RESUMEN
BACKGROUND: Conquering acquired resistance to osimertinib remains a major challenge in treating patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Thus, we aimed to determine the safety and efficacy of combination treatment with osimertinib and afatinib for patients with acquired resistance to osimertinib. METHODS: This open-label phase I study was a feasibility study of the combination of afatinib and osimertinib for patients with advanced EGFR-positive NSCLC who had progressive disease after receiving osimertinib. The primary endpoint was to determine the maximum tolerated dose (MTD). We enrolled patients who received afatinib at three different dose levels (level 1, 20 mg; level 2, 30 mg; level 3, 40 mg) combined with osimertinib at a standard dose of 80 mg once per day. RESULTS: Thirteen patients were enrolled in this study. The MTD was defined as 30 mg afatinib when combined with daily oral administration of osimertinib (80 mg). The most frequent adverse events were diarrhea (76.9%), anemia (76.9%), and rash (69.2%). Considering the toxicity profiles during all treatment periods, the recommended oral dose of afatinib was determined as 20 mg daily, with an osimertinib dose of 80 mg. For all evaluable patients (n = 12), the response rate was 7.7% and the disease-control rate was 46.2%. CONCLUSION: Combination therapy with osimertinib and afatinib was tolerable; however, the synergistic effect of afatinib with osimertinib may be limited in osimertinib-resistant patients. TRIAL REGISTRATION: Japan Registry of Clinical Trials ID: jRCTs051180008, registered date: 08/11/2018.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Afatinib , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , MutaciónRESUMEN
Although immune checkpoint inhibitors have improved the survival of small cell lung cancer (SCLC) patients, their efficacy in SCLC patients who relapsed after systemic chemotherapy is unclear. This retrospective study aimed to investigate the utility of treatment with atezolizumab plus carboplatin and etoposide in SCLC patients previously treated with platinum-based chemotherapy. We retrospectively screened consecutive eight SCLC patients who received atezolizumab plus carboplatin and etoposide after platinum-based chemotherapy. We evaluated the efficacy of this treatment and its association with programmed cell death-ligand 1 (PD-L1) expression. Three and five patients had sensitive relapse and refractory relapse for first-line platinum-based chemotherapy, respectively. The overall response rate and disease control rate was 37.5% and 75.0%, respectively. Median progression-free survival was 4.0 months. Out of three patients who achieved clinical response, two patients had refractory relapse for first-line platinum-based chemotherapy. No patient exhibited PD-L1 expression. Atezolizumab plus carboplatin and etoposide therapy was effective in SCLC patients with sensitive and refractory relapse and might be a second-line treatment option for SCLC patients previously treated with platinum-based chemotherapy.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Etopósido/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/biosíntesis , Carboplatino/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Immune-related adverse events (irAEs) and hyperprogressive disease (HPD) are serious problems arising in the early period of monotherapy (MT) with programmed cell death protein 1 (PD-1) and programmed cell death ligand1 (PD-L1) inhibitors. However, the frequency and clinical features of these problems in patients receiving combination therapy (CT) with cytotoxic chemotherapy in addition to these agents remain unclear. We retrospectively screened patients with pathologically confirmed advanced or recurrent non-small cell lung cancer (NSCLC) who had received PD-1/PD-L1 inhibitors at Kurume University Hospital between February 2016 and March 2020. We recruited 210 patients, of whom 172 (81.9%) had received PD-1/PD-L1 inhibitor MT and 38 (18.1%) had received CT. The incidence of irAE during the 3 months after treatment initiation was significantly higher in the MT group (57 of 172, 33.1%) than in the CT group (6 of 38, 15.8%) (p = 0.049). During the same period, the incidence of pneumonitis was also higher in the MT group (18 of 172, 10.9%) than in the CT group (0 of 38) (p = 0.049). A similar trend was observed in patients who had received these treatments on a first line basis. The HPD rate was significantly lower in the CT group (1 of 34, 2.9%) than in the MT group (25 of 142, 17.6%) (p = 0.031). The incidences of HPD and irAE, especially pneumonitis, during 3 months after treatment initiation were relatively lower in the CT group than in the MT group. The mechanisms underlying these differences warrant further study.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Incidencia , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estudios RetrospectivosRESUMEN
