Early Incorporation to Palliative Care (EPC) in Patients With Advanced Non-Small Cell Lung Cancer: The PACO Randomized Clinical Trial.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) experience a considerable disease burden, evident in symptomatic and psychological spheres. Advanced cancer represents a complex scenario for patients and the healthcare team. Early palliative care (EPC) has been proven as a clinically meaningful strategy in this context by several randomized trials but not in a resource-limited setting. This study aimed to evaluate the effect of EPC compared with standard oncological care (SOC) in patients with metastatic NSCLC in Mexico. MATERIALS AND METHODS: A prospective, randomized clinical trial was conducted at Instituto Nacional de Cancerologia in Mexico. All patients had histologically confirmed metastatic NSCLC without previous treatment. Patients were randomly assigned (1:1) to receive SOC or SOC + EPC. The EPC group was introduced to the palliative care team at baseline after randomization, which was integrated by psychologists, bachelor's in nutrition, specialized nurses, and physicians. Patients randomized to this arm had programmed visits to meet with the team at baseline and through the 2nd, 4th-, and 6th cycles thereafter. The primary endpoint was overall survival (OS); secondary outcomes included quality of life (QoL), anxiety and depression, and symptom intensity. They were assessed using the instruments EORTC QLQ-C30 questionnaire, Edmonton Symptom Assessment Scale (ESAS), and the Hospital Anxiety and Depression Scale (HADS) (clinicaltrials.gov [NCT01631565]). Questionnaires were completed at baseline, at 2nd, 4th, and 6th cycles of treatment. RESULTS: Between March 2012 and June 2015, 201 patients were assessed for eligibility and 146 were enrolled and allocated to receive EPC (73) or SOC (73). Median OS for patients in the EPC vs SOC arm was 18.1 months (95% CI, 7.9-28.4) and 10.5 months (95% CI, 4.7-16.2) (P = .029). Having a poor performance status (HR 1.7 [1.2-2.5]; P = .004) and allocation to the control group (HR 1.5 [1.03-2.3]; P = .034) were independently associated with a worse OS. Those patients with a global QoL > 70 at baseline had a better OS if they were In the EPC arm (38.7 months (95% CI, 9.9-67.6) vs SOC 21.4 months (95% CI, 12.4-30.3)). Mean QoL had a numerical improvement in patients allocated to EPC after 6 cycles of follow-up, nonetheless this difference was not statistically significant (55.1 ±â€…23.7 vs 56.9 ±â€…25.3; P = .753). There were no significant differences in anxiety and depression at all study points. CONCLUSIONS: EPC is associated with a significant improvement in OS, although, we observed that the greatest benefit of providing EPC was observed in those with a global QoL > 70 at baseline. This study did not identify significant changes in terms of QoL or symptom burden between the study groups after follow-up. Evidence robustly suggests that EPC should be considered part of the multidisciplinary treatment of metastatic NSCLC patients since diagnosis. According to our study, EPC can be implemented in low- or middle-income countries (LMIC).

Mirtazapine as Appetite Stimulant in Patients With Non-Small Cell Lung Cancer and Anorexia: A Randomized Clinical Trial.

Importance: Currently there is no standard therapy to improve cancer-related anorexia, hampering survival. Mirtazapine has been suggested as a feasible option in this context. Objectives: To assess the effect of mirtazapine on appetite and energy consumption in patients with advanced non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This randomized, double-blind, placebo-controlled clinical trial including adults was performed in a tertiary cancer care center from August 2018 to May 2022 with a follow-up of 8 weeks. Overall, 134 patients were screened; 114 were assessed for eligibility and 28 were excluded. Interventions: Patients were randomized in a 1:1 ratio to receive mirtazapine, 15 mg, or placebo for 2 weeks followed by a dose escalation to 30 mg until week 8 or placebo. Both groups received nutritional assessment and dietary advice. Main outcomes and measures: Appetite was assessed by the Anorexia Cachexia Scale and energy intake. Dietary parameters were evaluated at baseline, 4 weeks, and 8 weeks, with a 24-hour dietary recall, and energy quantification based on the Mexican system of nutritional equivalents. Results: A total of 86 patients met the inclusion criteria and were randomized to the placebo (n = 43) or the mirtazapine group (n = 43). The mean (SD) age was 63.5 (11.2) years, 41 were women (57.7%) and had adenocarcinoma, Eastern Cooperative Oncology Group performance status scale score of 1, stage IV NSCLC, and were receiving first-line treatment. Baseline characteristics were similar between groups. There was no difference in appetite scores in patients who received mirtazapine or placebo after 4 and 8 weeks. After 4 weeks, mirtazapine significantly increased energy intake (379.3 kcal; 95% CI, 1382.6-576.1; P < .001) including proteins (22.5 g; 95% CI, 11.5-33.4; P = .001), carbohydrates (43.4 g; 95% CI, 13.1-73.8; P = .006), and fats (13.2 g; 95% CI, 6.0-20.4; P = .006). Fats intake was significantly higher in patients in the mirtazapine group (14.5 g vs 0.7 g; P = .02) after 8 weeks. The mirtazapine group significantly decreased the proportion of patients with sarcopenia (82.8% vs 57.1%, P = .03) at 8 weeks. Patients on mirtazapine tolerated the treatment well, but reported a higher perception of nightmares at 2 weeks based on a 10 cm VAS score (0 [25th-75th percentile, 0-1] vs 0 [25th-75th percentile, 0-0] in the control group; P = .009) but this finding was nonsignificant after 4 and 8 weeks. Conclusion and Relevance: In this randomized clinical trial of patients with advanced NSCLC, there was no difference in appetite scores in all patients who received mirtazapine or placebo, but the mirtazapine group had a significant increase in energy intake through the 4- and 8-week follow-up, mainly in fat intake, which is a better and crucial source of energy. The addition of mirtazapine in the treatment of patients with advanced NSCLC and anorexia may help these patients achieve their energy requirements and improve health-related quality of life, specifically emotional and cognitive functioning. Trial Registration: ClinicalTrials.gov Identifier: NCT04748523.

