Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

Response rate and toxicity of second-line therapy with docetaxel (75 mg m À2 ) or docetaxel, irinotecan, and lenogastrim (60 mg m À2 , 200 mg m À2 , and 150 mg m À2 day À1 , respectively) were compared in 108 patients with stage IIIb -IV non-small-cell lung cancer. Addition of irinotecan to docetaxel does not improve response rate, and increases gastrointestinal toxicity. Treatment with platinum-based chemotherapy improves survival and quality of life in patients with advanced non-small-cell lung cancer (NSCLC) (Souquet et al, 1993; Non-small Cell Lung Cancer Collaborative Group, 1995; Cullen et al, 1999;Anderson et al, 2000;Ranson et al, 2000;Schiller et al, 2002). Since two trials demonstrated clinically beneficial effects of docetaxel in second-line setting (Fossella et al, 2000;Shepherd et al, 2000), docetaxel 75 mg m À2 is currently considered the standard regimen to which other experimental schedules should be compared.Irinotecan, a semisynthetic water-soluble analogue of camptothecin, has shown activity in NSCLC patients as single agent and in combination with docetaxel (Fukuoka et al, 1992; Adjei et al, 2000;Masuda et al, 2000;Satouchi et al, 2001;Negoro et al, 2003). Moreover, Irinotecan demonstrated activity as single agent in pretreated patients (Sanchez et al, 2003). In our trial the efficacy of the combination of docetaxel and irinotecan compared to single-agent docetaxel as second-line treatment in NSCLC was investigated. Primary end point of this randomised phase II study was tumour response rate. Secondary end points were toxicity, progression-free survival and overall survival. The treatment regimen was based on a phase II study, which demonstrated activity of docetaxel and irinotecan in patients with recurrent ovarian cancer (Mäenpää et al, 1999). In this study, neutropenia was the main toxicity; therefore, we added a granulocyte colony-stimulating factor to our treatment regimen. PATIENTS AND METHODS Patient selectionInclusion criteria for enrolment in the trial were age X18 years, stage IIIb-IV NSCLC, failure or relapse after first-line chemotherapy, at least one measurable or evaluable tumour lesion, performance status p2 according to the Eastern Cooperative Oncology Group scale, life expectancy of X3 months, adequate bone marrow reserve (neutrophils X1.5 Â 10 9 l À1 , platelets X100 Â 10 9 l À1 , haemoglobin X6.2 mmol l À1 ), renal function (serum creatinine p1.25 times the upper normal limit), and liver function (serum bilirubinpthe upper limit of the institutional reference value, serum alanine aminotransferase (ALAT) and serum aspartate aminotransferase (ASAT) p2.5 times the upper normal limit, alkaline phosphatase p5 times the upper normal limit). Prior radiotherapy was allowed as long as the irradiated area did not contain the sole measurable or evaluable lesion. Exclusion criteria were active infection, second primary malignancies (except carcinoma in situ of the cervix, adequately treated basal cell carcinoma of the skin, and other cancer curatively treated without recurrence for a...

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8082 Background: Prognostic factors for newly diagnosed aNSCLC have been extensively studied, but less information is available on factors associated with outcome of 2nd-line treatment. Better knowledge of prognostic factors could be helpful to better select patients for further chemotherapy after failure of 1st-line treatment. Methods: The analysis is based on individual patient data collected for 2 meta-analyses on 2nd-line treatment of aNSCLC, one comparing weekly vs every 3 week docetaxel (Di Maio, J Clin Oncol 2007; 25:1377), and one comparing single-agent vs doublet chemotherapy (Di Maio, J Clin Oncol in press). Primary endpoint was overall survival (OS). All analyses were stratified by trial. Results: Out of 11 trials, 2 trials were excluded due to missing information on baseline characteristics considered in multivariate analysis. Of the other 9 trials (1239 pts), 1197 pts (97%) had complete information: 78%/22% males / females, 83%/17% younger / older than 70, 28%/59%/13% Performance Status (PS) 0 / 1 / 2, 18%/82% stage IIIB / IV, 32%/47%/21% squamous / adenocarcinoma / other histology. 84% were pretreated with platin and 44% had obtained objective response (OR) to 1st line treatment. With 956 deaths, median OS was 7.4 months. At multivariate analysis, prognosis was significantly influenced by gender (worse in males vs females, Hazard Ratio [HR] 1.23 [95%CI 1.04–1.45], p=0.01), by PS (worse in PS1 vs PS0, HR 1.36 [1.16–1.59], p=0.0001 and in PS2 vs PS0, HR 3.01 [2.41–3.76], p<0.00001), by tumor histology (better in adenocarcinoma vs squamous, HR 0.85 [0.73–0.99], p=0.04 and worse in other histology vs squamous, HR 1.27 [1.05–1.52], p=0.01), by stage (worse in stage IV vs IIIB, HR 1.28 [1.07–1.53], p=0.007), by type of previous treatment (worse for pts pretreated with platin vs pts not pretreated with platin, HR 1.49 [1.14–1.93], p=0.003), and worse for pts not obtaining OR vs pts obtaining OR during 1st line (HR 1.25 [1.10–1.44], p=0.001). Conclusions: In addition to patient-related (gender, PS) or tumor-related factors (histology, stage), prognosis of pts eligible for 2nd line treatment of aNSCLC is significantly conditioned by previous use of platin and response to 1st line treatment. No significant financial relationships to disclose.