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Lung cancer remains one of the tumour diagnoses with high lethality, although innovative treatment approaches have yielded improvements in local control and survival rates. There is still no consensus on how to treat local relapse in patients after first-line treatments. Radiotherapy may be considered in this situation; however, data supporting its effectiveness are rare. The purpose of this retrospective analysis was to evaluate outcomes of patients re-irradiated for thoracic tumours in terms of overall survival (OS), local progression-free survival (LPFS), toxicity and dose–volume parameters. Sixty-two patients with locally recurrent previously irradiated lung cancer were analysed retrospectively (NSCLC n = 52, SCLC n = 10). Target volumes both in lung and mediastinum were re-irradiated with conventional three-dimensional or intensity-modulated radiotherapy techniques. Median overall dose of re-irradiation was 38.5 Gy (range 20–60 Gy) with a median single dose per fraction of 2 Gy (1.8–3.0 Gy). Clinical documents and treatment plans were evaluated. Median follow-up was 8.2 months (range 0–27 months). OS following re-irradiation was 9.3 months (range: 0–27 months) and LPFS was 6.5 months (range: 0–24 months). OS and LPFS were not affected by histology, total dose or patient age and gender. OS was improved in patients whose re-irradiation volumes included less than two mediastinal lymph node stations (p = 0.016). Twelve patients suffered from pneumonitis ≥grade II (19%) and two from pneumonitis grade III. One patient presumably died from pneumonitis grade V. A slight decline in forced expiratory volume (FEV1) was detected in post-re-irradiation lung function testing. Re-irradiation is an option for patients with tumour recurrence to control local progression and lower the symptom burden. Oncological outcome appears to be affected by size, location of mediastinal target volumes and lung function. Prospective clinical trials are warranted to substantiate the role of re-irradiation in recurrent lung cancer.

Background Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years’ follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results After 40.3 months’ minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50–0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61–0.81). Rates of treatment-related hepatic adverse events (primarily grade 1–2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions After 3 years’ minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.

The aim of this work was to evaluate exercise behavior and physical fitness of advanced lung cancer patients shortly after primary diagnosis. Between November 2013 and December 2016, advanced lung cancer patients (n = 227, mean age 62.2 years) were enrolled shortly after diagnosis and 211 patients were tested for endurance capacity (six-minute walk test) and strength performance (maximum voluntary isometric contraction of upper and lower extremities). Current and previous exercise and walking behavior were assessed using a self-reported questionnaire regarding type, frequency, intensity, and duration. Paired Student’s t tests were used to compare physical fitness to reference data. The relation of potential determinants with physical fitness was assessed using linear regression analysis. Exercise behavior was superior in the year before diagnosis compared to the time of study enrollment. Patients reduced frequency, intensity, and duration of sports/exercise after their lung cancer diagnosis. We observed significantly lower endurance capacity (p

Background In 2007, the European Organization for Research and Treatment of Cancer (EORTC) study ( ClinicalTrials.gov identifier, NCT00016211 ) demonstrated a beneficial effect on overall survival (OS) with the use of prophylactic cranial irradiation (PCI) for extensive disease (ED) small-cell lung cancer (SCLC). Nevertheless, debate is ongoing regarding the role of PCI, because the patients in that trial did not undergo magnetic resonance imaging (MRI) of the brain before treatment. Also, a recent Japanese randomized trial showed a detrimental effect of PCI on OS in patients with negative pretreatment brain MRI findings. Materials and Methods We examined the medical records of 136 patients with ED SCLC who had initially responded to chemotherapy and undergone PCI from 2007 to 2015. The outcomes, radiation toxicity, neurologic progression-free survival, and OS after PCI were analyzed. Survival and correlations were calculated using log-rank and univariate Cox proportional hazard ratio analyses. Results The median OS and the median neurologic progression-free survival after PCI was 12 and 19 months, respectively. No significant survival difference was seen for patients who had undergone MRI before PCI compared with patients who had undergone contrast-enhanced computed tomography (P = .20). Univariate analysis for OS did not show a statistically significant effect for known cofactors. Conclusion In the present cohort, PCI was associated with improved survival compared with the PCI arm of the EORTC trial, with a nearly doubled median OS period. Also, the median OS was prolonged by 2 months compared with the irradiation arm of the Japanese trial.

The purpose of this study was to evaluate prognostic factors associated with overall survival (OS) and neurological progression free survival (nPFS) in small-cell lung cancer (SCLC) patients with brain metastases who received whole-brain radiotherapy (WBRT). From 2003 to 2015, 229 SCLC patients diagnosed with brain metastases who received WBRT were analyzed retrospectively. In this cohort 219 patients (95%) received a total photon dose of 30 Gy in 10 fractions. The prognostic factors evaluated for OS and nPFS were: age, Karnofsky Performance Status (KPS), number of brain metastases, synchronous versus metachronous disease, initial response to chemotherapy, the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class and thoracic radiation. Median OS after WBRT was 6 months and the median nPFS after WBRT was 11 months. Patients with synchronous cerebral metastases had a significantly better median OS with 8 months compared to patients with metachronous metastases with a median survival of 3 months (p

