Search

PURPOSE Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia ( P ≤ .001); febrile neutropenia ( P = .002); and alopecia ( P < .001) were significantly lower, whereas grade 3 or 4 nausea ( P = .004) was more common. CONCLUSION In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Item does not contain fulltext PURPOSE: Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing. METHODS: A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated. RESULTS: A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436). CONCLUSION: We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing. CLINICAL TRIAL NUMBER: Clinicaltrials.gov identifier: NCT03655821. 01 januari 2023

Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing.A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated.A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436).We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing.Clinicaltrials.gov identifier: NCT03655821.

WOS:000571476500010 PubMed ID: 32745892 Objectives: Expression of the Notch-family ligand delta-like protein 3 (DLL3), a potential therapeutic target in small cell lung cancer (SCLC), has not been assessed in the real-world setting. To identify the real-world utility of DLL3 as an SCLC therapeutic target, we performed the largest retrospective international noninterventional study to date to evaluate DLL3 prevalence in SCLC patients. Materials and Methods: DLL3 expression was assessed using immunohistochemistry in archived histological and cytological specimens (independent and paired) and correlated to patient demographics, clinical disease characteristics, and survival. The primary endpoint was the proportion of patients with DLL3 expression in >= 25 % of tumor cells. DLL3 expression concordance was assessed in paired specimens. Results: Independent tumor specimens were collected from 1073 patients. The mean age at biopsy was 66 years (SD, 10); 682 (64 %) patients were male. Paired specimens were collected from 36 patients. The mean age at biopsy was 62 years (SD, 11); 16 (44 %) patients were male. Most patients had ECOG performance status of 0-1, were smokers/ex-smokers, and received >= 1 prior therapy. Positive DLL3 expression (defined as >= 25 % of tumor cells) was identified in 895/1050 (85 %) patients with 1 specimen and evaluable DLL3 expression; 719/1050 (68 %) patients had high DLL3 expression (defined as >= 75 % of tumor cells). DLL3 expression concordance was 88 % between paired specimens (n = 17; Cohen's kappa P value, .9412). There was no significant difference in median overall survival from SCLC diagnosis for evaluable patients with nonmissing data based on DLL3 expression (negative DLL3 expression [n = 139], 9.5 months; positive DLL3 expression [n = 747], 9.5 months; all evaluable patients [n = 893, 9.5 months). Conclusion: These real-world epidemiologic findings indicate that DLL3 is robustly expressed across SCLC disease stages and remains stable despite treatment, consistent with available clinical trial data. There was no prognostic role for DLL3 observed in this study for overall survival. AbbVie AbbVie provided financial support for the study and provided each site with the assay, detection kit, and reagent control. AbbVie participated in the design, study conduct, analysis and interpretation of data, and the writing, review, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Ashley Skorusa, PhD, of Bio Connections, LLC, funded by AbbVie.

BACKGROUND: This open-label Phase III trial (NCT02264990) evaluated the PARP inhibitor, veliparib, combined with carboplatin/paclitaxel versus chemotherapy alone for first-line treatment of patients with advanced non-squamous non-small cell lung cancers (NSCLC). A 52-gene expression classifier (LP52) previously shown to identify patients more likely to respond to veliparib was evaluated as a planned correlative analysis.; MATERIALS AND METHODS: Adult current or former smokers with advanced non-squamous NSCLC were randomized 1:1 to veliparib (120 mg daily for 7 days/cycle) with carboplatin and paclitaxel or to investigators' choice of platinum doublet chemotherapy (up to 6, 21-day cycles), with optional pemetrexed maintenance. Prospective analysis of the LP52 signature was conducted using a clinical Qiagen/HTG assay. The primary endpoint was overall survival (OS) in LP52+ patients.; RESULTS: Overall, 595 patients received veliparib+carboplatin/paclitaxel (n=298) or chemotherapy alone (n=297); 13% (n=40) in each arm were LP52+. The primary endpoint was not met; median OS was 11.2 months with veliparib+carboplatin/paclitaxel versus 9.2 months with chemotherapy alone in the LP52+ subgroup (hazard ratio [HR] 0.644, 95% confidence interval [CI]: 0.396-1.048; P=.113). In the overall population, median OS was 12.1 months in both arms (HR 0.986, 95% CI: 0.827-1.176; P=.846). No new safety signals were observed.; CONCLUSION: In patients with non-squamous NSCLC, there was no significant improvement in OS with veliparib+carboplatin/paclitaxel versus chemotherapy alone, although a trend toward improved OS in the LP52+ population suggests this subgroup may benefit from veliparib. Statistical power was limited due to the small sample size. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Contains fulltext : 249097.pdf (Publisher’s version ) (Open Access) Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin-related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P = .196) or volume of distribution (+7% change, P = .002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.

Background: Retrospective studies suggest that low molecular weight heparin may delay the development of metastasis in patients with resected NSCLC. Methods: Multicentre phase 3 study with patients with completely resected NSCLC who were randomised after surgery to receive chemotherapy with or without nadroparin. The main exclusion criteria were R1/2 and wedge/segmental resection. FDG-PET was required. The primary endpoint was recurrence-free survival (RFS). Results: Among 235 registered patients, 202 were randomised (nadroparin: n = 100; control n = 102). Slow accrual enabled a decrease in the number of patients needed from 600 to 202, providing 80% power to compare RFS with 94 events (α = 0.05; 2-sided). There were no differences in bleeding events between the two groups. The median RFS was 65.2 months (95% CI, 36—NA) in the nadroparin arm and 37.7 months (95% CI, 22.7—NA) in the control arm (HR 0.77 (95% CI, 0.53–1.13, P = 0.19). FDG-PET SUVmax ≥10 predicted a greater likelihood of recurrence in the first year (HR 0.48, 95% CI 0.22–0.9, P = 0.05). Conclusions: Adjuvant nadroparin did not improve RFS in patients with resected NSCLC. In this study, a high SUVmax predicted a greater likelihood of recurrence in the first year. Clinical trial registration: Netherlands Trial registry: NTR1250/1217.

Background: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma.Methods: We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS.Findings: Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4(+) T-helper, CD8(+) Tand NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS.Interpretation: Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies. (C) 2020 The Authors. Published by Elsevier B.V.

Contains fulltext : 238572.pdf (Publisher’s version ) (Closed access) Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]

Contains fulltext : 220632.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Pemetrexed is a pharmacotherapeutic cornerstone in the treatment of non-small cell lung cancer. As it is primarily eliminated by renal excretion, adequate renal function is essential to prevent toxic exposure. There is growing evidence for the nephrotoxic potential of pemetrexed, which even becomes a greater issue now combined immuno-chemotherapy prolongs survival. Therefore, the aim of this study was to describe the incidence of nephrotoxicity and related treatment consequences during pemetrexed-based treatment. METHODS: A retrospective cohort study was conducted in the Jeroen Bosch Hospital, Den Bosch, the Netherlands. All patients that received at least 1 cycle of pemetrexed based therapy were included in the dataset. The primary outcome was defined as a >/=25 % reduction in eGFR. Additionally, the treatment consequences of decreased renal function were assessed. Logistic regression was used to identify risk factors for nephrotoxicity during treatment with pemetrexed. RESULTS: Of the 359 patients included in this analysis, 21 % patients had a clinically relevant decline in renal function after treatment and 8.1 % of patients discontinued treatment due to nephrotoxicity. Cumulative dose (>/=10 cycles of pemetrexed based therapy) was identified as a risk factor for the primary outcome measure (adjusted OR 5.66 (CI 1.73-18.54)). CONCLUSION: This study shows that patients on pemetrexed-based treatment are at risk of developing renal impairment. Risk significantly increases with prolonged treatment. Renal impairment is expected to become an even greater issue now that pemetrexed-based immuno-chemotherapy results in longer survival and thus longer treatment duration.

