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Background: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor., Patients and Methods: Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS)., Results: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T., Conclusion: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm., Competing Interests: Disclosure GVS received honoraria from AstraZeneca, Eli Lilly, MSD, Pfizer, Roche, Johnson & Johnson, Takeda; consulting or advisory role for Eli Lilly, BeiGene and AstraZeneca, received institutional research funding from Eli Lilly and MSD and received travel, accommodations from Bayer. SN received honoraria or consulted for Eli Lilly, Amgen, BeiGene, AstraZeneca, Bristol Myers Squibb, Abbvie, Boehringer Ingelheim, MSD, Roche, Pfizer and Takeda. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

This article is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose is to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non -small cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context., Competing Interests: Competing interests: MP: Research support from Boehringer-Ingelheim, GlaxoSmithKline, Merck Sharp and Dohme and Roche and honoraria for lectures, consultation or advisory board participation from Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, AstraZeneca and AbbVie. FW: Research support from Boehringer Ingelheim, Genentech and Roche. Honoraria for lectures, consultation and advisory board participation from UCB, Roche and Boehringer Ingelheim. CM: Honoraria from Lilly and Boehringer Ingelheim. EM: Research support from AstraZeneca, Merck KGaA, advisory board participation from Merck KGaA. CZ: Honoraria from Ariad, Novartis, Boehringer Ingelheim, Roche and AstraZeneca.

Although the effectiveness of screening for lung cancer remains controversial, it is a fact that most lung cancers are diagnosed at an advanced stage outside of lung cancer screening programs. In 2013, the U.S. Preventive Services Task Force revised its lung cancer screening recommendation, now supporting lung cancer screening by low-dose computed tomography in patients at high risk. This is also endorsed by many major medical societies and advocacy group stakeholders, albeit with different eligibility criteria. In Europe, population-based lung cancer screening has so far not been recommended or implemented, as some important issues remain unresolved. Among them is the open question of how enlarging pulmonary nodules detected in lung cancer screening should be managed. This article comprises two parts: a review of the current lung cancer screening approaches and the potential therapeutic options for enlarging pulmonary nodules, followed by a meeting report including consensus statements of an interdisciplinary expert panel that discussed the potential of the different therapeutic options., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Personalized and precision medicine is gaining recognition due to the limitations by standard diagnosis and treatment; many areas of medicine, from cancer to psychiatry, are moving towards tailored and individualized treatment for patients based on their clinical characteristics and genetic signatures as well as novel imaging techniques. Advances in whole genome sequencing have led to identification of genes involved in a variety of diseases. Moreover, biomarkers indicating severity of disease or susceptibility to treatment are increasingly being characterized. The continued identification of new genes and biomarkers specific to disease subtypes and individual patients is essential and inevitable for translation into personalized medicine, in estimating both, disease risk and response to therapy. Taking into consideration the mostly unsolved necessity of tailored therapy in oncology the innovative project MOBIT (molecular biomarkers for individualized therapy) was designed. The aims of the project are: (i) establishing integrative management of precise tumor diagnosis and therapy including systematic biobanking, novel imaging techniques, and advanced molecular analysis by collecting comprehensive tumor tissues, liquid biopsies (whole blood, serum, plasma), and urine specimens (supernatant; sediment) as well as (ii) developing personalized lung cancer diagnostics based on tumor heterogeneity and integrated genomics, transcriptomics, metabolomics, and radiomics PET/MRI analysis. It will consist of 5 work packages. In this paper the rationale of the Polish MOBIT project as well as its design is presented. (iii) The project is to draw interest in and to invite national and international, private and public, preclinical and clinical initiatives to establish individualized and precise procedures for integrating novel targeted therapies and advanced imaging techniques., (Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Background: Pre-planned futility analyses are commonly used in oncology studies. The LUME-Lung 2 study (NCT00806819; 1199.14) was stopped early based on a pre-planned, non-binding futility analysis of investigator-assessed progression-free survival (PFS), although subsequent analysis showed that the primary endpoint of improvement in centrally reviewed PFS was met. Retrospective analyses were conducted to understand the discrepancy between interim futility and final analyses., Materials and Methods: LUME-Lung 2 investigated nintedanib in combination with pemetrexed versus placebo‒pemetrexed for the treatment of patients with advanced or recurrent non-squamous non-small cell lung cancer who had relapsed or failed one prior line of chemotherapy. Pre-planned futility analysis was carried out by the Data Monitoring Committee (DMC) after 50% of the events for the primary PFS analysis (713 events) had occurred; the threshold for futility was a conditional power of < 20%. Conditional/predictive powers and hazard ratios were calculated retrospectively after varying percentages of events had occurred for both investigator- and centrally reviewed PFS., Results: At the time of the pre-planned futility analysis, the conditional power was 10.3% and the predictive power was 18.5%; no safety issues were identified. Retrospective analysis showed that the conditional and predictive powers fluctuated considerably over time for both investigator- and centrally reviewed PFS and that the power only dropped by a notable amount, and below the futility threshold, at the time of the futility analysis., Conclusions: Retrospective investigations suggest that, had the DMC analysis been carried out at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued. The design of futility analyses requires careful consideration and confirming negative futility outcomes by second analysis may be appropriate., Trial Number: NCT00806819., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Over the past few years, there have been considerable advances in the treatments available to patients with metastatic or locally advanced NSCLC, particularly those who have progressed during first-line treatment. Some of the treatment options available to patients are discussed here, with a focus on checkpoint inhibitor immunotherapies (nivolumab and pembrolizumab) and antiangiogenic agents (bevacizumab, ramucirumab, and nintedanib). It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. In this review, we explore the theory and potential of this novel treatment option for patients with advanced NSCLC. We discuss the growing body of evidence that proangiogenic factors can modulate the immune response (both by reducing T-cell infiltration into the tumor microenvironment and through systemic effects on immune-regulatory cell function), and we examine the preclinical evidence for combining these treatments. Potential challenges are also considered, and we review the preliminary evidence of clinical efficacy and safety with this novel combination in a variety of solid tumor types., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Despite the efficacy of a number of first-line treatments, most patients with advanced-stage non-small cell lung cancer (NSCLC) experience disease progression that warrants further treatment. In this review, we examine the role of novel active agents for patients who progress after first-line therapy and who are not candidates for targeted therapies. More therapeutic options are needed for the management of patients with NSCLC after failure of first-line chemotherapy. A PubMed search was performed for articles from January 2012 to May 2015 using the keywords NSCLC, antiangiogenic, immunotherapy, second-line, novel therapies and English language articles only. Relevant papers were reviewed; papers outside that period were considered on a case-by-case basis. A search of oncology congresses was performed to identify relevant abstracts over this period. In recent years, antiangiogenic agents and immune checkpoint inhibitors have been added to our armamentarium to treat patients with advanced NSCLC who have progressed on first-line chemotherapy. These include nintedanib, a triple angiokinase inhibitor; ramucirumab, a vascular endothelial growth factor receptor-2 antibody; and nivolumab, pembrolizumab and atezolizumab, just three of a growing list of antibodies targeting the programmed death receptor-1 (PD-1)/PD ligand-1 pathway. Predictive and prognostic factors in NSCLC treatment will help to optimise treatment with these novel agents. The approval of new treatments for patients with NSCLC after the failure of first-line chemotherapy has increased options after a decade of few advances, and holds promise for future evolution of the management of NSCLC., Competing Interests: Competing interests: FC has received advisory board and/or lecture fees from Boehringer Ingelheim, Roche, AstraZeneca, Pfizer, Novartis, Bristol-Myers Squibb and Clovis Oncology. LC has received honoraria from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb and AstraZeneca. RD has received advisory board and/or lecture fees from Boehringer Ingelheim, Roche, AstraZeneca, Pfizer, Novartis and Clovis Oncology. DE is a consultant for ARIAD Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Eli Lilly, EMD Serono, Genentech, Golden Biotech, Helsinn Therapeutics and Sandoz. DF has received consultant fees from Eli Lilly and speaker bureau fees from Bristol-Myers Squibb. KK has received advisory board and/or lecture fees from Eli Lilly, Roche, AstraZeneca, Pfizer, Novartis, Clovis Oncology, Bristol-Myers Squibb and Merck Sharpe & Dohme. TLC has received advisory board and/or lecture fees from Boehringer Ingelheim, Sanofi and Synta. NL is a researcher for the University Health Network, which received a research grant from Novartis. CM has received honoraria for expert study advice and travel support from Boehringer Ingelheim. MP has received research grants from Novartis and honoraria from Eli Lilly, Boehringer Ingelheim, Pfizer and Clovis Oncology. LP-A has given scientific advice to Pfizer, Clovis Oncology, Roche, Boehringer Ingelheim, AstraZeneca, Eli Lilly and Bristol-Myers Squibb. MP has received honoraria for advisory boards from Eli Lilly, Roche and Boehringer Ingelheim. RP has received speaker's fees and honoraria for advisory boards from Boehringer Ingelheim, and honoraria for data safety monitoring board membership from Synta Pharmaceuticals, and Merck Sharpe & Dohme. EQ participated in clinical trials involving nivolumab, pembrolizumab, nintedanib, ramucirumab and ganetespib. MR has received compensated consultant fees from Hoffmann-La Roche, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe & Dohme, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim and Samsung, and honoraria for lectures from Hoffmann-La Roche, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe & Dohme, AstraZeneca, Pfizer and Boehringer Ingelheim. ES has received honoraria for participating in advisory boards and lecture fees from Boehringer Ingelheim. EV has received consultant/advisory fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, Clovis Oncology, Eisai, Eli Lilly, GeneCentric, Genentech, Merck, Synta, Transgene and VentiRx. CZ has received honoraria from Hoffmann-La Roche, Eli Lilly, Boehringer Ingelheim and AstraZeneca.

