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Journal of Clinical Oncology, Vol 23, No 9 (March 20), 2005: pp. 2108 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.178
Thymidylate Synthase Expression in Colorectal Cancer: The Never-Ending StoryMedical Oncology University Campus Bio-Medico, Rome, Italy To the Editor: Popat et al1 report an interesting and comprehensive meta-analysis about the actual clinical problem regarding the role of thymidylate synthase (TS) as a prognostic factor in colorectal cancer (CRC) patients. We read this article with great interest and attention and would like to highlight some points about the methods and results obtained by the authors. First of all, we consider overall survival in metastatic CRC a confounding end point for meta-analysis evaluation. The role of first-line chemotherapy in advanced CRC patients is actually well established, but the impact of further-line chemotherapy is clearly defined as well.2-4 As a consequence of this, overall survival should be considered only a surrogate end point in meta-analysis, aiming to evaluate the prognostic role of a biologic parameter because of the proven prognostic impact of first-line treatment in CRC patients. This consideration is powered by the demonstrated significant role of second-line chemotherapies. For all the above-mentioned reasons, we think that the only parameter that could be considered of interest in these patients is the progression free survival. This is why most of the data presented by the authors in the article regarding overall survival should be carefully interpreted. In addition to this, cumulative number of patients included in the three studies aiming at evaluating the prognostic role of TS on progression-free survival (only 254 patients) is not sufficient to provide conclusive information. Furthermore, one of the three studies performed TS expression analysis on the primary tumor or on lymph-node metastasis, while the remaining two studies focused on metastatic disease. For these reasons, these data cannot lead to any final conclusion about the role of TS as a prognostic factor in metastatic CRC. We would like to also stress some points about the analysis performed in the adjuvant setting. The meta-analysis considered all patients treated for CRC, and this could represent an important bias. Rectal cancer may be treated with radiotherapy or chemoradiation both before and after surgery.5 In Popat’s study, the possible role that radiotherapy could play in the determination of prognosis in rectal patients is not mentioned, and this could lead to misinterpretation of the results. Moreover, there are some findings that TS polymorphisms could represent a predictive factor for response to preoperative fluorouracil-based chemoradiation in rectal cancer. Therefore, this bias could have been amplified. We very much appreciated that in the Discussion section of their article, Popat et al underlined the methodologic problems related to the present meta-analysis. However, the conclusion of the present paper regarding the role of TS expression as a determinant of prognosis in CRC may be overestimated, and this should be carefully evaluated by the readers. In conclusion, we believe that for the time being, there is not yet clear evidence that TS expression assessment may represent a clinical prognostic factor for CRC patients. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Popat S, Matakidou A, Houlston RS: Thymidylate synthase expression and prognosis in colorectal cancer: A systematic review and meta-analysis. J Clin Oncol 22:529-536, 2004 2. Cunningham D, Pyrhonen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998[CrossRef][Medline] 3. Rougier P, Van Custem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998[CrossRef][Medline]
4. 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 5. Minsky BD, Coia L, Haller DG, et al: Radiation therapy for rectosigmoid and rectal cancer: Results of the 1992-1994 Patterns of Care process survey. J Clin Oncol 16:2542-2547, 1998[Abstract]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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