Treatment of resectable stage IIIA non-small cell lung cancer

Surgical treatment of stage IIIA non-small cell lung cancer (NSCLC) remains a controversial area in the management of lung cancer despite being considered as part of combined modality therapy over the last two decades (1). The heterogeneity of stage III disease and the need for a multidisciplinary approach adds complexity to the treatment of resectable stage III NSCLC. Prospective randomized trials including surgery have consistently faced problems in recruiting. Multicenter trials in different countries: the United Kingdom (2), USA (3), France (4) or Japan (5) were terminated early as a result of poor accrual. This may in part be due to the low frequency of suitable patients for surgical treatment. Two modern randomized studies have been published comparing concurrent chemoradiotherapy (CRT) treatments with and without surgery. In the Intergroup 0139 trial (6), patients with stage III N2 disease were treated with concurrent induction chemotherapy plus radiotherapy. If no progression occurred, patients in the surgical group underwent resection and those in the chemoradiation group continued radiotherapy. A total of 396 eligible patients were randomized and there were no differences in overall survival (OS) between the two groups. However, in an exploratory analysis, survival was improved for the patients who underwent lobectomy, but not pneumonectomy, compared with definitive concurrent chemoradiation. In the ESPATUE trial (7) patients with resectable stage IIIA N2 and selected stage IIIB NSCLC were randomized to surgery or definitive concurrent CRT boost after induction chemotherapy followed by concurrent CRT. A total of 245 eligible patients were recruited to induction therapy over a 10-year period, 161 of them were finally randomized to surgery or tailored dose-scaled CRT. It should be pointed out that 63% of those patients were stage IIIB. There was no difference in OS between the arms. Although both trials were planned to demonstrate superiority in the surgery arm, they failed to show any benefit from surgery in terms of OS. Consequently, definitive concurrent CRT is the only strategy which can be given category 1 recommendation for most stage III NSCLC patients

Fasting plasma glucose is an independent predictor of survival in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy

Background: Diabetes is related with increased cancer mortality across multiple cancer types. Its role in lung cancer mortality is still unclear. We aim to determine the prognostic value of fasting plasma glucose (FPG) and diabetes mellitus in patients with locally advanced non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy. Methods: One-hundred seventy patients with stage III NSCLC received definitive concurrent chemoradiotherapy from 2010 to 2014. Clinico-pathological data and clinical outcome was retrospectively registered. Fifty-six patients (33%), met criteria for type 2 diabetes mellitus (T2DM) at baseline. The prognostic value of FPG and other clinical variables was assessed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and Cox proportional models and log-rank test were used. Results: With a median follow-up of 36 months, median PFS was 8.0 months and median OS was 15.0 months in patients with FPG ≥7 mmol/L compared to 20 months (HR 1.13; 95% CI 1.07-1.19, p  8.5%) (HR 4.53; 95% CI 2.21-9.30; p < 0.001) and those receiving insulin (HR 3.22; 95% CI 1.90-5.46 p < 0.001) had significantly independent worse OS. Conclusion: Baseline FPG level is an independent predictor of survival in our cohort of patients with locally advanced NSCLC treated with concurrent chemoradiotherapy. Studies in larger cohorts of patients are warranted to confirm this relevant association

Elevated Levels of the Complement Activation Product C4d in Bronchial Fluids for the Diagnosis of Lung Cancer

Molecular markers in bronchial fluids may contribute to the diagnosis of lung cancer. We previously observed a significant increase of C4d-containing complement degradation fragments in bronchoalveolar lavage (BAL) supernatants from lung cancer patients in a cohort of 50 cases and 22 controls (CUN cohort). The present study was designed to determine the diagnostic performance of these complement fragments (hereinafter jointly referred as C4d) in bronchial fluids. C4d levels were determined in BAL supernatants from two independent cohorts: the CU cohort (25 cases and 26 controls) and the HUVR cohort (60 cases and 98 controls). A series of spontaneous sputum samples from 68 patients with lung cancer and 10 controls was also used (LCCCIO cohort). Total protein content, complement C4, complement C5a, and CYFRA 21-1 were also measured in all cohorts. C4d levels were significantly increased in BAL samples from lung cancer patients. The area under the ROC curve was 0.82 (95% CI = 0.71-0.94) and 0.67 (95% CI = 0.58-0.76) for the CU and HUVR cohorts, respectively. In addition, unlike the other markers, C4d levels in BAL samples were highly consistent across the CUN, CU and HUVR cohorts. Interestingly, C4d test markedly increased the sensitivity of bronchoscopy in the two cohorts in which cytological data were available (CUN and HUVR cohorts). Finally, in the LCCCIO cohort, C4d levels were higher in sputum supernatants from patients with lung cancer (area under the ROC curve: 0.7; 95% CI = 0.56-0.83). In conclusion, C4d is consistently elevated in bronchial fluids from lung cancer patients and may be used to improve the diagnosis of the disease