Background: All patients with malignant mesothelioma develop progressive disease after first line therapy. Some studies have addressed maintenance therapy, none showed a great impact. Gemcitabine, an active drug in mesothelioma, was tested in the NVALT19 study in a switch maintenance setting. Methods: This open label randomized phase II study in 18 Dutch hospitals, recruited patients with unresectable mesothelioma who did not progress after first line chemotherapy (platinum-pemetrexed), World Health Organization performance status ≤ 2 and an adequate organ function. Key exclusion criteria were seriously disabling conditions or symptomatic central nervous system metastases. Patient were 1:1 randomised to maintenance gemcitabine (1250 mg/m2, intravenous, day 1 and 8, 3 weeks schema) or best supportive care (BSC,) using minimisation method. Primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Safety was analysed in all participants who received one dose of study drug. Findings: From March 20, 2014, to February 27, 2019, 130 patient were randomized (65 to gemcitabine and 65 to BSC). PFS was significant longer with gemcitabine (median 6.2) than with BSC (3·2 months; hazard ratio (HR) 0·46; 95% confidence interval [CI], 0·31 to 0·68; p

Background All malignant mesothelioma (MM) patients progress after first-line therapy. We examined whether switch maintenance gemcitabine in patients, who did not show progression after first-line platinum-pemetrexed, could prolong time to disease progression. Methods NVALT19 was an open label, randomized phase II trial, conducted in The Netherlands. Main eligibility criteria were pathologically proven MM, ECOG-PS 0-2 and completion of 4-6 cycles of first-line platinum-pemetrexed without progression. Patients were randomized 1:1 between gemcitabine (1250 mg/m2 day 1 and 8 of 3 weekly schedule) or best supportive care (BSC). Gemcitabine was given until disease progression, severe toxicity or patient request for discontinuation. Primary endpoint was progression free survival (PFS) determined by local physician according to modified RECIST (mRECIST) or death in the intention-to-treat population. It was computed that 118 events would yield 90% power to detect an increase in PFS from median 3.5 months to median 6 months at 90% confidence level. Results Between March 2014 and February 2019, 130 patients were randomized, 65 in each arm. PFS was significantly longer with gemcitabine (median 6.2 months [range 4.6-8.7m]) than in the BSC arm (3.2 [2.8-4.2m]; hazard ratio 0.42; 95% confidence interval [CI], 0.28-0.63; p Conclusions Switch maintenance gemcitabine after first-line chemotherapy significantly improves the PFS in malignant mesothelioma, with a manageable toxicity profile. Clinical trial identification NTR4132. Legal entity responsible for the study Stichting NVALT studies. Funding Dutch Cancer Society and Stichting NVALT studies. Disclosure All authors have declared no conflicts of interest.

Background: Nitroglycerin ( NTG) increases tumor blood flow and oxygenation by inhibiting hypoxia- inducible- factor ( HIF)- 1. A randomized phase II study has shown improved outcome when NTG patches were added to vinorelbine/ cisplatin in patients with advanced nonsmall- cell lung cancer ( NSCLC). In addition, there is evidence that the combination of bevacizumab and HIF- 1 inhibitors increases antitumor activity. Patients and methods: In this randomized phase II trial, chemo- naive patients with stage IV nonsquamous NSCLC were randomized to four cycles of carboplatin ( area under the curve 6)- paclitaxel ( 200 mg/ m2)- bevacizumab 15 mg/ kg on day 1 every 3 weeks with or without NTG patches 15 mg ( day - 2 to + 2) followed by bevacizumab with or without NTG until progression. Response was assessed every two cycles. Primary end point was progression- free survival ( PFS). The study was powered ( 80%) to detect a decrease in the hazard of tumor progression of 33% at a = 0.05 with a two- sided log- rank test when 222 patients were enrolled and followed until 195 events were observed. Results: Between 1 January 2011 and 1 January 2013, a total of 223 patients were randomized; 112 control arm and 111 experimental arm; response rate was 54% in control arm and 38% in experimental arm. Median [ 95% confidence interval ( CI)] PFS in control arm was 6.8 months ( 5.6- 7.3) and 5.1 months ( 4.2- 5.8) in experimental arm, hazard ratio ( HR) 1.27 ( 95% CI 0.96- 1.67). Overall survival ( OS) was 11.6 months ( 8.8- 13.6) in control arm and 9.4 months ( 7.8- 11.3) in experimental arm, HR 1.02 ( 95% CI 0.71- 1.46). In the experimental arm, no additional toxicity was observed except headache ( 6% versus 52% in patients treated with NTG). Conclusion: Adding NTG to first- line carboplatin- paclitaxel- bevacizumab did not improve PFS and OS in patients with stage IV nonsquamous NSCLC.

Background In most reported cases of lung trauma with water proofing products, volatile organic compounds (VOC) have a prominent role. Here we report on a case involving ten workers exposed to a sprayed product containing nanoparticles in a water solution with only a few percent VOC. Case presentation Ten workers suffered from respiratory symptoms following spray impregnation of hardwood furniture using a waterproofing product that contained positively charged fluorinated acrylate copolymer solid cores with a median diameter of 70 nm (1.3 w%) in aqueous suspension with 3.3 w% VOC and 0.3 w% quaternary ammonium. The worker who applied one liter of the product in a wood workshop, using an air mix spray gun, did not report any health complaints. Another worker, who entered the workshop 3 h later and had rolled and smoked two cigarettes, was hospitalized with severe chemical pneumonitis. A chest X-ray (CXR) showed bilateral infiltrative impairment in the lower lobe regions. On the next day a second CXR showed increased patchiness marking in all fields. A high-resolution Computer Tomography (CT)-scan demonstrated extensive bilateral areas of ground-glass opacities predominantly in the lower regions of the upper lobes, the right middle lobe and the apical regions of the lower lobes, compatible with severe chemical pneumonitis. On the following morning, nine workers in an adjacent workplace in the same building, experienced dry cough, chest tightness and substernal pain upon physical exercise. Reconstruction of the spray application in a climate chamber confirmed trimethyl silanol, glycol ethers and fluoroalkenes in the gas phase. Immediately after the spray application, aerosols were observed at a maximum concentration of 6.3 × 104 cm−3. Mass concentrations were 0.095 and 10 mg/m3 in the size ranges 5.6-560 nm and 0.22-30 μm, respectively, decreasing to less than 10 μg/m3 in both size ranges after 15 h. Conclusion The hospitalized worker had smoked cigarettes contaminated with fluoropolymers which is a plausible explanation for the lung trauma. Respiratory symptoms in the nine workers may be caused by inhalation of particles that became airborne by resuspension from surfaces when workers entered the adjacent workplace the next day. A contribution from VOC appears less likely because measurements and modelling showed that concentrations in the mg/m3 range could have occurred only if the building was assumed to be completely airtight. Electronic supplementary material The online version of this article (10.1186/s12995-017-0180-7) contains supplementary material, which is available to authorized users.

