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Journal of Clinical Oncology, Vol 24, No 25 (September 1), 2006: pp. 4051-4053 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.1803
Thymidine Phosphorylase and Capecitabine: A Predictive Marker for Therapy Selection?University of North Carolina, Chapel Hill School of Medicine, Department of Medicine and the Lineberger Cancer Center, Chapel Hill, NC
Washington University School of Medicine, Departments of Medicine, Molecular Biology & Pharmacology, and Genetics, and the Siteman Cancer Center, St Louis, MO 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.1 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.2 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 al3). FU is then either degraded by dihydropyrimidine dehydrogenase (DPD)4 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.5-7 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.8-10 In a capecitabine-containing combination trial presented in this issue of the Journal of Clinical Oncology, Meropol et al11 evaluated TP, TS, and DPD for their ability to predict response to capecitabine when used in a first-line 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.12-16 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.17-20 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/m2 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/m2 on days 1 and 8 of a 21- day 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.21 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.6,22 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. Several issues are of concern, however, in the interpretation of this result. First, although primary tumor TP levels significantly predicted response rate, TTP, and overall survival, this was not consistently the case for the metastatic tumors assayed despite a similar trend. This may speak to the relatively small number of patient samples assayed and the heterogeneity of tumor cells found within the many metastases present within individual patients. Second, we cannot glean from the results presented whether there is a dose-response of TP expression (ie, whether tumors with 1+ TP behave any differently than those with 3+ TP levels). This will require larger studies to be completed, but will be critical in defining those patients for whom it is clinically and ethically appropriate to offer biomarker-driven therapy in the front-line setting. Third, the protein results (via IHC) were compared with reverse transcriptase polymerase chain reaction analysis of mRNA from formalin-fixed, paraffin-embedded tissue. Reverse transcriptase polymerase chain reaction was inferior to IHC in this small study, although a trend for similar results was intact. Lastly, it is unlikely that a polygenic disease such as CRC will have a monogenic therapeutic solution. In this study neither TS nor DPD, both factors that have been shown to predict resistance to FU in prior studies, were predictive for the clinical outcome end points under analysis. One might therefore be concerned that the positive results for prediction by TP represent statistical chance in the face of multiple comparisons. That said, the fact that the TP hypothesis was the primary hypothesis does provide some reassurance that this result will be reproducible in other groups of similar patients. An important aspect of this study lies in the ability to conduct a prospectively planned analysis of tumor markers in tissues collected at multiple clinical investigator sites. In particular, the majority of the clinical sites detailed in both the author affiliations and the acknowledgment sections are from community-based practices. This goes against the view that translational research cannot be conducted in a community setting (where most patients are treated), but rather is consistent with the old adage, "where there is a will, there is a way." The commitment of the study participants to translational research is to be commended; the desire to conduct such research is the only way the field of oncology will make progress in the current complicated landscape where multiple regimens of unpredictable toxicity and effectiveness are available for most tumor types. This translational success should serve as a model for advancement of any clinical trial involving a biomarker-driven hypothesis. We are still left with the question of what to do with this association between TP and outcome. A traditional reaction is to call for a confirmatory study to confirm this prospectively collected, yet retrospectively conducted, biomarker observation. On the basis of these results, one could envision a trial in which patients are randomly assigned to combinations of either irinotecan or oxaliplatin combined with either capecitabine or FU that would both allow for direct testing of the hypothesis that TP expression can predict response to capecitabine versus FU. Unfortunately, the number of potential markers of response and the number of agents is multiplying quickly, and the cooperative groups that are likely to shepherd such studies will have to be choosy about