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Despite advances in palliative chemotherapy, patients with advanced non-small cell lung cancer (NSCLC) eventually experience disease progression during or after completion of first-line chemotherapy, which requires salvage therapy. Second- or third-line therapy in selected patients is recommended in the current guidelines. Although fourth-line therapy is often performed in daily practice in some countries, there are few reports about the clinical benefits of fourth-line therapy.A retrospective review was conducted on 383 patients who underwent at least first-line palliative chemotherapy for advanced NSCLC (stage IV or stage IIIB/recurrent disease unsuitable for definitive local therapy). Overall survival (OS) and clinicopathological characteristics were analyzed according to the lines of chemotherapy as well as for all study patients.The median OS for all patients after the initiation of first-line therapy was 11 months. The median OS for patients who received fourth- or further-line therapy (77 patients) was longer than that of patients who received third- or lesser-line therapy (27 versus 9 months, p0.0001). In multivariate analysis, fourth- or further-line therapy was independently associated with favorable OS (hazard ratio: 0.44, 95% confidence interval: 0.34-0.57, p0.0001) along with recurrent disease, female, age70 years, and ECOG performance status (PS) 0 or 1. Median OS after the start of fourth-line therapy was 9 months. Good PS (ECOG PS 0, 1) at the initiation of fourth-line therapy (10 versus 2 months, p0.0001) and disease control (10 versus 7 months, p=0.011) after first-line therapy were associated with favorable OS in univariate analysis, while poor PS (ECOG PS ≥2) was an independent prognostic factor for poor outcome (p0.0001).The present study suggests that advanced NSCLC patients with good PS after progression from third-line therapy could be considered as reasonable candidates for fourth-line therapy in clinical practice.

Background Platinum-based concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced unresectable non-small cell lung cancer (NSCLC). The determination of parameters that may predict the result of the treatment has strong clinical implications. Patients and methods Pretreatment tumor biopsy specimens from 39 patients with locally advanced NSCLC (stage IIIA: 5, stage IIIB: 34) were analyzed for p53, Bcl-2, Bax and ERCC1 expression by immunohistochemistry. All patients were treated with cisplatin-based CCRT. Twenty-four patients received induction chemotherapy followed by CCRT (60 Gy/30 fractions, 6 mg/m 2 of cisplatin daily). The most commonly administered induction chemotherapy regimen was VIP (etoposide, ifosfamide, cisplatin; 20 patients). Fifteen patients received the same CCRT without induction chemotherapy. Results High expression of p53, Bcl-2, Bax and ERCC1 was observed in 15 (38%), 19 (49%), 17 (44%) and 12 (31%) patients, respectively. High expression of Bcl-2 was significantly associated with longer survival duration (20 months vs. 9 months, P = 0.008) and better response to the treatment (74% vs. 30%, P = 0.01). In multivariate analysis, Bcl-2 expression was the only significant independent prognostic factor of overall survival ( P = 0.007) among the pretreatment patients characteristics. Conclusions High expression of Bcl-2 may be a useful prognostic factor in locally advanced NSCLC patients treated with cisplatin-based CCRT.

Backgroud Alterations in apoptosis and DNA damage repair related proteins are associated with resistance to chemotherapy, which is the most important cause of treatment failure in advanced non-small cell lung cancer (NSCLC). Patients and methods Pretreatment tumor biopsy specimens from 50 patients with NSCLC including stage IIIB with malignant pleural effusion or stage IV or recurrent disease were analyzed for p53, Bcl-2, Bax, and ERCC1 expression by immunohistochemistry. All patients were treated with platinum-based third-generation doublet chemotherapy, in which gemcitabine and cisplatin was the most commonly administered regimen (17 patients). Results High expression of p53, Bcl-2, Bax, and ERCC1 was observed in 24 (48%), 8 (16%), 32 (63%), and 28 (55%) patients, respectively. In univariate analysis, high expression of ERCC1 demonstrated a trend of association with poor overall survival (OS) (median, 8 months vs. 11 months; P =0.055). High expression of p53, Bcl-2, Bax was not correlated with patient outcome. High expression of ERCC1 was an independent prognostic factor for poor OS ( P =0.002) along with poor performance status ( P =0.028) and lack of disease control ( P =0.001) in multivariate analysis. Conclusions High expression of ERCC1 may be a useful prognostic factor for poor outcome in advanced NSCLC patients treated with platinum and third-generation doublet chemotherapy.

Summary Background Alterations in apoptosis-related proteins and DNA damage repair proteins are associated with resistance to chemotherapy or radiotherapy, which is the most important cause of treatment failure in small cell lung cancer (SCLC). Patients and methods Pretreatment tumor biopsy specimens from 77 patients with SCLC (limited stage: 40, extensive stage: 37) were analyzed for p53, bcl-2, bax and ERCC1 expression by immunohistochemistry. All patients were treated with platinum-based doublets. The most commonly used regimen was etoposide/cisplatin (50 patients). In patients with limited stage SCLC, thoracic irradiation was performed either concurrently with chemotherapy or sequentially. Results High expression of p53, bcl-2, bax and ERCC1 was observed in 40 (52%), 72 (94%), 38 (49%) and 13 (17%) patients, respectively. High expression of ERCC1 was associated with poor OS (1-year, 23% vs. 53%; p = 0.026). When grouped according to stage, a significant correlation between high expression of ERCC1 and poor outcome was observed only in patients with limited stage SCLC (p = 0.017). High expression of p53, bcl-2 and bax was not correlated with patient outcome. Multivariate analysis showed that extensive stage (p = 0.006) and male gender (p = 0.009) were independent predictors of poor OS, while high expression of ERCC1 failed to reach statistical significance despite a trend (p = 0.057). In limited stage patients, high expression of ERCC1 was an independent prognostic factor for poor OS (p = 0.046), along with male gender (p = 0.033). Conclusions High expression of ERCC1 protein may be a useful predictor of poor outcome in SCLC patients treated with chemotherapy with or without radiotherapy, especially in limited stage SCLC.