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Purpose: New therapeutic approaches are being developed based on findings that several genetic abnormalities underlying non-small-cell lung cancer (NSCLC) can influence chemosensitivity. The identification of molecular markers, useful for therapeutic decisions in lung cancer, is thus crucial for disease management. The present study evaluated single-nucleotide polymorphisms (SNPs) in XRCC3, XPD and Aurora kinase A in NSCLC patients in order to assess whether these biomarkers were able to predict the outcomes of the patients. Methods: The Spanish Lung Cancer Group prospectively assessed this clinical study. Eligible patients had histologically confirmed stage IV or IIIB (with malignant pleural effusion) NSCLC, which had not previously been treated with chemotherapy, and a World Health Organization performance status (PS) of 0-1. Patients received intravenous doses of vinorelbine 25 mg/m on days 1 and 8, and cisplatin 75 mg/m on day 1, every 21 days for a maximum of 6 cycles. Venous blood was collected from each, and genomic DNA was isolated. SNPs in XRCC3 T241M, XPD K751Q, XPD D312N, AURORA 91, AURORA 169 were assessed. Results: The study included 180 patients. Median age was 62 years; 87 % were male; 34 % had PS 0; and 83 % had stage IV disease. The median number of cycles was 4. Time to progression was 5.1 months (95 % CI, 4.2-5.9). Overall median survival was 8.6 months (95 % CI, 7.1-10.1). There was no significant association between SNPs in XRCC3 T241M, XPD K751Q, XPD D312N, AURORA 91, AURORA 169 in outcome or toxicity. Conclusions: Our findings indicate that SNPs in XRCC3, XPD or Aurora kinase A cannot predict outcomes in advanced NSCLC patients treated with platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: New therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying NSCLC could influence chemosensitivity. In this study, we assessed whether the presence of polymorphisms in ERCC1, XPD, RRM1 and MDR1 genes can affect the efficacy and the tolerability of cisplatin and vinorelbine in NSCLC patients. Material and methods: Eligible patients had histological confirmed stage IV or IIIB (with malignant pleural effusion) non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy; World Health Organization performance status (PS) 0–1. Patients received intravenous doses of vinorelbine 25mg/m2 on day 1 and 8 and cisplatin 75mg/m2 on day 1, every 21 days, for a maximum of eight cycles. Results: 94 patients were included. Median age was 61 years; 84% were male; WHO performance status (PS) was 0 in 24%; and 88% of patients had stage IV disease. The median number of cycles was 6. Overall median survival was 10.92 months (95% CI 9.0–12.9). Overall median time to progression was 5.89 months (95% CI 5.2–6.6). Results of the multivariate analysis for time to progression showed that ECOG 0 (hazard ratio [HR] ECOG 1 vs. ECOG 0, 1.74; p =0.036), MDR13435CC (HR CT vs. CC, 2.01; p =0.017; HR TT vs. CC, 1.54; p =0.22), and decreasing age (HR of age, 0.97; p =0.016) were the most powerful prognostic factors significantly related to lower risk of progression. Whereas ECOG 0 was the only prognostic factor for survival (HR ECOG 1 vs. ECOG 0, 3.02; p =0.001). There was no significant association between any of the SNPs analysed and the occurrence of vinorelbine and cisplatin-related toxicity. Conclusion: In our results, the most important prognostic factors associated with lower risk of progression were MDR1 3435 CC genotype, PS 0 and younger age. [ABSTRACT FROM AUTHOR]

Summary: Background:: Among the cytotoxic agents commonly combined with cisplatin in the treatment of advanced NSCLC, vinorelbine has led to significant outcome improvements. Adding more than four cycles of the combination regimen increase toxicities. The availability of an oral form of vinorelbine appeared as a particularly convenient way to provide a consolidation treatment to patients who have achieved an objective response or stable disease. Patients and methods:: This multi-centre phase II open-label, non-comparative study was designed to evaluate the treatment with four cycles of the combination chemotherapy with oral vinorelbine at the dose of 60mg/m2 on day 1 and day 8 for the first cycle and then 80mg/m2 plus cisplatin 80mg/m2 on day 1 every 3 weeks followed for patients with objective response or stable disease by consolidation therapy with oral vinorelbine at 80mg/m2 weekly on patients with unresectable localised or metastatic non-small-cell lung cancer (NSCLC). The primary endpoint was tumor response. The secondary objectives were progression free-survival, overall survival and toxicity assessment. Visual analogue scales (VAS) filled by the patients were also used to evaluate subjective changes under treatment, reflecting patients’ clinical benefit. Results:: Fifty-six patients enrolled into the study from April 2001 to April 2002 received the combination regimen. Twenty-five patients (43.9%) also received the subsequent consolidation treatment. Partial tumor responses were obtained in 13 patients (26.5%, 95% CI 15.0–41.1) of 49 evaluable patients. Stable disease was observed in 22 (44.9%) of patients. The median duration of response was 6 months (95% CI 4.3–8.2). The median progression free-survival was 4.2 months (95% CI 2.8–6). The median overall survival time was 10 months (95% CI 7.4–14) and the 1 year survival was 42.6%. The main toxicities recorded were haematological. Grade 3 and 4 neutropenia were observed in 16 patients (29.1%). Nausea, vomiting and fatigue were the major non-haematological toxicities reported. Among the symptoms recorded by the patients on VAS scales (appetite, fatigue, pain, cough, dyspnea, haemoptysis), except anorexia, all symptoms were improved during the combination therapy and in the consolidation phase. Conclusion:: This study confirms that the efficacy of the cisplatin/oral vinorelbine combination in NSCLC is comparable to cisplatin/I.V. vinorelbine. This study also suggests that consolidation therapy with vinorelbine alone may probably prolong the efficacy of the combination regimen. The convenience offered to patients by an oral form of vinorelbine is a definite asset for consolidation therapy. [Copyright &y& Elsevier]