prioritization of the markers to be studied and the particular questions to be asked. Is the question of whether to administer capecitabine or FU important enough to commit hundreds of patients and many thousands of dollars to achieve an answer at this time? The answer likely is a resounding "no." Alternatively, it may be time to follow up prospectively conducted biomarker studies, such as this study of TP and capecitabine, with a biomarker-directed phase II study. The data on response, TTP, and overall survival give us several end points on which to power a trial of CAPIRI, in which positive staining for TP is among the inclusion criteria. The sample size will need to be adequate to provide data that are adequate to convince the cooperative groups, the payers, or our clinical colleagues (and our patients) that it is a concept worth taking forward. This will require a multidisciplinary approach, in which pathologists take an active role to enable clinical-grade IHC testing, in addition to the cadre of medical oncology, radiation oncology, surgery, imaging, nursing, pharmacy, and other clinician scientists that make up the modern management of most cancer patients. Yes, taking more of an individualized approach to cancer therapy will be hard work, but isn't it what we are supposed to be doing anyway? Authors' Disclosures of Potential Conflicts of Interest
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Author Contributions
ACKNOWLEDGMENTS This work was supported in part by NIH Pharmacogenetics research network (Grant No. U01 GM63340). REFERENCES 1. O'Neil BH, Goldberg RM: Chemotherapy for advanced colorectal cancer: Let's not forget how we got here (until we really can). Semin Oncol 32:35-42, 2005[Medline] 2. McLeod HL, Church RD: Molecular predictors of prognosis and response to therapy in colorectal cancer. Cancer Chemother Biol Response Modif 21:791-801, 2003[Medline] 3. Van Cutsem E, Cunningham D, Hoff PM, et al: Thymidine phosphorylase (TP) activation: Convenience through innovation. Oncologist 6:1-2, 2001 (suppl 4) 4. McLeod HL, Sludden J, Murray GI, et al: Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours. Br J Cancer 77:461-465, 1998[Medline] 5. Kidd EA, Yu J, Li X, et al: Variance in the expression of 5-fluorouracil pathway genes in colorectal cancer. Clin Cancer Res 11:2612-2619, 2005 6. Salonga D, Danenberg KD, Johnson M, et al: Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 6:1322-1327, 2000 7. Collie-Duguid ES, Johnston SJ, Boyce L, et al: Thymidine phosphorylase and dihydropyrimidine dehydrogenase protein expression in colorectal cancer. Int J Cancer 94:297-301, 2001[CrossRef][Medline] 8. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001 9. Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19:4097-4106, 2001 10. Twelves C, Wong A, Nowacki MP, et al: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352:2696-2704, 2005 11. Meropol NJ, Gold PJ, Diasio RB, et al: Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 24:4069-4078, 2006 12. Diaz-Rubio E, Evans TR, Tabemero J, et al: Capecitabine (Xeloda) in combination with oxaliplatin: A phase I, dose-escalation study in patients with advanced or metastatic solid tumors. Ann Oncol 13:558-565, 2002 13. Tewes M, Schleucher N, Achterrath W, et al: Capecitabine and irinotecan as first-line chemotherapy in patients with metastatic colorectal cancer: Results of an extended phase I study. Ann Oncol 14:1442-1448, 2003 14. Bajetta E, Di Bartolomeo M, Mariani L, et al: Randomized multicenter phase II trial of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma. Cancer 100:279-287, 2004[CrossRef][Medline] 15. Kim TW, Kang WK, Chang HM, et al: Multicenter phase II study of oral capecitabine plus irinotecan as first-line chemotherapy in advanced colorectal cancer: A Korean Cancer Study Group trial. Acta Oncol 44:230-235, 2005[Medline] 16. Jordan K, Kellner O, Kegel T, et al: Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers. Clin Colorectal Cancer 4:46-50, 2004[Medline] 17. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004 18. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 19. Comella P: Randomized trial comparing the addition of oxaliplatin or irinotecan to high-dose leucovorin and 5-fluorouracil intravenous bolus every two weeks in metastatic colorectal carcinoma: Southern Italy Cooperative Oncology Group 0103. Clin Colorectal Cancer 3:186-189, 2003[Medline] 20. Colucci G, Gebbia V, Paoletti G, et al: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: A multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23:4866-4875, 2005 21. Fuchs CS, Marshall J, Mitchell E, et al: A randomized trial of first-line irinotecan/fluoropyrimidine combinations with or without celecoxib in metastatic colorectal cancer (BICC-C). J Clin Oncol 24:147s, 2006 (suppl; abstr 3506) 22. Hasegawa S, Seike K, Koda K, et al: Thymidine phosphorylase expression and efficacy of adjuvant doxifluridine in advanced colorectal cancer patients. Oncol Rep 13:621-626, 2005[Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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