BACKGROUND: Liquid biopsy allows the identification of patients whose tumors harbor specific mutations in a minimally invasive manner. No prospective data have been available for the efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) who develop resistance to first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and who test positive for the TKI resistance-conferring T790M mutation of EGFR by liquid biopsy. Therefore, a phase 2 study was conducted to assess the efficacy and safety of osimertinib in such patients. METHODS: Eligible patients had advanced or recurrent NSCLC with known TKI-sensitizing mutations of EGFR, had documented disease progression after treatment with at least 1 first- or second-generation EGFR TKI, and were positive for the T790M mutation in plasma according to the Cobas EGFR Mutation Test v2 (Roche Diagnostics) or droplet digital polymerase chain reaction analysis. Patients were treated with osimertinib (80 mg/d) until disease progression. The primary endpoint was the overall response rate (ORR) in patients positive for T790M in plasma by the Cobas assay. RESULTS: Between June 2016 and November 2017, 276 patients were screened for their T790M status with a liquid biopsy. Seventy-four patients were positive for T790M in plasma, and 53 of these individuals were enrolled in the study. The ORR for evaluable patients positive for T790M in plasma by the Cobas assay (n = 49) was 55.1% (95% confidence interval [CI], 40.2%-69.3%). The median progression-free survival for all evaluable patients (n = 52) was 8.3 months (95% CI, 6.9-12.6 months). CONCLUSIONS: The results demonstrate the utility of liquid biopsy for the detection of T790M with the Cobas EGFR Mutation Test v2. Plasma genotyping with this assay is informative for treatment selection in clinical practice when tumor sampling is not feasible.
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Acrilamidas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Acrilamidas/sangre , Adulto , Anciano , Anciano de 80 o más Años , Compuestos de Anilina/sangre , Antineoplásicos/sangre , Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Detección Precoz del Cáncer , Receptores ErbB/sangre , Receptores ErbB/genética , Femenino , Humanos , Japón , Biopsia Líquida , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/sangreRESUMEN
Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNα2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Factores Inmunológicos/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/sangre , Quimiocina CXCL2/sangre , Estudios de Cohortes , Sustancias de Crecimiento/sangre , Humanos , Interferón alfa-2/sangre , Neoplasias Pulmonares/sangre , Metaloproteinasa 2 de la Matriz/sangre , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
BACKGROUND: The cobas® epidermal growth factor receptor (EGFR) Mutation Test v2 designed for cell-free DNA (cfDNA) is approved as a companion diagnostic for osimertinib therapy. The aim of this study was to evaluate the concordance of EGFR mutation detection between paired primary or recurrent samples, and cerebrospinal fluid (CSF) cytology samples of lung cancer patients. METHODS: In total, 26 lung cancer patients with supernatant cytology cfDNA in CSF were analysed for EGFR mutations using the cobas® EGFR Mutation Test v2.0 designed for cfDNA, and the concordance rates between CSF cfDNA and primary or recurrent samples were investigated. RESULTS: Of the 26 CSF cytology cfDNA samples, 46.1% (12/26) were valid and 53.9% (14/26) were invalid. Sensitivity, specificity and accuracy between the valid CSF cfDNA samples and primary or recurrent samples for detection of EGFR mutation, including T790M were 87.5%, 100.0% and 91.7%, respectively. Amounts of both inflammatory cells and tumour cells in CSF cytology were higher in the valid evaluation samples than in the invalid samples (P < .05), and mutant EGFR was detected in 80.0% (4/5) of the valid CSF cytology cfDNA samples with a negative cytology diagnosis. CONCLUSIONS: The cobas® EGFR Mutation Test v2.0 can accurately detect EGFR mutations, including T790M, from supernatant cfDNA of CSF cytology samples. Utilisation of supernatant cytology cfDNA in CSF will allow us to perform both EGFR mutation analysis and cytopathological diagnosis at the same time. This represents a new role of cytology in patient treatment, based on assured sample quality.
