Abstract Background Stereotactic body radiotherapy (SBRT) has been introduced for small lung tumors due to excellent local control and few side effects, even though there are no comparative studies. ...SPACE (Stereotactic Precision And Conventional radiotherapy Evaluation) is the first randomized phase II trial comparing SBRT and conventional fractionated radiotherapy (3DCRT). Methods Patients with stage I medically inoperable NSCLC were randomized to receive SBRT to 66 Gy in 3 fractions (one week) or 3DCRT to 70 Gy (7 weeks). Patients were followed to assess efficacy, toxicity and HRQL. Findings Between 2007 and 2011, 102 patients were randomized. Mean age 74 (57–86), 60% women, the vast majority (92%) had COPD or cardiovascular comorbidity. The SBRT arm included more patients with T2-tumors ( p = 0.02) and male gender ( p = 0.35). The median follow-up was 37 months with a 1-, 2- and 3-year PFS of: SBRT: 76%, 53%, 42% and 3DCRT: 87%, 54% 42%, HR = 0.85 (95% CI 0.52–1.36) with no difference between the groups and no difference in OS (HR = 0.75, 95% CI 0.43–1.30). At the end of the study 70% of SBRT patients had not progressed compared to 59% (3DCRT, p = 0.26). Toxicity was low with no grade 5 events. Pneumonitis of any grade was observed in 19% (SBRT) and 34% (3DCRT, p = 0.26), and esophagitis in 8% and 30% respectively ( p = 0.006). HRQL was evaluated with the EORTC QLQ 30 and LC14 module and patients treated with 3DCRT experienced worse dyspnea ( p = 0.01), chest pain ( p = 0.02) and cough (>10 points difference). Interpretation There was no difference in PFS and OS between SBRT and conventionally treated patients despite an imbalance of prognostic factors. We observed a tendency of an improved disease control rate in the SBRT group and they experienced better HRQL and less toxicity. SBRT is convenient for patients and should be considered standard treatment for patients with inoperable stage I NSCLC.
Summary Background Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer. However, the optimum number of treatment cycles remains ...controversial. Therefore, we did a systematic review and meta-analysis of individual patient data to compare the efficacy of six versus fewer planned cycles of platinum-based chemotherapy. Methods All randomised trials comparing six versus fewer planned cycles of first-line platinum-based chemotherapy for patients with advanced non-small-cell lung cancer were eligible for inclusion in this systematic review and meta-analysis. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients with an objective response, and toxicity. Statistical analyses were by intention-to-treat, stratified by trial. Overall survival and progression-free survival were compared by log-rank test. The proportion of patients with an objective response was compared with a Mantel-Haenszel test. Prespecified analyses explored effect variations by trial and patient characteristics. Findings Five eligible trials were identified; individual patient data could be collected from four of these trials, which included 1139 patients—568 of whom were assigned to six cycles, and 571 to three cycles (two trials) or four cycles (two trials). Patients received cisplatin (two trials) or carboplatin (two trials). No evidence indicated a benefit of six cycles of chemotherapy on overall survival (median 9·54 months 95% CI 8·98–10·69 in patients assigned to six cycles vs 8·68 months 8·03–9·54 in those assigned to fewer cycles; hazard ratio HR 0·94 95% CI 0·83–1·07, p=0·33) with slight heterogeneity between trials (p=0·076; I2 =56%). We recorded no evidence of a treatment interaction with histology, sex, performance status, or age. Median progression-free survival was 6·09 months (95% CI 5·82–6·87) in patients assigned to six cycles and 5·33 months (4·90–5·62) in those assigned to fewer cycles (HR 0·79, 95% CI 0·68–0·90; p=0·0007), and 173 (41·3%) of 419 patients assigned to six cycles and 152 (36·5%) of 416 patients assigned to three or four cycles had an objective response (p=0·16), without heterogeneity between the four trials. Anaemia at grade 3 or higher was slightly more frequent with a longer duration of treatment: 12 (2·9%) of 416 patients assigned to three-to-four cycles and 32 (7·8%) of 411 patients assigned to six cycles had severe anaemia. Interpretation Six cycles of first-line platinum-based chemotherapy did not improve overall survival compared with three or four courses in patients with advanced non-small-cell lung cancer. Our findings suggest that fewer than six planned cycles of chemotherapy is a valid treatment option for these patients. Funding None.
