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1.
Isr Med Assoc J ; 22(1): 22-26, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31927801

RESUMO

BACKGROUND: Prophylactic cranial irradiation (PCI) exclusion in favor of brain magnetic resonance imaging (MRI) staging and surveillance in the management of small cell lung cancer (SCLC) is controversial yet accepted by some centers. The use of MRI suggests performing stereotactic radiosurgery (SRS) treatment for limited brain metastases. Data regarding SRS efficacy in this setting is limited. OBJECTIVES: To assess intracranial objective response rate (iORR), progression-free survival (iPFS), intracranial failure patterns, overall survival (OS) and time-to-whole-brain radiation therapy (WBRT)/death, whichever occurred first (TTWD) with SRS in SCLC. METHODS: The study comprised 10 consecutive SCLC patients with brain metastases treated with SRS and followed-up at Davidoff Cancer center between Aug 2012 and March 2019. Brain MRI images were reviewed by a neuro-radiology specialist. RESULTS: iORR was 57% as assessed by response assessment in neuro-oncology brain metastases. Intracranial progression developed in 8 patients. Median iPFS was 4.0 months (95% confidence interval [95%CI] 1.7-7.2). In-site, off-site and combined pattern of intracranial failure was seen in 0, 5, and 3 patients, respectively; median number of new brain lesions following SRS was 4 (range, 1-12). SRS was performed 10 additional times in 6 patients (median number of lesions irradiated per round was 1, range 1-5). WBRT was administered in 3 patients. Median TTWD was 20.9 months (95% CI, 1.9-26.8). Median OS since SRS administration was 23.2 months (95% CI, 4.2-not reached). CONCLUSIONS: MRI surveillance with multiple rounds of SRS may serve a reasonable alternative to PCI or therapeutic WBRT in SCLC.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Pulmonares/patologia , Radiocirurgia , Carcinoma de Pequenas Células do Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Intervalo Livre de Progressão , Radiocirurgia/métodos , Resultado do Tratamento
2.
Eur J Cancer ; 120: 122-131, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31518968

RESUMO

AIM: Immune-related toxicities of immune checkpoint inhibitors (CPIs) require prompt diagnosis and treatment. Atherosclerosis has an inflammatory component; we speculated this inflammation could be enhanced by CPIs. We aimed to evaluate the risk of acute vascular events (AVEs) on CPIs. METHODS: Patients treated by CPIs in Sheba Medical Center (Israel) between January 2015 and May 2018 were retrospectively identified from electronic medical records. AVEs were identified and verified by chart review. Age, sex, diabetes, hypertension, smoking, dyslipidemia, previous AVE, renal failure, cancer type and specific treatments were evaluated as potential risk factors. AVE rate on CPIs was compared with that on chemotherapy or on combined chemo-immunotherapy in patients with lung adenocarcinoma. Survival of patients with AVEs was compared with that of patients without AVEs. RESULTS: CPI was administered to 1215 patients. AVEs within six months after CPI initiation occurred in 2.6% (95% confidence interval [CI]: 1.8-3.6) of patients, more common than in later time periods. In lung adenocarcinoma, event rate was 5.2% (95% CI: 2.8-9.2). Lung adenocarcinoma, prior AVE, hypertension and dyslipidemia were correlated with AVEs. AVE rate in patients with non-small cell lung cancer adenocarcinoma was similar whether on chemotherapy or on CPI. Survival of patients with AVEs was worse than that of those without AVEs. CONCLUSION: The similarly increased rates of AVEs for patients on CPI, on chemotherapy or on both suggest that although CPI may not augment the risk of AVE over that of chemotherapy, it carries a similar and significant risk of such adverse event. Caution should be exercised for patients with risk factors for AVEs.

3.
J Immunother ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31498181

RESUMO

The existing data with regard to immune-related neutropenia (irN), a rare (incidence-1%) immune-related adverse event of immune checkpoint inhibitors, are scarce. Eight patients with irN were identified through internal databases of 3 participating Israeli cancer centers. In addition, 11 original articles focusing on the clinical course of 24 patients with irN were selected during the PubMed search. Descriptive analysis of clinical and pathologic factors related to irN was performed (n=32); the effect of these on the irN outcomes was assessed. An algorithm for irN evaluation and treatment was proposed. The median time-to-onset of irN (n=32) was 60 days (range, 10-465 d). Grade 3-5 irN, febrile neutropenia, and irN-related death occurred in 81%, 50%, and 9% of patients, respectively. In all, 56%, 22%, 62%, and 25% of patients received PO corticosteroids, IV corticosteroids, granulocyte colony-stimulating factor (GCSF), and intravenous immunoglobulins (IVIG), respectively, with an improvement/resolution rate of 84%. Odds ratios for irN improvement/resolution were as follows: 1.40 [95% confidence interval (CI), 0.03-68.72], 0.43 (95% CI, 0.04-4.22), 2.60 (95% CI, 0.07-97.24), 0.36 (95% CI, 0.03-4.38), 4.02 (95% CI, 0.16-99.48), 2.01 (95% CI, 0.32-12.70), 1.08 (95% CI, 0.02-49.89), 0.42 (95% CI, 0.06-2.91), and 2.73 (95% CI, 0.42-17.51) for granulocyte hyperplasia, granulocyte/all lineage hypoplasia, granulocyte maturation blockade, lymphocyte infiltration on bone marrow biopsy, IV corticosteroids, PO corticosteroids, cyclosporine, IVIG, and GCSF, respectively (P>0.05 for all factors). IrN recurrence rate following immune checkpoint inhibitors rechallenge was 80%. IrN is a rare, life-threatening, early-onset immune-related adverse event. Differentiating between the central, peripheral, and modified peripheral types allows a better prognosis definition. Corticosteroids and GCSF represent the main treatment approaches; IVIG and cyclosporine should be used as salvage treatment.