Asunto(s)
Ácidos Nucleicos Libres de Células/líquido cefalorraquídeo , Citodiagnóstico , Neoplasias Pulmonares/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Receptores ErbB/líquido cefalorraquídeo , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación/genéticaRESUMEN
BACKGROUND: Antibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy. METHODS: JAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m2 every 3 weeks. Randomisation was stratified by PD-L1 expression (≥1% vs <1% of tumour cells), which was measured with the 73-10 assay, and histology (squamous vs non-squamous). The primary endpoint was overall survival, analysed when roughly 337 events (deaths) had occurred in the PD-L1-positive population. Efficacy was analysed in all PD-L1-positive patients (ie, PD-L1 expression in ≥1% of tumour cells) randomly assigned to study treatment (the primary analysis population) and then in all randomly assigned patients through a hierarchical testing procedure. Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02395172. Enrolment is complete, but the trial is ongoing. FINDINGS: Between March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11·4 months [95% CI 9·4-13·9] vs 10·3 months [8·5-13·0]; hazard ratio 0·90 [96% CI 0·72-1·12]; one-sided p=0·16). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3-5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes. INTERPRETATION: Compared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile. FUNDING: Merck and Pfizer.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Docetaxel/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Fitogénicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Docetaxel/efectos adversos , Femenino , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Factores de Tiempo , Resultado del TratamientoRESUMEN
Small-cell lung cancer (SCLC) combined with epidermal growth factor receptor (EGFR) mutations is extremely rare, and standard chemotherapeutic strategies have not yet been established. In the present study, we report a case of a 67-year-old man who presented with combined SCLC with EGFR mutation (exon 19 deletion). Systemic chemotherapy with cisplatin and irinotecan was initiated as first-line chemotherapy, and computed tomography findings revealed tumor shrinkage after two cycles of chemotherapy. However, after the third cycle of the treatment, disease progression was observed including the appearance of pleural and pericardial effusion. Cytologic examination of pleural and pericardial effusion revealed adenocarcinoma and no characteristics of SCLC, and an EGFR mutation was detected, in line with the initial diagnosis. Afatinib was then administered as second-line chemotherapy, which resulted in a partial response that lasted for 6 months. Re-biopsy after resistance to first-line chemotherapy suggested that the adenocarcinoma component harboring the EGFR mutation became dominant in association with disease progression, and afatinib provided clinical efficacy as second-line chemotherapy.
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Afatinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Anciano , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Carcinoma Pulmonar de Células Pequeñas/metabolismoRESUMEN
BACKGROUND: The use of immune-checkpoint inhibitors in cancer treatment has become increasingly common, resulting in an increase in the incidence of related side effects. Diarrhoea and colitis have been previously documented as gastrointestinal tract-related side effects of immune-checkpoint inhibitors. Although PD-1/PD-L1 inhibitors produce fewer side effects than CTLA-4 inhibitors, diarrhoea and colitis continue to be reported. However, little is known about the endoscopic features associated with PD-1/PD-L1 inhibitors. In this report, we describe three cases of colitis induced by a PD-1 inhibitor nivolumab. These cases showed endoscopic findings characteristic of ulcerative colitis (UC). Treatment was in accordance with UC therapy, which resulted in beneficial outcomes. CASE PRESENTATION: Three patients with lung cancer treated with nivolumab presented with diarrhoea with (case 2) or without haematochezia (cases 1 and 3). Treatment with nivolumab was ceased and colonoscopy was performed, revealing endoscopic features similar to those of UC. These patients were diagnosed with nivolumab-induced colitis. Case 1 was treated with mesalazine, whereas cases 2 and 3 were treated with corticosteroids. Subsequently, their symptoms improved. CONCLUSIONS: Nivolumab-induced colitis exhibited similar characteristics to UC. Treatment was similar to that for UC and was successful.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Colitis Ulcerosa/inducido químicamente , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Antiinflamatorios no Esteroideos/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Diarrea/inducido químicamente , Diarrea/tratamiento farmacológico , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Humanos , Masculino , Mesalamina/uso terapéutico , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , NivolumabRESUMEN
Pemetrexed (PEM) is an antimetabolite drug that interferes with enzymes involved in DNA synthesis and also the folate-dependent metabolic processes necessary for DNA replication and homocysteine homeostasis. Continuation maintenance with PEM after induction therapy with PEM plus cisplatin has been the standard form of first-line chemotherapy for advanced non-squamous non-small cell lung cancer. The regimen has a low incidence of bone marrow suppression, and the incidences of anemia, leukopenia, neutropenia and thrombocytopenia exceeding grade 3 are less than 5%. Here we report a 68-year-old Japanese man with stage IIIB (cT4N3M0) lung adenocarcinoma who received 4 cycles of chemotherapy with PEM 500 mg/m2 and cisplatin 75 mg/m2 every three weeks, which resulted in a partial response, and then continued to receive maintenance PEM monotherapy. After 11 cycles of PEM maintenance therapy, the patient's platelet count decreased, and progressed to pancytopenia within two months. A bone marrow puncture revealed replacement with fatty marrow. As other diseases possibly responsible for pancytopenia were ruled out, we diagnosed the patient as having aplastic anemia. This is the first reported case of aplastic anemia to have occurred during PEM therapy. Clinicians should bear in mind that PEM can potentially trigger severe pancytopenia, including aplastic anemia.