This study aimed to investigate which factors were associated with the administration of chemotherapy for patients with stage IV non-small cell lung cancer (NSCLC), and their relation to survival at a population-based level. All patients with NSCLC stage IV from 2001 to 2012 were identified in the Netherlands Cancer Registry in the Eindhoven area (n = 5,428). Chemotherapy use and survival were evaluated by logistic and Cox regression analyses, respectively. The proportion of patients receiving chemotherapy increased from 30% in 2001 to 48% in 2012. Higher rates were found among younger patients [multivariable odds ratio (OR(≤ 64_vs._≥ 75_years)): 1.8 (95%CI 1.6-2.1)], high socioeconomic status [OR(high_vs._low): 1.8 (95%CI 1.6-2.2)], no comorbidity [OR0_vs._≥ 2 : 1.5 (95%CI 1.3-1.8)], diagnosed in recent years [OR(2010-2012_vs._2001-2003): 2.0 (95%CI 1.6-2.3)] and adenocarcinoma [ORsquamous_vs._adenocarcinoma : 0.8 (95%CI 0.6-0.9)]. Having liver metastasis was associated with reduced odds (OR(liver_ vs._brain): 0.8 (95%CI 0.7-1.0). The variation between hospitals was large, up to OR 2.0 (95%CI 1.5-2.6). Median survival increased from 18 weeks in 2001-2003 to 21 weeks in 2010-2012 (log-rank p = 0.007), and was 35 weeks in patients with and 10 weeks without chemotherapy. The multivariable hazard of death reduced significantly over time [HR(2001-2003_vs._2010-2012): 1.1 (95%CI 1.0-1.2), HR(2004-2005_vs._2010-2012): 1.2 (95%CI 1.1-1.3)] and only remained significant for 2004-2006 after additional adjustment for chemotherapy [final multivariable model, HR(2004-2006_vs._2010-2012): 1.1 (95%CI 1.0-1.2)]. Besides, prognostic factors were having chemotherapy [final multivariable model: HR 0.4 (95%CI 0.4-0.4)], female sex [HRmale_vs._female : 1.1 (95%CI 1.0-1.1)], socioeconomic status [HR(intermediate_and_high_vs._low) both 0.9 (95%CI 0.9-1.0)], comorbidity [HR(unknown_vs._≥ 2): 1.3 (95%CI 1.2-1.5)], histology [HRother_vs._adenocarcinoma : 1.1 (95%CI 1.1-1.2)], and location of metastasis [range: 1.2 (HR(lymph_nodes_vs._brain)) - 1.6 (HR(liver_vs._brain))]. In conclusion, population-based survival increased due to increasing administration rates of chemotherapy. The administration of chemotherapy was affected by hospital of diagnosis and both patient and tumour characteristics. Identifying patients who benefit from chemotherapy should become a key issue.

Contains fulltext : 125242.pdf (Publisher’s version ) (Open Access) BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome in non-small-cell lung cancer (NSCLC). However, in preclinical models and early phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect. PATIENTS AND METHODS: A randomized phase II study was carried out in patients with advanced NSCLC who had progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15 days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end point was progression-free survival (PFS). RESULTS: Two hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the combination arm. The adjusted hazard ratio for PFS was 0.76 [95% confidence interval (CI) 0.58-1.02; P = 0.06], for overall survival (OS) 0.67 (95% CI 0.49-0.91; P = 0.01) favoring the combination arm. This improvement was primarily observed in NSQ subgroup. Common Toxicity Criteria grade 3+ toxic effect occurred in 20% versus 56%, rash in 7% versus 15% and febrile neutropenia in 0% versus 6% in monotherapy and combination therapy, respectively. CONCLUSIONS: PFS was not significantly different between the arms. OS was significantly improved in the combination arm, an effect restricted to NSQ histology. STUDY REGISTRATION NUMBER: NCT00835471.

Ten workers suffered from respiratory complaints after spray impregnation of hardwood furniture with a waterproofing product that contained a fluorinated acrylate copolymer in an aqueous suspension. One litre of the product was sprayed during 4 min inside a workshop area with a volume of ca. 2 400 m 3 . A worker, who entered the workshop 3 h after the impregnation, was hospitalised with dyspnea, severe hypoxia, cough, blank sputum, fever, tremors and tingling extremities. Later a severe chemical pneumonitis was diagnosed. On the following morning, 15 h after the impregnation, nine workers in an adjacent room of 1 200 m 3 in the same building experienced the following respiratory symptoms: dry cough, chest tightness and sub-sternal chest pain. No other sources of causative exposure could be identified. Reconstruction of the spray application in a 20 m 3 steel chamber showed trimethyl silanol, glycol ethers and fluoroalkenes as major volatile organic compounds (VOCs). The fluoroalkenes reached their maximum concentrations 1–2 h after application and persisted in the gas phase along with trimethyl silanol and the glycol ethers. Immediately after the spray application aerosols were observed in a maximum concentration of 6.3 × 104 cm –3 (5.6 to 560 nm). Mass concentrations were 0.095 and 10 mg/m 3 in the size ranges 5.6 to 560 nm and 0.22 to 30 µm, respectively. After 15 h the mass concentrations of the airborne particle had decreased to values less than 10 µg/m 3 in both size ranges. The worker who developed chemical pneumonitis was a smoker. We hypothesise that rolling and smoking cigarettes contaminated with fluoropolymer was causative. The respiratory symptoms in the 9 workers exposed 15 hours after the spray event may be caused by combined exposure to trimethyl silanol, glycol ethers and fluoroalkenes, which persisted in the gas phase up to 24 h after application of the product.

Purpose The phase III PROCLAIM study evaluated overall survival (OS) of concurrent pemetrexed-cisplatin and thoracic radiation therapy (TRT) followed by consolidation pemetrexed, versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy. Patients and Methods Patients with stage IIIA/B unresectable nonsquamous non–small-cell lung cancer randomly received (1:1) pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously every 3 weeks for three cycles plus concurrent TRT (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles (arm A), or standard therapy with etoposide 50 mg/m2 and cisplatin 50 mg/m2 intravenously, every 4 weeks for two cycles plus concurrent TRT (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy (arm B). The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS hazard ratio of 0.74 with a type 1 error of .05. Results Enrollment was stopped early because of futility. Five hundred ninety-eight patients were randomly assigned (301 to arm A, 297 to arm B) and 555 patients (283 in arm A, 272 in arm B) were treated. Arm A was not superior to arm B in terms of OS (hazard ratio, 0.98; 95% CI, 0.79 to 1.20; median, 26.8 v 25.0 months; P = .831). Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% v 76.8%; P = .001), including neutropenia (24.4% v 44.5%; P < .001), during the overall treatment period. Conclusion Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexed was not superior to standard chemoradiotherapy for stage III unresectable nonsquamous non–small-cell lung cancer.