Quimioterapia con fármacos nuevos en el cáncer de pulmón de célula no pequeña avanzado

[spa] El cáncer de pulmón es el cáncer más frecuente en todo el mundo. A principio de la década de los 90 aparecieron varios fármacos con una actividad prometedora en cáncer de pulmón de célula no pequeña (CPCNP). El núcleo de esta tesis doctoral son dos publicaciones que contribuyen al desarrollo de dos de estos nuevos fármacos: gemcitabina e irinotecan (CPT-11). El primer estudio se titula: Randomized phase III study of gemcitabine-cisplatin versus etoposide cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer y fue publicado en el Journal of Clinical Oncology 1999;17:12-18. El objetivo principal fue comparar la eficacia, en forma de tasa de respuesta, de la combinación de gemcitabina y cisplatino con la de una combinación convencional: etopósido y cisplatino en pacientes con CPCNP avanzado. Un total de 135 pacientes con CPCNP avanzado fueron randomizados a recibir o bien gemcitabina 1250 mg/m2 ev días 1 y 8 o etopósido 100 mg/m2 ev el día 1, en ciclos de 21 días. La tasa de respuesta (validada externamente) fue superior para los pacientes que recibieron gemcitabina-cisplatino que para los pacientes que recibieron etopósido-cisplatino (40.6% versus 21,9%; p=0,02). Esta tasa de respuesta superior se asociaba a un retraso significativo en el tiempo a la progresión (6,9 meses versus 4,3 meses) sin empeoramiento de la calidad de vida. No hay una diferencia estadísticamente significativa en supervivencia entre las dos ramas (8.7 meses para gemcitabina-cisplatino versus 7,2 meses para etopósido-cisplatino; p= 0.18). La toxicidad global para las dos combinaciones fue similar. Las náuseas y vómitos fueron más frecuentes en el brazo de gemcitabina que en el de etopósido, aunque la diferencia no era significativa. Gemcitabina-cisplatino producía menos alopecia grado 3 (13% versus 51%) y menos neutropenia grado 4 (28 versus 56%) pero más trombocitopenia grado 3 y 4 (56 versus 13%) que etopósido-cisplatino. Sin embargo no hubo complicaciones relacionadas con trombocitopenia en el brazo de gemcitabina. El segundo estudio se titula: Three-week schedule of irinotecan and cisplatin in advanced non-small cell lung cancer: a multicentre phase II study y fue publicado en Lung Cancer 2003;39:201-207. El objetivo principal era valorar la eficacia de la combinación, irinotecan-cisplatino en CPCNP avanzado, medida por tasa de respuesta. Se utilizó una pauta nueva de irinotecan y cisplatino consistente en una sola dosis de los dos fármacos cada tres semanas que proporcionaba la mayor dosis-intensidad de ambos agentes. Se reclutaron setenta y cuatro pacientes con CPCNP estadio IIIB (no candidatos a radioterapia) o estadio IV para recibir CPT-11 200 mg/ m2 iv y cisplatin 80 mg/m2 iv el día 1 cada 3 semanas. Las dosis-intensidades relativas para CPT-11 y cisplatino fueron 92% y 95%, respectivamente. No se observaron respuestas completas. Veinticinco pacientes de 73 obtuvieron una remisión parcial (34,2%). Las remisiones parciales se confirmaron en 18 pacientes (24.7%: IC 95%, 15,6-36,1%). La mediana de supervivencia fue de 8,2 meses, 9,7 meses para los pacientes con performance status (PS) 0 y 1, y 4 meses para aquellos con PS=2. La tasa de supervivencia al año fue el 31%. Las toxicidades clínivcas más importantes fueron diarrea retardada grado 3 y 4 (29% de los pacientes) y neutropenia febril (14% de los pacientes). En conclusión: 1) Cuando se compara con etopósido y ciaplatino, gemcitabina y cisplatino proporciona una tasa de respuestas significativamente superior y un retraso en tiempo a la progresión de la enfermedad sin empeorar la calidad de vida. 2) La combinación de CPT-11 y cisplatino una vez cada tres semanas es factible y activa en pacientes con CPCNP avanzado y PS 0 y 1, sin embargo los resultados no parecen superiores a los publicados con otras pautas