A consistent pain management together with treatment of dyspnoea belongs to the main issues in symptom control in particular in palliative thoracic oncology. Together with the medicamentous therapy the psychologic and social circumstances of the affected patients have to be considered as factors influencing the experience of pain. The therapeutic fundament according to the WHO guideline for cancer pain is the opiate based medicamentous adjustment combined with non-opioids. In principle, this should be performed preferably orally, as simply as possible, according to a fix drug schedule and individually adjusted to the needed dosage. Breakthrough pain has to be treated with rapidly efficacious, non-retarded analgetics. The typical adverse reaction profile for opiates like constipation and initial nausea should be considered prophylactically by applying concurrent medication with adjuvants. Co-analgesic drugs like anticonvulsiva or corticosteroids could support the analgetic effect and are used preferably in case of neuropathic pain. Primary aim in analgesic therapy is to achieve the best possible pain reduction and hence to safeguard quality of life.

Denise Bernhardt,1–3,* Sophie Aufderstrasse,1,2,* Laila König,1–3 Sebastian Adeberg,1–4 Farastuk Bozorgmehr,5,6 Petros Christopoulos,5,6 Rami A El Shafie,1,2 Juliane Hörner-Rieber,1–3 Jutta Kappes,6,7 Michael Thomas,5,6 Felix Herth,6,7 Martin Steins,5 Jürgen Debus,1–4 Stefan Rieken1–3 1Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany; 2Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany; 3Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany; 4Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 5Department of Thoracic Oncology, Thoraxklinik, Heidelberg University, Translational Lung Research Centre Heidelberg (TLRC-H), Heidelberg, Germany; 6German Centre for Lung Research (DZL), Heidelberg, Germany; 7Department of Pneumology, Thoraxklinik, Heidelberg University, Heidelberg, Germany *These authors contributed equally to this work Background: Systemic inflammation appears to play a role in the progression of numerous solid tumors by promoting tumor proliferation. Our current study aimed to evaluate the role of inflammatory markers in limited disease (LD) small-cell lung cancer (SCLC) patients undergoing thoracic chemoradiotherapy (TCR). Patients and methods: We retrospectively analyzed a total number of 350 SCLC patients diagnosed with LD SCLC who received TCR between 1999 and 2017 and had available blood tests within 2 weeks prior to the start of TCR. Serum C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), hemoglobin (Hb) levels, and platelet count (Pc) were evaluated as potential inflammatory markers. Kaplan–Meier survival analysis was performed for overall survival (OS). For comparison of survival curves, the log-rank (­Mantel–Cox) test was used. Univariate and multivariate Cox proportional HRs were used to assess the influence of cofactors on OS. Results: Univariate analysis for OS revealed a statistically significant effect for LDH >400 U/L (HR 2.05 U/L; 95% CI 1.29–3.26 U/L;P=0.002), prophylactic cranial irradiation (PCI; HR 0.58; 95% CI 0.40–0.85;P=0.005), CRP >50 mg/L (HR 1.49 mg/L; 95% CI 1.05–2.10 mg/L;P=0.026), and Karnofsky performance scale (KPS) 70 years), Hb levels, and Pc did not influence survival. In multivariate analysis, OS was significantly affected by PCI (HR 0.64; 95% CI 0.43–0.94; P=0.026), LDH >400 U/L (HR 1.91 U/L; 95% CI 1.21–3.05 U/L;P=0.006), and CRP >50 mg/L (HR 1.43 mg/L; 95% CI 1.01–2.04 mg/L;P=0.045). KPS (≤70%) did not influence survival in multivariate analysis. Conclusion: Elevated CRP and LDH seem to be the independent prognostic factors for OS in LD SCLC patients undergoing TCR. However, elevated NLR was not found to be an independent prognostic factor for OS if taken prior to TCR. LDH and CRP are easily available blood tests and do not require additional resources for routine use and could be useful for clinical decision making. Keywords: small-cell lung cancer, limited disease, comorbidity, NLR, LDH, CRP

Die Prognose des Lungenkarzinoms bleibt trotz Fortschritten in der Therapie weiterhin ernst. Die Behandlung hangt dabei entscheidend vom Tumorstadium und von individuellen Faktoren der Patienten ab. Dieser Beitrag gibt Ihnen ein Update zur stadienabhangigen Therapie des Lungenkarzinoms.

The epidermal growth factor receptor (EGFR) has been implicated in a multiplicity of cancer-related signal transduction pathways like cellular proliferation, adhesion, migration, neoangiogenesis and apoptosis inhibition, all of which are important features of cancerogenesis and tumour progression. Its tyrosine kinase activity plays a central role in mediating these processes and has been intensely studied to exploit it as a therapeutic target. Inhibitors of this pathway have been developed and assessed in trials with significant efficacy in clinical applications. The current review focuses in particular on the clinical data of EGFR tyrosine kinase inhibition in different tumour entities, preferably non-small cell lung cancer and pancreatic cancer with emphasis to the approved small molecule erlotinib. Its clinical applications, evidence-based efficacy and toxicity as well as predictive markers of response are discussed.