Introduction: To compare dynamic volume perfusion computed tomography (dVPCT) parameters with Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for prediction of therapy response and overall survival (OS) in non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) patients treated with conventional chemotherapy., Methods: A total of 173 lung cancer patients (131 men; 61 ± 10 years) undergoing dVPCT before (T1) and after chemotherapy (T2) and follow-up were prospectively included. dVPCT-derived blood flow, blood volume, mean transit time, and permeability (PERM) were assessed, compared between NSCLC and SCLC and patients' response to therapy was determined according to RECIST 1.1., Results: One hundred of one hundred and seventy-three patients underwent dVPCT at T1 and T2 within a median of 44 (range, 31-108) days. dVPCT values were differing in NSCLC and SCLC, but were not significantly differing between patients with partial response, stable, or progressive disease. Eighty-five patients (NSCLC = 72 and SCLC = 13) with a follow-up for greater than or equal to 6 months were analyzed for OS. Fifty-six of eighty-five patients died during follow-up. Receiver operating characteristic analysis determined T1/T2 with highest predictive values regarding OS for blood flow, blood volume, mean transit time, and permeability (area under the curve: 0.53, 0.61, 0.54, and 0.53, respectively, all p > 0.05). Kaplan-Meier statistics revealed OS of patient groups assigned according to dVPCT T1/T2 cutoff values was not differing for neither dVPCT parameter, whereas RECIST groups significantly differed in OS (p = 0.02). Cox proportional hazards regression determined progressive disease status to independently predict OS (p = 0.004), while none of the dVPCT parameters did so., Conclusions: dVPCT values, differ between NSCLC and SCLC, are not related to RECIST 1.1 classification and do not improve OS prediction in lung cancer patients treated with conventional chemotherapy.

The availability of antineoplastic monoclonal antibodies, small molecules and newer cytotoxics such as pemetrexed, the EGFR-tyrosine kinase inhibitors erlotinib, gefitinib, afatinib as well as the anti-angiogenic bevacizumab and the ALK-inhibitor crizotinib has recently changes the treatment algorithm of advanced non-small cell lung cancer. Decision making in 2014 is characterized by customizing therapy, by selecting a specific therapeutic regimen based on the histotype and the genotype of the tumour. This refers to first-line induction therapy and maintenance therapy as well, but also to subsequent lines of therapy since anti-neoplastic drugs and regimens used upfront clinically influence the selection of agents/regimes considered for second-/third-line treatment. Consequently, therapy customization through tumour histology and molecular markers has significantly influenced the work of pathologists around the globe and the process of obtaining an extended therapeutically relevant tumour diagnosis. Not only histological sub-typing became standard but molecular information is also considered of increasing importance for treatment selection. Routine molecular testing in certified laboratories must be established, and the diagnostic process should ideally be performed under the guidance of evidence based recommendation. The process of investigating and implementing medical targeting in lung cancer therefore, requires advanced diagnostic techniques and expertise and because of its large dimension is costly and influenced by the limitation of financial and clinical resources., (Copyright © 2014. Published by Elsevier Urban & Partner Sp. z o.o.)

Background: Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: An FORTIS-M trial was an international, multicenter, randomized, double-blind comparison of talactoferrin (1.5 g p.o. BID) versus placebo BID, in patients with stage IIIB/IV NSCLC whose disease had failed two or more prior regimens. Treatment was administered for a maximum of five 14-week cycles. The primary efficacy end point was overall survival (OS); secondary end points included 6- and 12-month survival, progression-free survival (PFS), and disease control rate (DCR)., Results: Seven hundred and forty-two patients were randomly assigned (2:1) to talactoferrin (497) or placebo (245). The median OS in the intent-to-treat (ITT) population was 7.66 months in the placebo arm and 7.49 months in the talactoferrin arm [hazard ratio (HR), 1.04; 95% CI, 0.873-1.24; P = 0.6602]. The 6-month survival rates were 59.9% (95% CI, 53.4% to 65.8%) and 55.7% (95% CI, 51.1% to 59.9%), respectively. The 12-month survival rates were 32.2% (95% CI, 26.3% to 38.2%) and 30.9% (95% CI, 26.8% to 35%), respectively. The median PFS rates were 1.64 months and 1.68 months, respectively (HR, 0.99; 95% CI, 0.835-1.16; P = 0.8073). The DCRs were 38.4 and 37.6%, respectively [stratified odds ratio (OR), 0.96; 95% CI, 0.698-1.33; P = 0.8336]. The safety profiles were comparable between arms., Conclusions: There was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens.