Nitroglycerin Plus Whole Intracranial Radiation Therapy for Brain Metastases in Patients With Non-Small Cell Lung Cancer: A Randomized, Open-Label, Phase 2 Clinical Trial.

PURPOSE: Hypoxia has been associated with chemoradioresistance secondary to vascular endothelial growth factor receptor induced by hypoxia-induced factor (HIF). Nitroglycerin (NTG) can reduce HIF-1 in tissues, and this may have antiangiogenic, proapoptotic, and antiefflux effects. Particularly, epidermal growth factor-mutated (EGFRm) tumor cell lines have been shown to overexpress both vascular endothelial growth factor and HIF. In this phase 2 study, we evaluated the effect of transdermal NTG plus whole brain radiation therapy (WBRT) in patients with non-small cell lung cancer (NSCLC) with brain metastases (BM). METHODS: This was an open-label, phase 2 clinical trial with 96 patients with NSCLC and BM. Patients were randomized 1:1 to receive NTG plus WBRT (30 Gy in 10 fractions) or WBRT alone. The primary endpoint was intracranial objective response rate (iORR) evaluated 3 months posttreatment. NTG was administered using a transdermal 36-mg patch from Monday through Friday throughout WBRT administration (10 days). The protocol was retrospectively registered at ClinicalTrials.gov (NCT04338867). RESULTS: Fifty patients were allocated to the control group, and 46 were allocated to the experimental group (NTG); among these, 26 (52%) had EGFRm in the control group and 21 (45.7%) had EGFRm in the NTG arm. In terms of the iORR, patients in the NTG group had a significantly higher response compared with controls (56.5% [n = 26/46 evaluable patients] vs 32.7% [n = 16/49 evaluable patients]; relative risk, 1.73; 95% confidence interval [CI], 1.08-2.78; P = .024). Additionally, patients who received NTG + WBRT had an independently prolonged intracranial progression-free survival (ICPFS) compared with those who received WBRT alone (27.7 vs 9.6; hazard ratio [HR], 0.5; 95% CI, 0.2-0.9; P = .020); this positively affected overall progression-free survival among patients who received systemic therapy (n = 88; HR, 0.5; 95% CI, 0.2-0.9; P = .043). The benefit of ICPFS (HR, 0.4; 95% CI, 0.2-0.9; P = .030) was significant in the EGFRm patient subgroup. No differences were observed in overall survival. A significantly higher rate of vomiting presented in the NTG arm of the study (P = .016). CONCLUSIONS: The concurrent administration of NTG and radiation therapy improves iORR and ICPFS among patients with NSCLC with BM. The benefit in ICPFS is significant in the EGFRm patient subgroup.

Modifying factors of PD-L1 expression on tumor cells in advanced non-small-cell lung cancer.