Angesichts der demographischen Entwicklung der kommenden Jahrzehnte wird der Anteil der alteren Lungenkrebs-Patienten bei einem aktuellen Altersmedian von 68 Jahren weiter ansteigen. Dabei ist hoheres Lebensalter grundsatzlich kein alleiniger Ausschlussgrund fur eine Therapiemodalitat, vielmehr mussen individuell Allgemeinzustand und Komorbiditatsstatus berucksichtigt werden. In den fruhen Stadien besteht in Hinsicht auf den Therapieerfolg eine leichtgradige Uberlegenheit fur die Lobektomie gegenuber einer sublobaren Resektion, im Falle einer funktionellen Inoperabilitat steht die stereotaktische Radiotherapie als sinnvolle Alternative zur Verfugung. Patienten in lokoregionar fortgeschrittenen Stadien werden wenn moglich radio-/chemotherapiert. Bei Einschrankungen wird auf eine kurativ dosierte alleinige Radiotherapie zuruckgegriffen. Im fernmetastasierten Stadium kommen Carboplatin-haltige Kombinationsschemata oder Monotherapien zur Anwendung. Hier sind im Besonderen stratifizierbare zielgerichtete Therapien bei der Detektion von pradiktiven Biomarkern zu berucksichtigen. Nicht zu vernachlassigen ist im fortgeschrittenen Stadium die fruhzeitige palliativmedizinische Versorgung im Hinblick auf Symptomkontrolle und psychosozialer Begleitung.

BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. METHODS We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. RESULTS The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P

Purpose Nivolumab, a programmed death-1 inhibitor, prolonged overall survival compared with docetaxel in two independent phase III studies in previously treated patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identifier: NCT01642004) or nonsquamous (CheckMate 057; ClinicalTrials.gov identifier: NCT01673867) non–small-cell lung cancer (NSCLC). We report updated results, including a pooled analysis of the two studies. Methods Patients with stage IIIB/IV squamous (N = 272) or nonsquamous (N = 582) NSCLC and disease progression during or after prior platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Minimum follow-up for survival was 24.2 months. Results Two-year overall survival rates with nivolumab versus docetaxel were 23% (95% CI, 16% to 30%) versus 8% (95% CI, 4% to 13%) in squamous NSCLC and 29% (95% CI, 24% to 34%) versus 16% (95% CI, 12% to 20%) in nonsquamous NSCLC; relative reductions in the risk of death with nivolumab versus docetaxel remained similar to those reported in the primary analyses. Durable responses were observed with nivolumab; 10 (37%) of 27 confirmed responders with squamous NSCLC and 19 (34%) of 56 with nonsquamous NSCLC had ongoing responses after 2 years’ minimum follow-up. No patient in either docetaxel group had an ongoing response. In the pooled analysis, the relative reduction in the risk of death with nivolumab versus docetaxel was 28% (hazard ratio, 0.72; 95% CI, 0.62 to 0.84), and rates of treatment-related adverse events were lower with nivolumab than with docetaxel (any grade, 68% v 88%; grade 3 to 4, 10% v 55%). Conclusion Nivolumab provides long-term clinical benefit and a favorable tolerability profile compared with docetaxel in previously treated patients with advanced NSCLC.

Patients with small-cell lung cancer (SCLC) demonstrate an exception in the treatment of brain metastases (BM), because in patients with SCLC whole brain radiotherapy (WBRT) only is the preferred treatment modality. The purpose of this study was to develop a prognostic score for patients with brain metastases from SCLC treated with WBRT.The present study was conducted utilizing a single-institution, previously described, retrospective database of patients with SCLC who were treated with WBRT (n = 221). Univariate and multivariate analyses were performed to generate the "brain metastases from SCLC score" (BMS score) based on favorable prognostic factors: Karnofsky performance status (KPS70), extracerebral disease status (stable disease/controlled), and time of appearance of BM (synchronous). Furthermore, the disease-specific graded prognostic assessment score as well as the recursive partitioning analysis (RPA) were performed and compared with the new BMS score by using the log-rank (Mantel-Cox) test.BMS score and RPA showed the most significant differences between classes (P .001). BMS score revealed a mean overall survival (OS) of 2.62 months in group I (0-1 points), 6.61 months in group II (2-3 points), and 12.31 months in group III (4 points). The BMS score also identified the group with the shortest survival (2.62 months in group I), and the numbers of patients in each group were most equally distributed with the BMS score.The new BMS score was more prognostic than the RPA and disease-specific graded prognostic assessment scores. The BMS score is easy to use and reflects known prognostic factors in contemporary patients with SCLC treated with WBRT. Future studies are necessary to validate these findings.

