regimens. In a capecitabinecontaining combination trial presented in this issue of the Journal of Clinical Oncology, Meropol et al evaluated TP, TS, and DPD for their ability to predict response to capecitabine when used in a firstline metastatic setting, in an attempt to identify patients who may have altered response to a capecitabine/irinotecan (CAPIRI) regimen. The clinical results achieved by the CAPIRI combination in this study confirm what has been observed in several other small trials. The time to progression of 7.6 months is slightly less than that which would be expected from a similar group of patients receiving either infusional fluorouracil, leucovorin, and oxaliplatin, or fluorouracil, leucovorin, and irinotecan, whereas the overall survival of 20.6 months places the regimen squarely in the middle of what would be expected based on larger randomized studies. In terms of toxicity, this study follows the pattern of several others in which capecitabine dosing, believed to have been established in phase I studies, had to be decreased in a phase II trial because of unexpectedly high rates of GI toxicity. As a result, the dosing regimen of capecitabine 900 mg/m bid is different from others already published, and adds to the confusion about the question of the correct dosing of capecitabine in combination. Irinotecan dosing was also decreased from an initial 125 to 100 mg/m on days 1 and 8 of a 21day cycle. After dose reduction, there did not seem to be any significant decrement in response rate, but optimal dosing of the CAPIRI combination remains an issue that still must be addressed by robust randomized studies before wholesale substitution of capecitabine for infusional (or bolus plus infusion) FU is to be considered an acceptable regimen in combination with irinotecan. In fact, the recently presented BICC-C trial examined three different regimens of FU/capecitabine and irinotecan (in addition to celecoxib for half the patients), and strongly suggested that FU, leucovorin, and irinotecan is the preferable regimen for the average patient both in terms of toxicity and overall survival. The potential importance of this study lies in the prospectively planned analysis of tumor markers. Positive staining for TP by immunohistochemistry (IHC), defined by the authors essentially as any visible TP by IHC in the primary tumors, predicted for a significantly higher response rate (65% v 27%) to the CAPIRI combination, and survival that was nearly double for patients with TP-positive tumors. Median time to progression (TTP) was also significantly longer in the patients with positive TP staining, when evaluating either the primary tumor (median TTP, 8.7 v 6.0 months; P .039) or metastatic lesions (median TTP, 8.7 v 5.4 months; P .002). These differences are clinically meaningful in addition to being statistically significant. Prior studies of the effect of TP expression on FU response have been small and retrospective, but generally have hinted that TP expression is a negative predictive factor for FU response. Thus, this study invites the intriguing possibility that we might in the future select capecitabine versus FU rationally based on analysis of tumor TP levels using inexpensive and widely available methodology. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 25 SEPTEMBER 1 2006