BACKGROUND: Programmed death ligand-1 (PD-L1) expression predicts immunotherapy utility in nononcogenic addictive lung adenocarcinoma (ADC). However, its reproducibility and reliability may be compromised outside clinical trials. This study aimed to evaluate factors associated with PD-L1 expression in lung ADC. METHODS: This observational study assessed 547 tumor samples with advanced lung ADC from January 2016 to December 2020 in a single cancer institution. Tumor samples were stained by at least one approved PD-L1 clone, SP263 (Ventana) or 22C3 (Dako), and stratified in tumor proportion score (TPS) <1%, 1-49%, or ≥50%. RESULTS: Of all the tumor samples, positive PD-L1 staining was higher in poorly differentiated tumors (67.3% vs. 32.7%, p < 0.001). Analytical factors associated with a PD-L1 high expression (TPS ≥ 50%) were the SP263 clone (19.6% vs. 8.2%, p < 0.001), time of archival tumor tissue <12 months (15.3% vs. 3.8%, p = 0.024), whenever the analysis was performed in the most recent years (2019-2020) (19.0% vs. 8.3%, p < 0.001), and whenever the analysis was performed by pathologists in the academic setting (Instituto Nacional de Cancerologia, INCan) (19.9% vs. 11.9%, p = 0.001). In the molecular analysis, EGFR wild-type tumors had an increased proportion of PD-L1 positive and PD-L1 high cases (60.2% vs. 47.9%, p = 0.006 and 17.4% vs.8.5%, p = 0.004). A moderate correlation (r = 0.69) in the PD-L1 TPS% was observed between the two different settings (INCan vs. external laboratories). CONCLUSION: Clinicopathological factors were associated with an increased PD-L1 positivity rate. These differences were significant in the PD-L1 high group and associated with the academic setting, the SPS263 clone, time of archival tumor tissue <12 months, and a more recent period in the PD-L1 analysis.

Financial Toxicity Among Older Mexican Adults With Cancer and Their Families: A Mixed-Methods Study.

PURPOSE: The financial toxicity (FT) of cancer is common among older adults in high-income countries, but little is known about the financial hardships faced by older patients with cancer living in developing countries. The aim of this study was to explore the financial burden of cancer among older Mexican adults and their relatives, as well as factors that might mitigate such burden. METHODS: This mixed-methods study included patients age 65 years and older with the 10 most common malignancies in Mexico and 3-24 months from diagnosis at two cancer centers in Mexico City and their relatives. For the quantitative component, patients and relatives answered the Spanish version of the Consumer Financial Protection Bureau Financial Well-Being Scale. Patients completed the Comprehensive Score for Financial Toxicity-Functional Assessment of Chronic Illness Therapy (COST-FACIT) scale and a 3-month, self-reported cost diary. For the qualitative component, focused interviews were used to explore the individual experiences of patients and their relatives. RESULTS: Ninety-six patients and their relatives were included, of whom 45% had stage IV disease. On the COST-FACIT scale, 9% reported no FT, 52% mild FT, 39% moderate FT, and 0% severe FT. The mean Consumer Financial Protection Bureau Financial Well-Being Scale score was 45.2, with 78% reporting poor financial well-being (score ≤ 50). On cost diaries, most expenses were associated with purchasing medications, including chemotherapy. Focused interviews showed that most patients and relatives had to acquire debt to face costs of cancer care. CONCLUSION: A high proportion of Mexican older adults with cancer reported FT and poor financial well-being. Understanding experiences associated with FT and strategies to mitigate it represents an essential first step to design public policies aimed at protecting older adults with cancer and their families from catastrophic spending.

Prophylactic Cranial Irradiation in Patients With High-Risk Metastatic Non-Small Cell Lung Cancer: Quality of Life and Neurocognitive Analysis of a Randomized Phase II Study.

PURPOSE: To this date, studies regarding the use of prophylactic cranial irradiation (PCI) versus standard of care (SoC) for patients with non-small cell lung cancer have shown limited benefit in survival outcomes, in addition to the potential effects on quality of life (QoL) and neurocognitive function (NCF). This randomized, phase II study evaluated the role of PCI in QoL and NCF, in a population comprised of subjects at a high risk for development of brain metastases (BM). METHODS AND MATERIALS: Eligible patients had histologically confirmed non-small cell lung cancer without baseline BM, harboring epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or elevated carcinoembryonic antigen (CEA) at diagnosis. Participants were assigned to receive SoC or SoC plus PCI (25 Gy in 10 fractions). Primary endpoint was BM at 24 months (BM-24), for which the study was powered. Secondary endpoints included QoL assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the Lung Cancer module (LC13) and NCF assessed using the Mini Mental State Examination (MMSE). Patients were followed every 3 months for a year for QoL and NCF. RESULTS: From May 2012 to December 2017, 84 patients were enrolled in the study, 41 were allocated to PCI while 43 received SoC. Efficacy outcomes are discussed in a separate article. The global health-QoL scores were similar at 3, 6, 9, and 12 months after randomization between both study arms, with no significant differences when comparing by groups. At 1-year postrandomization, median global health QoL scores were 83 (p25-p75: 75-83) and 83 (p25-p75: 75-83) in the control and experimental arms, respectively. There were no significant changes in terms of the mean differences between subjects in either study arm when analyzing the change between baseline and 12-month scores (16.4 ± 19.9 vs 12.9 ± 14.7; P = .385). Seventeen patients were alive at database lockdown in February 2020, without significant differences in median MMSE (30 [p25-75: 29-30] vs 30 [p25-75: 28-30]) or QLQ-C30 scores (75.0 [p25-75: 50-87.2] vs 67.0 [p25-75: 50.0-100.0]). CONCLUSIONS: Among a selected high-risk population for developing BM, PCI did not significantly decrease QoL or neurocognitive function as assessed using the MMSE. Future studies are warranted to assess this observation, using more varied and sensitive tools available to date.

