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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.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Caquexia/etiologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Imunoterapia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/terapia , Redução de PesoRESUMO
Importance: Because of socioeconomic factors, many patients with advanced non-small cell lung cancer (NSCLC) do not receive immunotherapy in the first-line setting. It is unknown if the combination of immunotherapy with chemotherapy can provide clinical benefits in immunotherapy-naive patients with disease progression after treatment with platinum-based chemotherapy. Objective: To evaluate the safety and efficacy of the combination of pembrolizumab plus docetaxel in patients with previously treated advanced NSCLC following platinum-based chemotherapy regardless of EGFR variants or programmed cell death ligand 1 status. Design, Setting, and Participants: The Pembrolizumab Plus Docetaxel for Advanced Non-Small Cell Lung Cancer (PROLUNG) trial randomized 78 patients with histologically confirmed advanced NSCLC in a 1:1 ratio to receive either pembrolizumab plus docetaxel or docetaxel alone from December 2016 through May 2019. Interventions: The experimental arm received docetaxel on day 1 (75 mg/m2) plus pembrolizumab on day 8 (200 mg) every 3 weeks for up to 6 cycles followed by pembrolizumab maintenance until progression or unacceptable toxic effects. The control arm received docetaxel monotherapy. Main Outcomes and Measures: The primary end point was overall response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival, and safety. Results: Among 78 recruited patients, 32 (41%) were men, 34 (44%) were never smokers, and 25 (32%) had an EGFR/ALK alteration. Forty patients were allocated to receive pembrolizumab plus docetaxel, and 38 were allocated to receive docetaxel. A statistically significant difference in ORR, assessed by an independent reviewer, was found in patients receiving pembrolizumab plus docetaxel vs patients receiving docetaxel (42.5% vs 15.8%; odds ratio, 3.94; 95% CI, 1.34-11.54; P = .01). Patients without EGFR variations had a considerable difference in ORR of 35.7% vs 12.0% (P = .06), whereas patients with EGFR variations had an ORR of 58.3% vs 23.1% (P = .14). Overall, PFS was longer in patients who received pembrolizumab plus docetaxel (9.5 months; 95% CI, 4.2-not reached) than in patients who received docetaxel (3.9 months; 95% CI, 3.2-5.7) (hazard ratio, 0.24; 95% CI, 0.13-0.46; P < .001). For patients without variations, PFS was 9.5 months (95% CI, 3.9-not reached) vs 4.1 months (95% CI, 3.5-5.3) (P < .001), whereas in patients with EGFR variations, PFS was 6.8 months (95% CI, 6.2-not reached) vs 3.5 months (95% CI, 2.3-6.2) (P = .04). In terms of safety, 23% (9 of 40) vs 5% (2 of 38) of patients experienced grade 1 to 2 pneumonitis in the pembrolizumab plus docetaxel and docetaxel arms, respectively (P = .03), while 28% (11 of 40) vs 3% (1 of 38) experienced any-grade hypothyroidism (P = .002). No new safety signals were identified. Conclusions and Relevance: In this phase 2 study, the combination of pembrolizumab plus docetaxel was well tolerated and substantially improved ORR and PFS in patients with advanced NSCLC who had previous progression after platinum-based chemotherapy, including NSCLC with EGFR variations. Trial Registration: ClinicalTrials.gov Identifier: NCT02574598.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/efeitos adversos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Resultado do TratamentoRESUMO
BACKGROUND: Previous studies have identified that patients with EGFR mutations tend to have better responses to targeted therapy, as well as chemotherapy; however, the effect of genetic alterations in terms of radiotherapy (RT)-related outcomes has not been fully assessed. We studied the impact of common non-small cell lung cancer (NSCLC) genetic alterations (EGFR, ALK and KRAS) in relation to objective response rate (ORR) to RT in patients with brain metastases. METHODS: From 2009-2015, 153 patients with an available genotyping status were treated with whole-brain irradiation (WBI) before receiving systemic therapy. Primary outcome was ORR; secondary outcomes included intracranial progression-free survival (IPFS) and overall survival (OS). RESULTS: Overall, ORR was 47.1%. ORR to RT varied significantly according to molecular status: EGFR (64.5%) ALK (54.5%) KRAS (20%) and WT (35.4%) (P = 0.001). EGFR mutation was the only independently associated factor for response to WBI (RR 3.52 [95% CI 1.6-7.7]; P = 0.002). Median IPFS was 10.8 months [95% CI 8.2-13.5] overall; however, IPFS also varied significantly according to molecular status: EGFR (18.2 months), ALK (18.4 months), KRAS (6.0 months) and WT (8.7 months) (P < 0.0001). OS for EGFR, ALK, KRAS and WT patients was 36.6, 32.2, 15.5 and 22.4 months, respectively (P = 0.014). Intracranial-ORR (HR 0.4 [95% CI 0.2-0.6], P < 0.001) and mutation status (HR 0.7 [95% CI 0.6-0.9], P < 0.042) were independently associated with a higher OS. CONCLUSIONS: RT response varies as per tumor molecular status. The presence of EGFR mutations favors the organ-specific response to RT, and is associated with longer OS in patients with NSCLC and BM. KEY POINTS: This study addressed for the first time the difference in radiotherapy-related outcomes in patients with different genotypes of non-small cell lung cancer (NSCLC) before they received systemic therapy. Results show that response to radiotherapy varies as per tumor molecular status, particularly EGFR-mutated tumors, have a favorable response to radiotherapy, contrary to KRAS-mutated tumors.
