Unresectable stage III non-small cell lung cancer: Insights from a Portuguese expert panel.

INTRODUCTION: The management of unresectable stage III non-small cell lung cancer (NSCLC) is clinically challenging and there is no current consensus on optimal strategies. Herein, a panel of Portuguese experts aims to present practical recommendations for the global management of unresectable stage III NSCLC patients. METHODS: A group of Portuguese lung cancer experts debated aspects related to the diagnosis, staging and treatment of unresectable stage III NSCLC in light of current evidence. Recent breakthroughs in immunotherapy as part of a standard therapeutic approach were also discussed. This review exposes the major conclusions obtained. RESULTS: Practical recommendations for the management of unresectable stage III NSCLC were proposed, aiming to improve the pathways of diagnosis and treatment in the Portuguese healthcare system. Clinical heterogeneity of patients with stage III NSCLC hinders the development of single standardised algorithm where all fit. CONCLUSIONS: A timely diagnosis and a proper staging contribute to the best management of each patient, optimizing treatment tolerance and effectiveness. The expert panel considered chemoradiotherapy as the preferable approach when surgery is not possible. Management of adverse events and immunotherapy as a consolidation therapy are also essential steps for a successful strategy.

Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC).

OBJECTIVE: The main aim of the study was to evaluate the efficacy and safety profile of Nivolumab, an immune-checkpoint-inhibitor antibody, in advanced, previously treated, Non-Small Cell Lung Cancer (NSCLC) patients, in a real world setting. METHODS: We performed a retrospective, multicentre data analysis of patients who were included in the Portuguese Nivolumab Expanded Access Program (EAP). Eligibility criteria included histologically or citologically confirmed NSCLC, stage IIIB and IV, evaluable disease, sufficient organ function and at least one prior line of chemotherapy. The endpoints included Overall Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Safety analysis was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and immune-related Adverse Events (irAEs) were treated according to protocol treatment guidelines. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Data was analysed using SPSS, version 21.0 (IBM Statistics). RESULTS: From June 2015 to December 2016, a total of 229 patients with advanced NSCLC were enrolled at 30 Portuguese centres. Clinical data were collected up to the end of July 2018. The baseline median age was 64 years (range 37-83) and the majority of patients were males (70.3%) and former/current smokers (69.4%). Patients with non-squamous histology predominated (88.1%), and 67.6% of the patients had received 2 or more prior lines of chemotherapy. Out of 229 patients, data was available for 219 patients (3 patients did not start treatment, while data was unavailable in 7 patients); of the 219 patients, 15.5% were not evaluated for radiological tumour assessment, 1.4% had complete response (CR), 21% partial response (PR), 31% stable disease (SD) and 31.1% progressive disease (PD). Thus, the ORR was 22.4% and DCR was 53.4% in this population. At the time of survival analysis the median PFS was 4.91 months (95% CI, 3.89-6.11) and median OS was 13.21 months (95% CI, 9.89-16.53). The safety profile was in line with clinical trial data. CONCLUSIONS: Efficacy and safety results observed in this retrospective analysis were consistent with observations reported in clinical trials and from other centres.

Elderly patients with advanced NSCLC: The value of geriatric evaluation and the feasibility of CGA alternatives in predicting chemotherapy toxicity.

Cancer is primarily a disease of the elderly, with the incidence of older patients with cancer expected to increase in the coming years. Despite remarkable advances during the last decade, lung cancer remains a leading cause of mortality worldwide, non-small cell lung cancer (NSCLC) being the dominant (85-90%) subtype. At diagnosis, 50% of NSCLC patients are ≥70 years and 15%, over 80 years of age. Due to their under-representation in clinical trials, current treatment decisions for older patients with cancer are based on a low level of scientific evidence. The little evidence that exists suggests that chemotherapy is effective in elderly NSCLC patients, but also indicates that they are at more risk of chemotherapy toxicity than younger adults. However, if carefully selected and monitored, elderly patients can benefit from standard chemotherapy regimens. The Comprehensive Geriatric Assessment (CGA) has historically been adopted to identify elderly patients who are unfit for chemotherapy, yet in clinical practice this is often not feasible as it is too time-consuming. Two promising new tools have emerged - the CRASH and CARG scores - to assign patients to varying intensities of chemotherapy based on a pre-therapy risk assessment. The strengths and shortcomings of each tool were discussed by a group of six advisors with expertise in the treatment of NSCLC. Based on a literature review and on their personal experience, CRASH and CARG were considered feasible toxicity prediction tools, appropriate for implementation in routine clinical practice, with a potentially high impact in optimizing therapy selection for elderly patients with cancer.