Supported by evidence from the LACE (Lung Adjuvant Cisplatin Evaluation) metaanalysis, cisplatin-based adjuvant chemotherapy is now recommended as the standard of care for patients with surgically resected early-stage non-small-cell lung cancer (NSCLC) per American Society of Clinical Oncology and European Society for Medical Oncology clinical practice guidelines. These standard regimens, which principally include cisplatin-etoposide and cisplatin-vinorelbine, are associated with long- and short-term toxicities. Hence, cisplatin-based regimens with an improved therapeutic index and optimal safety and tolerability profile are still needed. Pemetrexed, an antifolate, is currently indicated for first-line, maintenance, and second-line therapy for advanced nonsquamous NSCLC. Pemetrexed-platinum, with or without targeted agents, has proven to be efficacious with an acceptable toxicity profile when given in the first-line metastatic setting. Therefore, it is reasonable that pemetrexed be investigated in the adjuvant setting. This review collates data from January 2000 through August 2012 on the use of pemetrexed-platinum regimens in the adjuvant setting either alone or in combination with targeted agents. To date, more than 1000 patients with early stage NSCLC have been enrolled in adjuvant therapy studies evaluating various pemetrexed-containing treatment regimens, and additional patients are being enrolled in ongoing studies. Current evidence appears to favor the combination with cisplatin over that with carboplatin. We await more robust safety and efficacy data from these ongoing adjuvant trials to define with clarity the role of pemetrexed-containing regimens in this setting., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We present the treatment rationale and study design of a multicenter, open-label, randomized, 2-arm, phase IIb study. Patients with stage IV or recurrent stage I to III non-small-cell lung cancer (NSCLC) whose disease does not progress after 4 cycles of first-line platinum-based chemotherapy will be randomized in a 1:1 ratio to 1 of 2 study arms. Patients will receive the cancer vaccine Vx-001 + Montanide ISA51 VG (Seppic, Paris, France) adjuvant subcutaneously, at a dose of 2 mg, or placebo + Montanide ISA51 VG adjuvant subcutaneously. The vaccination protocol comprises 2 injections with the TYR-Vx001 or placebo (1 at day 0 and another at week 3) and 4 injections with the ARG-Vx001 or placebo, at weeks 6, 9, 12, and 15. After the treatment assessment at week 18, patients will receive the ARG-Vx001 or placebo every 12 weeks starting from week 27 until disease progression, unacceptable toxicity, withdrawal of informed consent, or death. The primary end point of this study is the survival rate at 12 months. Secondary end points include time-to-event comparison of overall survival and comparison of time to treatment failure. Exploratory objectives include comparison of disease control rate after the end of subsequent second-line treatments, comparisons of vaccine immune responses, comparison of survival rate at 12 months in patients with vaccine-induced immune response detected after the second and sixth injections, identification of biomarkers on lymphocytes and on tumors, and comparison of safety and tolerability., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: To determine the prevalence and clinicopathological features of ROS1 fusions in Chinese patients with non-small-cell lung cancer (NSCLC)., Methods: Formalin-fixed and paraffin-embedded (FFPE) tissue sections from 392 patients with NSCLC were screened for ROS1 fusions by multiplex RT-PCR and all ROS1 fusions were validated by direct sequencing. The relationship between ROS1 fusions and clinicopathological features and the prognostic effect of the ROS1 fusion status on survival were analyzed., Results: In this study, 8 of 392 (2.0%) evaluable samples were found to harbor ROS1 fusions. Of the ROS1-positive patients, seven presented with adenocarcinoma, and one with adenosquamous carcinoma. The ratio of female to male and never smoker to smokers in a ROS1 fusion-positive group was 5:3. There was no statistically significant difference in age, sex, smoking history, histological type and pathological stage between ROS1 fusion-positive and ROS1 fusion-negative patients. ROS1 fusion-negative patients had a significantly longer survival when compared with ROS1 fusion-positive patients (P = 0.041). Lower pathological stage, younger age and ROS1 fusion-negative status were significantly associated with better prognosis on multivariate analysis., Conclusions: ROS1 fusions occurred in ∼2.0% of Chinese patients with NSCLC and had no specific clinicopathological feature. ROS1 fusion-negative patients may have a better survival than ROS1 fusion-positive patients.

Introduction: Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma., Methods: Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan-Meier estimates and proportional hazards models, was performed for overall survival among patients with non-small-cell lung cancer (NSCLC) and SCLC., Results: Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA., Conclusion: In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.

Background: Bone metastases are a significant and undertreated clinical problem in patients with advanced lung cancer., Design: We reviewed the incidence of bone metastases and skeletal-related events (SREs) in patients with lung cancer and examined the burden on patients' lives and on health care systems. Available therapies to improve survival and lessen the impact of SREs on quality of life (QoL) were also investigated., Results: Bone metastases are common in lung cancer; however, owing to short survival times, data on the incidences of SREs are limited. As with other cancers, the costs associated with treating SREs in lung cancer are substantial. Bisphosphonates reduce the frequency of SREs and improve measures of pain and QoL in patients with lung cancer; however, nephrotoxicity is a common complication of therapy. Denosumab, a recently approved bone-targeted therapy, is superior to zoledronic acid in increasing the time to first on-study SRE in patients with solid tumours, including lung cancer. Additional roles of bone-targeted therapies beyond the prevention of SREs are under investigation., Conclusions: With increasing awareness of the consequences of SREs, bone-targeted therapies may play a greater role in the management of patients with lung cancer, with the aim of delaying disease progression and preserving QoL.

Background: Bone metastases are common in patients with advanced non-small-cell lung cancer (NSCLC) and can have devastating consequences. Preventing or delaying bone metastases may improve outcomes., Patients and Methods: This study evaluated whether zoledronic acid (ZOL) delayed disease progression or recurrence in patients with controlled stage IIIA/B NSCLC after first-line therapy. Patients received vitamin D and calcium supplementation and were randomized to i.v. ZOL (every 3-4 weeks) or no treatment (control). The primary end point was progression-free survival (PFS)., Results: No significant intergroup differences were observed in PFS or overall survival (OS). Median PFS was 9.0 months with ZOL versus 11.3 months for control. Fifteen ZOL-treated (6.6%) and 19 control patients (9.0%) developed bone metastases. Estimated 1-year OS was 81.8% for each group. ZOL safety profile was consistent with previous clinical data, but with higher discontinuations versus control. Fifteen ZOL-treated (6.6%) and five control patients (2.3%) had renal adverse events. Two cases of osteonecrosis of the jaw were reported., Conclusions: ZOL did not significantly affect PFS or OS in stage IIIA/B NSCLC patients with controlled disease, with a trend toward worsening PFS in the longer-term follow-up. Few patients experienced bone metastases, possibly limiting the potential ZOL impact on disease course.

Introduction: Tasisulam sodium (hereafter referred to as tasisulam) is a novel anticancer compound that induces apoptosis and exhibits antiangiogenesis activity in a broad range of cancer models, including non-small-cell lung cancer (NSCLC)., Methods: Tasisulam was administered as a 2-hour infusion every 21 days as third-line treatment in patients with advanced (stage IIIB/IV) NSCLC., Results: Thirty-two patients received a Cmax target dose of 420 µg/ml. Median time to progression was 3.12 months, median progression-free survival was 2.69 months, and median overall survival was 8.48 months. There were no objective responses; 43.8% of patients achieved stable disease. A high rate of grade-4 hematologic toxicity in the first 30 patients led to exploration of a lower Cmax target dose of 380 µg/ml. The rate of grade-4 hematologic toxicity (thrombocytopenia and/or neutropenia) at the 380-µg/ml dose (n = 20) was 20% versus 34% at the 420-µg/ml dose., Conclusions: Tasisulam has only modest activity as a third-line treatment of patients with unresectable/metastatic NSCLC. The high rate of grade-4 hematologic toxicity observed with this highly albumin- bound compound in this patient population provided challenges for fixed Cmax-based dosing. Alternative dosing methods, including varying the Cmax target dose by predose albumin, are under investigation in other studies.

The current third consensus on the systemic treatment of non-small-cell lung cancer (NSCLC) builds upon and updates similar publications on the subject by the Central European Cooperative Oncology Group (CECOG), which has published such consensus statements in the years 2002 and 2005 (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137). The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree (Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137; Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy for NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated that not only readdresses previous disease-related issues but also expands toward recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages based upon levels of evidence in the light of a rapidly expanding array of individual therapeutic options.

Background: This open-label phase III study assessed the addition of Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 to gemcitabine/cisplatin chemotherapy in patients with non-small-cell lung cancer (NSCLC)., Patients and Methods: Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomized (1:1) to receive six or fewer 3-week cycles of i.v. gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin alone (75 mg/m2 on day 1, control arm) or combined with s.c. PF-3512676 0.2 mg/kg on days 8 and 15 of each chemotherapy cycle and weekly thereafter until progression or unacceptable toxicity (experimental arm). No crossover was planned. The primary end point was overall survival (OS)., Results: A total of 839 patients were randomized. Baseline demographics were well balanced. Median OS (11.0 versus 10.7 months; P=0.98) and median progression-free survival (PFS) (both 5.1 months) were similar between groups. Grade≥3 hematologic adverse events (AEs), injection-site reactions, and influenza-like symptoms were more frequently reported among patients receiving PF-3512676. At the first-interim analysis, the Data Safety Monitoring Committee recommended study discontinuation. Administration of PF-3512676 was halted based on efficacy futility and increased grade≥3 AEs (experimental arm)., Conclusions: Addition of PF-3512676 to gemcitabine/cisplatin chemotherapy did not improve OS or PFS but did increase toxicity.