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Quinase do Linfoma Anaplásico/genética , Neoplasias Encefálicas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/radioterapia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Receptores ErbB/genética , Feminino , Seguimentos , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Radioterapia/mortalidade , Taxa de SobrevidaRESUMO
OBJECTIVE: CD47 is an antiphagocytic molecule that contributes to tumor cell resistance in host immune surveillance. CD47 overexpression correlated with tumor progression and shorter survival in lung cancer. However, the expression and functional significance of CD47 in Non-Small Cell Lung Cancer (NSCLC) has not been completely understood. MATERIALS AND METHODS: In this retrospective study, CD47 expression was immunohistochemically examined in tumor biopsies from 169 NSCLC patients. The association of CD47 levels (H-score) with clinicopathological characteristics and survival outcomes was evaluated. RESULTS: CD47 protein was detected in 84% of patients with a median expression of 80% (0-100). Tumor CD47 levels above 1% and 50% were found in 84% and 65.7% of patients, respectively. While, median CD47 staining index was 160 (0-300). Patients were divided into two groups according to CD47 expression (high or low), using a cutoff value of 150. High CD47 expression was associated with wood smoke exposure (71.1% vs 28.9%, P = .013) and presence of EGFR (+) mutations (66.7% vs 33.3%, P = .04). Survival analysis carried out in the whole population did not show any association of CD47 expression and survival outcome. However, in patients with EGFR (+) mutations, CD47 expression was associated with higher progression-free survival (PFS) (12.2 vs. 4.4 months, P = .032). When the survival analysis was performed according to CD47 levels (cut off value: 150), both, PFS and overall survival (OS) were shortened in patients with a high expression of CD47 (10.7 vs. NR, P = .156) and (29.2 vs. NR months P = .023), respectively. CONCLUSIONS: CD47 overexpression is not a prognostic factor for PFS and OS in NSCLC patients. However, the presence of EGFR mutations and high expression of CD47 were associated with shortened PFS and OS. Coexpression of these markers represents a potential biomarker and characterizes a therapeutic niche for lung cancer.
