Mariano Provencio

Oral Vinorelbine and Cisplatin as Induction Chemotherapy and Concomitant Chemo-Radiotherapy in Stage III Non-small Cell Lung Cancer: Final Results of an International Phase II Trial

Introduction: Cisplatin in combination with vinorelbine has reported an optimal activity/tolerance ratio when used in combination with radiotherapy in locally advanced unresectable non-small cell lung cancer. The currently available oral formulation of vinorelbine should be easier to use assuming a similar activity profile. An international phase II trial with vinorelbine oral and cisplatin as induction followed by oral vinorelbine and cisplatin with concomitant radiotherapy was implemented to evaluate the efficacy in terms of objective response (OR) following this combination as primary end point and duration or response, progression-free survival, overall survival, and safety as secondary endpoints. Material and Methods: The study included patients between 18 and 75 years, with histologically proven untreated locally advanced inoperable stage IIIA/IIIB (supraclavicular lymph nodes and pleural effusion excluded) non-small cell lung cancer, adequate bone marrow, hepatic and renal function, Karnofsky performance status ≥80%. Patients were treated with oral vinorelbine 60 mg/m2 day 1,8 cycle 1 and 80 mg/m2 day 1,8 cycle 2 (if no grade 3-4 toxicity) and cisplatin 80 mg/m2 day 1 every 3 weeks for 2 cycles as induction. Patients without progression received oral vinorelbine 40 mg/m2 day 1, 8 and cisplatin 80 mg/m2 day 1 every 3 weeks for 2 more cycles with radiotherapy 66 Gy in 6.5 weeks. Results: Patient and disease characteristics (n = 54) included: median age 57 years; female sex 24%; stage IIIA 48% and IIIB 52%; Squamous carcinoma 59%, Karnofsky performance status 100% (range, 80-100%) 50%, patients ≥5% weight loss at baseline 7%. Relative dose intensities of oral vinorelbine/cisplatin were 86%/93% and 97%/98% at induction and in combination with radiotherapy, respectively. Forty-one patients (76%) increased oral vinorelbine from 60 to 80 mg/m2 day during induction (reasons for nonescalation: hematological 7 patients, nonhematological 2 patients, error 4 patients). After two cycles of chemotherapy induction, the OR intent-to-treat in the 54 patients was 37%. Toxicities during induction were as follows: Neutropenia G3-4 (28%), Febrile Neutropenia (7%), nausea G3 (11%), vomiting G3-4 (9%), anorexia G3 (4%), diarrhea G4 (2%), constipation G3 (2%). Forty-seven out of 54 (87%) patients received concomitant chemo-radiotherapy. Median radiotherapy delivered dose was 66 Gy. Tolerance: 9% G3 Neutropenia; 4% G3 dysphagia/radiation; 2% G3 radiation dermatitis. Late pulmonary fibrosis was reported in one patient (1.8%). One month after completion of chemo-radiotherapy, the overall OR intent-to-treat in the 54 patients was 54% (95% CI: 40-67%). With a median follow-up of 37 months (95% CI: 34-41) the median progression-free survival and overall survival were: 12.5 (95% CI: 9.6-16.4) and 23.4 (95% CI: 17.6-29.8) months, respectively. Conclusion: Oral vinorelbine in combination with cisplatin is an effective combination in stage IIIA/IIIB patients. The excellent tolerance profile allowed to complete concomitant chemo-radiotherapy in 87% of patients. Oral vinorelbine in combination with cisplatin is a new and promising option that facilitates the administration of concomitant chemo-radiotherapy with high rates of treatment completion.

Small cell lung cancer in never-smokers.

Our aim was to describe the characteristics of a case-series of never-smoker small cell lung cancer (SCLC) cases. Cases of SCLC were selected from a prospective, multicenter, hospital-based case–control study performed in Spain. Participants were never-smokers older than 30u2005years with an anatomo-pathological confirmation of primary lung cancer. We collected clinical and epidemiological variables according to the studys protocol. We included 19 SCLC cases, 18 females (94.7%), median age 75u2005years (interquartile range (IQR) 70–80u2009years). Median residential radon concentration was 195u2005Bq·m−3 (IQR 130–229u2009Bq·m−3). 10 patients had limited disease and nine had extended disease. Median survival was 242u2005days (IQR 94–496u2009days); 1- and 2-year survival were 36.8% and 17.6%, respectively. Survival was much higher for individuals with limited disease than for those with extended disease (median 336 versus 235u2005days; 1-year survival 50% versus 22.2% and 2-year survival 27% versus 0%, respectively). Performance status at diagnosis was closely related to survival. SCLC is an infrequent, highly aggressive disease in never-smokers. Survival is poor, even for limited disease. Age at diagnosis in SCLC is higher than that observed for never-smokers with adenocarcinoma. Residential radon exposure is higher than the action levels recommended by the World Health Organization. Small cell lung cancer in never-smokers has a poor survival and is diagnosed at older ages than other lung cancers http://ow.ly/USS2W