Metronomic oral vinorelbine for the treatment of advanced non-small cell lung cancer: a multicenter international retrospective analysis.

PURPOSE: Metronomic oral vinorelbine (MOV) could be a treatment option for unfit patients with advanced non-small cell lung cancer (NSCLC) based on its safety profile and high patient compliance. METHODS: We retrospectively collected data on 270 patients [median age 76 (range 48-92) years, M/F 204/66, PS 0 (27)/1 (110)/≥ 2 (133), median of 3 serious comorbidities] with stage IIIB-IV NSCLC treated with MOV as first (T1) (67%), second (T2) (19%) or subsequent (T3) (14%) line. Schedules consisted of vinorelbine 50 mg (138), 40 mg (68) or 30 mg (64) three times a week continuously. RESULTS: Patients received an overall median of 6 (range 1-25) cycles with a total of 1253 cycles delivered. The overall response rate was 17.8% with 46 partial and 2 complete responses and 119 patients (44.1%) experienced stable disease > 12 weeks with an overall disease control rate of 61.9%. Median overall time to progression was 5 (range 1-21) months [T1 7 (1-21), T2 5.5 (1-19) and T3 4 (1-19) months] and median overall survival 9 (range 1-36) months [T1 10 (1-31), T2 8 (1-36) and T3 6.5 (2-29) months]. Treatment was extremely well tolerated with 2% (25/1253) G3/4 toxicity (mainly G3 fatigue and anemia) and no toxic deaths. We observed the longer OS 14 (range 7-36) months in a subset of squamous NSCLC patients receiving immunotherapy after metronomic oral vinorelbine. CONCLUSION: We confirmed MOV as an extremely safe treatment in a large real world population of advanced NSCLC with an interesting activity mainly consisting of long-term disease stabilization. We speculate the possibility of a synergistic effect with subsequent immunotherapy.

18F-FDG PET/CT in lung cancer. The added value of quantification / PET/TC con 18F-FDG en el cáncer de pulmón. Valor adicional de la cuantificación

Objective. To test a software application for the quantification of metabolic heterogeneity and to evaluate its superiority in relation to visual interpretation. To investigate if a quantitative analysis adds information to the interpretation of 18F-FDG-PET/CT. Material and methods. The study analyzed 215 patients with a 18F-FDG-PET/CT done for the initial staging of lung cancer between March 2011 and December 2015. The study included 57 (26.5%) women and 158 (73.5%) men, with ages ranging from 34 to 88 years (mean±SD: 67.23±10.04). There were 82 surgical stages (I, II, IIIA), and 133 non-surgical stages (IIIB, IV). The primary tumour was analyzed quantitatively by obtaining the following parameters: SUVmax, metabolic active tumour volume (MATV), total lesion glycolysis (TLG), and the entropy heterogeneity index (ET). Heterogeneity was assessed visually. Death dates and/or the follow-up time were registered, ranging from 0.70 to 67.60 months (mean±SD: 23.20±17.68). Results. In multivariate analysis, ET emerged as a better predictor of survival than visual analysis of heterogeneity that was not statistically significant. The C-index determination demonstrated that all quantitative parameters were statistically-significant predictors of survival. Cut-offs were obtained in order to compare survival times. A multivariate analysis was performed. In the total population, the best predictor was the TNM stage, but MATV, ET, and male gender were statistically significant and independent predictors of survival. In stages without surgical indication, the best predictor was the TNM stage, but the MATV and male gender were statistically significant and independent predictors of survival. In the surgical stages, ET was the only statistically significant and independent predictor of survival. Conclusions. Quantification adds prognostic information to the visual analysis of 18F-FDG-PET/CT (AU)