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Adenocarcinoma de Pulmão/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Antígeno CD47/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/mortalidade , Neoplasias Pulmonares/mortalidade , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Antígeno CD47/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
IMPORTANCE: Metformin hydrochloride is emerging as a repurposed anticancer drug. Preclinical and retrospective studies have shown that it improves outcomes across a wide variety of neoplasms, including lung cancer. Particularly, evidence is accumulating regarding the synergistic association between metformin and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). OBJECTIVE: To assess the progression-free survival (PFS) in patients with advanced lung adenocarcinoma who received treatment with EGFR-TKIs plus metformin compared with those who received EGFR-TKIs alone. DESIGN, SETTING, AND PARTICIPANTS: Open-label, randomized, phase 2 trial conducted at the Instituto Nacional de Cancerología (INCan), Mexico City, Mexico. Eligible patients were 18 years or older, had histologically confirmed stage IIIB-IV lung adenocarcinoma with an activating EGFR mutation. INTERVENTIONS: Patients were randomly allocated to receive EGFR-TKIs (erlotinib hydrochloride, afatinib dimaleate, or gefitinib at standard dosage) plus metformin hydrochloride (500 mg twice a day) or EGFR-TKIs alone. Treatment was continued until occurrence of intolerable toxic effects or withdrawal of consent. MAIN OUTCOMES AND MEASURES: The primary outcome was PFS in the intent-to-treat population. Secondary outcomes included objective response rate, disease control rate, overall survival (OS), and safety. RESULTS: Between March 31, 2016, and December 31, 2017, a total of 139 patients (mean [SD] age, 59.4 [12.0] years; 65.5% female) were randomly assigned to receive EGFR-TKIs (n = 70) or EGFR-TKIs plus metformin (n = 69). The median PFS was significantly longer in the EGFR-TKIs plus metformin group (13.1; 95% CI, 9.8-16.3 months) compared with the EGFR-TKIs group (9.9; 95% CI, 7.5-12.2 months) (hazard ratio, 0.60; 95% CI, 0.40-0.94; P = .03). The median OS was also significantly longer for patients receiving the combination therapy (31.7; 95% CI, 20.5-42.8 vs 17.5; 95% CI, 11.4-23.7 months; P = .02). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first study to prospectively show that the addition of metformin to standard EGFR-TKIs therapy in patients with advanced lung adenocarcinoma significantly improves PFS. These results justify the design of a phase 3, placebo-controlled study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03071705.
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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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , México , Pessoa de Meia-Idade , Pós-Menopausa , Pré-Menopausa , Estudos Retrospectivos , Fatores Sexuais , Taxa de SobrevidaRESUMO
OBJECTIVE: To analyze the mortality trend of lung cancer (LC) in Mexico, according to the municipality marginalization index (MMI) by age group and sex, during the period 1998-2016. MATERIALS AND METHODS: The information on mortality, population and MMI was obtained from the National Institute of Statistics and Geography (INEGI) and the National Council of Population (Conapo). The adjusted LC mortality rate trends were analyzed using the joinpoint regression analysis. A total of 126 132 deaths were included. RESULTS: The adjusted LC mortality rate decreased from 7.83 to 4.97 100 000 inhabitants during the period from 1998-2016, but the decrease was found to be less in women and in areas with very high marginalization. CONCLUSIONS: Unequal reduction in LC mortality according to the degree of marginalization are related to early diagnosis, timely treatment and inequity in medical services. This inequity affects mainly the populations of women, highly marginalized groups and older populations.
OBJETIVO: Analizar la tendencia de mortalidad por cáncer de pulmón (CP) en México, según el índice de marginación municipal (IMM) por grupo de edad y sexo, de 1998 a 2016. MATERIAL Y MÉTODOS: La información sobre mortalidad, población e IMM se obtuvo del Instituto Nacional de Estadística y Geografía (INEGI) y del Consejo Nacional de Población (Conapo). Las tendencias de la tasa de mortalidad ajustada para CP se analizaron mediante el análisis de regresión de joinpoint. Se incluyeron 126 132 defunciones. RESULTADOS: La tasa de mortalidad ajustada por CP disminuyó de 7.83 a 4.97 por 100 000 habitantes durante el periodo 1998-2016. CONCLUSIONES: La reducción desigual en la mortalidad por CP, de acuerdo con el grado de marginación, está relacionada con en el diagnóstico temprano, el tratamiento oportuno y la inequidad en los servicios médicos. Esta inequidad afecta principalmente a las mujeres, a los grupos altamente marginados y a las poblaciones más envejecidas.
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Neoplasias Pulmonares/mortalidade , Adulto , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Mortalidade/tendências , Marginalização Social , Fatores de TempoRESUMO
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.
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Fatores Sexuais , Taxa de Sobrevida , Estudos Retrospectivos , Pré-Menopausa , Pós-Menopausa , MéxicoRESUMO
Abstract: Objective: To analyze the mortality trend of lung cancer (LC) in Mexico, according to the municipality marginalization index (MMI) by age group and sex, during the period 1998-2016. Materials and methods: The information on mortality, population and MMI was obtained from the National Institute of Statistics and Geography (INEGI) and the National Council of Population (Conapo). The adjusted LC mortality rate trends were analyzed using the joinpoint regression analysis. A total of 126 132 deaths were included. Results: The adjusted LC mortality rate decreased from 7.83 to 4.97 100 000 inhabitants during the period from 1998-2016, but the decrease was found to be less in women and in areas with very high marginalization. Conclusions: Unequal reduction in LC mortality according to the degree of marginalization are related to early diagnosis, timely treatment and inequity in medical services. This inequity affects mainly the populations of women, highly marginalized groups and older populations.