Brigatinib in ALK-positive non-small cell lung cancer: real-world data in the Latin American population (Bri-world extend CLICaP).

Background: Brigatinib has demonstrated its efficacy as first-line therapy and in further lines for ALK-positive non-small cell lung cancer (NSCLC) patients; however, real-world data in Latin America are scarce. Methods: From January 2018 to March 2020, 46 patients with advanced ALK-positive NSCLC received brigatinib as second or further line of therapy in Mexico and Colombia. The primary end point was progression-free survival (PFS); secondary end point was time to treatment discontinuation (TTD). Results: At a median follow-up of 9.3 months, the median PFS was 15.2 months (95% CI: 11.6-18.8), and TTD was 18.46 months (95% CI: 9.54-27.38). The estimated overall survival at 12 months was 80%. Safety profile was consistent with previously published data. Conclusion: Brigatinib is an effective treatment for previously treated ALK-positive NSCLC patients in a real-world setting.

The Role of a Cachexia Grading System in Patients with Non-Small Cell Lung Cancer Treated with Immunotherapy: Implications for Survival.

OBJECTIVE: The association between cancer-induced weight-loss (CIWL) and poor clinical outcomes in patients treated with immunotherapy is scarcely understood. We evaluated the use of a cachexia-grading system in IO-treated non-small cell lung cancer (NSCLC) patients in order to predict clinical outcomes. MATERIALS: 300 patients with NSCLC, who received immunotherapy during any line of therapy, were included. All patients were graded according to a previously validated cachexia scale, which takes into consideration body mass index (BMI) and weight loss, stratifying patients into five risk categories (0 [pre-cachexia] - 4 [refractory cachexia]). Primary endpoint was overall survival (OS). RESULTS: Ninety-one (30.3%) patients were classified in the low risk category, 176 (58.6%) were classified in the intermediate risk category and 33 (11%) were in the high risk category. Patients classified as low-risk had a significantly longer OS compared with those with intermediate or high risk (22.4 mo, [95%CI: 16.6-NR] vs. 17.1 [95%CI: 13.5-22.4] vs. 8.0 [3.9-18.4]; p < 0.001). In the multivariate analysis, after adjusting for age, hemoglobin and ORR, hazard of death increased as per the cachexia risk scale (Hazard ratio: 1.62 [1.22-2.16]; p = 0.001). CONCLUSION: Cachexia is independently associated with worse OS in NSCLC patients who receive immunotherapy, highlighting the role for nutritional assessment.

Risk of Developing Checkpoint Immune Pneumonitis and Its Effect on Overall Survival in Non-small Cell Lung Cancer Patients Previously Treated With Radiotherapy.

INTRODUCTION: Immune checkpoint inhibitor-related pneumonitis (ICIP) is a potentially life threatening immune-related adverse event (irAE), especially in non-small cell lung cancer (NSCLC) patients. Currently, the potential for increased irAE in patients who receive radiotherapy is scarcely known, although a connection between antitumor immune responses and irAEs has been suggested. In this study, we evaluated the development of ICIP in non-small cell lung cancer patients with prior radiotherapy, treated with immunotherapy in the second-line. METHODS: In this retrospective trial, we included patients treated with second-line immunotherapy at the National Cancer Institute in Mexico City from February 2015 to February 2018. Clinical, radiological and treatment variables were evaluated according to the presence of ICIP as defined by the Common Terminology Criteria for Adverse Events (4.0) in patients with or without a previous (≥months) history of radiotherapy. RESULTS: Among 101 NSCLC patients who received treatment with ICIs, 22 patients (21.8%) were diagnosed with ICIP, of which 73% (16/22) had a history of radiotherapy (OR 6.04, 95% CI 2.03-18.0, p < 0.001). Median progression free survival and overall survival were similar in patients who developed ICIP compared with those who did not, however, patients who presented grade ≥ 2 ICIP had an increased risk of mortality (HR 2.54, 95% CI 1.20-5.34, p = 0.014). CONCLUSION: In this real-world cohort of NSCLC patients treated with ICI, the history of prior radiotherapy was associated with increased risk for ICIP development. Unlike other irAEs, grade ≥ 2 ICIP is an independent prognostic factor for decreased survival in NSCLC patients.

Cost-effectiveness analysis of first and second-generation EGFR tyrosine kinase inhibitors as first line of treatment for patients with NSCLC harboring EGFR mutations.