Introduction: Recently, histology has emerged as a predictive factor for pemetrexed efficacy in non-small cell lung cancer (NSCLC). These analyses evaluate whether the differential efficacy of pemetrexed by NSCLC histology is reproducible and consistent across three registration studies of different lines of therapy (first-line/second-line and maintenance settings)., Methods: The reported studies for patients with advanced NSCLC were pemetrexed versus docetaxel in previously treated patients (N = 571), cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (N = 1725), and maintenance pemetrexed plus best supportive care versus placebo plus best supportive care (N = 663). Cox models of overall survival (OS) and progression-free survival (PFS) were used to test for a significant treatment-by-histology interaction (THI). A significant THI indicates that the efficacy benefit for pemetrexed relative to the control arm is greater in patients with nonsquamous histology than in those with squamous histology. Subsequent Cox models were used to estimate hazard ratios for OS and PFS according to histology., Results: Histology was well balanced between treatment arms in each study. Across all three studies, no clinically relevant differences were observed for the safety profile of pemetrexed among histologic groups. THIs were statistically significant in all three studies for OS (p = 0.001, 0.002, and 0.033, respectively) and PFS (p = 0.004, 0.002, and 0.036, respectively)., Conclusions: These analyses demonstrate a statistically significant interaction between treatment effect and NSCLC histology, indicating superior efficacy of pemetrexed in nonsquamous patients compared with other standard treatment options. Thus, histology is consistently predictive of the improved efficacy of pemetrexed in patients with nonsquamous NSCLC.

Introduction: The placebo-controlled, phase III AVAiL trial evaluated bevacizumab plus cisplatin and gemcitabine as first-line therapy in patients with advanced, nonsquamous non-small cell lung cancer. A retrospective subgroup analysis was performed to assess the efficacy and safety of bevacizumab-based therapy in elderly patients aged 65 years or older in AVAiL., Methods: Patients received cisplatin 80 mg/m and gemcitabine 1250 mg/m for up to six cycles plus 7.5 mg/kg bevacizumab, 15 mg/kg bevacizumab, or placebo every 3 weeks until disease progression. The primary end point was progression-free survival. Secondary endpoints included objective response rate, overall survival, and safety., Results: Data were evaluated for 304 patients aged 65 years or older (median age 68 years). Most of the patients were Caucasian (87%) and the majority had adenocarcinoma (83%). In the combined bevacizumab arms, 143 patients (79%) completed ≥4 cycles of chemotherapy. Patients who received bevacizumab derived an improvement in progression-free survival compared with placebo (7.5 mg/kg bevacizumab: hazard ratio [HR] = 0.71, p = 0.023; 15 mg/kg bevacizumab: HR = 0.84, p = 0.25). Objective response rates were 40, 29, and 30% in the 7.5 mg/kg bevacizumab, 15 mg/kg bevacizumab, and placebo arms, respectively. Overall survival was similar for each bevacizumab arm versus placebo (7.5 mg/kg bevacizumab: HR = 0.84, p = 0.31; 15 mg/kg bevacizumab: HR = 0.88, p = 0.44). There were no particular safety signals of concern in elderly patients., Conclusions: This analysis of the randomized, phase III AVAiL trial shows that bevacizumab-based therapy improves outcomes for elderly patients with non-small cell lung cancer. Furthermore, bevacizumab-based therapy is well tolerated in elderly patients.

Introduction: Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have recently been characterized in a subset of patients with advanced non-small cell lung cancer (NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The EGFR-TKI gefitinib has been approved in Europe for the treatment of adult patients with locally advanced or metastatic NSCLC with activating mutations of the EGFR TK. Because EGFR mutation testing is not yet well established across Europe, biomarker-directed therapy only slowly emerges for the subset of NSCLC patients most likely to benefit: those with EGFR mutations., Methods: The "EGFR testing in NSCLC: from biology to clinical practice" International Association for the Study of Lung Cancer-European Thoracic Oncology Platform multidisciplinary workshop aimed at facilitating the implementation of EGFR mutation testing. Recommendations for high-quality EGFR mutation testing were formulated based on the opinion of the workshop expert group., Results: Co-operation and communication flow between the various disciplines was considered to be of most importance. Participants agreed that the decision to request EGFR mutation testing should be made by the treating physician, and results should be available within 7 working days. There was agreement on the importance of appropriate sampling techniques and the necessity for the standardization of tumor specimen handling including fixation. Although there was no consensus on which laboratory test should be preferred for clinical decision making, all stressed the importance of standardization and validation of these tests., Conclusion: The recommendations of the workshop will help implement EGFR mutation testing in Europe and, thereby, optimize the use of EGFR-TKIs in clinical practice.

Background: Bevacizumab, the anti-vascular endothelial growth factor agent, provides clinical benefit when combined with platinum-based chemotherapy in first-line advanced non-small-cell lung cancer. We report the final overall survival (OS) analysis from the phase III AVAiL trial., Patients and Methods: Patients (n = 1043) received cisplatin 80 mg/m(2) and gemcitabine 1250 mg/m(2) for up to six cycles plus bevacizumab 7.5 mg/kg (n = 345), bevacizumab 15 mg/kg (n = 351) or placebo (n = 347) every 3 weeks until progression. Primary end point was progression-free survival (PFS); OS was a secondary end point., Results: Significant PFS prolongation with bevacizumab compared with placebo was maintained with longer follow-up {hazard ratio (HR) [95% confidence interval (CI)] 0.75 (0.64-0.87), P = 0.0003 and 0.85 (0.73-1.00), P = 0.0456} for the 7.5 and 15 mg/kg groups, respectively. Median OS was >13 months in all treatment groups; nevertheless, OS was not significantly increased with bevacizumab [HR (95% CI) 0.93 (0.78-1.11), P = 0.420 and 1.03 (0.86-1.23), P = 0.761] for the 7.5 and 15 mg/kg groups, respectively, versus placebo. Most patients ( approximately 62%) received multiple lines of poststudy treatment. Updated safety results are consistent with those previously reported., Conclusions: Final analysis of AVAiL confirms the efficacy of bevacizumab when combined with cisplatin-gemcitabine. The PFS benefit did not translate into a significant OS benefit, possibly due to high use of efficacious second-line therapies.

Background: Baseline patient and disease characteristics are investigated in non-small-cell lung cancer (NSCLC) in an effort to predict response to treatment and optimize patients' outcomes. Histology has recently been identified in multiple NSCLC phase III trials as a predictive factor for survival in patients receiving pemetrexed regimens., Methods: Cox-adjusted models were used to further analyze a randomized phase III study in 1725 chemonaive patients with stage IIIB or IV NSCLC and Eastern Cooperative Oncology Group performance status (PS) of zero or one who received cisplatin plus pemetrexed (CP; C, 75 mg/m(2) and P, 500 mg/m(2)) or cisplatin plus gemcitabine (CG; C, 75 mg/m(2) and G, 1250 mg/m(2)) every 21 days., Results: Histology was confirmed to be predictive of CP efficacy and may also be prognostic. Gender, ethnicity, disease stage, smoking status, and PS were not predictive in either treatment arm but were shown to be prognostic in the nonsquamous population, consistent with the results in the overall NSCLC population., Conclusions: NSCLC histology significantly predicts efficacy outcomes for patients receiving pemetrexed. Several other factors are prognostic for the overall study population as well as a subset of patients with advanced nonsquamous NSCLC.

Introduction: Docetaxel consolidation therapy (DCT) after concurrent cisplatin/docetaxel chemoradiation therapy (CRT) produces high tumor control in non-small-cell lung cancer (NSCLC); toxicity is, however, considerable. We aimed to determine the maximally tolerated dose (MTD) for DCT., Patients and Methods: Patients with inoperable stage IIIB NSCLC received docetaxel 20 mg/m2 and cisplatin 25 mg/m2 on days 1, 8, 15, 22, 29, and 36, with concurrent radiation therapy 5 days per week for a total dose of 66 Gy. Patients achieving stable disease, partial response, or complete response were given DCT on days 71, 92, and 113. DCT was started with 75 mg/m2 and titrated depending on tolerability. The MTD of docetaxel was defined as the dose preceding that at which 3 or more patients experienced dose-limiting toxicity (DLT)., Results: Of 23 patients enrolled (median age, 58.8 years +/- 7.3 years), 19 received complete CRT (4 withdrew because of toxicity). Of the patients receiving complete CRT, 1 patient died and 1 became operable, leaving 17 patients eligible for DCT starting at 75 mg/m2. After the third patient with DLT, dose was reduced to 60 mg/m2. Median survival was 27.6 months +/- 23.1 months. Median TTP was 12.4 months +/- 10.7 months., Conclusion: The MTD of DCT after concurrent cisplatin/docetaxel CRT was determined to be 60 mg/m2, but toxicity was considerable. The benefit-risk ratio of DCT has, however, been questioned by a placebo-controlled phase III trial. Further phase III trials need to consider further stratification factors (pretreatment forced expiratory volume [FEV]1, hemoglobin, performance, and stage) to define a role for DCT in patients with NSCLC.