Resumen: Objetivo: Analizar la tendencia de mortalidad por cáncer de pulmón (CP) en México, según el índice de marginación municipal (IMM) por grupo de edad y sexo, de 1998 a 2016. Material y métodos: La información sobre mortalidad, población e IMM se obtuvo del Instituto Nacional de Estadística y Geografía (INEGI) y del Consejo Nacional de Población (Conapo). Las tendencias de la tasa de mortalidad ajustada para CP se analizaron mediante el análisis de regresión de joinpoint. Se incluyeron 126 132 defunciones. Resultados: La tasa de mortalidad ajustada por CP disminuyó de 7.83 a 4.97 por 100 000 habitantes durante el periodo 1998-2016. Conclusiones: La reducción desigual en la mortalidad por CP, de acuerdo con el grado de marginación, está relacionada con en el diagnóstico temprano, el tratamiento oportuno y la inequidad en los servicios médicos. Esta inequidad afecta principalmente a las mujeres, a los grupos altamente marginados y a las poblaciones más envejecidas.
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Neoplasias Pulmonares/mortalidade , Fatores de Tempo , Mortalidade/tendências , Marginalização Social , México/epidemiologiaRESUMO
Malignant pleural effusion (MPE) is an indicator of advanced disease (stage M1a) in patients with non-small cell lung cancer (NSCLC). Typically, these patients are candidates for palliative treatment. There is a lack of evidence about the radical surgical treatment in carcinomatous pleuritis with massive effusion. Here, we present data from a specific subset of patients with MPE treated with systemic therapy and aggressive surgical therapy. M1a NSCLC adenocarcinoma patients with MPE and without extra-thoracic disease were included. After receiving systemic therapy, all patients underwent surgical treatment, which included pneumonectomy or lobectomy, plus mediastinal dissection. Following surgery, patients received radiotherapy to thoracic wall and mediastinum. A total of six patients were analyzed. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status ≤1, two patients harbored EGFR mutation and were treated with tyrosine kinase inhibitors (TKIs), the other four patients were treated with pemetrexed and platin as first-line treatment. Following systemic therapy, two patients had a pneumonectomy, four patients had a lobectomy plus pleurectomy performed. All patients continued with maintenance systemic therapy, and achieved complete responses, according to RECIST 1.1 criteria. The media progression-free survival (PFS) time was 15.9 months (95% CI: 15.6-55.5 months). At the last follow-up, all patients were still alive, with 4 of them without signs of macroscopic tumoral activity. The median overall survival (OS) was not reached. NSCLC patients with MPE without extra-thoracic disease could benefit from an aggressive surgical approach following standard of care systemic therapy. However, considering the low sample size of this study and the relatively low incidence of MPE without extra-thoracic disease, further prospective multi-center studies are necessary to evaluate aggressive surgery as a therapeutic option.
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BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive tumor, associated with poor prognosis. There is a lack of information about the clinical and pathological features related with survival in the Latin American population. METHODS: The MeSO-CLICaP registry identified 302 patients with advanced MPM diagnosed and treated between January 2008 and March 2016. The Cox model was applied to determine the variables associated with survival. A random forest tree model was built to predict the response to first-line chemotherapy among Latin American patients. RESULTS: The median age was 61.1 years (SD 10.6 years), 191 (63.2%) were men, 65.9% were ever smokers, and 38.7% had previous exposure to asbestos. A total of 237 (78.5%) had epithelioid tumors, and 188 (62.3%) and 114 (37.7%) cases had stage III or IV MPM, respectively. A total of 49 patients (16.2%) underwent pleurectomy, 57 (18.9%) received radiotherapy, and 279 patients received first-line platinum-based chemotherapy. The overall response rate to first-line chemotherapy was 40.4%, progression-free survival to first-line treatment was 5.7 months (95% CI 4.9-6.5), and 63 (20.8%) patients had pemetrexed maintenance. The median overall survival was 16.8 months (95% CI 13.0-20.5), and multivariate analysis found that stage (P = 0.013), and pleurodesis (P = 0.048), were independent prognostic factors for first-line overall survival. The model to predict response to first-line chemotherapy obtained a 0.98 area under the curve, a sensitivity of 93%, and a specificity of 95% for detecting responders and non-responders. CONCLUSION: This study identifies factors associated with clinical benefit from chemotherapy among advanced MPM Latin American patients, emphasizing the impact of histology and the clinical benefit of chemotherapy on outcomes.