BACKGROUND: Tyrosine-kinase inhibitors (TKIs) have become the cornerstone treatment of patients with non-small cell lung cancer that harbor oncogenic EGFR mutations. The counterpart of these drugs is the financial burden that they impose, which often creates a barrier for accessing treatment in developing countries. The aim if the present study was to compare the cost-effectiveness of three different first and second generation TKIs. METHODS: We designed a retrospective cost-effectiveness analysis of three different TKIs (afatinib, erlotinib, and gefitinib) administered as first-line therapy for patients with NSCLC that harbor EGFR mutations. RESULTS: We included 99 patients with the following TKI treatment; 40 treated with afatinib, 33 with gefitinib, and 26 with erlotinib. Median PFS was not significantly different between treatment groups; 15.4 months (95% CI 9.3-19.5) for afatinib; 9.0 months (95% CI 6.3- NA) for erlotinib; and 10.0 months (95% CI 7.46-14.6) for gefitinib. Overall survival was also similar between groups: 29.1 months (95% CI 25.4-NA) for afatinib; 27.1 months (95% CI 17.1- NA) for erlotinib; and 23.7 months (95% CI 18.6-NA) for gefitinib. There was a statistically significant difference between the mean TKIs costs; being afatinib the most expensive treatment. This difference was observed in the daily cost of treatment (p < 0.01), as well as the total cost of treatment (p = 0.00095). Cost-effectiveness analysis determined that afatinib was a better cost-effective option when compared with first-generation TKIs (erlotinib and gefitinib). CONCLUSION: In our population, erlotinib, afatinib, and gefitinib were statistically equally effective in terms of OS and PFS for the treatment of patients with advanced EGFR-mutated NSCLC population. Owing to its marginally increased PFS and OS, the cost-effectiveness analysis determined that afatinib was a slightly better cost-effective option when compared with first-generation TKIs (erlotinib and gefitinib).

Baseline Dysgeusia in Chemotherapy-Naïve Non-Small Cell Lung Cancer Patients: Association with Nutrition and Quality of Life.

Purpose: Dysgeusia can be found in 50% of cancer patients undergoing chemotherapy. Nonetheless, dysgeusia can be present in treatment-naïve patients, and may negatively impact nutrition and quality of life.Methods: Treatment-naïve non-small cell lung cancer (NSCLC) was assessed for dysgeusia using a self-reporting questionnaire and a rinse stimuli technique. Patients were evaluated in terms of health-related quality of life (HRQL) using the EORTC-QLQ-C30 questionnaire and in terms of nutrition using the subjective global assessment (SGA), energy consumption and body composition.Results: Among 65 treatment-naïve patients, dysgeusia was self-reported in 35%. Using the rinse stimuli technique, most of the patients perceived taste stimuli with a minimal concentration, but could not recognize the taste. Patients with dysgeusia presented significantly less lean-body mass (P = 0.027), and higher fat mass (P = 0.027). Additionally, these patients had significantly more gastrointestinal symptoms including nausea (P = 0.042), anorexia (P = 0.004), and early satiety (P < 0.0001). Dysgeusia was also associated with less food consumption (P = 0.010). Last, patients with dysgeusia had clinically-significant alterations in HRQL scales.Conclusion: Presence of dysgeusia in NSCLC patients before undergoing chemotherapy is associated with worse nutritional outcomes. The routine assessment of dysgeusia in treatment-naïve patients should be encouraged to timely assess and follow nutritional parameters.

Characteristics of non-small cell lung cancer: differences by sex and hormonal status in a Mexican population.

OBJECTIVE: To analyze the differences in the clinico-pathological and molecular characteristics of non-small cell lung cancer (NSCLC) as well as the clinical outcome of patients by sex and hormonal status. MATERIALS AND METHODS: We performed a retrospective study among 1 104 NSCLC patients. Clinic-pathologic data was recorded and survival outcomes were compared between male and female sex patients, and further by pre and postmenopausal status in females. RESULTS: Women were significantly more likely to be non-smokers (p<0.001), had higher frequency of wood-smoke exposure (p<0.001), EGFR-sensitizing mutations (p<0.001), had better performance status (p=0.020) and had a better overall survival (OS) compared to men (p=0.021). Differences were found also by hormonal status, postmenopausal women had a longer OS compared to premenopausal women (31.1 vs. 19.4 months p=0.046).