Contains fulltext : 165952.pdf (Publisher’s version ) (Open Access) OBJECTIVES: Symptomatic brain metastases (BM) occur frequently after chemoradiotherapy (CRT) for stage III NSCLC. Aim of the current study was to determine whether the specific chemotherapy used in a CRT regimen influences BM development. MATERIALS AND METHODS: Retrospective multicenter study including all consecutive stage III NSCLC who completed CRT. Primary endpoints: symptomatic BM development, whether this was the only site of first relapse. Differences between regimens were assessed with a logistic regression model including known BM risk factors and the specific chemotherapy: concurrent versus sequential (cCRT/sCRT), within cCRT: daily low dose cisplatin (LDC)-cyclic dose polychemotherapy; LDC-(non-)taxane cyclic dose; LDC-polychemotherapy subgroups of >/=50 patients. RESULTS: Between January 2006 and June 2014, 838 patients were eligible (737 cCRT, 101 sCRT). 18.2% developed symptomatic BM, 8.0% had BM as only site of first relapse. BM patients were significantly younger, female, had more advanced N-stage and had adenocarcinoma histology. In both cCRT and sCRT BM were found in 18% (p=0.904). In cyclic dose cCRT (N=346) and LDC (N=391) BM were found in 18.8% and 17.9%, respectively (p=0.757). In 7.2% and 8.7%, respectively, BM were the only site of first relapse (p=0.463). The chemotherapy used (cCRT versus sCRT) had no influence on BM development, not for all brain relapses nor as only site of first relapse (OR 0.88 (p=0.669), OR 0.93 (p=0.855), respectively). LDC versus cyclic dose cCRT was not significantly different: neither for all brain relapses nor as only site of first relapse (OR 0.96 (p=0.819), OR 1.21 (p=0.498), respectively). Comparable results were found for LDC versus cyclic dose non-taxane (N=277) and cyclic dose taxane regimens (N=69) and for cCRT regimens with >/=50 patients (LDC versus cisplatin/etoposide (N=188), cisplatin/vinorelbin (N=65), weekly cisplatin/docetaxel (N=60)). CONCLUSION: approximately 18% developed symptomatic BM after stage III diagnosis, not dependent on type of chemotherapy regimen used within a CRT treatment.

Purpose To compare gefitinib with placebo in chemotherapy naïve patients with advanced non–small-cell lung cancer (NSCLC) and poor performance status. Patients and Methods NSCLC patients (chemotherapy naïve, WHO performance status 2 or 3; unfit for chemotherapy; stage IIIB/IV) were randomly assigned to gefitinib (250 mg/d) plus best supportive care (BSC; n = 100) or placebo plus BSC (n = 101). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), quality of life (QOL), pulmonary symptom improvement (PSI), and safety. Correlation of gefitinib efficacy with EGFR gene copy number (fluorescent in situ hybridization [FISH]) was explored. Results Hazard ratios (HRs; gefitinib:placebo) were 0.82 (95% CI, 0.60 to 1.12; P = .217) for PFS and 0.84 (95% CI, 0.62 to 1.15; P = .272) for OS. As expected for this patient population, OS for both arms was poor, at about 3 months. ORRs were 6.0% (gefitinib) and 1.0% (placebo). QOL and PSI rates were 21.1% and 28.3% (gefitinib) and 20.0% and 28.3% (placebo), respectively. In EGFR FISH-positive patients (n = 32), HRs were 0.29 (95% CI, 0.11 to 0.73) for PFS and 0.44 (95% CI, 0.17 to 1.12) for OS. No unexpected adverse events occurred. Conclusion There was no statistically significant difference in PFS, OS, and ORRs after treatment with gefitinib or placebo, in the overall population; improvements in QOL and symptoms were similar in both groups. Tolerability profile of gefitinib was consistent with previous studies. PFS was statistically significantly improved for gefitinib-treated patients with EGFR FISH-positive tumors.

Introduction Disease management and costs of treatment of patients with unresectable advanced non-small-cell lung cancer (NSCLC) in The Netherlands are not well known. Methods A retrospective medical chart review was performed by collecting data from the time of diagnosis until the time of death or the end of the evaluation period. In addition to the demographic data, information was collected on the overall management of the patient. Hospital resource utilisation data collected included number of outpatient specialist visits, number and length of hospitalisation, type and number of diagnostic and laboratory procedures, type and number of radiotherapy cycles and detailed information on chemotherapy. To evaluate the economic impact of second-line treatment, a distinction was made between patients who received only best supportive care (BSC, group A) and those who received chemotherapy as a second-line treatment in addition to BSC (group B). The study was performed from the hospital perspective and reports on 2005 costs. Results Of 102 patients, 74 belonged to group A and 28 to group B. Patient management included a multidisciplinary approach, the extent of which depended on symptoms of the disease and presence of metastases. The average total treatment cost per patient per year of unresectable advanced NSCLC in The Netherlands was €32,840 in group A and €31,187 in group B. In both groups, hospitalisation was the major cost driver. In group B second-line chemotherapy was the second largest contributor of the costs. In spite of the difference in numbers of treatment lines provided to patients in groups A and B the total average costs per patient per year were comparable. Overall, the management of unresectable advanced NSCLC appeared to conform with current guidelines in The Netherlands. Conclusion These patients show high medical resource consumption, with hospitalisation being the main cost driver in both groups. As economic arguments are becoming increasingly important in medical decision making on both national and local levels, this information is relevant for both policy makers and specialists. These data can also be used in future research to evaluate the economic impact of new therapies in NSCLC, especially of those that aim to treat patients in an outpatient setting.

The progression-free survival (PFS) of cyclophosphamide/doxorubicin/etoposide (CDE) and carboplatin/paclitaxel (CP) was compared in chemonaive patients with extensive disease small-cell lung cancer (ED-SCLC). A total of 203 patients were randomised to three-weekly CDE (n=102) or CP (n=101) for five cycles. Tumour response rates in CDE and CP were 60% and 61%. PFS of CP was 5.2 months, PFS of CDE 4.9 months (p=0.60). The major difference in toxicity between CDE and CP was grade 4 leukocytopaenia in 64% and 9% of the patients (p This study failed to demonstrate any benefit in PFS with CP compared with CDE. CP was associated with significantly less haematological toxicity, leading to 37% less hospital admissions for febrile neutropaenia. (c) 2007 Elsevier Ltd. All rights reserved.