An international expanded access program was initiated to provide access to treatment with pemetrexed prior registration and reimbursement for malignant mesothelioma (MM). Chemonaïve and pretreated patients with inoperable MM of the pleura or peritoneum were eligible. This report describes the results obtained in German centers. Investigators could choose between three treatments: Pemetrexed 500 mg/m(2) alone (P) or in combination with cisplatin 75 mg/m(2) (PC) or carboplatin AUC 5 (PCb). From November 2002 to June 2004, a total of 567 patients (554 with pleural MM; 41% pretreated) were included. Of 548 evaluable patients with pleural MM, 191 received P, 137 PC and 220 PCb. Patients in the P group were more often pretreated (70%) and had worse performance status compared with the other groups. In the P, PC, and PCb groups overall response rate (ORR) was 16%, 24% and 18%, median time to progression (TTP) was 5.5, 8.2, and 6.9 months, and median overall survival (OS) was 8.7, 11.3 and 9.7 months respectively. Efficacy outcomes were better for chemonaïve than for pretreated patients, and P was less hematotoxic than PC or PCb. Treatment of pleural MM with pemetrexed alone or in combination with platinum was safe and active as first and second-line therapy., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Introduction: Previously published results from a randomized phase III study of pemetrexed plus cisplatin in patients with malignant pleural mesothelioma (MPM) demonstrated a significant survival benefit and higher response rate compared with cisplatin. Although pemetrexed was under review by regulatory agencies, an International Expanded Access Program (EAP) provided more than 3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed in combination with cisplatin or carboplatin in 13 countries. This manuscript reports the safety and efficacy data from the nonrandomized open-label study in chemonaïve patients receiving pemetrexed plus platinum under the EAP., Methods: Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed 500 mg/m in combination with either cisplatin 75 mg/m or carboplatin AUC 5, once every 21 days with standard premedication. Efficacy data were recorded at the end of study participation., Results: A total of 1704 chemonaïve patients received pemetrexed plus cisplatin (n = 843) or pemetrexed plus carboplatin (n = 861) and were evaluated for safety. The efficacy evaluable population consisted of 745 patients in the pemetrexed plus cisplatin group and 752 patients in the pemetrexed plus carboplatin group for whom physician-reported tumor response was available. The pemetrexed plus cisplatin group demonstrated a response rate of 26.3% compared with 21.7% for the pemetrexed plus carboplatin group, with similar 1-year survival rates (63.1% versus 64.0%) and median time to progressive disease (7 months versus 6.9 months). The most common grade 3/4 hematologic toxicity was neutropenia in 23.9% of the pemetrexed plus cisplatin group and 36.1% of the pemetrexed plus carboplatin group., Conclusion: This large EAP confirmed the activity of pemetrexed plus cisplatin and pemetrexed plus carboplatin in chemonaïve patients with MPM, demonstrating clinically similar time to progressive disease and 1-year survival rates.

Metastatic non-small-cell lung cancer remains a fatal disease with a median survival of < 1 year. A critical challenge is to develop predictive markers for customizing platinum-based treatment. The first studies focused on the excision repair cross-complementing 1 (ERCC1) gene in this difficult task. Several layers of evidence indicate that ERCC1 mRNA expression could be a predictive marker for cisplatin alone or in combination with certain drugs such as etoposide, gemcitabine, and 5-fluorouracil but not in combination with antimicrotubule drugs. Several retrospective studies demonstrated an impressive survival advantage for gemcitabine plus cisplatin but not for other combinations in tumors with low ERCC1 expression. A customized phase III ERCC1-based trial met the primary endpoint of improvement in response but not in survival, leading us to hypothesize that docetaxel might not be the most appropriate partner for cisplatin in the presence of low ERCC1 levels or for gemcitabine in the presence of high ERCC1 levels. A phase II study demonstrated the feasibility of combining carboplatin, gemcitabine, docetaxel, and vinorelbine according to ERCC1 and ribonucleotide reductase subunit M1 expression levels. These findings highlight the importance of continual learning, and decision-making strategies for customizing treatment should reflect the limitations of our knowledge., (Copyright © 2008 Elsevier Inc. All rights reserved.)

The essential role of angiogenesis in tumor growth and metastasis is well established. The key mediator of angiogenesis, vascular endothelial growth factor (VEGF), is a rational target for novel therapy. High VEGF levels correlate positively with reduced overall survival (OS) and relapse-free survival. Several molecular targeted agents that inhibit VEGF or its receptors are currently in late-stage development or available for the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Bevacizumab is a humanized monoclonal antibody against VEGF that has proven efficacy when combined with different chemotherapy regimens. In the pivotal US phase III trial (E4599) combining bevacizumab with carboplatin/paclitaxel, significantly improved clinical outcomes were observed in terms of OS, progression-free survival (PFS), and response rate (RRs). Although the phase III AVAiL (Avastin in Lung Cancer) trial (BO17704) combining bevacizumab with cisplatin/gemcitabine also showed improved outcomes in terms of PFS and RR, OS data is immature. Bevacizumab is the first agent to improve clinical outcomes when combined with doublet chemotherapy and administered until disease progression. Herein, key clinical data from trials of antiangiogenic agents in the first-line treatment of NSCLC are discussed, with a focus on bevacizumab, currently the only approved antiangiogenic agent for the treatment of NSCLC. The optimal integration of these agents into current and future first-line treatment regimens will be discussed, stressing the importance of therapeutic administration until disease progression. The promising activity of antiangiogenic agents in the advanced disease setting, allied with growing understanding of their novel modes of action, holds therapeutic promise for their future application in early-stage disease.

Background: Although surgery offers the best chance of cure for patients with non-small cell lung cancer (NSCLC), the overall 5-year survival rate is modest, and improvements are urgently needed. In the 1990s, much interest was generated from two small trials that reported striking results with neo-adjuvant chemotherapy, and therefore our intergroup randomised trial was designed to investigate whether, in patients with operable non-small cell lung cancer of any stage, outcomes could be improved by giving platinum-based chemotherapy before surgery., Methods: Patients were randomised to receive either surgery alone (S), or three cycles of platinum-based chemotherapy followed by surgery (CT-S). Before randomisation, clinicians chose the chemotherapy that would be given from a list of six standard regimens. The primary outcome measure was overall survival, which was analysed on an intention-to-treat basis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN25582437., Results: 519 patients were randomised (S: 261, CT-S: 258) from 70 centres in the UK, Netherlands, Germany, and Belgium. Most (61%) were clinical stage I, with 31% stage II, and 7% stage III. Neo-adjuvant chemotherapy was feasible (75% of patients received all three cycles of chemotherapy), resulted in a good response rate (49% [95% CI 43%-55%]) and down-staging in 31% (25%-37%) of patients, and did not alter the type or completeness of the surgery (lobectomy: S: 56%, CT-S: 60%, complete resection: S: 80%, CT-S: 82%). Post-operative complications were not increased in the CT-S group, and no impairment of quality of life was observed. However, there was no evidence of a benefit in terms of overall survival (hazard ratio [HR] 1.02, 95% CI 0.80-1.31, p=0.86). Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant chemotherapy (1507 patients, HR 0.88, 95% CI 0.76-1.01, p=0.07), equivalent to an absolute improvement in survival of 5% at 5 years, Interpretation: Although there was no evidence of a difference in overall survival with neo-adjuvant chemotherapy, the result is statistically consistent with previous trials, and therefore adds considerable weight to the current evidence.