OBJETIVO: Analizar las diferencias en las características clínico-patológicas, moleculares y en la evolución del cáncer de pulmón de células no pequeñas (CPCNP) por sexo y estadio hormona. MATERIAL Y MÉTODOS: Estudio retrospectivo (N=1 104) en pacientes con CPCNP. Se recabaron datos clínico-patológicos y desenlaces de sobrevida y se compararon entre hombres y mujeres, y entre mujeres pre y postmenopáusicas. RESULTADOS: . Las mujeres de este estudio tuvieron significativamente mayor probabilidad de ser no fumadoras (p<0.001), tener exposición a humo de leña (p<0.001), mutaciones en EGFR (p<0.001), mejor estado funcional (p=0.020), y una mejor sobrevida global (SG) en comparación con los hombres (p=0.021). Estas diferencias también se encontraron en cuestión al estatus hormonal, con las mujeres postmenopáusicas presentando una mayor sobrevida en comparación con las premenopáusicas (31.1 vs.19.4 meses; p=0.046). CONCLUSIONES: Los presentes resultados apoyan las diferencias en la presentación del CPCNP de acuerdo con el sexo y estatus hormonal.

Characteristics of non-small cell lung cancer: differences by sex and hormonal status in a Mexican population / Características del cáncer de pulmón de células no pequeñas: diferencias por sexo y estado hormonal en una población mexicana

Abstract: Objective: To analyze the differences in the clinico-pathological and molecular characteristics of non-small cell lung cancer (NSCLC) as well as the clinical outcome of patients by sex and hormonal status. Materials and methods: We performed a retrospective study among 1 104 NSCLC patients. Clinic-pathologic data was recorded and survival outcomes were compared between male and female sex patients, and further by pre and postmenopausal status in females. Results: Women were significantly more likely to be non-smokers (p<0.001), had higher frequency of wood-smoke exposure (p<0.001), EGFR-sensitizing mutations (p<0.001), had better performance status (p=0.020) and had a better overall survival (OS) compared to men (p=0.021). Differences were found also by hormonal status, postmenopausal women had a longer OS compared to premenopausal women (31.1 vs. 19.4 months p=0.046). Conclusion: Our results support the differences in lung cancer presentation by sex and also by hormonal status.

Resumen: Objetivo: Analizar las diferencias en las características clínico-patológicas, moleculares y en la evolución del cáncer de pulmón de células no pequeñas (CPCNP) por sexo y estadio hormonal. Material y métodos: Estudio retrospectivo (N=1 104) en pacientes con CPCNP. Se recabaron datos clínico-patológicos y desenlaces de sobrevida y se compararon entre hombres y mujeres, y entre mujeres pre y postmenopáusicas. Resultados: Las mujeres de este estudio tuvieron significativamente mayor probabilidad de ser no fumadoras (p<0.001), tener exposición a humo de leña (p<0.001), mutaciones en EGFR (p<0.001), mejor estado funcional (p=0.020), y una mejor sobrevida global (SG) en comparación con los hombres (p=0.021). Estas diferencias también se encontraron en cuestión al estatus hormonal, con las mujeres postmenopáusicas presentando una mayor sobrevida en comparación con las premenopáusicas (31.1 vs. 19.4 meses; p=0.046). Conclusión: Los presentes resultados apoyan las diferencias en la presentación del CPCNP de acuerdo con el sexo y estatus hormonal.

FAACT-Anorexia Cachexia Scale: Cutoff Value for Anorexia Diagnosis in Advanced Non-Small Cell Lung Cancer Patients.

Lung cancer (LC) has a high rate of anorexia, which negatively affects quality-of-life and prognosis; however prevalence values may vary as per diagnostic test. There is no standard for anorexia diagnosis, currently the anorexia cachexia scale (A/CS) has been proposed as a tool for diagnosing anorexia with a consensus cutoff value of ≤24, nonetheless a validated cutoff value is required. The A/CS was evaluated in advanced Non-Small Cell Lung Cancer (NSCLC) patients to establish a cutoff value. The appetite item from the QLQ-C30 questionnaire and survival served as a standard reference. The cutoff value was associated with clinical and nutritional characteristics along with quality-of-life. Three hundred and twelve (312) NSCLC patients were evaluated. The mean A/CS value was 31 ± 9 and the identified cutoff value was 32.5 (sensitivity: 80.3% and specificity: 85%). The proportion of anorexia accurately diagnosed with the cutoff value of 24 was 26%, while with 32 it was 50%. The A/CS cutoff value of 32 was associated with clinical parameters, nutritional consumption, and quality-of-life, and independently associated with overall survival. A score of ≤32 in the A/CS is proposed for anorexia diagnosis in order to identify patients at risk of complications involving malnutrition related to LC.

Targeted next generation sequencing identified a high frequency genetic mutated profile in wood smoke exposure-related lung adenocarcinoma patients.