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Neoplasias Pulmonares/epidemiologia , Mesotelioma/epidemiologia , Platina/uso terapêutico , Neoplasias Pleurais/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Feminino , Humanos , América Latina/epidemiologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Mesotelioma/cirurgia , Mesotelioma Maligno , Pessoa de Meia-Idade , Pemetrexede/uso terapêutico , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/patologia , Neoplasias Pleurais/cirurgia , Intervalo Livre de Progressão , Procedimentos Cirúrgicos Torácicos/métodosRESUMO
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.
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Anorexia/diagnóstico , Caquexia/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/complicações , Neoplasias Pulmonares/complicações , Adenocarcinoma/complicações , Adenocarcinoma/tratamento farmacológico , Idoso , Anorexia/terapia , Apetite , Caquexia/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Comportamento Alimentar , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Valores de Referência , Inquéritos e QuestionáriosRESUMO
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.
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Nintedanib is an oral angiokinase inhibitor used as second-line treatment for non-small cell lung cancer. New radiotracers, such as 68Ga-DOTA-E-[c(RGDfK)]2, that target αvß3 integrin might have an impact as a noninvasive method for assessing angiogenesis inhibitors. Methods: From July 2011 through October 2015, 38 patients received second-line nintedanib plus docetaxel. All patients underwent PET/CT with 68Ga-DOTA-E-[c(RGDfK)]2 radiotracer and blood-sample tests to quantify angiogenesis factors (fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor AB) before and after completing 2 therapy cycles. Results: Of the 38 patients, 31 had available baseline and follow-up PET/CT. Baseline lung tumor volume addressed with 68Ga-DOTA-E-[c(RGDfK)]2 PET/CT correlated with serum vascular endothelial growth factor levels, whereas baseline lung/liver SUVmax index correlated with platelet-derived growth factor AB. After treatment, the overall response rate and disease control rate were 7.9% and 47.3%, respectively. A greater decrease in lung tumor volume (-37.2% vs. -27.6%) was associated with a better disease control rate in patients (P = 0.005). Median progression-free survival was 3.7 mo. Nonsmokers and patients with a higher baseline lung tumor volume were more likely to have a higher progression-free survival (6.4 vs. 3.74 [P = 0.023] and 6.4 vs. 2.1 [P = 0.003], respectively). Overall survival was not reached. Patients with a greater decrease in lung SUVmax (not reached vs. 7.1 mo; P = 0.016) and a greater decrease in the lung/spleen SUVmax index (not reached vs. 7.1; P = 0.043) were more likely to have a longer overall survival. Conclusion:68Ga-DOTA-E-[c(RGDfK)]2 PET/CT is a potentially useful tool for assessing responses to angiogenesis inhibitors. Further analysis and novel studies are warranted to identify patients who might benefit from this therapy.
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Adenocarcinoma de Pulmão/tratamento farmacológico , Docetaxel/uso terapêutico , Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel/química , Indóis/uso terapêutico , Oligopeptídeos/química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adenocarcinoma de Pulmão/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do TratamentoRESUMO
Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (NSCLC) cases. In combination with radiotherapy or chemotherapy, first-line treatments with antibodies against EGFR, including cetuximab and necitumumab, have demonstrated benefits by increasing overall survival (OS), particularly in patients who overexpress EGFR. The present study evaluated the interobserver agreement among three senior pathologists, who were blinded to the clinical outcomes and assessed tumor samples from 85 patients with NSCLC using the H-score method. EGFR immunohistochemistry was performed using a qualitative immunohistochemical kit. The reported (mean ± standard deviation) H-scores from each pathologist were 111±102, 127±103 and 128.53±104.03. The patients with average H-scores ≥1, ≥100, ≥200 and between 250-300 were 85.9, 54.1, 28.2 and 12.9, respectively. Patients who had an average H-score >100 had a shorter OS time compared with those with lower scores. Furthermore, patients with EGFR mutations who were treated with EGFR-tyrosine kinase inhibitors (TKIs) and had an average H-score >100 had a longer OS time compared with those with an average H-score <100. The interobserver concordance for the total H-scores were 0.982, 0.980 and 0.988, and for a positive H-score ≥200, the interobserver concordance was 0.773, 0.710 and 0.675, respectively. The determination of EGFR expression by the H-score method is highly reproducible among pathologists and is a prognostic factor associated with a poor OS in all patients. Additionally, the results of the present study suggest that patients with EGFR mutations that are treated with EGFR-TKIs and present with a high H-score have a longer OS time.