Whole brain radiation therapy (WBRT) is historically the standard of care for patients with brain metastases (BM) from small-cell lung cancer (SCLC), although locally ablative treatments are the standard of care for patients with 1–4 BM from other solid tumors. The objective of this analysis was to find prognostic factors influencing overall survival (OS) and intracranial progression-free survival (iPFS) in SCLC patients with single BM (SBM) treated with WBRT. A total of 52 patients were identified in the authors’ cancer center database with histologically confirmed SCLC and contrast-enhanced magnet resonance imaging (MRI) or computed tomography (CT), which confirmed SBM between 2006 and 2015 and were therefore treated with WBRT. A Kaplan-Meier survival analysis was performed for OS analyses. The log-rank (Mantel-Cox) test was used to compare survival curves. Univariate Cox proportional-hazards ratios (HRs) were used to assess the influence of cofactors on OS and iPFS. The median OS after WBRT was 5 months and the median iPFS after WBRT 16 months. Patients that received surgery prior to WBRT had a significantly longer median OS of 19 months compared to 5 months in the group receiving only WBRT (p = 0.03; HR 2.24; 95% confidence interval [CI] 1.06–4.73). Patients with synchronous disease had a significantly longer OS compared to patients with metachronous BM (6 months vs. 3 months, p = 0.005; HR 0.27; 95% CI 0.11–0.68). Univariate analysis for OS revealed a statistically significant effect for metachronous disease (HR 2.25; 95% CI 1.14–4.46; p = 0.019), initial response to first-line chemotherapy (HR 0.58; 95% CI 0.35–0.97; p = 0.04), and surgical resection (HR 0.36; 95% CI 0.15–0.88; p = 0.026). OS was significantly affected by metachronous disease in multivariate analysis (HR 2.20; 95% CI 1.09–4.45; p = 0.028). Univariate analysis revealed that surgery followed by WBRT can improve OS in patients with SBM in SCLC. Furthermore, synchronous disease and response to initial chemotherapy appeared to be major prognostic factors. Multivariate analysis revealed metachronous disease as a significantly negative prognostic factor on OS. The value of WBRT, stereotactic radiosurgery (SRS), or surgery alone or in combination for patients with a limited number of BM in SCLC should be evaluated in further prospective clinical trials.

Aufgrund der zumeist Jahrzehnte langen Latenzzeit von der Asbestexposition als den auslosenden Hauptrisikofaktor bis zur eigentlichen Krankheitsmanifestation sind vorzugsweise altere Patienten im 6.–8. Lebensjahrzehnt von einem Pleuramesotheliom betroffen. Dies erfordert in der klinischen Praxis altersadaptierte Verfahren von der Diagnostik, im Weiteren uber die palliative Pleuraerguss-Entlastung mittels eingelegtem Pleura-Dauerkatheter oder mit Talkum-Pleurodese bis hin zu operativen Resektionen in Form der Pleurektomie und Dekortikation. Systemtherapeutisch steht seit 2004 der Multi-Target-Enzyminhibitor Pemetrexed als Antifolat im Vordergrund der therapeutischen Bemuhungen in Kombination mit Platin-Derivaten oder als Monotherapeutikum. Bei Tumorrezidiven und/oder Progredienz kann abhangig von Allgemeinzustand und Patientenwunsch auf Gemcitabine oder Vinorelbin zuruckgegriffen werden.

Comprehensively investigate the association of CT morphology and clinical findings of adenocarcinoma with EGFR mutation status. Retrospectively included 282 patients who was pathologically proved as lung adenocarcinoma with known EGFR mutation status (mutations: 138 patients, female: 86, median age: 66 years; wildtype: 144 patients, female: 67, median age: 62 years) and their pre-treatment CT scans were analyzed. CT findings and clinical information were collected. Univariate and multivariable logistic regression analysis were performed. Adjusted for age, gender and smoking history of two groups, significantly more patients with pleural tags, pleural and liver metastases were found in the EGFR mutated group (P = 0.007, 0.004, and 0.043, respectively). Multivariable logistic regression analysis found that the model included age, gender, smoking history, air bronchogram, pleural tags, pleural and liver metastasis had a moderate predictive value for EGFR mutation status (AUC = 0.741, P < .0001). Exon-19 deletion was associated with air bronchogram which adjusted for age, gender and smoking history (P = 0.007, OR: 2.91, 95%CI: 1.25-7.79). The evidence of pleural tags, pleural and liver metastases go along with a higher probability of EGFR mutation in adenocarcinoma patients and air bronchogram is positively associated with Exon-19 deletion mutation.

Introduction Cachexia and sarcopenia are associated with poor outcome and increased chemotherapy-induced toxicity in lung cancer patients. However, the complex interplay of obesity, sarcopenia and cachexia, and its impact on survival in the context of first-line-chemotherapy is not yet understood. Methods In 200 consecutively recruited lung cancer patients (70 female, mean age 62y; mean BMI 25 kg/m2; median follow-up 15.97 months) with routine staging-CT before and after chemotherapy (CTX, mean interval: 4.3 months), densitometric quantification of total (TFA), visceral (VFA), and subcutaneous-fat-area (SFA), inter-muscular-fat-area (IMFA), muscle-density (MD), muscle-area (MA) and skeletal-muscle-index (SMI) was performed retrospectively to evaluate changes under chemotherapy and the impact on survival. Results We observed increases in TFA, VFA, SFA, VFA/SFA, and IMFA (p