BACKGROUND: Wood smoke exposure (WSE) has been associated with an increased risk of lung cancer development. WSE has been related with high frequency of EGFR mutations and low frequency of KRAS mutations. The aim of this study was to evaluate large scale genomic alterations in lung adenocarcinomas associated with WSE using targeted next generation sequencing. METHODS: DNA multi-targeted sequencing was performed in 42 fresh-frozen samples of advanced lung adenocarcinomas. The TruSeQ Cancer Panel (Illumina) was used for genomic library construction and sequencing assays. RESULTS: WSE rate was higher in women (p=0.037) and non-smokers (p=0.001). WSE correlated with mutations in the genes SMARCB1 (p=0.002), Ataxia telangiectasia mutated (p=0.004), Kinase Insert Domain Receptor (p=0.006), and were borderline significant in RET and EGFR exon. Genomic alterations significantly co-occurred in the tumor suppressor gene ATM with the following genes: SMARCB1, EGFR exon 7, RET and KDR. Clinical factors associated with poor prognosis were ECOG ≥ 2 (p= 0.014), mutations in KDR (p= 0.004) and APC genes (p < 0.001). CONCLUSIONS: Lung adenocarcinoma patients with WSE showed a distinctive mutated profile for the SMARCB1, ATM, EGFR exon 7, RET and KDR genes. ECOG status and KDR gene mutations were significantly associated with poor prognosis.

Levels of peripheral blood polymorphonuclear myeloid-derived suppressor cells and selected cytokines are potentially prognostic of disease progression for patients with non-small cell lung cancer.

Polymorphonuclear-MDSC (PMN-MDSC) have emerged as an independent prognostic factor for survival in NSCLC. Similarly, cytokine profiles have been used to identify subgroups of NSCLC patients with different clinical outcomes. This prospective study investigated whether the percentage of circulating PMN-MDSC, in conjunction with the levels of plasma cytokines, was more informative of disease progression than the analysis of either factor alone. We analyzed the phenotypic and functional profile of peripheral blood T-cell subsets (CD3+, CD3+CD4+ and CD3+CD8+), neutrophils (CD66b+) and polymorphonuclear-MDSC (PMN-MDSC; CD66b+CD11b+CD15+CD14-) as well as the concentration of 14 plasma cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 p70, IL-17A, IL-27, IL-29, IL-31, and IL-33, TNF-α, IFN-γ) in 90 treatment-naïve NSCLC patients and 25 healthy donors (HD). In contrast to HD, NSCLC patients had a higher percentage of PMN-MDSC and neutrophils (P < 0.0001) but a lower percentage of CD3+, CD3+CD4+ and CD3+CD8+ cells. PMN-MDSC% negatively correlated with the levels of IL1-ß, IL-2, IL-27 and IL-29. Two groups of patients were identified according to the percentage of circulating PMN-MDSC. Patients with low PMN-MDSC (≤ 8%) had a better OS (22.1 months [95% CI 4.3-739.7]) than patients with high PMN-MDSC (9.3 months [95% CI 0-18.8]). OS was significantly different among groups of patients stratified by both PMN-MDSC% and cytokine levels. In sum, our findings provide evidence suggesting that PMN-MDSC% in conjunction with the levels IL-1ß, IL-27, and IL-29 could be a useful strategy to identify groups of patients with potentially unfavorable prognoses.

Characteristics of progression to tyrosine kinase inhibitors predict overall survival in patients with advanced non-small cell lung cancer harboring an EGFR mutation.

BACKGROUND: Non-small cell lung cancer (NSCLC) harboring EGFR-sensitizing mutations has a distinct biology and heterogeneous clinical behavior. We evaluated the characteristics to progression such as clinical patterns of progression (dramatic, gradual, and local) with the prognosis of NSCLC patients treated with tyrosine kinase inhibitors (TKIs). METHODS: We reviewed 123 advanced-NSCLC patients with an EGFR-sensitizing mutation treated with TKIs (gefitinib, erlotinib and afatinib). We assessed patients according to clinical factors and progression pattern to TKIs at three centers. RESULTS: For all patients, 58.5%, 31.7% and 9.8% harbored exon19 deletion, exon21 L858R mutation and other-sensitivity mutations, respectively. Median progression-free survival (PFS) was 8.8 months (95% CI: 7.9-9.7). Sixty percent of patients were asymptomatic. Dramatic-progression was the most frequent pattern (50.4%), followed by gradual-progression (32.5%), and local-progression (17.1%). Median overall survival (OS) was 23.1 months (95% CI: 17.4-28.9). In the univariate analysis, factors associated to a longer OS included pattern [gradual-progression (32.1), dramatic (19.5) and local (18.8 months), P=0.008], and the time to progression to TKI [>12 months (38.5), 6-12 months (19.1), <6 months (9.6), P<0.001]. Multivariate analysis showed that only time to progression to TKI was independently associated to OS and PFS. CONCLUSIONS: Factors at TKI progression associated to a longer OS can define a subset of patients who may benefit from continued TKI therapy, as well as from local-ablative therapy in progression sites, especially in patients without T790M or who lack access to third-generation TKI.

The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial.