Introduction: This randomized phase II trial evaluated single-agent pemetrexed or sequential pemetrexed/gemcitabine in patients with non-small cell lung cancer (NSCLC) who were elderly (> or = 70 years) or younger than 70 years and ineligible for platinum-based chemotherapy., Methods: Chemonaive patients with stage IIIB/IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 2 received either 500 mg/m2 of pemetrexed (day 1, every 3 weeks) for eight cycles, or the same dosage of pemetrexed for cycles 1 and 2 and then 1200 mg/m2 of gemcitabine (days 1 and 8, every 3 weeks) for cycles 3 and 4 (repeated once for a total of eight cycles). All patients were given vitamin B12 and folic acid supplementation., Results: From July 2003 to July 2004, 87 patients (44 pemetrexed; 43 pemetrexed/gemcitabine) received treatment. The median time to progression was 4.5 (95% confidence interval: 3.0-9.3) and 4.1 months (95% confidence interval: 1.7-5.8) for the pemetrexed and pemetrexed/gemcitabine arms, respectively, and the median progression-free survival time was 3.3 months for both arms. Tumor response rates for the pemetrexed and pemetrexed/gemcitabine arms were 4.5% and 11.6%, respectively. The median overall survival time was 4.7 months for the pemetrexed arm and 5.4 months for the pemetrexed/gemcitabine arm, with respective 1-year survival rates of 28.5% and 28.1%. Grade 3/4 hematologic toxicity consisted of neutropenia (4.5% pemetrexed; 2.3% pemetrexed/gemcitabine), febrile neutropenia (4.5% pemetrexed; 4.7% pemetrexed/gemcitabine), thrombocytopenia (4.5% pemetrexed; 7.0% pemetrexed/gemcitabine), and anemia (6.8% pemetrexed; 4.7% pemetrexed/gemcitabine). No grade 3/4 nonhematologic toxicities exceeded 4.7% in either arm., Conclusions: Single-agent pemetrexed and sequential pemetrexed/gemcitabine have shown moderate activity and are well tolerated as first-line treatments for advanced NSCLC in elderly patients or patients unsuitable for platinum-based combination chemotherapy.

Background: Chemotherapy has been widely accepted as standard for palliation in advanced non-small-cell lung cancer. Gemcitabine and docetaxel are active as single agents. Our previous experience indicates that single-agent therapy, if given sequentially, could be an alternative to doublet combination chemotherapy and that sequence and schedule matter., Patients and Methods: Chemotherapy-naive patients with stage IIIB-IV non-small-cell lung cancer were randomized to receive first-line 3-weekly gemcitabine or docetaxel. At progression, patients received second-line therapy with the other agent. Treatment was considered feasible if 30% of the evaluable patients had > or = 2 cycles of first-line and 2 cycles of second-line therapy and patient survival was > or = 7 months from the start of treatment. For efficacy, time to progression, overall survival, response, and quality of life were analyzed., Results: Three hundred thirty patients received gemcitabine followed by docetaxel or docetaxel followed by gemcitabine. Treatment was feasible for 60 patients (38%) with gemcitabine followed by docetaxel and for 80 patients (49%) with docetaxel followed by gemcitabine; treatment favored docetaxel followed by gemcitabine (P = 0.03539). Median survival for gemcitabine followed by docetaxel and docetaxel followed by gemcitabine was 6.3 months and 8.6 months, and 1-year survival rate was 28% and 31%, respectively. Objective response rates were < or = 10% for both treatment strategies. Quality of life was significantly better in gemcitabine followed by docetaxel (P = 0.005)., Conclusion: Single-agent gemcitabine and docetaxel are feasible as defined for both sequences but treatment favors docetaxel followed by gemcitabine. Thus, it is reasonable to state that single-agent therapy given sequentially might be a candidate for palliation and therefore should be investigated in comparison with combination therapy.

Purpose: The combination of ifosfamide, carboplatin, and etoposide (ICE) is highly effective in treating small cell lung cancer (SCLC). Myelosuppression resulting in leukopenia and thrombocytopenia is the dose-limiting toxicity., Patients and Methods: This phase 3 study assessed 2-year survival improvement with dose intensification of ICE chemotherapy (ICT) in patients with good-prognosis SCLC. Patients received up to six cycles of ICT with filgrastim-supported sequential reinfusion of peripheral blood progenitor cells every 14 days, or standard ICE (SCT) every 28 days., Results: Eighty-three patients were randomized to ICT (n = 42) or SCT (n = 41). Median survival was significantly improved with ICT (30.3 mo) versus SCT (18.5 mo; p = 0.001); 2-year survival was 55% for ICT and 39% for SCT (p = 0.151). Time to progression (TTP) was significantly improved, with 15 months for ICT versus 11.1 months for SCT (p = 0.0001). Overall response rates were 100 and 88% for ICT and SCT, respectively (p = 0.0258). SCT was associated with significantly less grade 3 and 4 leukopenia at day 8 (p < 0.0001), less thrombocytopenia at day 14 (p < 0.0001), and more favorable platelet nadir (p < 0.0001). The need for platelet and red blood cell transfusions significantly increased in the ICT group (p < 0.0001). Nonhematologic adverse events in both groups were comparable and mostly grade 1 or 2., Conclusion: Patients receiving ICT with filgrastim achieved significant increases in median survival and TTP despite an increased need for transfusions.

Background: The aim of this prognostic factor analysis was to investigate if a patient's self-reported health-related quality of life (HRQOL) provided independent prognostic information for survival in non-small cell lung cancer (NSCLC) patients., Patients and Methods: Pretreatment HRQOL was measured in 391 advanced NSCLC patients using the EORTC QLQ-C30 and the EORTC Lung Cancer module (QLQ-LC13). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap validation technique was used to assess the stability of the outcomes., Results: The final multivariate Cox regression model retained four parameters as independent prognostic factors for survival: male gender with a hazard ratio (HR) = 1.32 (95% CI 1.03-1.69; P = 0.03); performance status (0 to 1 versus 2) with HR = 1.63 (95% CI 1.04-2.54; P = 0.032); patient's self-reported score of pain with HR= 1.11 (95% CI 1.07-1.16; P < 0.001) and dysphagia with HR = 1.12 (95% CI 1.04-1.21; P = 0.003). A 10-point shift worse in the scale measuring pain and dysphagia translated into an 11% and 12% increased in the likelihood of death respectively. A risk group categorization was also developed., Conclusion: The results suggest that patients' self-reported HRQOL provide independent prognostic information for survival. This finding supports the collection of such data in routine clinical practice.

Background: Gefitinib is an orally active epidermal growth factor receptor tyrosine kinase inhibitor with activity in previously treated patients with advanced-stage non-small-cell lung cancer (NSCLC). However, little is known of its activity as monotherapy in chemotherapy-naive patients. This phase II study (1839IL/0456) evaluated first-line gefitinib in patients with advanced-stage NSCLC., Patients and Methods: Eligible patients with proven inoperable stage III/IV NSCLC, no previous chemotherapy, and a performance status of 0-2 received gefitinib 250 mg per day until disease progression. Patient reevaluation was performed by radiography and computed tomography at regular intervals., Results: Fifty-eight of 59 patients were available for analysis. Response rate (complete plus partial responses) was 5% (3 of 58 patients); 40% (23 of 58 patients) exhibited stable disease (overall disease control rate, 45% [26 of 58 patients]). Median progression-free survival was 7 weeks, and median overall survival was 29 weeks. All responders were women and/or nonsmokers with adenocarcinoma or bronchoalveolar carcinoma. Gefitinib treatment was well tolerated; skin toxicities occurred in 71% of patients, including severe skin toxicities in 2 patients, and mild to moderate diarrhea occurred in 50% of patients., Conclusion: Gefitinib monotherapy has some efficacy in chemotherapy-naive patients with advanced-stage or metastatic NSCLC. However, activity seems to be limited to particular patient groups.