The purpose of this study was to document the influence of chronic obstructive pulmonary diseases (COPD) on stage at diagnosis, treatment strategy, and survival for unselected cancer patients (35 years and older) diagnosed between 1995 and 2004 in the Eindhoven Cancer Registry. Follow-up of all patients was complete up to January 1st, 2006. Twelve percent of all cancer patients had COPD at the time of cancer diagnosis, being about 15% in elderly patients (65+) and up to 30% among lung cancer patients, middle-aged males and all females with oesophageal and laryngeal cancer, and middle-aged women with renal cancer. Stage at diagnoses was not significantly different between cancer patients with or without COPD, except for lung cancer patients who were diagnosed at an earlier stage. Nevertheless, non-small cell lung cancer (NSCLC) patients with COPD less frequently underwent surgery, and chemotherapy, and more often radiotherapy. In the presence of COPD, women with oesophageal cancer underwent surgery less often, and patients with laryngeal cancer received radiotherapy more often. The effect of COPD on the type of oncological treatment was not different for middle-aged (35-64 years) and elderly cancer patients. In a multivariate Cox-regression model, COPD was associated with a significantly worse survival, especially for elderly patients with colon, rectum, larynx, prostate or urinary bladder cancer. In conclusion, not surprisingly, COPD is related with age and smoking-associated tumours. Therapy of cancer patients with COPD was different for head and neck tumours and primary tumours in the chest organs (above the diaphragm), for whom radiotherapy, as an alternative treatment option, was available. As COPD, especially at older age, is frequently associated with a worse prognosis, further prospective investigation of interactions seems warranted. Further, closer involvement of pulmonologists and COPD nurses in elderly cancer patients might be warranted.

Anaemia seriously threatens the quality of life (QOL) in cancer patients receiving chemotherapy. In this article results are presented on the lung cancer population from a Dutch observational study. This study addressed the real-life situation of recombinant human erythropoietin (r-Hu-EPO or epoetin alfa) treatment in anaemic cancer patients receiving chemotherapy, with a focus on efficacy. In total 781 patients were enrolled in the observational study, including 382 patients with lung cancer. At enrolment patients were receiving epoetin alfa treatment and/or patients had a haemoglobin (Hb) level/=11.3g/dl. Analysis was focused on lung cancer patients who were treated with epoetin alfa (n=343). Type of cancer, chemotherapy agents, type of anaemia management and Hb levels were documented. Hb development was analysed and the effect of epoetin alfa treatment was investigated. In total 343 lung cancer patients were treated with epoetin alfa: 210 patients with non-small cell lung cancer (NSCLC) and 133 patients with small cell lung cancer (SCLC). The majority of patients (99.4%) received 40,000 IU epoetin alfa once weekly. Before epoetin alfa treatment was started during chemotherapy, Hb levels decreased with a rate of 1.3g/dl per 4 weeks, both for NSCLC as well as for SCLC. Epoetin alfa treatment was started on average at an Hb level of 10.6g/dl for NSCLC and 10.4g/dl for SCLC, respectively. Hb increases of 0.5-0.6g/dl per 4 weeks and 0.2g/dl per 4 weeks were reached for NSCLC and SCLC, respectively. Although significant increases of Hb levels were reached, the epoetin alfa treatment could not fully correct the Hb decrease which had taken place during chemotherapy before the start of epoetin alfa, resulting in suboptimal Hb levels. In contrast, early intervention with epoetin alfa (start in first week of chemotherapy at Hb11.3g/dl) was especially effective for NSCLC patients where it resulted in a stabilization of Hb at baseline level. For SCLC patients this strategy was less effective. Furthermore, early intervention seemed to diminish the need for a blood transfusion, i.e., the higher the Hb at epoetin initiation the more patients did not receive any blood transfusion. Results from this observational study demonstrate that epoetin alfa treatment corrects chemotherapy-related anaemia in both NSCLC as well as SCLC patients. Early epoetin alfa intervention seems advantageous for lung cancer patients both in terms of maintaining adequate Hb levels during chemotherapy as well as reducing transfusions.

IntroductionThe lung is the most common extraabdominal site for metastases from colorectal cancer. Patients with untreated metastatic disease have a median survival of less than 10 months and a 5-year survival of less than 5%. The purpose of this study was to evaluate long-term survival in patients who underwent pulmonary resection for metastases from colorectal cancer.MethodsBetween January 1990 and January 2005, 23 patients underwent 29 operations for resection of lung metastases.ResultsMedian age was 68 years (range: 46–80 years). Median follow-up was 30 months (range: 12–149 months). The 2- and 5-year overall survival rates were 64 and 26%, respectively. Of the 23 patients, 16 patients had a solitary lesion, and seven patients had multiple lesions. The 5-year survival rates were 23 and 33%, respectively (not significant). The median disease-free interval (DFI)—the interval between colon resection and the appearance of lung metastases—was 43 months (1–168). Ten patients had DFIs 36 months. The 3-year survival rates were 20 and 38%, respectively (not significant). Recurrence of lung metastases was diagnosed in seven patients; three patients underwent second resections. They are alive today, with a median follow-up of 18 months. Patients who did not undergo second resections had a median survival of 12 months.ConclusionsPulmonary resection for metastases from colorectal cancer does produce longer survival, even in patients with multiple lesions and recurrent metastases.

Management of small cell lung cancer (SCLC) among elderly is complex because of decreased organ functions and interactions with comorbidity. Since elderly patients are often excluded from clinical trials, little is known about the way they are treated and outcome. We evaluated the prognostic effects of rising age and comorbidity in unselected Dutch SCLC patients (Eindhoven Cancer Registry). Elderly patients received chemotherapy less often and the dose was also reduced more often. Cardiovascular diseases, hypertension or diabetes lowered the proportion receiving combined chemotherapy and radiotherapy among patients with limited disease. About 80% of the patients receiving chemotherapy suffered from a side effect, which was not related to age. After adjustment for age, gender, stage and treatment modality, comorbidity had a negligible prognostic effect. Chemotherapy (in combination with radiotherapy) seemed to improve survival, however, toxicity and quality of life in these patients should be evaluated thoroughly in future randomized studies.

The chance for elderly patients with NSCLC to receive chemotherapy decreases significantly with age. In addition, older patients are often underrepresented in clinical trials. Consequently, due to the paucity of data, evidence-based decisions with regard to chemotherapy treatment strategies in the elderly are lacking.We performed a literature search to identify mainly randomized trials focusing on treatment of NSCLC in older patients with chemotherapy and targeted therapy, toxicity and quality of life. In conclusion, the efficacy of regular chemotherapy and targeted therapy seems quite similar in older patients compared to their younger counterparts, with increased toxicity, but acceptable. However, these data are mostly derived from subgroup analyses and highly selected fit patients, which may not represent the general older population.Further research is necessary to investigate the role of a comprehensive geriatric assessment in older patients, before the start of a chemotherapeutic treatment. Proteomic tests can have potential in the future, if these tests turn out to be able to separate patients with advanced NSCLC into groups with better or worse outcomes. It can be of special interest for the elderly population, to prevent unnecessary side effects of a possible inferior treatment.