Objectives Patients with brain metastases from small-cell lung cancer (SCLC) who underwent prior prophylactic cranial irradiation (PCI) are often treated with a second course of whole brain radiation therapy (Re-WBRT) or stereotactic radiosurgery (SRS) for purposes of palliation in symptomatic patients, hope for increased life expectancy or even as an alternative to untolerated steroids. Up to date there is only limited data available regarding the effect of this treatment. This study examines outcomes in patients in a single institution who underwent cerebral re-irradiation after prior PCI. Methods We examined the medical records of 76 patients with brain metastases who had initially received PCI between 2008 and 2015 and were subsequently irradiated with a second course of cerebral radiotherapy. Patients underwent re-irradiation using either Re-WBRT (88%) or SRS (17%). The outcomes, including symptom palliation, radiation toxicity, and overall survival (OS) following re-irradiation were analyzed. Survival and correlations were calculated using log-rank, univariate, and multivariate Cox proportional hazards-ratio analyses. Treatment-related toxicity was classified according to CTCAE v4.0. Results Median OS of all patients was 3 months (range 0–12 months). Median OS after Re-WBRT was 3 months (range 0–12 months). Median OS after SRS was 5 months (range 0–12 months). Karnofsky performance status scale (KPS ≥50%) was significantly associated with improved OS in both univariate (HR 2772; p = 0,009) and multivariate analyses (HR 2613; p = 0,024) for patients receiving Re-WBRT. No unexpected toxicity was observed and the observed toxicity remained consistently low. Symptom palliation was achieved in 40% of symptomatic patients. Conclusions In conclusion, cerebral re-irradiation after prior PCI is beneficial for symptom palliation and is associated with minimal side effects in patients with SCLC. Our survival data suggests that it is primarily useful in patients with adequate performance status.

Background: Patients with advanced stage non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) often experience multidimensional impairments, affecting quality of life during their course of disease. In lung cancer patients with operable disease, several studies have shown that exercise has a positive impact on quality of life and physical functioning. There is limited evidence regarding efficacy for advanced lung cancer patients undergoing palliative treatment. Therefore, the POSITIVE study aims to evaluate the benefit of a 24-week exercise intervention during palliative treatment in a randomized controlled setting. Methods/design: The POSITIVE study is a randomized, controlled trial investigating the effects of a 24-week exercise intervention during palliative treatment on quality of life, physical performance and immune function in advanced, non-operable lung cancer patients. 250 patients will be recruited in the Clinic for Thoracic Diseases in Heidelberg, enrolment begun in November 2013. Main inclusion criterion is histologically confirmed NSCLC (stage IIIa, IIIb, IV) or SCLC (Limited Disease-SCLC, Extensive Disease-SCLC) not amenable to surgery. Patients are randomized into two groups. Both groups receive weekly care management phone calls (CMPCs) with the goal to assess symptoms and side effects. Additionally, one group receives a combined resistance and endurance training (3x/week). Primary endpoints are quality of life assessed by the Functional Assessment of Cancer Therapy for patients with lung cancer (FACT-L, subcategory Physical Well-Being) and General Fatigue measured by the Multidimensional Fatigue Inventory (MFI-20). Secondary endpoints are physical performance (maximal voluntary isometric contraction, 6-min walk distance), psychosocial (depression and anxiety) and immunological parameters and overall survival. Discussion: The aim of the POSITIVE trial is the evaluation of effects of a 24-week structured and guided exercise intervention during palliative treatment stages. Analysis of various outcomes (such as quality of life, physical performance, self-efficacy, psychosocial and immunological parameters) will contribute to a better understanding of the potential of exercise in advanced lung cancer patients. In contrast to other studies with advanced oncological patients the POSITIVE trial provides weekly phone calls to support patients both in the intervention and control group and to segregate the impact of physical activity on quality of life. Trial registration: ClinicalTrials.gov NCT02055508 (Date: December 12, 2013)

Herpel E, Schnabel P A, Steins M, Dienemann H, Herth F J F, Thomas M, Schirmacher P & Warth A (2012) Histopathology 61, 465–472 Assessment of thymidylate synthase expression in biopsy specimens and corresponding resection specimens of non-small-cell lung cancer Aims: Pemetrexed (Pem) is a potent inhibitor of thymidylate synthase (TS), and has shown efficacy in the treatment of non-small-cell lung cancer (NSCLC). TS expression in NSCLC biopsy specimens may correlate with the tumour responses to TS-inhibiting agents. As TS is not homogeneously expressed, our aim was to test whether TS expression in biopsy specimens may be representative for the whole tumour and can be used for therapeutic assessment. Methods and results: We immunohistochemically analysed TS expression in biopsy and corresponding resection specimens of 100 consecutive NSCLCs. The samples were subgrouped according to TS expression levels, and the degree of agreement between the biopsy and the corresponding resection specimen was calculated. TS expression-based grouping according to one cut-off criterion (high or low expression) led to concordant results between biopsy and resection specimens. When more than one cut-off criterion was used, the results were significantly different. Conclusions: Thymidylate synthase expression levels in NSCLC biopsy specimens may correspond to TS expression of the whole tumour when robust scoring systems are applied. Further studies are needed to determine whether high or low TS expression in NSCLC biopsy specimens is of predictive value, and whether it may allow the selection of patients who will benefit from Pem treatment.