Background: A randomized phase II study was performed to determine whether single-agent gemcitabine or docetaxel with the introduction of the opposite agent in case of disease progression (ie, in the second-line setting) is feasible and effective in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: The doses were 1,000 mg/m2 for gemcitabine and 35 mg/m2 for docetaxel, each given on days 1, 8, and 15 every 4 weeks. After a planned interim analysis, the docetaxel/gemcitabine arm (ie, docetaxel followed by gemcitabine) was closed after enrollment of 49 patients because of poor predefined feasibility. A total of 98 patients were recruited to the gemcitabine/docetaxel arm (ie, gemcitabine followed by docetaxel)., Results: Quality of life remained near baseline levels during the administration of 6 cycles of gemcitabine/docetaxel chemotherapy, whereas it deteriorated after 2 cycles of docetaxel/gemcitabine. Toxicity was comparable between arms. Median times to progression were 4.3 months and 2.2 months with gemcitabine/docetaxel and docetaxel/gemcitabine, respectively, and median overall survival times were 9 months (gemcitabine/docetaxel) and 5 months (docetaxel/gemcitabine; P=0.029, Wilcoxon rank-sum test)., Conclusion: These results indicate that first-line gemcitabine followed by second-line weekly docetaxel is feasible, with promising survival in patients with advanced NSCLC.

Background: A phase III trial in patients with malignant pleural mesothelioma demonstrated a survival advantage for pemetrexed plus cisplatin compared with single-agent cisplatin. Because post-study chemotherapy (PSC) may have influenced the outcome of the trial, we examined its use and association with survival., Patients and Methods: Eighty-four patients from the pemetrexed plus cisplatin arm and 105 patients from the single-agent cisplatin arm received PSC. Kaplan-Meier survival estimates were compared by treatment groups, and by PSC and non-PSC subgroups., Results: The percentage of patients receiving PSC was imbalanced between the treatment arms. Fewer pemetrexed plus cisplatin treated patients received PSC (37.2% versus 47.3%). A multiple regression analysis performed in this trial showed that PSC had a statistically significant correlation with prolonged survival (P <0.01), adjusting for baseline prognostic factors and treatment intervention. The adjusted hazard ratio for PSC over non-PSC subgroups was 0.56 (confidence interval 0.44-0.72)., Conclusions: PSC in malignant pleural mesothelioma was significantly associated with prolonged survival. It is not known whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival tended to receive more PSC. The pemetrexed plus cisplatin treatment group had a statistically significant survival advantage even though fewer patients from that arm of the trial received PSC. The potentially beneficial role of PSC should be assessed in prospective trials.

Despite improvements in conventional treatment, patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis, leaving a significant unmet need for novel treatments. One such novel, biologically targeted agent is the orally active epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. This open-label pilot trial investigated the safety, pharmacokinetics, and efficacy of 2 doses of gefitinib (250 and 500 mg per day) combined with docetaxel (75 mg/m2) in patients with locally advanced or metastatic NSCLC as first- and second-line chemotherapy. Eighteen patients were recruited: 6 received gefitinib 250 mg per day plus docetaxel; 12 received gefitinib 500 mg per day plus docetaxel. Combination therapy was feasible with no overlapping toxicities. No patients experienced dose-limiting toxicities (DLTs) at 250 mg per day; 1 patient had 2 DLT events at 500 mg per day (grade 3 rash and diarrhea for >4 days). Adverse events were mild to moderate, including fatigue, mucositis, nausea, anorexia, rash, diarrhea, and fever. Docetaxel did not appear to alter steady-state exposure to gefitinib. The effect of gefitinib on exposure to docetaxel was equivocal; with the exception of 2 patients in the gefitinib 250 mg per day dose group, there appeared to be no trend toward a higher or lower exposure to docetaxel when given in the presence of gefitinib compared with that when given alone. Combination therapy was associated with antitumor activity and responses were seen with gefitinib in 2 of 6 patients at 250 mg per day and 4 of 12 patients at 500 mg per day. This combination is feasible and has an acceptable and predictable safety profile, as well as associated antitumor activity.

Most gastrointestinal stromal tumors (GISTs) carry activating mutations of the KIT gene encoding the receptor tyrosine kinase KIT. In a previous study we were able to show an association between the lack of KIT mutations (wild-type GISTs) and the presence of a significant epithelioid tumor component. A very recent study described the occurrence of PDGFRalpha mutations in KIT wt GISTS. Therefore, we studied a panel of 87 GISTs for mutations in the hot spot regions of the PDGFRalpha gene with single strand conformation polymorphism analysis and sequencing and correlated the PDGFRalpha status with pathomorphological data. We detected 20 cases with exon 18 mutations but none with exon 12 mutations. The mutations were located in the second kinase domain of PDGFRalpha with 16 point mutations, and four larger deletions of 9 to 12 bp. All cases with mutations in the PDGFRalpha gene revealed wild-type KIT in common regions of mutation, ie, exons 9 and 11. Most interestingly, the occurrence of PDGFRalpha mutations was significantly associated with a higher frequency of epithelioid or mixed morphology (18 of 20 cases, P < 0.0001) and gastric location (all cases, P = 0.0008). Our data indicate that GISTs represent distinctive entities, differing in genetic, biological, and morphological features.

Background: Platinum-based combination chemotherapy is currently recommended as the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), but its benefit seems limited to fit patients with a performance status (PS) of 0 or 1. For PS2 patients, there is no consensus on standard treatment. With the aims of reviewing the evidence supporting each of these therapeutic options, possibly reaching a consensus for treatment of PS2 patients affected by advanced NSCLC in clinical practice, and suggesting the priorities for clinical research in this field, an European Experts Panel took place in Avellino, Italy in April 2003., Results: and conclusions On the basis of current evidence, chemotherapy treatment appears justified for patients with advanced NSCLC and PS2. Single-agent chemotherapy (gemcitabine, vinorelbine, taxanes) could be the preferred option, although carboplatin-based or low-dose cisplatin-based doublets may represent alternative options. Stronger evidence is expected from new clinical research specifically focused on PS2 patients. Single-agent chemotherapy should be the standard arm against which experimental treatments are tested in randomised trials dedicated to PS2 patients. High priority should be given to the evaluation of tolerability and efficacy of platinum-based combinations, and to the testing of new biological agents. Another research priority is the improvement of supportive care. Patients strongly need symptomatic improvement: end points such as symptom relief, clinical benefit and quality of life should have a central position in trials dedicated to PS2 NSCLC patients.

Background: The purpose of this study was to evaluate ALIMTA (pemetrexed disodium, LY231514), a multi-targeted antifolate with first-line activity against non-small-cell lung cancer (NSCLC), in a second-line setting., Patients and Methods: Patients with NSCLC were eligible for this phase II study if they had progressive disease within 3 months after first-line chemotherapy or progression while being treated with first-line chemotherapy. In 81 patients studied, two cohorts of patients were assigned based on whether the first-line therapy had included a platinum regimen. ALIMTA was administered at 500 mg/m2 by 10-min intravenous infusion once every 21 days., Results: The response rate in the 79 evaluable patients with poor prognostic features was 8.9% [95% confidence interval (CI) 2.6% to 15.1%]. The response rate in the platinum-pretreated group was 4.5% and 14.1% in the non-platinum-pretreated group. The median duration of response was 6.8 months (95% CI 3.4-7.8 months, 0% censoring). The median survival time was 5.7 months (95% CI 4.0-8.3 months, 7.6% censoring). The probability of survival for at least 6 months was estimated to be 48%. The median time to disease progression was 2 months (95% CI 1.4-2.8 months, 0% censoring). The principal toxicity was myelosuppression, which was reversible., Conclusions: ALIMTA is active in a second-line setting in non-platinum-pretreated NSCLC patients progressing within 3 months of first-line chemotherapy. This study demonstrates that it is possible to evaluate new drugs against NSCLC in a second-line setting.