BACKGROUND: Over one half of the patients diagnosed with advanced lung cancer experience anorexia. In addition to its high incidence, cancer-induced anorexia promotes the development of the anorexia-cachexia syndrome, which is related to poor clinical outcomes. Recently, drugs derived from cannabinoids, such as Nabilone, have been recognized for their appetite improvement properties; however, clinical trials to support their use in cancer patients are necessary. METHODS: This is a randomized, double-blind, placebo-controlled clinical trial to assess the effect of Nabilone vs. placebo on the appetite, nutritional status, and quality of life in patients diagnosed with advanced Non-small cell lung cancer (NSCLC) (NCT02802540). RESULTS: A total of 65 patients from the outpatient clinic at the National Institute of Cancer (INCan) were assessed for eligibility and 47 were randomized to receive Nabilone (0.5 mg/2 weeks followed by 1.0 mg/6 weeks) or placebo. After 8 weeks of treatment, patients who received Nabilone increased their caloric intake (342-kcal) and had a significantly higher intake of carbohydrates (64 g) compared to patients receiving placebo (p = 0.040). Quality of life also showed significant improvements in patients in the experimental arm of the trial, particularly in role functioning (p = 0.030), emotional functioning (p = 0.018), social functioning (p = 0.036), pain (p = 0.06), and insomnia (p = 0.020). No significant change in these scales was seen in the control group. CONCLUSION: Nabilone is an adequate and safe therapeutic option to aid in the treatment of patients diagnosed with anorexia. Larger trials are necessary in order to draw robust conclusions in regard to its efficacy in lung cancer patients.

Expression of PD-1/PD-L1 and PD-L2 in peripheral T-cells from non-small cell lung cancer patients.

Binding of programmed death-1 (PD-1) with its ligands (PD-L1/2) transmits a co-inhibitory signal in activated T-cells that promotes T-cell exhaustion, leading to tumor immune evasion. The efficacy of antibodies targeting PD-1 and PD-L1 has led to a paradigm shift in lung cancer treatment but the prognostic and predictive value of tumor PD-L1 expression remains controversial. Evaluating PD-1, PD-L1/2 expression in peripheral blood cells may serve as a potential biomarker for prognosis and response to therapy. In this prospective observational study, plasma cytokine levels and PD-1, PD-L1 and PD-L2 expression was evaluated in circulating CD3+, CD3+CD4+ and CD3+CD8+ cells from 70 treatment-naïve patients with advanced NSCLC (Stage IIIB and IV) and from 10 healthy donors. The primary objective was to assess OS according to PD-1, PD-L1, PD-L2 expression status on PBMCs and lymphocyte subsets. Our results indicate that the percentage of PD-L1+CD3+, PD-L1+CD3+CD8+ PD-L2+PBMCs, PD-L2+CD3+, PD-L2+CD3+CD4+ cells was higher in patients than in healthy donors. Survival was decreased among patients with a high percentage of either PD-1+PBMCs, PD-1+CD3+, PD-L1+CD3+, PD-L1+CD3+CD8+, PD-L2+CD3+, PD-L2+CD3+CD4+, or PD-L2+CD3+CD8+ cells. IL-2 and TNF-α showed the strongest association with PD-L1 and PD-L2 expression on specific subsets of T-lymphocytes. Our findings suggest that increased PD-1/PD-L1/PDL-2 expression in PBMCs, particularly in T-cells, may be an additional mechanism leading to tumor escape from immune control. This study is registered with ClinicalTrials.gov, number NCT02758314.

Survival of Patients with Advanced Non-Small Cell Lung Cancer Enrolled in Clinical Trials.

BACKGROUND: Up-to-date oncological therapy has been accomplished through the results of clinical trials (CTs). We analyzed the overall survival (OS) of patients with non-small cell lung cancer (NSCLC) and its relation to CT enrollment. METHODS: The study included 1,042 patients with advanced NSCLC treated at the Instituto Nacional de Cancerología. All patients received treatment according to the national and international guidelines. Data were collected from medical records. Patients were subgrouped on the basis of their CT enrollment as follows: participants in any CT (ACT), exclusively intervention CTs (ICT) or exclusively pharmaceutical-sponsored CTs (PCT). RESULTS: The CT enrollment effect was assessed through a multivariate Cox proportional hazards model. Thirty percent of the patients were in ACT, 28.3% in ICT and 13.7% in PCT. Female gender (p = 0.001), adenocarcinoma histology (p = 0.018), positive EGFR mutation (p = 0.006), and better ECOG performance status (<2) (p ≤ 0.0001) were more frequent in patients enrolled in CT; further, tobacco smoking (p ≤ 0.0001) and KRAS mutation (p = 0.001) were more frequent in patients who were not enrolled in a CT. CONCLUSION: Enrollment in ACT was associated with a better OS (hazard ratio: 0.47-0.74). NSCLC patients enrolled in a CT have an improved survival in an independent manner to other prognostic factors.