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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.
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Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos como Assunto , Neoplasias Pulmonares/mortalidade , Participação do Paciente , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores Sexuais , Fumar , Taxa de SobrevidaRESUMO
BACKGROUND: Transcription factors such as retinoic acid receptor alpha (RARα) and beta (RARß) and Yin Yang 1 (YY1) are associated with the progression of non-small cell lung cancer (NSCLC). In particular, a lack of RARß expression is associated with NSCLC development. The aim of this study was to analyze the expression of RARα, RARß and YY1 and their relationship with prognosis in patients with advanced NSCLC. METHODS: The expression of RARα, RARß and YY1 was assessed by immunohistochemistry and quantitative computerized image software. RESULTS: Eighty-five patients treated with platinum-based chemotherapy were included in the analysis. The mean and standard deviation of the nuclear expression of RARα, RARß and YY1 were 184.5 ± 124.4, 18 ± 27 and 16.6 ± 20.5, respectively. The nuclear expression of RARß was associated with the nuclear expression of YY1 (R 2 = 0.28; p value < 0.0001). Patients with high nuclear expression of YY1 were likely to be non-smokers (61.9 vs 40.5 %). Median progression-free survival (PFS) was 5.9 months (3.48-8.28). Low expression of RARα was independently associated with worse PFS following chemotherapy (10.3 vs 5.46 months p = 0.040). Median overall survival (OS) was 15.6 months (4.5-26.7), and lower nuclear expression of RARß was independently associated with shorter OS (27.5 vs 8.7 months; p = 0.037). CONCLUSION: Our study suggests that the loss of RARs is associated with a worse prognosis and these receptors could be a potential molecular target for NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Cisplatino/uso terapêutico , Neoplasias Pulmonares , Receptores do Ácido Retinoico , Receptor alfa de Ácido Retinoico , Fator de Transcrição YY1 , Adulto , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Diagnóstico por Computador , Intervalo Livre de Doença , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Fatores de Transcrição , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismoRESUMO
BACKGROUND: C-met and its ligand, hepatocyte growth factor (HGF) have been associated with the resistance mechanism of EGFR-TKIs. HGF was evaluated as a clinical-marker of response in NSCLC patients treated with afatinib. METHODS: Sixty-six patients with stage IIIB/IV lung adenocarcinoma and progression to any-line chemotherapy received afatinib 40 mg/day. Mutational EGFR and HER2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Serum HGF content was measured by ELISA before and 2 months after the start of treatment. HGF levels were assessed with the objective response rate (ORR), progression-free-survival (PFS), and overall survival (OS). This trial was registered on ClinicalTrials.gov: NCT01542437. RESULTS: Fifty patients (75 %) were EGFR mutation positive. Response was achieved in 59 % of all patients and 78 % of EGFR mutated patients. Median PFS was 10 [95 % CI 6.8-13.1] and 14.5 months [10.9-18.9] for all and EGFR mutated patients, respectively. Median OS was 22.8 [17.5-28.1] and 32.4 months [18.3-46.6] for all and EGFR mutated patients, respectively. Patients with reduced serum HGF levels had improved ORR (75 % vs 44 %; p = 0.011), PFS (15.1 [2.9-27.3] vs 6.5 months [3.9-9.1]; p = 0.005) and OS (NR vs 14.5 months [7.8 - 21.3] p = 0.007). A reduction in serum HGF levels was an independent factor associated with longer PFS (HR 0.40; p = 0.021) and OS (HR 0.31; p = 0.006) in all and EGFR mutated patients. CONCLUSIONS: A reduction in serum HGF levels was associated with improved outcomes in patients treated with afatinib. These results suggest HGF might have a role as a mechanism of resistance to EGFR-TKIs. HGF could represent a potential therapeutic target to prevent or reverse resistance particularly in EGFR mutated patients.