PURPOSE Based on 5-year or shorter-term follow-up data in recent randomized trials, adjuvant cisplatin-based chemotherapy is now generally recommended after complete surgical resection for patients ...with non-small-cell lung cancer (NSCLC). We evaluated the results of the International Adjuvant Lung Cancer Trial study with three additional years of follow-up. PATIENTS AND METHODS Patients with completely resected NSCLC were randomly assigned to three or four cycles of cisplatin-based chemotherapy or to observation. Cox models were used to evaluate treatment effect according to follow-up duration. Results The trial included 1,867 patients with a median follow-up of 7.5 years. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio HR, 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06). CONCLUSION These results confirm the significant efficacy of adjuvant chemotherapy at 5 years. The difference in results beyond 5 years of follow-up underscores the need for the long-term follow-up of other adjuvant lung cancer trials and for a better identification of patients deriving long-term benefit from adjuvant chemotherapy.
A Japanese randomized trial showed superior survival for patients with extensive-disease (ED) small-cell lung cancer (SCLC) receiving irinotecan plus cisplatin compared with etoposide plus cisplatin. ...The present trial evaluated the efficacy of irinotecan plus carboplatin (IC) compared with oral etoposide plus carboplatin (EC).
Patients with ED SCLC were randomly assigned to receive either IC, which consisted of carboplatin (area under the curve = 4; Chatelut formula) and irinotecan (175 mg/m2) intravenously both on day 1, or EC, which consisted of carboplatin as in IC and etoposide (120 mg/m(2)/d) orally on days 1 through 5. Courses were repeated every 3 weeks with four cycles planned. Doses were reduced by one third in patients with a WHO performance status (PS) of 3 to 4 and/or age older than 70 years. Primary end point was overall survival (OS). Secondary end points were quality of life (QOL) and complete response (CR) rate.
Of 220 randomly assigned patients, 209 were eligible for analysis (IC, n = 105; EC, n = 104). Thirty-five percent were older than 70 years, and 47% had a PS of 2 to 4. The groups were well balanced with respect to prognostic factors. OS was inferior in the EC group (hazard ratio = 1.41; 95% CI, 1.06 to 1.87; P = .02). Median survival time was 8.5 months for IC compared with 7.1 months for EC. One-year survival rate was 34% for IC and 24% for EC. CR was seen in 18 IC patients compared with seven EC patients (P = .02). There were no statistically significant differences in hematologic grade 3 or 4 toxicity. Grade 3 or 4 diarrhea was more common in the IC group. QOL differences were small, with a trend toward prolonged palliation with the IC regimen.
IC prolongs survival in ED SCLC with slightly better scores for QOL.
Aims
Erlotinib is a tyrosine kinase inhibitor used in the treatment of non‐small cell lung cancer highly metabolized by the cytochrome P450 (CYP) 3A. Hence, CYP3A4 activity might be a useful ...predictor of erlotinib pharmacokinetics in personalized medicine. The effect of erlotinib on CYP3A activity was therefore studied in non‐small cell lung cancer patients.
Methods
The study included 32 patients scheduled for erlotinib monotherapy. CYP3A activity was assessed using quinine as a probe before and during erlotinib treatment. Plasma from blood samples drawn 16 hours post quinine administration were analysed using HPLC with fluorescence detection to determine the quinine/3‐OH‐quinine ratio.
Results
Matched samples, available from 13 patients, showed an induction of CYP3A activity (P = 0.003, Wilcoxon's signed rank test) after 2 months of treatment. The quinine/3‐OH‐quinine ratio decreased from 20.2 (± 13.4) at baseline to 11.0 (± 4.34). Single‐point samples, available from 19 patients, supported the decrease in ratio (P = 0.007, Mann–Whitney U‐test).
Generally, females had a higher CYP3A activity both at baseline and after two months of treatment. Statistical analysis by gender also showed significant increase in CYP3A activity (males, n = 10, P = 0.001, and females, n = 22, P = 0.001).
Conclusions
An induction of CYP3A activity was observed after 2 months of erlotinib treatment which was also seen when subdividing based on gender. It could be important to take this into consideration for patients co‐administering other CYP3A‐metabolizing drugs during erlotinib treatment and also makes it difficult to use baseline CYP3A activity to predict erlotinib pharmacokinetics.
Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene ...expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.