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Adenocarcinoma/tratamiento farmacológico , Anemia Aplásica/inducido químicamente , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Pemetrexed/efectos adversos , Pemetrexed/uso terapéutico , Adenocarcinoma del Pulmón , Anciano , Humanos , MasculinoRESUMEN
Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, is anticipated to prolong survival with inhibition of angiogenesis in patients with non-small-cell lung cancer. Rare life-threatening adverse events affecting the digestive tract have been reported, such as gastrointestinal hemorrhage and bowel perforation. A 62-year-old Japanese woman who was diagnosed as having stage IIIB (cT4N2M0) lung adenocarcinoma received chemotherapy with bevacizumab, pemetrexed and carboplatin every 3 weeks for four cycles, which resulted in a partial response, and then continued with maintenance bevacizumab monotherapy. Fourteen days after completion of the seventh cycle of bevacizumab maintenance therapy, the patient developed sudden abdominal pain with more than 10 episodes of hematochezia per day. On the basis of colonoscopic and pathological findings, ulcerative colitis (UC) with severe pancolitis was diagnosed. This case was unresponsive to medical treatment and required subtotal colectomy for management of the ulcerative colitis. This is the first reported case of ulcerative colitis occurring during bevacizumab therapy. The anti-angiogenesis activity of bevacizumab may have been involved in the development and exacerbation of UC in this patient.
Asunto(s)
Antineoplásicos/efectos adversos , Bevacizumab/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Inhibidores de la Angiogénesis , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Estadificación de NeoplasiasRESUMEN
BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is known to be associated with a high incidence of adverse events. However, few studies have investigated the correlation between obesity and the risk of TBLC-related adverse events, especially in Asians, who are known to have characteristic differences in height and weight as compared to individuals of other ethnicities. METHODS: We retrospectively assessed 102 Japanese patients who underwent TBLC for the diagnosis of interstitial lung disease to evaluate the correlation between patient characteristics and the occurrence of TBLC-related adverse events (hemorrhage, pneumothorax, and acute exacerbation of interstitial lung disease). RESULTS: TBLC-related adverse events occurred in 19 patients (18.6 %), with hemorrhage being the most common adverse event (in 14 patients, 13.7 %). There was no correlation between age, sex, or pulmonary function test results and the occurrence of adverse events. The body mass index (BMI) cut-off predicting the occurrence of all adverse events was 26.6 kg/m2 (sensitivity of 0.389 and specificity of 0.852), and that predicting the occurrence of adverse events of hemorrhage was 26.8 kg/m2 (sensitivity of 0.462 and specificity of 0.907). Among patients with a BMI >26.8 kg/m2, adverse events of hemorrhage occurred in 37.5 % of cases, which was higher than among those with a BMI <26.8 kg/m2. CONCLUSIONS: Obesity is a risk factor for the incidence of TBLC-related adverse events, particularly adverse events of hemorrhage, in Japanese patients. The BMI cut-off values that predicted an increased frequency of TBLC-related adverse events and hemorrhage specifically were 26.6 and 26.8 kg/m2, respectively.