To assess the therapeutic activity of accelerated cisplatin and high-dose epirubicin with erythropoietin and G-CSF support as induction therapy for patients with stage IIIa-N2 non-small-cell lung cancer (NSCLC). Patients with stage IIIa-N2 NSCLC were enrolled in a phase II trial. They received cisplatin 60 mg m(-2) and epirubicin 135 mg m(-2) every 2 weeks for three courses combined with erythropoietin and G-CSF. Depending on results of clinical response to induction therapy and restaging, patients were treated with surgery or radiotherapy. In total, 61 patients entered from March 2001 to April 2004. During 169 courses of induction chemotherapy, National Cancer Institute of Canada (NCI-C) grade III/IV leucocytopenia was reported in 35 courses (20.7%), NCI-C grade III/IV thrombocytopenia in 26 courses (15.4%) and NCI-C grade III/IV anaemia in six courses (3.6%). Main cause of cisplatin dose reduction was nephrotoxicity (12 courses). Most patients received three courses. There were no chemotherapy-related deaths. Three patients were not evaluable for clinical response. Twenty-eight patients had a partial response (48.3%, 95% CI: 36-61.1%), 24 stable disease and six progressive disease. After induction therapy, 30 patients underwent surgery; complete resection was achieved in 19 procedures (31.1%). Radical radiotherapy was delivered to 25 patients (41%). Six patients were considered unfit for further treatment. Median survival for all patients was 18 months. Response rate of accelerated cisplatin and high-dose epirubicin as induction chemotherapy for stage IIIa-N2 NSCLC patients is not different from more commonly used cisplatin-based regimen.

The objective of this phase II study was to document activity and toxicity of docetaxel and cisplatin as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) before definitive local treatment. Forty-six chemotherapy-nai¨ve patients (median age 60 years) were included. Treatment consisted of 3 cycles of docetaxel (85 mg/m2 on day 1), followed by cisplatin (40 mg/m2/day on days 1 and 2) every 21 days. Grade 3–4 leukopenia and neutropenia occurred in 45.7% and 65.2% of the patients, respectively. Among 8 cases of febrile neutropenia (17.4%), one (2.2%) resulted in early death. Common grade 3–4 non-haematological toxicities were nausea (17.4%) and vomiting (13%). Eighty-five percent of the patients received three courses; six stopped prematurely due to toxicity, one due to protocol violation. Response rate was the primary endpoint of this study. Considering eligible patients (n = 40), 18 responses (1 complete and 17 partial responses) were observed (response rate 45%; 95% Confidence interval (CI): 29.3%–61.5%). In stage IIIA-N2 NSCLC patients, docetaxel-cisplatin could be administered and demonstrated manageable toxicity with modest efficacy.

Purpose Recently, a Dutch, randomized, phase III trial demonstrated that, in small-cell lung cancer patients at risk of chemotherapy-induced febrile neutropenia (FN), the addition of granulocyte colony-stimulating factor (GCSF) to prophylactic antibiotics significantly reduced the incidence of FN in cycle 1 (24% v 10%; P = .01). We hypothesized that selecting patients at risk of FN might increase the cost-effectiveness of GCSF prophylaxis. Methods Economic analysis was conducted alongside the clinical trial and was focused on the health care perspective. Primary outcome was the difference in mean total costs per patient in cycle 1 between both prophylactic strategies. Cost-effectiveness was expressed as costs per percent-FN-prevented. Results For the first cycle, the mean incremental costs of adding GCSF amounted to 681 euro (95% CI, −36 to 1,397 euro) per patient. For the entire treatment period, the mean incremental costs were substantial (5,123 euro; 95% CI, 3,908 to 6,337 euro), despite a significant reduction in the incidence of FN and related savings in medical care consumption. The incremental cost-effectiveness ratio was 50 euro per percent decrease of the probability of FN (95% CI, −2 to 433 euro) in cycle 1, and the acceptability for this willingness to pay was approximately 50%. Conclusion Despite the selection of patients at risk of FN, the addition of GCSF to primary antibiotic prophylaxis did not result in cost savings. If policy makers are willing to pay 240 euro for each percent gain in effect (ie, 3,360 euro for a 14% reduction in FN), the addition of GCSF can be considered cost effective.

Response rate and toxicity of second-line therapy with docetaxel (75 mg m(-2)) or docetaxel, irinotecan, and lenogastrim (60 mg m(-2), 200 mg m(-2), and 150 mug m(-2) day(-1), respectively) were compared in 108 patients with stage IIIb - IV non-small-cell lung cancer. Addition of irinotecan to docetaxel does not improve response rate, and increases gastrointestinal toxicity.

Purpose The objective of this study was to determine the accuracy of (early) response measurements using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG PET) with respect to survival of patients with stage IIIA-N2 non–small-cell lung cancer (NSCLC) undergoing induction chemotherapy (IC), with a comparative analysis of PET methods. Patients and Methods In a prospective multicenter study, PET was performed in patients before IC and after one and three cycles. Computed tomography (CT) was performed before and after IC. Glucose consumption (metabolic rate of glucose [MRglu]) was measured using Patlak graphical analysis and correlated with simplified methods. Mediastinal lymph node (MLN) status was assessed visually. Cox proportional hazards analysis was used to determine the prognostic relevance of CT and PET measures of response with respect to survival. Results Complete PET data sets were available in 47 patients. Median survival was 21 months. MLN status after IC by PET predicted survival (hazard ratio [HR], 2.33; 95% CI, 1.04 to 5.22; P = .04) in contrast with CT (HR, 1.87; 95% CI, 0.81 to 4.30; P = .14). Residual MRglu after IC proved to be the best prognostic factor (HR, 1.95; 95% CI, 1.28 to 2.97; P = .002). Multivariate stepwise analysis showed that PET identified prognostically different strata in patients considered responsive according to CT. Residual MRglu after one cycle selected patients with different outcomes (HR, 2.04; 95% CI, 1.18 to 3.52; P = .01). Simplified quantitative 18FDG PET methods were correlated with Patlak graphical analysis during and after therapy (r ≥ 0.90). Conclusion 18FDG PET has additional value over CT in monitoring response to IC in patients with stage IIIA-N2 NSCLC, and it seems feasible to predict survival early during IC. Simple semiquantitative and complex PET methods perform equally well.