Cardiovascular comorbidity is common in small cell lung cancer (SCLC) and may significantly affect treatment tolerability and patient outcome. Still, there are no established biomarkers for objective ...and dynamic assessment as a tool for improved treatment decisions. We have investigated circulating levels of midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial-natriuretic peptide (MR-proANP), copeptin (surrogate for vasopressin) and suppression-of-tumorigenicity-2 (ST2), all known to correlate with various aspects of cardiovascular function, in a SCLC cohort (N = 252) from a randomized, controlled trial (RASTEN). For all measured biomarkers, protein levels were inversely associated with survival, particularly with ST2 and MR-proADM, where the top versus bottom quartile was associated with an adjusted hazard ratio of 2.40 (95% CI 1.44−3.98; p = 0.001) and 2.18 (95% CI 1.35−3.51; p = 0.001), respectively, in the entire cohort, and 3.43 (95% CI 1.73−6.79; p < 0.001) and 3.49 (95% CI 1.84−6.60; p < 0.001), respectively, in extensive disease patients. A high combined score of MR-proADM and ST2 was associated with a significantly reduced median OS of 7.0 months vs. 14.9 months for patients with a low combined score. We conclude that the cardiovascular biomarkers MR-proADM and ST2 strongly correlate with survival in SCLC, warranting prospective studies on the clinical utility of MR-proADM and ST2 for improved, individualized treatment decisions.
Abstract The aims of the study were to investigate lung cancer patients' quality of life (QoL) over time in a palliative setting and to determine how QoL is influenced by symptoms, coping capacity, ...and social support. One hundred and five consecutive patients with incurable lung cancer were included. A comprehensive set of questionnaires was used at baseline, including the Assessment of Quality of Life at the End of Life, Cancer Dyspnea Scale, Visual Analog Scale of Dyspnea, Hospital Anxiety and Depression scale, Sense of Coherence Questionnaire, and Social Support Survey, of which the first four were used also at three, six, nine, and 12 months. Dyspnea, depression, and global QoL deteriorated over time. Performance status, anxiety, depression, components of dyspnea, pain, and the meaningfulness component of coping capacity correlated with global QoL at all, or all but one follow-up measurements. In a multivariate analysis with global QoL as the dependent variable, depression was a significant predictor at four out of five assessments, whereas coping capacity, anxiety, performance status, pain, and social support entered the model at one or two assessments. Emotional distress and coping capacity influence QoL and might be targets for intervention in palliative care.
Early identification of subjects running an increased risk of contracting COPD enables focus on individual preventive measures. The slope of the alveolar plateau of the single-breath nitrogen washout ...test (N
2
-slope) is a sensitive measure of small-airway dysfunction. However, its role remains unexplored in predicting hospital admission or death related to COPD,
i.e.
incident COPD events, in relation to the presence of various respiratory symptoms.
A random population sample of 625 men, aged 50 (n=218) or 60 years (n=407), was followed for 38 years for incident COPD events. At baseline, a questionnaire on respiratory symptoms and smoking habits was collected, spirometry and the single-breath nitrogen test were performed, and the N
2
-slope was determined. Proportional hazard regression (Cox regression) analysis was used for the prediction model.
The N
2
-slope improved the prediction of COPD events significantly beyond that of respiratory symptoms weighted all together and other covariates (hazard ratio 1.63, 95% CI 1.20–2.22; p<0.005), a prediction applicable to subjects without (p=0.001) and with (p<0.05) airway obstruction. Dyspnoea and wheezing were the most predictive symptoms. The combination of the N
2
-slope and number of respiratory symptoms notably resulted in an effective prediction of incident COPD events even in nonobstructive subjects, as evidenced by a predicted incidence of ∼70% and ∼90% for a very steep N
2
-slope combined with many respiratory symptoms in subject without and with airway obstruction, respectively.
The alveolar N
2
-slope should be considered in the critical need for further research on early diagnosis of COPD.
This paper discusses how Swedish police education actors navigate the act of introducing new police officers to tasks in an organisation permeated by a new public management ideology. This study's ...empirical data derive from four studies on intra-professional police educators and police probationers. By interpreting and analysing these data using a theoretical framework based on styles of thought and reflexivity, a picture of how Swedish police organisations contain two somewhat contradictory thought styles emerges. The findings indicate that a reflexive awareness of this situation is crucial for educators to properly prepare new police officers for complex and important tasks. This paper contributes to current vocational training and education methods by offering new perspectives on how professional development can be enhanced in law enforcement and similar occupations.
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