BackgroundIn advanced non-small-cell lung cancer (NSCLC), with the increasing number of active compounds available in salvage settings, survival after progression to first-line chemotherapy seems to have improved. A literature survey was conducted to examine whether survival post-progression (SPP) has improved over the years and to what degree SPP correlates with overall survival (OS).Methods and FindingsMedian progression-free survival (MPFS) time and median survival time (MST) were extracted in phase III trials of first-line chemotherapy for advanced NSCLC. SPP was pragmatically defined as the time interval of MST minus MPFS. The relationship between MPFS and MST was modeled in a linear function. We used the coefficient of determination (r 2) to assess the correlation between them. Seventy trials with 145 chemotherapy arms were identified. Overall, median SPP was 4.7 months, and a steady improvement in SPP was observed over the 20 years (9.414-day increase per year; p<0.001) in parallel to the increase in MST (11.253-day increase per year; p<0.001); MPFS improved little (1.863-day increase per year). Overall, a stronger association was observed between MST and SPP (r 2 = 0.8917) than MST and MPFS time (r 2 = 0.2563), suggesting SPP and MPFS could account for 89% and 25% of the variation in MST, respectively. The association between MST and SPP became closer over the years (r 2 = 0.4428, 0.7242, and 0.9081 in 1988–1994, 1995–2001, and 2002–2007, respectively).ConclusionsSPP has become more closely associated with OS, potentially because of intensive post-study treatments. Even in advanced NSCLC, a PFS advantage is unlikely to be associated with an OS advantage any longer due to this increasing impact of SPP on OS, and that the prolongation of SPP might limit the original role of OS for assessing true efficacy derived from early-line chemotherapy in future clinical trials.

We investigated the relationships between genetic factors and clinical outcome in Japanese non-small-cell lung cancer (NSCLC) patients treated with gefitinib. Ninety-eight NSCLC patients who had been treated with gefitinib, were screened for mutations in epidermal growth factor receptor (EGFR) exons 18-21, KRAS exon2, and polymorphisms including the CA simple sequence repeat in intron1 (CA-SSR1) and single nucleotide polymorphisms in the promoter region (2216G/T and 2191C/A), using a PCRbased assay and direct sequencing. The EGFR copy number status was also evaluated using a fluorescence in situ hybridization assay. EGFR and KRAS mutations were found in 38 (38.8%) and 8 (8.2%) of the 98 patients, respectively. A high EGFR copy number status was identified in 31 (41.3%) of the 75 assessable patients. Drug-sensitive EGFR mutations limited to exon19 deletions and L858R were independent predictive factors of a stronger sensitivity to gefitinib (p 5 0.0002), the overall survival (OS) (p 5 0.0036), and prolonged progression-free survival (PFS) (p < 0.0001). The EGFR copy number status was not related to a sensitivity to gefitinib and prolonged OS and PFS. Regarding polymorphisms, patients with a short CA-SSR1 showed a prolonged OS as compared with those with a long length in patients with a drug-sensitive EGFR mutation, although this difference was not significant (p 5 0.13). Thus, drug-sensitive EGFR mutations predict a favorable clinical outcome and a high EGFR copy number may not be related to clinical benefits in gefitinib-treated Japanese patients with NSCLC. Our findings also suggest that the CA-SSR1 length may influence the clinical outcome in patients with a drug-sensitive EGFR mutation. ' 2006 Wiley-Liss, Inc.

BackgroundFew studies have formally assessed whether treatment outcomes have improved substantially over the years for patients with extensive disease small-cell lung cancer (ED-SCLC) enrolled in phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials.Methods and FindingsWe searched for trials that were reported between January 1981 and August 2008. Phase III randomized controlled trials were eligible if they compared first-line, systemic chemotherapy for ED-SCLC. Data were evaluated by using a linear regression analysis. Results: In total, 52 trials were identified that had been initiated between 1980 and 2006; these studies involved 10,262 patients with 110 chemotherapy arms. The number of randomized patients and the proportion of patients with good performance status (PS) increased over time. Cisplatin-based regimens, especially cisplatin and etoposide (PE) regimen, have increasingly been studied, whereas cyclophosphamide, doxorubicin, and vincristine–based regimens have been less investigated. Multiple regression analysis showed no significant improvement in survival over the years. Additionally, the use of a PE regimen did not affect survival, whereas the proportion of patients with good PS and the trial design of assigning prophylactic cranial irradiation were significantly associated with favorable outcome.Conclusions and SignificanceThe survival of patients with ED-SCLC enrolled in phase III trials did not improve significantly over the years, suggesting the need for further development of novel targets, newer agents, and comprehensive patient care.

The excision repair cross-complementation group 1 (ERCC1) and BRCA1 have been identified as predictors of clinical outcomes among patients with non-small-cell lung cancer (NSCLC) treated with cisplatin-based chemotherapy. In this study, we immunohistochemically examined the ERCC1 and BRCA1 protein expression levels in 35 patients with metastatic mediastinal lymph nodes obtained prior to treatment as retrospective study. These patients had been enrolled in our studies on neoadjuvant chemotherapy with cisplatin and irinotecan (15 patients) or chemoradiotherapy with cisplatin and docetaxel plus concurrent thoracic radiation (20 patients). The relations between the ERCC1 or BRCA1 protein expression and the clinical outcomes of the patients were then examined. The rates of radiological response and pathological effectiveness were significantly higher among patients with ERCC1-negative tumors, compared with those with positive tumors in the neoadjuvant chemotherapy group (radiological response rates; 100% vs. 42.8%, P=0.013; pathological effectiveness; 100% vs. 47.1%, P=0.038), but no associations were observed in the neoadjuvant chemoradiotherapy group. Regarding survival, no significant differences in overall survival or disease-free survival were observed between patients with ERCC1-negative and positive tumors in both the neoadjuvant chemotherapy and chemoradiotherapy groups. In summary, we showed that a ERCC1-negative protein status was significantly related to tumor responsiveness to neoadjuvant chemotherapy with cisplatin and irinotecan, but such a status was not a clear prognostic predictor to cisplatin-based neoadjuvant therapy in NSCLC patients. Further study is needed to clarify the value of molecular predictors for customizing therapy for patients with NSCLC.

No abstract