Residential radon, EGFR mutations and ALK alterations in never-smoking lung cancer cases

The aim of this study was to assess if residential radon exposure might cause EGFR mutations or ALK rearrangements in never-smokers. We designed a multicentre case–control study in a radon-prone area (Galicia, Spain); only lung cancer cases were included in the study. We obtained residential radon measurements and clinical information for all the participants. We compared the median values of residential radon between patients with EGFR mutations or ALK rearrangements versus those without them. 323 patients were included. Median age was 70u2005years and 19.5% were males. 42 and 15% of patients were EGFR- and ALK-positive, respectively. The most frequent EGFR alterations were exon 19 deletions and exon 21 (L858R) single-point substitution mutations. ALK-positive patients were 10u2005years younger than ALK-negative patients. Residential radon levels were two-fold higher in patients with exon 19 deletions compared with patients with exon 21 (L858R) single-point substitution mutations (216 versus 118u2005Bq·m−3; p=0.057). There were no differences in residential radon levels by EGFR mutation status. ALK-positive patients (n=12) essentially had two-fold residential radon levels compared with ALK-negative patients (290 versus 164u2005Bq·m−3, respectively). Residential radon may have a role in the molecular signature of lung cancer in never-smokers, although more studies with larger sample sizes are needed to support this hypothesis. Residential radon might cause genetic alterations in driver genes for lung cancer in never-smokers http://ow.ly/1u4P302JdBs

Residential radon and lung cancer characteristics in never smokers

Abstract Purpose: The aim of this study is to assess if there is a relationship between residential radon and lung cancer histological types and patients’ age at diagnosis. Materials and methods: We conducted a multicenter hospital-based case-control study with eight participating hospitals. We included 216 never-smoking cases with primary lung cancer and 329 never-smoking controls. Controls were frequency matched with cases on age and sex distribution. Of them, 198 cases (91.7%) and 275 controls (83.5%) had residential radon measurements. Results: Lung cancer risk reached statistical significance only for adenocarcinoma (Odds ratio [OR] 2.19; 95% Confidence interval [CI] 1.44–3.33), for other histologies the results were marginally significant. Residential radon level was higher for patients diagnosed before 50 and 60 years old than for older lung cancer cases. Conclusions: Residential radon in never smokers seems to be a risk factor for all lung cancer histologies. Individuals diagnosed at a younger age have a higher residential radon concentration, suggesting an accumulative effect on lung cancer appearance.

Alpha-1 Antitrypsin Deficiency and Lung Cancer Risk: A Case-Control Study in Never-Smokers

Background: Never-smokers comprise up to 25% of all lung cancer cases. They could have different molecular pathways for lung cancer induction compared with smokers. Alpha-1 antitrypsin (AAT) deficiency is a hereditary trait whose main characteristic is early onset of lung emphysema. Our aim is to know if AAT-deficient carriers have a higher risk of lung cancer in a study performed exclusively in never-smokers. Methods: We designed a multicentre hospital-based case–control study, which included incident never-smoking lung cancer cases. Controls were never-smokers attending nonmajor surgery at the participating hospitals. Controls were frequency matched on age and gender with cases. We determined AAT variants (alleles S and Z) through polymerase chain reaction. Results: Two hundred and twelve cases and 318 controls were included. PiSS individuals showed a lung cancer risk of 4.64 (95% confidence interval: 1.08–19.92) compared with those with normal genotype (PiMM). When the analysis was restricted to women, the risk for PiSS increased to 7.58 (95% confidence interval: 1.40–40.87). This risk for homozygous SS was even higher for individuals exposed to environmental tobacco smoke (greater than 20 years). The presence of other alleles did not show any effect on lung cancer risk. Conclusions: Never smoking SS homozygous individuals pose an increased risk of lung cancer. The risk is higher for individuals exposed to environmental tobacco smoke.