PD-1 checkpoint inhibitors are associated with a specific spectrum of immune-related adverse events. This spectrum is different from toxicities known for kinase inhibitors or cytotoxic drugs. Since PD-1 directed therapies show effectivity in an increasing number of malignant diseases, their clinical usage will increase rapidly. Therefore clinicians from different specialities such as medical oncology, internal medicine, family doctors and emergency unit staff should be aware of the adverse effects of PD-1 checkpoint inhibitors to avoid delays in diagnosis and treatment. Based on pooled data from pivotal trials as reported by the European Medicines Agency, the present paper reviews incidences and kinetics of onset and resolution of immune-mediated "adverse events of specific interest" (AEOSI) of both approved PD-1 inhibitors nivolumab and pembrolizumab. In general, the severity of AEOSI is mild to moderate (grade 1-2); the frequency of immune-mediated but also idiopathic grade 3-4 adverse drug reactions is ⩽2% for any event term. Recommendations for the diagnosis, monitoring and management of the relevant dermatological, gastrointestinal, pulmonary, endocrine, renal and hepatic toxicities are convened by an expert panel that consolidated and clarified treatment recommendations after the onset of AEOSI. Although the time of onset is not predictable - the medians range from 1 to 6months - the huge majority of events is reversible, with no impact of the time of onset. By the systemic use of glucocorticoids, notably methylprednisolone or equivalents, most AEOSI are well manageable. Non-steroidal immunosuppressants may be used in certain cases of refractory/recalcitrant, long-lasting immune toxicities. With regard to the outstanding clinical activity of the anti-PD-1 antibodies, therapy restart is the principal therapeutic option after recovery of grade 2 AEOSI, or diminution of higher grade skin or endocrine events to mild severity. Early diagnosis and close clinical monitoring are essential for successful management of immune-related adverse events.

Lung cancer is the leading cause of cancer-related mortality in Germany. Improvements in our understanding of cancer biology have led to the development of novel agents that inhibit the tumour vasculature in order to induce subsequent tumour cell death. In this context, the inhibition of tumour-related angiogenesis - the growth of new vessels from pre-existing vessels - has become an attractive target for anticancer therapy. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has already been approved in combination with platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) without predominant squamous cell histology. Moreover, small molecule inhibitors targeting multiple angiogenic receptors have also shown promise when combined with standard chemotherapy. As a different approach, vascular disrupting agents (VDAs) have been designed to particularly target preexisting blood vessels which may lead to a vascular shut-down. In the present review, both principles of action and current clinical data on anti-angiogenic agents and VDAs in the treatment of patients with NSCLC are reviewed.

Palliative care should be part of respiratory medi- cine for two reasons: First, many respiratory dis- eases - besides thoracic tumours - need palliative care in the late stages of the disease. Second, dys- pnoea is a common symptom in advanced, prima- ry extrapulmonary diseases and the knowledge of respiratory specialists can be beneficial in the treatment of this symptom. In this paper we des- cribe frequent symptoms of advanced pulmonary diseases and their treatment. Moreover, we focus on the structure of palliative care in Germany.

Purpose Current guidelines recommend postoperative radiation therapy (PORT) for incompletely resected non-small cell lung cancer (NSCLC). However, there is still a paucity of evidence for this approach. Hence, we analyzed survival in 78 patients following radiotherapy for incompletely resected NSCLC (R1) and investigated prognostic factors. Patients and methods All 78 patients with incompletely resected NSCLC (R1) received PORT between December 2001 and September 2014. The median total dose for PORT was 60Gy (range 44–68Gy). The majority of patients had locally advanced tumor stages (stage IIA (2.6%), stage IIB (19.2%), stage IIIA (57.7%) and stage IIIB (20.5%)). 21 patients (25%) received postoperative chemotherapy. Results Median follow-up after radiotherapy was 17.7 months. Three-year overall (OS), progression-free (PFS), local (LPFS) and distant progression-free survival (DPFS) rates were 34.1, 29.1, 44.9 and 51.9%, respectively. OS was significantly prolonged at lower nodal status (pN0/1) and following dose-escalated PORT with total radiation doses >54Gy ( p =0.012, p =0.013). Furthermore, radiation doses >54Gy significantly improved PFS, LPFS and DPFS ( p =0.005; p =0.050, p =0.022). Interestingly, survival was neither significantly influenced by R1 localization nor by extent (localized vs. diffuse). Multivariate analyses revealed lower nodal status and radiation doses >54.0Gy as the only independent prognostic factors for OS ( p =0.021, p=0.036). Conclusion For incompletely resected NSCLC, PORT is used for improving local tumor control. Local progression is still the major pattern of failure. Radiation doses >54Gy seem to support improved local control and were associated with better OS in this retrospective study.