Asunto(s)
Broncoscopía , Enfermedades Pulmonares Intersticiales , Humanos , Estudios Retrospectivos , Japón/epidemiología , Biopsia/efectos adversos , Biopsia/métodos , Broncoscopía/métodos , Enfermedades Pulmonares Intersticiales/epidemiología , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/diagnóstico , Pulmón/patología , Factores de Riesgo , Obesidad/complicaciones , Obesidad/epidemiología , Hemorragia/epidemiología , Hemorragia/etiologíaRESUMEN
INTRODUCTION: Traditionally, relapsed SCLC has been classified as "sensitive" or "refractory" on the basis of cutoff values (60 or 90 d) for the duration between the last chemotherapy and disease progression. Nevertheless, these cutoff values are not derived from rigorous analytical methods, and their applicability to contemporary treatments remains uncertain. METHODS: We conducted a retrospective multicenter study on patients with extensive-stage SCLC who underwent second-line therapy after platinum-doublet chemotherapy with or without immune checkpoint inhibitor (ICI) resistance before (pre-ICI cohort) and after (post-ICI cohort) approval of combination immunotherapy. We selected the optimal platinum-free interval cutoff value with the lowest two-sided p value in the multivariable Cox regression model for second-line overall survival. The internal validity of the chosen cutoff value was assessed using twofold cross-validation. RESULTS: There were 235 and 98 patients in the pre-ICI and post-ICI cohorts, respectively. In the pre-ICI cohort, the optimal cutoff was 59 days (p = 0.0001); the hazard ratio calculated using twofold cross-validation was 1.31 (95% confidence interval: 0.95-1.82]). In the post-ICI cohort, although the 60- and 90-day cutoff values could predict prognosis (60 d; p = 0.002, 90 d; p = 0.005), the optimal cutoff value was 75 days (p = 0.0002), which resulted in a median second-line overall survival of 15.9 and 5.0 months for patients with sensitive and refractory relapse, respectively (hazard ratio = 2.77, 95% confidence interval: 1.56-4.93). CONCLUSIONS: We clarified the previously ambiguous cutoff values for classifying relapsed SCLC and revealed that the 75-day cutoff most accurately predicts subsequent prognosis than the traditional cutoffs in the post-ICI era.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Pronóstico , Inmunoterapia , Estudios RetrospectivosRESUMEN
BACKGROUND: Recently, the addition of antiprogrammed cell death-ligand 1 (PD-L1) monoclonal antibodies, including durvalumab and atezolizumab to platinum-based chemotherapy, has demonstrated clinical benefits in patients with untreated advanced small cell lung cancer (SCLC). However, these clinical trials comprised small populations of elderly patients with SCLC. Therefore, the safety of anti-PD-L1 immunotherapy plus platinum and etoposide in elderly patients remains unclear. METHODS: This prospective, multicenter, single-arm study was designed to evaluate the safety and efficacy of durvalumab plus carboplatin and etoposide in untreated elderly patients (aged > 75) with extensive stage (ES) SCLC. A total of 40 patients were recruited. Patients received up to four cycles of durvalumab 1500 mg and carboplatin at a dose equivalent to an area under the curve of 5 on day 1, and etoposide 80 mg/m2 on days 1 to 3 every 3 weeks as induction treatment, followed by durvalumab maintenance treatment every 4 weeks. The primary endpoint was safety as measured by adverse events according to the Common Terminology Criteria for Adverse Events version 5.0, laboratory analyses, vital signs, and physical examination. Key secondary endpoints were objective response rate, median progression-free survival, 12-month overall survival rate, and the completion rate for four cycles of induction chemotherapy. DISCUSSION: The present study was designed to evaluate the safety of durvalumab plus carboplatin and etoposide in elderly patients with ES-SCLC.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Tortugas , Humanos , Anciano , Animales , Carboplatino , Etopósido , Estudios Prospectivos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos Fase II como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
Primary tracheal adenoid cystic carcinoma (TACC) is a rare malignancy without an established treatment. Central airway obstruction due to TACC often decreases the quality of life and has life-threatening consequences. A 19-year-old man with unresectable TACC and central airway obstruction suffered from progressive cough and dyspnea after exercise. Proton beam therapy (PBT) was selected as the preferred treatment over systemic anti-cancer chemotherapy for TACC. PBT led to complete remission of TACC and the almost complete disappearance of the respiratory symptoms without adverse events. PBT is a useful and safe treatment for unresectable primary TACC.