Alcohol consumption and lung cancer risk in never smokers: a pooled analysis of case-control studies

BackgroundnLung cancer is the deadliest cancer in developed countries but the etiology of lung cancer risk in never smokers (LCRINS) is largely unknown. We aim to assess the effects of alcohol consumption, in its different forms, on LCRINS.nnnMethodsnWe pooled six multi-center case-control studies developed in the northwest of Spain. Cases and controls groups were composed of never smokers. We selected incident cases with anatomopathologically confirmed lung cancer diagnoses. All participants were personally interviewed. We performed two groups of statistical models, applying unconditional logistic regression with generalized additive models. One considered the effect of alcohol type consumption and the other considered the quantity of each alcoholic beverage consumed.nnnResultsnA total of 438 cases and 863 controls were included. Median age was 71 and 66, years, respectively. Adenocarcinoma was the predominant histological type, comprising 66% of all cases. We found that any type of wine consumption posed an OR of 2.20 OR 95%CI 1.12-4.35), and spirits consumption had an OR of 1.90 (95%CI 1.13-3.23). Beer consumption had an OR of 1.33 (95%CI 0.82-2.14). These results were similar when women were analyzed separately, but for men there was no apparent risk for any alcoholic beverage. The dose-response analysis for each alcoholic beverage revealed no clear pattern.nnnConclusionsnWine and spirits consumption might increase the risk of LCRINSs, particularly in females. These results have to be taken with caution given the limitations of the present study.

Environmental tobacco smoke exposure and EGFR and ALK alterations in never smokers' lung cancer. Results from the LCRINS study

Environmental tobacco smoke (ETS) exposure is a main risk factor of lung cancer in never smokers. Epidermal Growth Factor Receptor (EGFR) mutations and ALK translocations are more frequent in never smokers lung cancer than in ever-smokers. We performed a multicenter case-control study to assess if ETS exposure is associated with the presence of EGFR mutations and its types and if ALK translocations were related with ETS exposure. All patients were never smokers and had confirmed lung cancer diagnosis. ETS exposure during childhood showed a negative association on the probability of EGRF mutation though not significant. Exposure during adulthood, at home or at workplace, did not show any association with EGFR mutation. The mutation type L858R seemed the most associated with a lower probability of EGFR alterations for ETS exposure at home in adult life. There is no apparent association between ETS exposure and ALK translocation. These results might suggest that ETS exposure during childhood or at home in adult life could influence the EGFR mutations profile in lung cancer in never smokers, reducing the probability of presenting EFGR mutation.

Cáncer de pulmón microcítico. Metodología y resultados preliminares del estudio SMALL CELL

espanolIntroduccion El cancer de pulmon de celula pequena (CPCP) es el tipo histologico mas agresivo de las neoplasias broncopulmonares. Representa en torno al 10-15% de todos los casos. Muy pocos estudios han analizado la influencia del radon residencial. Se pretende conocer los factores de riesgo del CPCP. Metodos Se diseno un estudio de casos y controles multicentrico y de base hospitalaria, con 11 hospitales de 4 comunidades autonomas. Resultados Se analizan los primeros 113 casos reclutados y de ellos 63 con resultados de radon residencial. La edad mediana al diagnostico fue de 63 anos y un 11% de los casos eran menores de 50 anos. El 22% de los casos eran mujeres. El 57% tenian enfermedad en estadio IV y el 95% eran fumadores o exfumadores. La concentracion mediana de radon residencial era de 128 Bq/m3. Un 8% de los casos tenian concentraciones superiores a 400 Bq/m3. Por sexo, la unica diferencia relevante fue en el porcentaje de mujeres nunca fumadoras, mas elevado que para los hombres (p Conclusiones Existe un diagnostico a una edad temprana en buena parte de los casos con CPCP y predomina la enfermedad metastasica al diagnostico. El radon residencial parece jugar un papel importante en la aparicion de la enfermedad, existiendo casos diagnosticados con concentraciones de radon muy elevadas EnglishIntroduction Small cell lung cancer (SCLC) is the most aggressive histologic type of lung cancer, and accounts for approximately 10%-15% of all cases. Few studies have analyzed the effect of residential radon. Our aim is to determine the risk factors of SCLC. Methods We designed a multicenter, hospital-based case-control study with the participation of 11 hospitals in 4 autonomous communities. Results Results of the first 113 cases have been analyzed, 63 of which included residential radon measurements. Median age at diagnosis was 63 years; 11% of cases were younger than 50 years of age; 22% were women; 57% had extended disease; and 95% were smokers or former smokers. Median residential radon concentration was 128 Bq/m3. Concentrations higher than 400 Bq/m3 were found in 8% of cases. The only remarkable difference by gender was the percentage of never smokers, which was higher in women compared to men (P Conclusions A high percentage of SCLC cases are diagnosed early and there is a predominance of disseminated disease at diagnosis. Residential radon seems to play an important role on the onset of this disease, with some cases having very high indoor radon concentrations.INTRODUCTIONnSmall cell lung cancer (SCLC) is the most aggressive histologic type of lung cancer, and accounts for approximately 10%-15% of all cases. Few studies have analyzed the effect of residential radon. Our aim is to determine the risk factors of SCLC.nnnMETHODSnWe designed a multicenter, hospital-based case-control study with the participation of 11 hospitals in 4 autonomous communities.nnnRESULTSnResults of the first 113 cases have been analyzed, 63 of which included residential radon measurements. Median age at diagnosis was 63 years; 11% of cases were younger than 50 years of age; 22% were women; 57% had extended disease; and 95% were smokers or former smokers. Median residential radon concentration was 128Bq/m3. Concentrations higher than 400Bq/m3 were found in 8% of cases. The only remarkable difference by gender was the percentage of never smokers, which was higher in women compared to men (P<.001). Radon concentration was higher in patients with stageIV disease (non-significant difference) and in individuals diagnosed at 63 years of age or older (P=.032).nnnCONCLUSIONSnA high percentage of SCLC cases are diagnosed early and there is a predominance of disseminated disease at diagnosis. Residential radon seems to play an important role on the onset of this disease, with some cases having very high indoor radon concentrations.