Introduction L’efficacite et la tolerance du pemetrexed + cisplatine (PC) et radiotherapie thoracique concomitante (RTTc), suivie d’une consolidation par P vs autres chimiotherapies ont ete evaluees ; les resultats intermediaires de tolerance ont ete presentes (Vokes et al., 2013). Methodes Cinq cent quatre-vingt-dix-huit patients (268 en Europe, 22 en France) avec un CBNPC non epidermoide de stade III non resecable ont ete randomises entre 3 cycles de PC + RTTc (66 Gy) suivi de 4 cycles de consolidation par pemetrexed vs le bras controle 2 cycles etoposide + cisplatine (EC) + RTTc (66 Gy) suivi de 2 cycles de consolidation par EC, vinorelbine + Cis ou paclitaxel + carboplatine. L’objectif principal est la survie globale (SG). La survie sans progression (SSP), le taux de reponse objective et la tolerance sont des objectifs secondaires. Cet essai de superiorite est concu pour atteindre 80 % de puissance en supposant un HR = 0,74 avec 355 evenements et un risque α bilateral a 0,05. Resultats Cinq cent cinquante-cinq patients ont ete traites : 283 par PC, 272 par EC. Les caracteristiques initiales etaient equilibrees : âge : 60/59 ; %femme : 41/40 ; %stade IIIB : 54/51 ; %stade par TEP-scan : 83/81 ; %ECOG PS1 : 51/50. La SG mediane pour PC vs EC etait de 26,8 m vs 25,0 m (HR 0,98 ; IC95 % : 0,79–1,20 ; p = 0,831) et la SSP mediane de 11,4 m vs 9,8 m (HR 0,86 ; IC95 % : 0,71–1,04 ; p = 0,130). Le taux de reponse pour PC vs EC etait de 35,9 % vs 33,0 % (p = 0,458) et le taux de controle de la maladie de 80,7 % vs 70,7 % (p = 0,004). Des toxicites de G3/4 possiblement liees au traitement (PC vs EC) sont survenues chez 64,0 % vs 76,8 % des pts (p = 0,001). Une incidence plus faible de neutropenie/granulocytopenie de G3/4 possiblement liees au traitement a ete observee dans le bras PC : 24,4 % vs 44,5 % (p Conclusion Le bras PC n’a pas ameliore la SG, mais montre un meilleur profil de tolerance que le bras EC.

Purpose: To compare the therapeutic efficacy of paclitaxel plus cisplatin (arm A) versus gemcitabine plus cisplatin (arm B) and arm A versus paclitaxel plus gemcitabine (arm C) in chemotherapy-naive patients with advanced non–small-cell lung cancer (NSCLC). Materials and Methods: Patients were randomly assigned to receive either paclitaxel 175 mg/m2 (3-hour infusion, day 1) or gemcitabine 1,250 mg/m2 (days 1 and 8) both combined with cisplatin 80 mg/m2 (day 1) or paclitaxel 175 mg/m2 (3-hour infusion, day 1) combined with gemcitabine 1,250 mg/m2 (days 1 and 8). Primary end point was comparison of overall survival for B versus A and C versus A. Secondary end points included response rate and duration, progression-free survival, toxicities, quality of life [QoL], and cost of treatment. Results: Four hundred eighty patients (arm A, 159; arm B, 160; arm C, 161 patients) were enrolled; all baseline characteristics were balanced. Median survival times were as follows: arm A, 8.1 months; arm B, 8.9 months; arm C, 6.7 months. Response rates were 31.8% for arm A, 36.6% for arm B, and 27.7% for arm C. Other than myelosuppression (B v A, P < .005), no statistically or clinically significant differences were observed for secondary end points. The average treatment costs were 25% higher in arm C as compared with arms A and B. Conclusion: Gemcitabine plus cisplatin and paclitaxel plus gemcitabine do not increase overall survival in patients with advanced NSCLC as compared with paclitaxel plus cisplatin. Treatment was well tolerated, and most QoL parameters were similar, but costs associated with the nonplatinum arm were highest.

The aim of this study was to document the activity and toxicity of paclitaxel (Taxol)/carboplatin when used as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) prior to definitive local treatment within a large, ongoing comparative study (EORTC 08941). 52 eligible, consenting, chemotherapy-naive patients with NSCLC, median age of 60 years, stage IIIA N2 disease and the ability to tolerate a pneumonectomy received paclitaxel 200 mg/m2 as a 3-h infusion followed by carboplatin at an area under the concentration curve (AUC) of 6 every 3 weeks for three courses. Most patients received three courses. No grade 3/4 anaemia or thrombocytopenia was documented. Over all of the cycles, 6% (3 patients) experienced grade 3 leucopenia while 63% (32/51 patients) experienced grade 3-4 neutropenia. There was 1 patient (2%) with febrile neutropenia, no early or toxic deaths and no hypersensitivity reactions. Severe non-haematological toxicity was uncommon, with the exception of grade 3 alopecia in 39%, lethargy in 8% and myalgia in 6%. Of the eligible patients (n=52), there was one complete response (CR) and 32 partial responses (PR), resulting in a response rate of 64% (95% Confidence Interval (CI) 49%-76%). Of the 15 eligible patients randomised to surgery after induction chemotherapy, 3 patients did not receive surgery and 2 patients (n=12) had no tumour in the mediastinal nodes (17%). Resections were considered complete in 2 of the 12. Median survival for all eligible patients (n=52) was 20.5 months (95% CI 16.1-31.2), with an estimated 1-year survival rate of 68.5% (95% CI 55.2-81.7). In patients with N2 stage IIIA NSCLC, paclitaxel/carboplatin is an active and very well-tolerated induction regimen.

Combined modality treatment (CMT) for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is at present studied extensively. To select patients with truly stage IIIA-N2 disease, however, proves to be difficult with current diagnostic tests. Distant metastases may become clinically overt during induction chemotherapy (IC) or shortly after, revealing the inaccuracies of current staging algorithms. A prospective study with [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in IIIA-N2 NSCLC patients was performed to assess its value in the selection of this patient group. Fifty-seven patients received a whole body FDG PET scan as part of an ongoing response monitoring trial. Results were compared with conventional staging. In 32/57 (56%) PET suggested upstaging, which was confirmed in 17/57 (30%) with a median follow-up of 16 (range 2-49) months. These results show that using the conventional staging algorithm a substantial group of patients was understaged. FDG PET improves the selection of patients suitable for CMT.

Item does not contain fulltext 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.

Although recombinant human interleukin-3 (rhIL-3) shortens both the duration of chemotherapy-induced neutropenia and thrombocytopenia, its effect on nadir counts is limited. Concurrent administration of rhIL-3 and chemotherapy may enhance this effect. However, simultaneous administration of other hematopoietic growth factors and chemotherapy has resulted in enhanced myelosuppression. We investigated whether concomitant administration of rhIL-3 and chemotherapy would result in enhanced myelosuppression. Twelve patients with relapsed small cell lung cancer received vincristine, ifosfamide, mesna, and carboplatin on day 1 every four weeks. RhIL-3 was administered subcutaneously on days 1-14 during cycle 1 at doses of 4 (three patients) or 8 micrograms/kg/day (nine patients). During cycle 2 patients received only chemotherapy. No significant difference in leukocyte (1.4 +/- 1.0 vs. 0.9 +/- 0.4 x 10(9)/l (mean +/- SD), neutrophil (0.5 +/- 0.6 vs. 0.2 +/- 0.2 x 10(9)/l), and platelet (64 +/- 60 vs. 38 +/- 58 x 10(9)/l) nadir counts were demonstrated. The hemoglobin nadir level was significantly higher during cycle 1 (6.5 +/- 1.1 vs. 5.5 +/- 0.9 mmol/l, P = 0.05). Both leukocyte and platelet recovery were significantly enhanced in the rhIL-3 cycle. There was no significant difference in chemotherapy postponement or platelet transfusions. As a result of severe headaches, rhIL-3 administration was discontinued in one patient at 8 micrograms. RhIL-3 during this chemotherapy regimen for relapsed small cell lung cancer did not enhance myelotoxicity but did improve bone marrow recovery. This observation may increase the application of rhIL-3, for instance in combination with other hematopoietic growth factors.