Objetivo. Valorar un software para cuantificar la heterogeneidad metabólica e investigar su superioridad en relación con la interpretación visual. Analizar si el análisis cuantitativo ofrece información adicional en la interpretación de los estudios 18F-FDG-PET/TC. Material y métodos. Se valoraron retrospectivamente 215 estudios 18F-FDG-PET/TC para estatificación inicial de cáncer de pulmón entre marzo de 2011 y diciembre de 2015; se incluyeron 57(26,5%) mujeres y 158(73,5%) hombres, con edades de 34 a 88 años (media±DE: 67,23±10,04); hubo 82 estadios quirúrgicos (I, II, IIIA) y 133 no quirúrgicos (IIIB, IV). El tumor primario fue analizado obteniendo los parámetros SUVmax, metabolic active tumour volume (MATV), total lesion glycolisys (TLG) y el índice de heterogeneidad entropía (ET). La heterogeneidad fue valorada visualmente. Se registró la fecha de fallecimiento y/o el tiempo de seguimiento, que osciló entre 0,70 y 67,60 meses (media±DE: 23,20±17,68). Resultados. En el análisis multivariante, la ET se mostró mejor predictor de supervivencia que el análisis visual de heterogeneidad, el cual no fue estadísticamente significativo. La determinación del C-index demostró que todos los parámetros cuantitativos fueron predictores de supervivencia estadísticamente significativos. Se obtuvieron puntos de corte para comparar los tiempos de supervivencia. En el análisis multivariante, el mejor predictor fue el TNM, pero el MATV, el ET y el género masculino demostraron ser predictores de supervivencia independientes estadísticamente significativos. En los estadios no quirúrgicos, el mejor predictor fue el TNM, pero el MATV y el género masculino demostraron ser predictores de supervivencia estadísticamente significativos e independientes. En los estadios quirúrgicos, la ET fue el único predictor de supervivencia estadísticamente significativo e independiente. Conclusiones. La cuantificación ofrece información pronóstica adicional al análisis visual del 18F-FDG-PET/TC (AU)

18F-FDG PET/CT in lung cancer. The added value of quantification.

OBJECTIVE: To test a software application for the quantification of metabolic heterogeneity and to evaluate its superiority in relation to visual interpretation. To investigate if a quantitative analysis adds information to the interpretation of 18F-FDG-PET/CT. MATERIAL AND METHODS: The study analyzed 215 patients with a 18F-FDG-PET/CT done for the initial staging of lung cancer between March 2011 and December 2015. The study included 57 (26.5%) women and 158 (73.5%) men, with ages ranging from 34 to 88 years (mean±SD: 67.23±10.04). There were 82 surgical stages (I, II, IIIA), and 133 non-surgical stages (IIIB, IV). The primary tumour was analyzed quantitatively by obtaining the following parameters: SUVmax, metabolic active tumour volume (MATV), total lesion glycolysis (TLG), and the entropy heterogeneity index (ET). Heterogeneity was assessed visually. Death dates and/or the follow-up time were registered, ranging from 0.70 to 67.60 months (mean±SD: 23.20±17.68). RESULTS: In multivariate analysis, ET emerged as a better predictor of survival than visual analysis of heterogeneity that was not statistically significant. The C-index determination demonstrated that all quantitative parameters were statistically-significant predictors of survival. Cut-offs were obtained in order to compare survival times. A multivariate analysis was performed. In the total population, the best predictor was the TNM stage, but MATV, ET, and male gender were statistically significant and independent predictors of survival. In stages without surgical indication, the best predictor was the TNM stage, but the MATV and male gender were statistically significant and independent predictors of survival. In the surgical stages, ET was the only statistically significant and independent predictor of survival. CONCLUSIONS: Quantification adds prognostic information to the visual analysis of 18F-FDG-PET/CT.

Virtual Kitchen Test. Assessing frontal lobe functions in patients with alcohol dependence syndrome.

INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "New Methodologies for Patients Rehabilitation". BACKGROUND: The ecological validity of paper-and-pencil neuropsychological tests is currently a matter of debate. Arguments in favor of alternatives indicate that paper-and-pencil forms are unable to account for both mental and functional aspects of cognitive functioning. OBJECTIVES: In this study we developed a new neuropsychological evaluation test - the Virtual Kitchen Test (VKT) - devised to evaluate frontal brain functioning in cognitively impaired individuals. We designed this test according to the rationale of the Trail Making Test (TMT), in order to capture frontal lobe abilities during a more ecologically valid task. METHODS: Forty-nine participants, 25 from a clinical sample of patients diagnosed with Alcohol Dependence Syndrome, plus 24 healthy participants. RESULTS: Execution errors and task completion time were significantly higher in the clinical sample. Also, scores on the new VKT showed moderate to high positive correlations with scores on the TMT. Furthermore, the overall discriminant performance of the VKT was high for both of its indicators. CONCLUSIONS: Overall results support the ability of the VKT to evaluate frontal lobe functions. The best cut-off scores based on this sample are discussed.

Spontaneous splenic rupture in a patient with small-cell lung cancer.

We report a case of a 66-year-old male patient presented to our pneumology ward with the diagnosis of neutropenic pneumonia. Therapy with granulocyte colony stimulating factors (G-CSF) and intravenous antibiotics was initiated as usual in this condition. The unexpected and acute onset of left-sided abdominal pain and sings of hypovolemic shock led us to a challenging diagnosis, rarely considered in non-traumatic patients. After pathological evaluation of the spleen, spontaneous splenic rupture due to G-CSF was our final diagnosis.