Treatment of resectable stage IIIA non-small cell lung cancer

Surgical treatment of stage IIIA non-small cell lung cancer (NSCLC) remains a controversial area in the management of lung cancer despite being considered as part of combined modality therapy over the last two decades (1). The heterogeneity of stage III disease and the need for a multidisciplinary approach adds complexity to the treatment of resectable stage III NSCLC. Prospective randomized trials including surgery have consistently faced problems in recruiting. Multicenter trials in different countries: the United Kingdom (2), USA (3), France (4) or Japan (5) were terminated early as a result of poor accrual. This may in part be due to the low frequency of suitable patients for surgical treatment. Two modern randomized studies have been published comparing concurrent chemoradiotherapy (CRT) treatments with and without surgery. In the Intergroup 0139 trial (6), patients with stage III N2 disease were treated with concurrent induction chemotherapy plus radiotherapy. If no progression occurred, patients in the surgical group underwent resection and those in the chemoradiation group continued radiotherapy. A total of 396 eligible patients were randomized and there were no differences in overall survival (OS) between the two groups. However, in an exploratory analysis, survival was improved for the patients who underwent lobectomy, but not pneumonectomy, compared with definitive concurrent chemoradiation. In the ESPATUE trial (7) patients with resectable stage IIIA N2 and selected stage IIIB NSCLC were randomized to surgery or definitive concurrent CRT boost after induction chemotherapy followed by concurrent CRT. A total of 245 eligible patients were recruited to induction therapy over a 10-year period, 161 of them were finally randomized to surgery or tailored dose-scaled CRT. It should be pointed out that 63% of those patients were stage IIIB. There was no difference in OS between the arms. Although both trials were planned to demonstrate superiority in the surgery arm, they failed to show any benefit from surgery in terms of OS. Consequently, definitive concurrent CRT is the only strategy which can be given category 1 recommendation for most stage III NSCLC patients

Longitudinal brain changes associated with prophylactic cranial irradiation in lung cancer

INTRODUCTION: The toxic effects of prophylactic cranial irradiation (PCI) and platinum-based chemotherapy on cognition in the lung cancer population have not yet been well established. In the present study we examined the longitudinal neuropsychological and brain structural changes observed in patients with lung cancer who were undergoing these treatments. METHODS: Twenty-two patients with small cell lung cancer (SCLC) who underwent platinum-based chemotherapy and PCI were compared with two control groups: an age- and education-matched group of healthy controls (n = 21) and a group of patients with non-SCLC (NSCLC, n = 13) who underwent platinum-based chemotherapy. All groups were evaluated using a neuropsychological battery and multimodal structural magnetic resonance imaging: T1-weighted and diffusion tensor imaging at baseline (before PCI for SCLC and chemotherapy for NSCLC) and at 3 months after treatment. T1 voxel-based morphometry and tract-based spatial statistics were used to analyze microstructural changes in gray matter (GM) and white matter (WM). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire was also completed. RESULTS: Patients with SCLC exhibited cognitive deterioration in verbal fluency over time. Structural magnetic resonance imaging showed decreases in GM at 3 months in the right subcortical regions, bilateral insular cortex, and superior temporal gyrus in patients with SCLC compared with both control groups. Additionally, patients with SCLC showed decreases in GM over time in the aforementioned regions plus in the right parahippocampal gyrus and hippocampus, together with changes in the WM microstructure of the entire corpus callosum. These changes had a limited impact on responses to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire, however. Patients with NSCLC showed no cognitive or brain structural differences after chemotherapy. CONCLUSIONS: This longitudinal study documents moderate neuropsychological deficits together with notable brain-specific structural changes (in GM and WM) in patients with SCLC after chemotherapy and PCI, suggesting that chemotherapy and especially PCI are associated with the development of cognitive and structural brain toxic effects

Geriatric assessment may help decision-making in elderly patients with inoperable, locally advanced non-small-cell lung cancer

Background: although concurrent chemoradiotherapy (cCRT) increases survival in patients with inoperable, locally advanced non-small-cell lung cancer (NSCLC), there is no consensus on the treatment of elderly patients. The aim of this study was to determine the prognostic value of the comprehensive geriatric assessment (CGA) and its ability to predict toxicity in this setting. Methods: we enrolled 85 consecutive elderly (⩾75 years) participants, who underwent CGA and the Vulnerable Elders Survey (VES-13). Those classified as fit and medium-fit by CGA were deemed candidates for cCRT (platinum-based chemotherapy concurrent with thoracic radiation therapy), while unfit patients received best supportive care. Results: fit (37%) and medium-fit (48%) patients had significantly longer median overall survival (mOS) (23.9 and 16.9 months, respectively) than unfit patients (15%) (9.3 months, log-rank P=0.01). In multivariate analysis, CGA groups and VES-13 were independent prognostic factors. Fit and medium-fit patients receiving cCRT (n=54) had mOS of 21.1 months (95% confidence interval: 16.2, 26.0). In those patients, higher VES-13 (⩾3) was associated with shorter mOS (16.33 vs 24.3 months, P=0.027) and higher risk of G3-4 toxicity (65 vs 32%, P=0.028). Conclusions: comprehensive geriatric assessment and VES-13 showed independent prognostic value. Comprehensive geriatric assessment may help to identify elderly patients fit enough to be treated with cCRT