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Obstrucción de las Vías Aéreas , Carcinoma Adenoide Quístico , Terapia de Protones , Neoplasias de la Tráquea , Masculino , Humanos , Adulto Joven , Adulto , Carcinoma Adenoide Quístico/radioterapia , Calidad de Vida , Tráquea/patología , Neoplasias de la Tráquea/radioterapia , Neoplasias de la Tráquea/diagnóstico , Neoplasias de la Tráquea/patologíaRESUMEN
PURPOSE: The purpose of this study was to find useful imaging features on non-contrast-enhanced magnetic resonance imaging (MRI) that can divide patients with thymic epithelial tumor (TET) into clinical stage I-II and III-IV groups under assumption that contrast media are contraindicated. MATERIALS AND METHODS: This retrospective study included 106 patients (median age, 60 years; range, 27-82 years; 62 women) with surgically resected TET who underwent MRI between August 1986 and July 2015. All cases were classified according to the 2015 WHO classification and staged using the eighth edition of the TNM system. Two radiologists independently evaluated 14 categories of MRI findings; the findings in patients with stage I-II were compared with those of patients with stage III-IV using a logistic regression model. Disease-specific survival associated with significant findings was calculated using the Kaplan-Meier method. RESULTS: Univariate analysis showed that stage III-IV patients were more likely to have tumors with an irregular contour, heterogeneity on T1WI, low-signal intensity on T2WI, irregular border with lung, findings of great vessel invasion (GVI) (hereafter, GVI sign), pericardial thickening/nodule, and lymphadenopathy (all, P < 0.01). On multivariable analysis, only two findings, irregular border between tumor and lung (odds ratio [OR], 272.8; 95% CI 26.6-2794.1; P < 0.001) and positive GVI sign (OR, 49.3; 95% CI 4.5-539.8; P = 0.001) remained statistically significant. Patients with one or both features had significantly worse survival (log-rank test, P < 0.001). CONCLUSION: For patients with TET who are unable to receive contrast for preoperative staging, the two image findings of an irregular border between tumor and lung and the positive GVI sign on non-contrast-enhanced MRI could be helpful in determining stage III-IV disease which is associated with a worse survival.
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Neoplasias del Timo , Humanos , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias del Timo/diagnóstico por imagen , Neoplasias del Timo/cirugía , Pronóstico , Imagen por Resonancia Magnética/métodos , Estadificación de NeoplasiasRESUMEN
Background: The standard of care for extensive-stage small cell lung cancer (ES-SCLC) is an immune checkpoint inhibitor (ICI) combined with platinum-etoposide (PE) chemotherapy. At initial diagnosis, about 25% of ES-SCLC patients have brain metastases, which are associated with a poor prognosis. The decision as to whether to treat brain metastases with local therapies such as surgery or radiotherapy before initiation of systemic chemoimmunotherapy is based on symptoms due to the brain lesions and the general condition of the patient. Subset analysis of the CASPIAN study showed that combination therapy with PE plus durvalumab (MEDI4736) is promising for ES-SCLC with brain metastases. However, data required in daily clinical practice, such as intracranial response rate and duration of intracranial response, are insufficient for such patients. Patients and Methods: We have designed a single-arm phase II trial of durvalumab plus PE for patients aged ≥20 years with chemotherapy-naïve ES-SCLC and at least one brain metastasis ≥5 mm in size that has not been previously treated. Patients receive durvalumab intravenously combined with four cycles of PE. Enrollment of 50 patients over 2 years at 25 oncology facilities in Japan is planned. The primary endpoint is intracranial response rate. Conclusion: This is the first prospective study to evaluate the effects of an ICI with PE specifically in ES-SCLC patients with brain metastases. If it demonstrates intracranial efficacy, this regimen will be a potential treatment option for such individuals, and radiation therapy or surgery for brain metastases can be avoided or postponed.
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BACKGROUND: Amino acid metabolism is essential for tumor cell proliferation and regulation of immune cell function. However, the clinical significance of free amino acids (plasma-free amino acids (PFAAs)) and tryptophan-related metabolites in plasma has not been fully understood in patients with non-small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors. METHODS: We conducted a single cohort observational study. Peripheral blood samples were collected from 53 patients with NSCLC before treatment with PD-1 (Programmed cell death-1) inhibitors. The plasma concentrations of 21 PFAAs, 14 metabolites, and neopterin were measured by liquid chromatography-mass spectrometry. Using Cox hazard analysis with these variables, a multivariate model was established to stratify patient overall survival (OS). Gene expression in peripheral blood mononuclear cells (PBMCs) was compared between the high-risk and low-risk patients by this multivariate model. RESULTS: On Cox proportional hazard analysis, higher concentrations of seven PFAAs (glycine, histidine, threonine, alanine, citrulline, arginine, and tryptophan) as well as lower concentrations of three metabolites (3h-kynurenine, anthranilic acid, and quinolinic acid) and neopterin in plasma were significantly correlated with better OS (p<0.05). In particular, the multivariate model, composed of a combination of serine, glycine, arginine, and quinolinic acid, could most efficiently stratify patient OS (concordance index=0.775, HR=3.23, 95% CI 2.04 to 5.26). From the transcriptome analysis in PBMCs, this multivariate model was significantly correlated with the gene signatures related to immune responses, such as CD8 T-cell activation/proliferation and proinflammatory immune responses, and 12 amino acid-related genes were differentially expressed between the high-risk and low-risk groups. CONCLUSIONS: The multivariate model with PFAAs and metabolites in plasma might be useful for stratifying patients who will benefit from PD-1 inhibitors.