[Anatomy for the bronchologist: a prospective study of the normal endobronchial anatomic variants]. / Anatomia endobrônquica: estudo prospectivo das variações anatómicas da árvore traqueobrônquica.

A comprehensive knowledge of the normal pattern of endobronchial branching is essential to any pulmonologist. The classification systems available are predominantly static descriptions and only seldom do they refer to possible variations within the normal spectrum. To evaluate all possible anatomical variants of the tracheobronchial tree we conducted a prospective study in our endoscopy unit between February, 1st and July, 10th (2009). A total of 181 individuals were included in the study. Anatomical variants were found to be present in 79 individuals (43% of total). Overall we found 20 different anatomical variants. Variations were more frequently found within the right upper lobe (16.6% of individuals). Middle lobe and lingula presented no variations. The variant most frequently found was the presence of a bifurcate pattern of the right upper bronchus (13.8%). The present study revealed a relatively high frequency of anatomical alternatives to the normal endobronchial branching pattern. Recognition of these variants and the frequency of their expression are fundamental for the bronchologist in establishing the limits of normal anatomy and preparing endobronchial techniques or surgical procedures.

[Pneumonia associated with health care versus community acquired pneumonia: different entities, distinct approaches]. / Pneumonia associada aos cuidados de saúde versus pneumonia adquirida na comunidade: entidades diferentes, abordagens distintas.

Healthcare-associated pneumonia (HCAP) is now identified as a unique entity that differs from community-acquired pneumonia (CAP), and in many ways is similar to nosocomial pneumonia (NP). Patients with the diagnosis of CAP and HCAP admitted to our Pneumology Unit during one year were retrospectively analysed. The objective was to compare the characteristics and the approach of these two entities. 197 patients were included, 144 with CAP and 53 with HCAP. Sex, age, comorbilities, Pneumonia Severity Index (PSI) score, radiological involvement, bacteriology, treatment and outcomes were analysed in the 2 groups. Compared to CAP, HCAP was associated with more severe disease, a higher mortality rate and greater length of hospitalization. HCAP differed from CAP mainly in bacteriology and outcomes.

Pleural effusion: what lies underneath?

Malignant mesothelioma is a tumour of serous surfaces mainly arising at the pleura or the peritoneum. The diagnosis encompasses multiple problems as there is no pathognomonic hallmark for the disease, there are multiple histological types and the differentiation from other tumours, such as adenocarcinoma or metastatic pleural disease, can represent quite a challenge. Usually a diagnosis of malignant mesothelioma carries a dismal prognosis with scarce therapeutical options.The present report concerns a patient with a diagnosis of malignant pleural mesothelioma with endobronchial extension. Biopsy specimens were obtained through fibreoptic bronchoscopy and blind needle pleural biopsy. The final diagnosis was only possible after careful histological evaluation with a combination of immunohistochemical markers.

An economic analysis of erlotinib, docetaxel, pemetrexed and best supportive care as second or third line treatment of non-small cell lung cancer.

AIM: Evaluate costs and benefits of erlotinib as 2nd or 3rd line treatment of advanced or metastatic nonsmall cell lung cancer (NSCLC) versus docetaxel, pemetrexed and best supportive care. MATERIALS AND METHODS: Cost-minimisation and cost-utility analysis were performed. Time horizon of two years. Portuguese National Health System (NHS) perspective was applied. Survival and time to progression were obtained from three clinical trials. Base-case analysis: 2nd or 3rd line patients with advanced or metastatic NSCLC. Quality Adjusted Life Years (QALYs) were obtained from a UK study. Resource consumption was estimated by a Portuguese panel of experts. Costs were calculated according to official Portuguese databases (updated to 2008). Only direct health costs were applied. Annual discount rate: 5%. Sensitivity analysis included different subpopulations, a three year time horizon and a probabilistic analysis. RESULTS: The cost per patient was lower with erlotinib (26,478 euro) than docetaxel (29,262 euro) or pemetrexed (32,762 euro) and higher than best supportive care (16,112 euro). QALYs per patient were higher with erlotinib (0.250) than docetaxel (0.225), pemetrexed (0.241) or best supportive care (0.186). Erlotinib was dominant in the cost-utility analysis, with a lower cost and a higher efficacy than docetaxel and pemetrexed. The sensitivity analysis confirmed the robustness of the base-case analysis results. CONCLUSIONS: The use of erlotinib instead of docetaxel or pemetrexed could contribute to annual savings for the NHS (substitution rates: 5%-65%) ranging from 135,046 euro-1,755,602 euro (docetaxel replacement) and 291,801 euro-3,793,409 euro (pemetrexed replacement), with a gain in terms of QALYs.