Targeted therapies are discussed as an approach to improve outcome in neuroendocrine tumors of the lung. With current treatment options like platinum derivates and etoposide, large cell neuroendocrine carcinoma of the lung (LCNEC) patients have a poor prognosis. Everolimus (RAD001) is an inhibitor of mTOR, a component of the PI3K/AKT/mTOR pathway known to be dysregulated in neuroendocrine tumors (NETs). In the presented trial for advanced LCNEC patients, daily RAD001 is combined in first-line with carboplatin and paclitaxel, a standard chemotherapy for this population. Enrolled patients receive 4 cycles of combined treatment followed by RAD001 maintenance therapy. The primary endpoint is the proportion of progression-free patients after 3 months. Main inclusion criteria are histologically confirmed stage IV LCNEC and at least one positive neuroendocrine marker. Main exclusion criteria are symptomatic CNS metastases and prior treatment for advanced LCNEC. Here a case report of a 56-year old patient with stage IV LCNEC enrolled in this trial is presented. The tumor histologically revealed NSCLC morphology of the large-cell type and a considerable CD56 and synaptophysin staining as well as a proliferation rate of more than 60% in Ki67 staining. The patient received in first-line 4 cycles of carboplatin and paclitaxel combined with RAD001 and subsequently RAD001 monotherapy for further 9 months. The tumor response revealed as per RECIST a partial remission during the first 3 months and an ongoing stabilization of the tumor for further 9 months before a disease progression was detected 12 months after initial diagnosis. At the fifth cycle of a second-line treatment with carboplatin and etoposide, the patient has still a stable disease 16 months after initial diagnosis of LCNEC. These data show that a combined therapy of carboplatin and paclitaxel with mTOR-inhibitor RAD001 in first-line might be a promising approach for more efficient treatment of LCNEC patients.

In den fruhen Stadien des nichtkleinzelligen Lungenkarzinoms (NSCLC) zeichnen sich derzeit die theoretisch moglichen Vorteile der neoadjuvanten Chemotherapie nur in klinischen Studien mit kleiner Patientenzahl ab. Ein Ungleichgewicht prognoserelevanter Patientensubgruppen zwischen den Armen mit und ohne neoadjuvanter Chemotherapie und ein so bedingter Unterschied im Hinblick auf das Uberleben in den jeweiligen randomisierten Studien ist dabei nicht auszuschliesen. Demgegenuber muss bereits jetzt eine platinbasierte adjuvante Kombinationschemotherapie nach kompletter Tumorresektion im Stadium IB–II sowie im inzidenziellen Stadium IIIA auf der Grundlage der Ergebnisse von 3 randomisierten Studien mit uber 3000 Patienten empfohlen werden (keine Komorbiditat, die eine platinbasierte Therapie ausschliest; guter Allgemeinzustand; postoperative Erholung innerhalb von 6 Wochen).

BACKGROUND: Severe immunohematologic complications after ABO-mismatched allogeneic blood peripheral blood progenitor cell (PBPC) transplantation (PBPCT), including pure red cell aplasia and immune hemolysis, have been described. Although several studies have addressed this issue, the clinical influence of blood group differences on transfusion requirements and survival is still discussed controversially, especially in the case of PBPCT. STUDY DESIGN AND METHODS: This single-center study is based on 143 patients receiving PBPCT after standard or reduced-intensity conditioning. The influence of blood group differences in the ABO, Rh, and Kell systems on red blood cell, platelet, and plasma transfusion requirements; length of hospitalization in transplantation unit; survival; and occurrence of graft-versus-host disease was investigated. Additionally, the influence of the conditioning regimen and irregular antibodies on the measures mentioned above was analyzed. RESULTS: Multivariate analysis demonstrated that minor and bidirectional ABO mismatch (p = 0.028) and Rh difference (p = 0.020) independently led to poorer survival. The Kell difference did not show significant influences on the measures mentioned above. A clinically relevant influence of blood group differences on transfusion requirements could not be demonstrated. Irregular antibodies also did not show significant influences. CONCLUSION: These findings indicate an influence of blood group differences in PBPCT on survival and must be studied in further detail.

Emerging data suggest an involvement of angiogenesis in the pathophysiology of acute myeloid leukemia (AML). Thus, antiangiogenic therapy could constitute a novel strategy for the treatment of AML. To test this hypothesis, a phase I/II dose-escalating trial was performed to study the safety and efficacy of thalidomide, a putative inhibitor of angiogenesis, in 20 patients with AML. Thirteen patients were assessable for both toxicity and response, tolerating a maximum dose of 200 to 400 mg daily for at least 1 month. Seven patients had to be prematurely withdrawn from drug administration owing to progressive disease and death (3 patients), personal decision (2 patients), or inability to tolerate thalidomide (2 patients). Overall, adverse events were fatigue, constipation, rash, and neuropathy (grade 1 to 2 in most patients). In 4 patients, a partial response, defined as reduction of at least 50% in the blast cell infiltration of the bone marrow accompanied by increases in platelet counts and hemoglobin values, was observed. One additional patient showed a hematologic improvement without fulfilling the criteria of a partial response. The responses lasted a median of 3 months (range, 1-8 months). In parallel, microvessel densities significantly decreased in these 5 patients during treatment with thalidomide (P