Características al diagnóstico y supervivencia de estadios i y ii de cáncer de pulmón

INTRODUCTIONnThe objective of our study was to describe the characteristics of patients diagnosed with stage I and II lung cancer in the health area of A Coruña (Galicia) and to determine their overall survival according to certain variables.nnnMETHODSnRetrospective case series in patients diagnosed between January 2011 and December 2015 with stage I and II primary lung cancer with a minimum follow-up of 18 months.nnnRESULTSn158 patients were included, 99 at stage I, with a median age of 69 years [range 20-90], predominantly men (81%). Adenocarcinoma was the most common histology (52.9%), followed by epidermoid carcinoma (33.1%). Asymptomatic patients (35.9%) presented more frequently in stage I. Median survival was 57 months (95% CI 48.1-65.9), with higher survival among women, patients under 70 years of age, and those who received surgical treatment.nnnCONCLUSIONSnEarly stage lung cancer in the health area of A Coruña occurs predominantly in men, in advanced age, and with adenocarcinoma histology. Survival was greater among patients with stage I disease, women, individuals aged under 70 years, and those treated surgically. Despite early diagnosis, median survival was less than 5 years.espanolIntroduccion El objetivo de nuestro estudio es detallar las caracteristicas de los pacientes diagnosticados en estadios i y ii de cancer de pulmon en el area sanitaria de A Coruna (Galicia) y conocer su supervivencia global en funcion de ciertas variables. Metodos Serie de casos de caracter retrospectivo en sujetos diagnosticados entre enero de 2011 y diciembre de 2015 de cancer pulmonar primario en estadios i y ii con un seguimiento minimo de 18 meses. Resultados Se incluyeron 158 pacientes, 99 en estadio i, con una edad mediana de 69 anos [rango 20-90] y mayoritariamente hombres (81%). El adenocarcinoma fue la histologia mas frecuente (52,9%) por encima del carcinoma epidermoide (33,1%). Los sujetos asintomaticos (35,9%) se presentaron mas frecuentemente en estadio i. La mediana de supervivencia fue de 57 meses (IC 95%: 48,1-65,9), con una mayor supervivencia para el sexo femenino, los menores de 70 anos y los pacientes que recibieron tratamiento quirurgico. Conclusiones El cancer de pulmon en estadios iniciales en el area de sanitaria de A Coruna presenta un predominio de hombres, edad avanzada y mayoritariamente adenocarcinomas. La supervivencia fue mayor en el estadio i, mujeres, menores de 70 anos y subsidiarios de tratamiento quirurgico. Pese a este diagnostico precoz, la mediana de supervivencia no alcanza los 5 anos. EnglishIntroduction The objective of our study was to describe the characteristics of patients diagnosed with stage I and II lung cancer in the health area of A Coruna (Galicia) and to determine their overall survival according to certain variables. Methods Retrospective case series in patients diagnosed between January 2011 and December 2015 with stage I and II primary lung cancer with a minimum follow-up of 18 months. Results 158 patients were included, 99 at stage I, with a median age of 69 years [range 20-90], predominantly men (81%). Adenocarcinoma was the most common histology (52.9%), followed by epidermoid carcinoma (33.1%). Asymptomatic patients (35.9%) presented more frequently in stage I. Median survival was 57 months (95% CI 48.1–65.9), with higher survival among women, patients under 70 years of age, and those who received surgical treatment. Conclusions Early stage lung cancer in the health area of A Coruna occurs predominantly in men, in advanced age, and with adenocarcinoma histology. Survival was greater among patients with stage I disease, women, individuals aged under 70 years, and those treated surgically. Despite early diagnosis, median survival was less than 5 years.