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Remarks on adjuvant chemotherapy with Tegafur-Uracil in Non-Small-Cell Lung Cancer
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Alfredo Cesario, Thoracic Surgeon Division of General Thoracic Surgery, Catholic University, Rome, Italy, Pierluigi Granone, Lorenzo Dominioni and Patrizia Russo
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alfcesario{at}rm.unicatt.it Alfredo Cesario, et al.
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Remarks on adjuvant chemotherapy with Tegafur-Uracil in Non-Small- Cell Lung Cancer Alfredo Cesario1, 2, Pierluigi Granone1, Lorenzo Dominioni3 and Patrizia Russo4 1 Division of General Thoracic Surgery, Catholic University, Rome, Italy 2 Clinical Respiratory Pathology Translational Laboratory, IRCCS San Raffaele, Rome, Italy 3 Center of Thoracic Surgery, Insubria University, Varese, Italy 4 Translational Research ¡§B¡¨ Department of Integrated Medical Oncology, National Cancer Institute, Genoa, Italy Corresponding Author Patrizia Russo, PhD 4Translational Research ¡§B¡¨ Department of Integrated Medical Oncology, National Cancer Institute. Largo Rosanna Benzi, 10 ¡V 16132 Genoa, Italy E-mail: patrizia.russo@istge.it Telephone: +390105600212 We read with interest the review by Visbal et al [1] recommending adjuvant platinum-based combination chemotherapy for patients after resection of early-stage NSCLC. In this review Visbal et al reported studies from Japan of adjuvant therapy with a combination of platinum and Tegafur-Uracil (UFT). Accordingly, Hamada and colleagues recently published [2], on the basis of a meta-analysis procedure, that adjuvant chemotherapy with UFT in pathological stage I Non Small Cell Lung Cancer (NSCLC) is beneficial, thus de facto addressing the dishomogeneity issue; indeed some trials had shown positive results (references no. 10, 11 article in [2]) and others negative ones (references no. 5, 12-14 article in [2]).Noticeably, Japanese population based studies report positive results whilst those one Caucasian report negative outcomes.We would like to briefly comment the evidences outlined in [1 and 2], focusing on the implications that genetic polymorphism explain observed inter-individual pharmacokinetic variability [3] on UFT mechanisms of transformation into its active metabolite, 5 fluorouracil (5-FU) based on the Thymidylate- Synthtase (TS) activity. In the TS encoding gene (TYMS), to date, three polymorphisms have been described.A first single nucleotide polymorphism (SNP) within the 5'-untranslated region of the TS gene, consisting of tandem repeats of 28 bp, has been implicated in modulating TS mRNA expression and TS mRNA translational efficiency [4]. Although there have been reports of four, five, and nine repeats within certain African and Asian populations [4], the vast majority of individual human TS alleles harbour either a double repeat (2R, TSER*2: *2 alleles containing TS enhancer region) or a triple repeat (3R, TSER*3) for this SNP, creating genotypes of 2R/2R, 2R/3R, and 3R/3R. Whereas TSER genotype and allele frequency is nearly similar in Caucasian (UK) and Southwest Asian (India, Pakistan, Nepal and Sri Lanka) subjects, TSER is different in East Asian (China and Japan) and Caucasian subjects with Caucasians (TSER*3/TSER*3 = 28%) and Southwest Asians TTSER*3/TSER*3 = 40%) significantly different from East Asian subjects (TSER*3/TSER*3 = 67%) [5].Small studies in cancer patients treated with 5FU have shown a correlation between TSERƒx3 and higher free TS protein levels [6] TSERƒx3 and reduced downstaging in rectal cancer [7] and TSERƒx3 and a lower response rate to 5FU treatment [8].Large-scale patient studies are now underway to define the role of the TSER SNP as related to outcome after 5-FU chemotherapy. Patients who are more likely to respond to chemotherapy, that is, those with tumours that are homozygous for the double-repeat variant, are more likely to suffer increased toxicity from therapy. This was supported in a study by Elsaleh and co-workers [9]. They evaluated patients with colorectal carcinoma who received 5-FU-based chemotherapy in an adjuvant setting and found that both homozygous and heterozygous variants of double-tandem repeat polymorphisms are associated with a survival benefit. These patients benefit from chemotherapy and have a longer survival (2R/2R > 2R/3R). On the other hand patients with the 3R/3R genotype do not benefit from chemotherapy [9].Furthermore Kawakami and Watanabe [10] identified an additional second, gender related, SNP within the second repeat of the TSERƒx3 allele and Ulrich [11] described a further third SNP in the TYMS gene. Both are differently expressed among ethnical groups, Caucasians and Singapore Chinese being on the opposite sides of the range (high for the former and low for the latter).Based on these evidences, the clinical interpretation of the interesting results reported in [1 and 2] is somewhat biased by the fact that the stratification for TYMS related SNP inter-patient variability appears to be a critical point:a) To stratify the meta-analysis records for the reported SNPs to better understand the variability of results inside a homogeneous population (East Asians only) with attention to sub-stratification for gender;b) To plan UFT and 5-FU based regimens in any setting of treatment strategy in populations other than East Asian. References 1. Visbal AL, Leighl NB, Feld R, et al. Adjuvant Chemotherapy for Early- Stage Non-small Cell Lung Cancer. Chest. 2005; 128:2933-2943 2. Hamada C, Tanaka F, Ohta M, et al. Meta-analysis of post-operative adjuvant chemotherapy with Tegafur-Uracil in Non Small Cell Lung Cancer. J Clin Oncol 2005; 23:4999-5006 3. Undevia SD, Gomez-Abuin G, Rataian MJ. Pharmacokynetic variability of anticancer agents. Nature Reviews Cancer 2005; 5:447-458 4. Nagasubramanian R, Innocenti F, Ratain MJ. Pharmacogenetics in cancer treatment. Annu Rev Med 2003; 54:437-452 5. Marsh S, McLeod HL. Thymidylate synthase pharmacogenetics in colorectal cancer. Clin Colorectal Cancer. 2001; 1:175-178; discussion 179-181 6. Kawakami K, Omura K, Kanehira E, et al. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 1999; 19:3249-3252 7. Villafranca E, Okruzhnov Y, Dominguez MA, et al. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol 2001; 19:1779-17786 8. Marsh S, McLeod HL. Thymidylate synthase pharmacogenetics in colorectal cancer. Clin Colorectal Cancer 2001; 1:175-1781 9. Elsaleh H, Iacopetta B. Microsatellite instability is a predictive marker for survival benefit from adjuvant chemotherapy in a population- based series of stage III colorectal carcinoma. Clin Colorectal Cancer1 2001; 2:104-109 10. Kawakami K, Watanabe G. Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res 2003; 63:6004-6007 11. Ulrich CM, Bigler J, Velicer CM, et al. Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 2000; 9:1381- 1385 |
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