The present study is the first on the trends in comorbidity among patients with small-cell lung cancer. In particular, hypertension and pulmonary, cardiac, and vascular disease have become more common. Multimorbidity and cardiac and digestive disease have affected survival in those with limited-stage disease, and cardiac and cerebrovascular disease have decreased the survival of patients with extensive disease. These data are relevant for treatment decisions and patient communication in daily clinical practice. Introduction: We evaluated the trends in the prevalence of comorbidity and its prognostic impact in a cohort of unselected patients with small-cell lung cancer (SCLC). Patients and Methods: All patients (n = 4142) diagnosed with SCLC from 1995 to 2012 were identified from the population-based Netherlands Cancer Registry in the Eindhoven region. Results: The prevalence of comorbidity increased from 55% in 1995 to 1998 to 76% in 2011 to 2012 and multimorbidity (ie, >= 2 concomitant diseases) from 23% to 51%. The prevalence of a comorbidity increased with age. Among the men, hypertension, cardiac disease, and diabetes, in particular, became more common (increased from 11% to 35%, from 19% to 36%, and from 7% to 18%, respectively). In the women, the rate of pulmonary disease, hypertension, and cardiac disease increased the most (increased from 18% to 30%, from 12% to 28%, and from 11% to 24%, respectively). Multimorbidity was associated with a slightly increased hazard of death, independent of treatment in those with limited-stage SCLC (hazard ratio [HR] for >= 2 comorbidities vs. no comorbidities, 1.2; 95% confidence interval [CI], 1.0-1.4). The prognostic effects of multimorbidity resulted from treatment in those with extensive-stage SCLC (HR for >= 2 comorbidities vs. no comorbidities, final model, 1.2; 95% CI, 1.0-1.2). The prognostic impact of the specific comorbidities varied, with digestive disease reducing the hazard and cardiac disease increasing the hazard in those with limited-stage SCLC (HR for digestive disease vs. no digestive disease, 0.7 [95% CI, 0.5-0.9], and HR for cardiac vs. no cardiac disease, 1.2 [95% CI, 1.0-1.3]). Also, cardiac and cerebrovascular disease increased the hazard in those with extensive-stage SCLC (HR 1.2 [95% CI, 1.0-1.3] and HR 1.3 [95% CI, 1.1-1.6], respectively). Conclusion: Comorbidity among patients with SCLC is very common and has been increasing. Multimorbidity was associated with a slightly increased hazard of death in those with limited-stage SCLC, independent of treatment. However, the prognostic effects in those with advanced-stage SCLC resulted from treatment. Digestive disease favorably affected survival and cardiac disease negatively affected the prognosis for those with limited-stage SCLC, and cardiac and cerebrovascular diseases had a negative prognostic effect for those with extensive-stage SCLC. With the burden of comorbidities in patients with SCLC increasing, more attention to individualized treatment approaches is needed. (C) 2015 Elsevier Inc. All rights reserved.

Objectives The aim was to determine if combined pemetrexed, cisplatin, and cetuximab was efficacious and safe as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC). Patients and methods In this single-arm, multicenter clinical trial, patients with Stage IIIB/IV nonsquamous NSCLC received first-line therapy consisting of pemetrexed (500mg/m 2 ) and cisplatin (75mg/m 2 ) on Day 1 (21-day cycles) plus weekly cetuximab (400mg/m 2 loading dose, then 250mg/m 2 ) for 4–6 cycles. Non-progressing patients received maintenance therapy consisting of pemetrexed and cetuximab as above until disease progression. All patients received vitamin supplementation, dexamethasone, and antihistamine prophylaxis. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), 1-year survival rate, translational research (TR) and safety. Results Of the 113 patients receiving study drug, 109 were protocol-qualified. All patients completed ≥1 cycle of induction, and 51 (45%) and 49 (43%) patients completed ≥1 cycle of maintenance with pemetrexed and cetuximab, respectively. The ORR ( n =109) was 38.5% (80% confidence interval [CI], 32.3–45.1%), all partial responses. Median PFS was 5.8 (80% CI, 4.4–6.7) months. One-year survival rate was 45% (80% CI, 39–51%). In exploratory analyses, there was some preliminary evidence of potential prognostic relationships with efficacy outcomes for epidermal growth factor receptor and thyroid transcription factor-1 protein expression, but not for KRAS mutation or for thymidylate synthase or folate receptor-alpha protein expression. Seventy-three (64.6%) patients had study drug-related Grade 3/4 adverse events (AEs). Drug-related serious AEs were reported in 31 (27.4%) patients. There were 3 (2.7%) potentially drug-related deaths on-study or within 30 days of follow up. Conclusion Pemetrexed, cisplatin, and cetuximab appeared efficacious and tolerable in advanced nonsquamous NSCLC patients. The TR outcomes are hypothesis-generating given the study's size and nonrandomized nature.

8506Background: aCT improves overall survival in pts with completely resected stage II/ III NSCLC. LMWH may also improve survival. We hypothesized that in pts with completely resected NSCLC adding ...

Purpose This trial evaluated the efficacy and safety of sorafenib plus gemcitabine/cisplatin in chemotherapy-naive patients with unresectable stage IIIB to IV nonsquamous non–small-cell lung cancer (NSCLC). Patients and Methods Between February 2007 and March 2009, 904 patients were randomly assigned to daily sorafenib (400 mg twice a day) or matching placebo plus gemcitabine (1,250 mg/m2 per day on days 1 and 8) and cisplatin (75 mg/m2 on day 1) for up to six 21-day cycles. Because of safety findings from the Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC (ESCAPE) trial, patients with squamous cell histology were withdrawn from the trial in February 2008 and excluded from analysis. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS) and time-to-progression (TTP). Results The primary analysis population consisted of 772 patients (sorafenib, 385; placebo, 387); the two groups had similar demographic and baseline characteristics. Median OS was similar in the sorafenib and placebo groups (12.4 v 12.5 months; hazard ratio [HR], 0.98; P = .401). By investigator assessment, sorafenib improved median PFS (6.0 v 5.5 months; HR, 0.83; P = .008) and TTP (6.1 v 5.5 months; HR, 0.73; P < .001). Grade 3 to 4 drug-related adverse events more than two-fold higher in the sorafenib group included hand-foot skin reaction (8.6% v 0.3%), fatigue (7.3% v 3.6%), rash (5.7% v 0.5%), and hypertension (4.2% v 1.8%). No unexpected toxicities were observed. Conclusion This study did not meet its primary end point of improved OS when sorafenib was added to first-line gemcitabine/cisplatin in patients with advanced nonsquamous NSCLC. Identification of predictive biomarkers is warranted in future trials of sorafenib.