Background: To determine whether the cost of prophylactic antibiotics during chemotherapy is offset by cost savings due to a decreased incidence of febrile leukopenia (FL)., Patients and Methods: Small-cell lung cancer (SCLC) patients were randomised to standard or intensified chemotherapy with granulocyte colony-stimulating factor to assess the impact on survival (n = 244). In addition, patients were randomised to prophylactic ciprofloxacin and roxithromycin or placebo to assess the impact on FL (n = 161). The economic evaluation examined the costs and effects of patients taking antibiotics versus placebo. Medical resource utilisation was documented prospectively, including 33 patients from one centre in The Netherlands (NL) and 49 patients from one centre in Germany (GE). The evaluation takes the perspective of the health insurance systems and of the hospitals. Sensitivity analyses were performed., Results: In the main trial, prophylactic antibiotics reduced the incidence of FL, hospitalisation due to FL and use of therapeutic antibiotics by 50%. In GE, the incidence of FL was not reduced by prophylaxis. This resulted in an average cost difference of only 35 Euros [95% confidence interval (CI) (-)1.713-2.263] in favour of prophylaxis (not significant). In NL, prophylaxis reduced the incidence of FL by nearly 50%, comparable with the results of the main trial, resulting in a cost difference of 2706 Euros [95% CI 810-5948], demonstrating savings in favour of prophylactic antibiotics of nearly 45%. Sensitivity analyses indicate that with an efficacy of prophylaxis of 50%, and with expected costs of antibiotic prophylaxis of 500 Euros or less, cost savings will incur over a broad range of baseline risks for FL; that is, a risk >10-20% for FL per cycle., Conclusions: Giving oral prophylactic antibiotics to SCLC patients undergoing chemotherapy is the dominant strategy in both GE and NL, demonstrating both cost-savings and superior efficacy. The sensitivity analyses demonstrate that, due to the efficacy of prophylactic antibiotics and their low unit cost, cost savings will incur over a broad range of baseline risks for FL. We recommend the use of prophylactic antibiotics in patients at risk for FL during chemotherapy.

Background: CDE (cyclophosphamide, doxorubicin, etoposide) is one of the standard chemotherapy regimens in the treatment of small-cell lung cancer (SCLC), with myelosuppression as dose-limiting toxicity. In this trial the impact of prophylactic antibiotics on incidence of febrile leucopenia (FL) during chemotherapy for SCLC was evaluated., Patients and Methods: Patients with chemo-naïve SCLC were randomized to standard-dose CDE (C 1,000 mg/m2 day 1, D 45 mg/m2 day 1, E 100 mg/m2 days 1-3. i.v., q 3 weeks, x5) or to intensified CDE chemotherapy (125% dose, q 2 weeks, x4, with filgrastim 5 microg/kg/day days 4-13) to assess the impact on survival (n = 240 patients). Patients were also randomized to prophylactic antibiotics (ciprofloxacin 750 mg plus roxithromycin 150 mg, bid. days 4-13) or to placebo in a 2 x 2 factorial design (first 163 patients). This manuscript focuses on the antibiotics question., Results: The incidence of FL during the first cycle was 25% of patients in the placebo and 11% in the antibiotics arm (P = 0.010; 1-sided), with an overall incidence through all cycles of 43% vs. 24% respectively (P = 0.007; 1-sided). There were less Gram-positive (12 vs. 4), Gram-negative (20 vs. 5) and clinically documented (38 vs. 15) infections in the antibiotics arm. The use of therapeutic antibiotics was reduced (P = 0.013; 1-sided), with less hospitalizations due to FL (31 vs. 17 patients, P = 0.013: 1-sided). However, the overall number of days of hospitalization was not reduced (P = 0.05; 1-sided). The number of infectious deaths was nil in the antibiotics vs. five (6%) in the placebo arm (P = 0.022; 2-sided)., Conclusions: Prophylactic ciprofloxacin plus roxithromycin during CDE chemotherapy reduced the incidence of FL, the number of infections, the use of therapeutic antibiotics and hospitalizations due to FL by approximately 50%, with reduced number of infectious deaths. For patients with similar risk for FL, the prophylactic use of antibiotics should be considered.

Background: Both gemcitabine and etoposide are active in the treatment of small-cell lung cancer (SCLC), and are characterised by mild toxicity profiles. The combination of both drugs was found to be feasible and active in a phase I dose-finding study in solid tumours. Therefore, a phase II trial was initiated to examine the activity and toxicity of this schedule in extensive disease SCLC., Patients and Methods: Forty-two chemo-naïve extensive disease SCLC patients were enrolled to receive gemcitabine 1000 mg/m2, days 1, 8 and 15, and etoposide 80 mg/m2, days 8, 9 and 10 of a 28-day cycle., Results: Thirty-seven patients were evaluable for efficacy (five received less than one cycle). No complete responses were observed, but partial responses were seen in 17 patients, yielding an overall response rate of 46%. The median duration of response was 5.8 months. Disease stabilisation was obtained in another 10 patients (27%). The median survival of the 37 protocol-qualified patients was 10.5 months (95% confidence interval (CI): 7.5-12.0). The levels of WHO grade 3 and 4 toxicities were low and clinically manageable., Conclusion: In comparison with standard platinum-based regimens, this combination of gemcitabine and etoposide resulted in a somewhat lower response rate, but a similar median survival time. Haematological toxicity was more pronounced than expected from the toxicity data of each agent individually. However, because of its mild non-haematological toxicity, and its ability to be administered in an outpatient setting, this combination provides a reasonable palliative option for patients with extensive disease SCLC.

Background: To evaluate the activity of MTA plus cisplatin in chemotherapy-naive patients with non-small cell lung cancer (NSCLC)., Patients and Methods: Thirty-six chemotherapy-naïve patients with NSCLC received 500 mg/m2 MTA plus 75 mg/m2 cisplatin every 21 days, with 4 mg dexamethasone orally twice daily on the day before, of, and after MTA administration., Results: Median age was 58 years. WHO performance status was 0-2. Eighteen patients each had stage IIIB and IV disease. Seventeen patients each had squamous-cell and adenocarcinoma; two had undifferentiated disease. Fourteen patients (39%; 95% confidence interval: 23%-57%) showed partial response; seventeen (47%) had stable disease. Median survival was 10.9 months. Twenty-one patients (59%) experienced grade 3 or 4 granulocytopenia without fever or infection. Five (14%) and six (17%) patients experienced grade 3 anemia and grade 3 or 4 thrombocytopenia, respectively. Nonhematological toxicities included grade 3 nausea in two patients (6%), and grade 3 and 4 diarrhea in one patient (3%) each. One patient each experienced grade 4 ALT and grade 3 bilirubin and AST elevations., Conclusions: MTA plus cisplatin is well tolerated and active against NSCLC. Further studies of this combination are warranted.

Background: This randomised study was designed to determine the response rate survival and toxicity of single-agent gemcitabine and cisplatin-etoposide in chemo-naïve patients with locally advanced or metastatic non-small-cell lung cancer., Patients and Methods: Gemcitabine 1,000 mg/m2 was given as a 30 min intravenous infusion on days 1, 8, 15 of a 28-day cycle, cisplatin 100 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 (following cisplatin), 2 and 3. Major eligibility criteria included histologically confirmed non-small-cell lung cancer, measurable disease, Zubrod PS 0-2; no prior chemotherapy, no prior radiation of the measured lesion, and no CNS metastases., Results: 146 patients were enrolled, 71 patients on gemcitabine and 75 patients on cisplatin-etoposide. Patient characteristics were well matched across both arms. Sixty-six gemcitabine patients and 72 cisplatin-etoposide patients were evaluable. Partial responses were seen in 12 gemcitabine patients (18.2%; 95% CI: 9.8-30) and 11 cisplatin-etoposide patients (15.3%; 95% CI: 7.9-25.7). Early indications show no statistical differences between the two treatments with respect to time to disease progression or survival. Haematological and laboratory toxicity were moderate and manageable. However, hospitalisation because of neutropenic fever was required for 6 (8%) cisplatin-etoposide patients but not for any gemcitabine patients. Non-haematological toxicity was more pronounced with significant differences in nausea and vomiting (grade 3 and 4: 11% gemcitabine vs. 29% cisplatin-etoposide; despite the allowance for 5-HT3 antiemetics during the first cycle of cisplatin-etoposide), and alopecia (grade 3 and 4:3% gemcitabine vs. 62% cisplatin-etoposide)., Conclusions: In this randomised study, single-agent gemcitabine was at least as active but better tolerated than the combination cisplatin-etoposide.