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Aminoácidos/uso terapéutico , Arginina , Carcinoma de Pulmón de Células no Pequeñas/patología , Glicina/uso terapéutico , Humanos , Inhibidores de Puntos de Control Inmunológico , Leucocitos Mononucleares/patología , Neoplasias Pulmonares/patología , Neopterin/uso terapéutico , Proyectos Piloto , Pronóstico , Ácidos Quinolínicos/uso terapéutico , TriptófanoRESUMEN
BACKGROUND: Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Combination therapies with first-generation EGFR-TKIs and bevacizumab have been reported to prolong progression-free survival (PFS). However, there are few data on the combination of afatinib and bevacizumab. METHODS: In this phase I trial, we evaluated the safety of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study consisted of two cohorts. In the dose-finding cohort, enrolled patients were treated with afatinib at a dose of 20, 30, or 40 mg/day (days 1-21) plus bevacizumab at a dose of 15 mg/kg (day 1) in 21-day cycles. This cohort was performed according to a 3 + 3 manner. In the expansion cohort, enrolled patients received the recommended dose (RD) based on the results of the dose-finding cohort. The serum trough concentration of afatinib was determined at the steady state. RESULTS: Seventeen patients were enrolled in this study (6 patients in the dose-finding cohort and 11 patients in the expansion cohort). There were no dose-limiting toxicities (DLTs) with afatinib at a dose of 30 mg/day. With afatinib at a dose of 40 mg/day, two of two patients experienced DLTs (grade 3 diarrhea) in cycle 1. With these results, afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg was determined as the RD. Eleven patients in the expansion cohort were treated with the RD. Common treatment-related adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs or cases of interstitial lung disease. Dose-proportional increases in serum afatinib trough concentrations at steady state were not observed. The response rates (RRs) and disease control rates were 55% and 100% in EGFR-TKI-naïve patients. Re-biopsy was performed in eight patients after progressive disease following the study treatment, and three patients acquired a T790M mutation. CONCLUSIONS: Afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg q3w is well tolerated.
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Adenocarcinoma is the most common histological type of non-small cell lung cancer (NSCLC), and various biomarkers for predicting its prognosis after surgical resection have been suggested, particularly in early-stage lung adenocarcinoma. Periostin (also referred to as POSTN, PN or osteoblast-specific factor) is an extracellular matrix protein, the expression of which is associated with tumor invasiveness in patients with NSCLC. In the present study, the novel approach, in which the thin-section CT findings prior to surgical resection and periostin expression of resected specimens were analyzed in combination, was undertaken to assess whether the findings could be a biomarker for predicting the outcomes following resection of T1 invasive lung adenocarcinoma. A total of 73 patients who underwent surgical resection between January 2000 and December 2009 were enrolled. A total of seven parameters were assessed in the thin-section CT scans: i) Contour; ii) part-solid ground-glass nodule or solid nodule; iii) percentage of solid component (the CT solid score); iv) presence of air-bronchogram and/or bubble-like lucencies; v) number of involved vessels; vi) shape linear strands between the nodule and the visceral pleura; and vii) number of linear strands between the nodule and the visceral pleura. Two chest radiologists independently assessed the parameters. Periostin expression was evaluated on the basis of the strength and extent of staining. Univariate and multivariate analyses were subsequently performed using the Cox proportional hazards model. There was a substantial to almost perfect agreement between the two observers with regard to classification of the seven thin-section CT parameters (κ=0.64-0.85). In the univariate analysis, a CT solid score >80%, pathological lymphatic invasion, tumor and lymph node status and high periostin expression were significantly associated with recurrence (all P<0.05). Multivariate analysis demonstrated that a CT solid score >80% and high periostin expression were risk factors for recurrence (P=0.002 and P=0.011, respectively). The cumulative recurrence rates among the three groups (both negative, CT solid score >80% or high periostin expression, or both positive) were significantly different (log-rank test, P<0.001). Although the solid component is already known to be a major predictor of outcome in lung adenocarcinomas according to previous studies, the combined analysis of CT solid score and periostin expression might predict the likelihood of tumor recurrence more precisely.