Purpose Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, showed promising activity in small-cell lung cancer (SCLC) in phase II trials. This phase III trial compared the safety and efficacy of amrubicin versus topotecan as second-line treatment for SCLC. Patients and Methods A total of 637 patients with refractory or sensitive SCLC were randomly assigned at a ratio of 2:1 to 21-day cycles of amrubicin 40 mg/m2 intravenously (IV) on days 1 to 3 or topotecan 1.5 mg/m2 IV on days 1 to 5. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival (PFS), and safety. Results Median OS was 7.5 months with amrubicin versus 7.8 months with topotecan (hazard ratio [HR], 0.880; P = .170); in refractory patients, median OS was 6.2 and 5.7 months, respectively (HR, 0.77; P = .047). Median PFS was 4.1 months with amrubicin and 3.5 months with topotecan (HR, 0.802; P = .018). ORR was 31.1% with amrubicin and 16.9% with topotecan (odds ratio, 2.223; P < .001). Grade ≥ 3 treatment-emergent adverse events in the amrubicin and topotecan arms were: neutropenia (41% v 54%; P = .004), thrombocytopenia (21% v 54%; P < .001), anemia (16% v 31%; P < .001), infections (16% v 10%; P = .043), febrile neutropenia (10% v 3%; P = .003), and cardiac disorders (5% v 5%; P = .759); transfusion rates were 32% and 53% (P < .001), respectively. NQO1 polymorphisms did not influence safety outcomes. Conclusion Amrubicin did not improve survival when compared with topotecan in the second-line treatment of patients with SCLC. OS did not differ significantly between treatment groups, although an improvement in OS was noted in patients with refractory disease treated with amrubicin.

The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (×500 field, 0.126 mm2) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/×500 field vs 11.2 (10.0-12.0)/×500 field, respectively (P

Objectives: Clinical manifestations of coronary heart disease result primarily from the progressive development of atherosclerotic plaques and subsequent thrombus formation; processes which may be accelerated by an enhanced expression of plasminogen activator inhibitor (PAI-1) in the vessel wall. In the present study, content and expression of PAI-1 were comparatively analyzed in human coronary arteries in relation to the presence and severity of atherosclerotic lesions. Methods: Segments of coronary arteries obtained from heart explants ( n = 15) were classified by the presence and types of atherosclerotic lesions. Antigen and activity levels of PAI-1 were determined in protein extracts of intimal and medial layers. In situ hybridization and immunohistochemical analyses were performed on serial sections of representative tissue specimens. Results: Total PAI-1 antigen consistently increased from macroscopically normal areas (MNAs) to early lesions (ELs) and to maximal levels in fibrous (FPs) and calcified (CPs) plaques. No PAI activity was detected, although PAI-1 in its free form was present in all vascular specimens. Both free PAI-1 and PAI-1 complexed with plasminogen activators were significantly increased in extracts of advanced lesions. However, there was a 2–3 fold molar excess of free versus complexed PAI-1 in FPs and CPs. These findings suggest the presence of relevant amounts of PAI-1 in its substrate rather than in its inhibitor conformation in areas of advanced lesions. Compared with MNAs, PAI-1 mRNA was strongly expressed within the thickened intima of ELs. The highest PAI-1 expression was observed in FPs and CPs, being mainly localized in areas surrounding the necrotic cores in co-localization with infiltrating macrophages. Conclusions: PAI-1 content is consistently increased in relation to the severity of the lesions in atherosclerotic coronary arteries. The concomitant elevation of PAI-1 mRNA suggests that the PAI-1 increase is regulated by local synthesis in the areas of atherosclerotic lesions.

9025Background: Nivo, afully human IgG4 programmed death-1 immune checkpoint inhibitor, is approved in the US for pts with previously treated metastatic NSCLC and in the EU for pretreated locally a...

Pemetrexed (Pem) is a potent inhibitor of thymidylate synthase (TS), and has shown efficacy in the treatment of non-small-cell lung cancer (NSCLC). TS expression in NSCLC biopsy specimens may correlate with the tumour responses to TS-inhibiting agents. As TS is not homogeneously expressed, our aim was to test whether TS expression in biopsy specimens may be representative for the whole tumour and can be used for therapeutic assessment.We immunohistochemically analysed TS expression in biopsy and corresponding resection specimens of 100 consecutive NSCLCs. The samples were subgrouped according to TS expression levels, and the degree of agreement between the biopsy and the corresponding resection specimen was calculated. TS expression-based grouping according to one cut-off criterion (high or low expression) led to concordant results between biopsy and resection specimens. When more than one cut-off criterion was used, the results were significantly different.Thymidylate synthase expression levels in NSCLC biopsy specimens may correspond to TS expression of the whole tumour when robust scoring systems are applied. Further studies are needed to determine whether high or low TS expression in NSCLC biopsy specimens is of predictive value, and whether it may allow the selection of patients who will benefit from Pem treatment.

Aims: Amrubicin, a 3rd gen. anthracycline and potent topoisomerase II inhibitor, has shown activity in SCLC. ACT-1 compared the safety and efficacy of amr vs. topo for 2nd line treatment of SCLC. Methods: 637 pts were random. 2:1 amr 40mg/m2 IV d 1–3 (n=424) vs. topo 1.5mg/m2 IV d 1–5 (n=213) with proph. WBC growth factors and antibiotics required in last 1/3 of trial. Endpoints: OS (primary), RR, PFS, and safety. Subgroup analyses used protocol-defined definitions: refract. pts had PD as best response to 1st line therapy or progressed