Elevated Levels of the Complement Activation Product C4d in Bronchial Fluids for the Diagnosis of Lung Cancer

Molecular markers in bronchial fluids may contribute to the diagnosis of lung cancer. We previously observed a significant increase of C4d-containing complement degradation fragments in bronchoalveolar lavage (BAL) supernatants from lung cancer patients in a cohort of 50 cases and 22 controls (CUN cohort). The present study was designed to determine the diagnostic performance of these complement fragments (hereinafter jointly referred as C4d) in bronchial fluids. C4d levels were determined in BAL supernatants from two independent cohorts: the CU cohort (25 cases and 26 controls) and the HUVR cohort (60 cases and 98 controls). A series of spontaneous sputum samples from 68 patients with lung cancer and 10 controls was also used (LCCCIO cohort). Total protein content, complement C4, complement C5a, and CYFRA 21-1 were also measured in all cohorts. C4d levels were significantly increased in BAL samples from lung cancer patients. The area under the ROC curve was 0.82 (95% CI = 0.71-0.94) and 0.67 (95% CI = 0.58-0.76) for the CU and HUVR cohorts, respectively. In addition, unlike the other markers, C4d levels in BAL samples were highly consistent across the CUN, CU and HUVR cohorts. Interestingly, C4d test markedly increased the sensitivity of bronchoscopy in the two cohorts in which cytological data were available (CUN and HUVR cohorts). Finally, in the LCCCIO cohort, C4d levels were higher in sputum supernatants from patients with lung cancer (area under the ROC curve: 0.7; 95% CI = 0.56-0.83). In conclusion, C4d is consistently elevated in bronchial fluids from lung cancer patients and may be used to improve the diagnosis of the disease

Geriatric assessment may help decision-making in elderly patients with inoperable, locally advanced non-small-cell lung cancer

Background: although concurrent chemoradiotherapy (cCRT) increases survival in patients with inoperable, locally advanced non-small-cell lung cancer (NSCLC), there is no consensus on the treatment of elderly patients. The aim of this study was to determine the prognostic value of the comprehensive geriatric assessment (CGA) and its ability to predict toxicity in this setting. Methods: we enrolled 85 consecutive elderly (⩾75 years) participants, who underwent CGA and the Vulnerable Elders Survey (VES-13). Those classified as fit and medium-fit by CGA were deemed candidates for cCRT (platinum-based chemotherapy concurrent with thoracic radiation therapy), while unfit patients received best supportive care. Results: fit (37%) and medium-fit (48%) patients had significantly longer median overall survival (mOS) (23.9 and 16.9 months, respectively) than unfit patients (15%) (9.3 months, log-rank P=0.01). In multivariate analysis, CGA groups and VES-13 were independent prognostic factors. Fit and medium-fit patients receiving cCRT (n=54) had mOS of 21.1 months (95% confidence interval: 16.2, 26.0). In those patients, higher VES-13 (⩾3) was associated with shorter mOS (16.33 vs 24.3 months, P=0.027) and higher risk of G3-4 toxicity (65 vs 32%, P=0.028). Conclusions: comprehensive geriatric assessment and VES-13 showed independent prognostic value. Comprehensive geriatric assessment may help to identify elderly patients fit enough to be treated with cCRT

Geriatric assessment may help decision-making in elderly patients with inoperable, locally advanced non-small-cell lung cancer

Background: although concurrent chemoradiotherapy (cCRT) increases survival in patients with inoperable, locally advanced non-small-cell lung cancer (NSCLC), there is no consensus on the treatment of elderly patients. The aim of this study was to determine the prognostic value of the comprehensive geriatric assessment (CGA) and its ability to predict toxicity in this setting. Methods: we enrolled 85 consecutive elderly (⩾75 years) participants, who underwent CGA and the Vulnerable Elders Survey (VES-13). Those classified as fit and medium-fit by CGA were deemed candidates for cCRT (platinum-based chemotherapy concurrent with thoracic radiation therapy), while unfit patients received best supportive care. Results: fit (37%) and medium-fit (48%) patients had significantly longer median overall survival (mOS) (23.9 and 16.9 months, respectively) than unfit patients (15%) (9.3 months, log-rank P=0.01). In multivariate analysis, CGA groups and VES-13 were independent prognostic factors. Fit and medium-fit patients receiving cCRT (n=54) had mOS of 21.1 months (95% confidence interval: 16.2, 26.0). In those patients, higher VES-13 (⩾3) was associated with shorter mOS (16.33 vs 24.3 months, P=0.027) and higher risk of G3-4 toxicity (65 vs 32%, P=0.028). Conclusions: comprehensive geriatric assessment and VES-13 showed independent prognostic value. Comprehensive geriatric assessment may help to identify elderly patients fit enough to be treated with cCRT