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Adenocarcinoma/tratamento farmacológico , Fator de Crescimento de Hepatócito/sangue , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Adenocarcinoma de Pulmão , Afatinib , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Quinazolinas/administração & dosagem , Quinazolinas/farmacologia , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/farmacologia , Resultado do TratamentoRESUMO
OBJECTIVE: Assess the cost-effectiveness of an EGFR-mutation testing strategy for advanced NSCLC in first-line therapy with either gefitinib or carboplatin-paclitaxel in Mexican institutions. METHODS: Cost-effectiveness analysis using a discrete event simulation (DES) model to simulate two therapeutic strategies in patients with advanced NSCLC. Strategy one included patients tested for EGFR-mutation and therapy given accordingly. Strategy two included chemotherapy for all patients without testing. All results are presented in 2014 US dollars. The analysis was made with data from the Mexican frequency of EGFR-mutation. A univariate sensitivity analysis was conducted on EGFR prevalence. Progression-free survival (PFS) transition probabilities were estimated on data from the IPASS and simulated with a Weibull distribution, run with parallel trials to calculate a probabilistic sensitivity analysis. RESULTS: PFS of patients in the testing strategy was 6.76 months (95 % CI 6.10-7.44) vs 5.85 months (95 % CI 5.43-6.29) in the non-testing group. The one-way sensitivity analysis showed that PFS has a direct relationship with EGFR-mutation prevalence, while the ICER and testing cost have an inverse relationship with EGFR-mutation prevalence. The probabilistic sensitivity analysis showed that all iterations had incremental costs and incremental PFS for strategy 1 in comparison with strategy 2. CONCLUSION: There is a direct relationship between the ICER and the cost of EGFR testing, with an inverse relationship with the prevalence of EGFR-mutation. When prevalence is >10 % ICER remains constant. This study could impact Mexican and Latin American health policies regarding mutation detection testing and treatment for advanced NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Genes erbB-1/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Quinazolinas/economia , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Análise Custo-Benefício , Intervalo Livre de Doença , Feminino , Gefitinibe , Humanos , América Latina , Masculino , México , Modelos Econométricos , Mutação , Paclitaxel/uso terapêutico , Inibidores de Proteínas Quinases/economia , Inibidores de Proteínas Quinases/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Quinazolinas/uso terapêuticoRESUMO
OBJECTIVE: Sixteen percent of US population is Hispanic, mostly Mexican. Recently, two independent American reports demonstrated a higher overall survival (OS) in Hispanic populations compared with non-Hispanic-white populations (NHW) with non-small-cell lung cancer (NSCLC), even when most Hispanic patients are diagnosed at advanced disease stages and have lower income status. We analyzed the clinical, pathological, and molecular characteristics as well as outcomes in a cohort of NSCLC Hispanic patients from the National Cancer Institute of Mexico that could explain this "Hispanic Paradox". MATERIAL AND METHODS: A cohort of 1260 consecutive NSCLC patients treated at the National Cancer Institute of Mexico from 2007 to 2014 was analyzed. Their clinical-pathological characteristics, the presence of EGFR and KRAS mutations and the prognosis were evaluated. RESULTS: Patients presented with disease stages II, IIIa, IIIb and IV at rates of 0.6, 4.8, 18.4 and 76.3%, respectively. NSCLC was associated with smoking in only 56.5% of the patients (76.7% of male vs. 33.0% of female patients). Wood smoke exposure (WSE) was associated with 37.2% of the cases (27.3% in men vs. 48.8% in women). The frequency of EGFR mutations was 27.0% (18.5% in males vs. 36.9% in females, p<0.001) and the frequency for KRAS mutations was 10.5% (10.3% men vs. 10.1% in women p=0.939). The median OS for all patients was 23.0 [95% CI 19.4-26.2], whereas for patients at stage IV, it was 18.5 months [95% CI 15.2-21.8]. The independent factors associated with the OS were the ECOG, disease stage, EGFR and KRAS mutation status. CONCLUSION: The high frequency of EGFR mutations and low frequency of KRAS mutations in Hispanic populations and different prevalence in lung cancer-related-developing risk factors compared with Caucasian populations, such as the lower frequency of smoking exposure and higher WSE, particularly in women, might explain the prognosis differences between foreign-born-Hispanics, US-born-Hispanics and NHWs.