4.
Isr Med Assoc J ; 21(6): 394-398, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31280508

RESUMO

BACKGROUND: The main acquired resistance mechanism to first- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant non-small cell lung cancer (NSCLC) is the propagation of T790M clones, which can be detected in circulating tumor DNA (ctDNA). OBJECTIVES: To analyze osimertinib outcomes according to T790M testing method. METHODS: The study comprised 33 consecutive patients with advanced EGFR mutant NSCLC who were diagnosed with a T790M mutation after progression on first- or second-generation EGFR TKIs and treated with osimertinib. The patients were divided into groups A (diagnosed by tumor testing) and B (by ctDNA testing). Osimertinib outcomes were compared between the groups. RESULTS: Objective response rate with osimertinib comprised 54% and 62% in groups A and B, respectively (P = 0.58). Median progression-free survival (PFS) with osimertinib was 8.9 months (95% confidence interval [95%CI] 1.8-17.5) and 9.1 months (95%Cl 5.3-12.6) in groups A and B, respectively (log-rank test 0.12, P = 0.73). Median overall survival (OS) was 13.8 months (95%CI 4.9-25.5) and 13.8 months (95%Cl 7.7-27.7) in groups A and B, respectively (log-rank test 0.09, P = 0.75). T790M testing technique did not affect PFS (hazard ratio [HR] 1.16, 95%CI 0.50-2.69, P = 0.73) or OS (HR = 1.16, 95%CI 0.45-3.01, P = 0.76). The proportion of patients diagnosed by ctDNA grew from 56% in 2015 to 67% in 2016-2017. CONCLUSIONS: Our study provides a ctDNA validation for the purpose of T790M testing in EGFR mutant NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , DNA Tumoral Circulante/sangue , Neoplasias Pulmonares/tratamento farmacológico , Piperazinas/uso terapêutico , Acrilamidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Humanos , Israel , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Resultado do Tratamento
5.
Clin Lung Cancer ; 20(4): 278-286.e1, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31060855

RESUMO

BACKGROUND: Real-life comparative data on BRAF inhibitors (BRAFi) and BRAFi + MEK inhibitors (MEKi) combination in BRAF-mutant (BRAFm) non-small-cell lung cancer (NSCLC) is lacking. PATIENTS AND METHODS: Consecutive BRAFm advanced NSCLC patients (n = 58) treated in 9 Israeli centers in 2009-2018 were identified. These were divided according to mutation subtype and treatment into groups A1 (V600E, BRAFi; n = 5), A2 (V600E, BRAFi + MEKi; n = 15), A3 (V600E, no BRAFi; n = 7), B1 (non-V600E, BRAFi ± MEKi; n = 7), and B2 (non-V600E, no BRAFi; n = 23); one patient received both BRAFi and BRAFi + MEKi. Safety, objective response rate, progression-free survival with BRAFi ± MEKi, and overall survival were assessed. RESULTS: Objective response rate was 40%, 67%, and 33% in groups A1, A2, and B1, respectively (P = .5 for comparison between groups A1 and A2). In group B1, G469A and L597R mutations were associated with response to BRAFi + MEKi. Median progression-free survival was 1.2 months (95% confidence interval [CI], 0.5-5.3), 5.5 months (95% CI, 0.7-9.3), and 3.6 months (95% CI, 1.5-6.7) for groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P = .04). Median overall survival with BRAFi ± MEKi was 1.7 months (95% CI, 0.5-NR), 9.5 months (95% CI, 0.2-14.9), and 7.1 months (95% CI, 1.8-NR) in groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P = .6). Safety profiles differed slightly, and similar treatment discontinuation rates were observed with BRAFi and BRAFi + MEKi. CONCLUSION: In the real-life setting, activity and safety of BRAFi + MEKi in V600E BRAFm NSCLC are comparable to those observed in prospective clinical trials; the combination of BRAFi + MEKi is superior to monotherapy with a BRAFi. Further research should be done to explore the impact of BRAFi + MEKi treatment on the natural history of BRAFm NSCLC.

7.
Oncol Res Treat ; 42(5): 275-282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30955009

RESUMO

BACKGROUND: Little is known regarding the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) efficacy and safety in the elderly. OBJECTIVES AND METHODS: Consecutive patients (n = 53) with ALK-positive advanced non-small cell lung cancer treated with an ALK TKI were identified through internal databases of three cancer centers and divided into groups A (< 65 years old; n = 34) and B (≥65 years old; n = 19). Progression-free survival (PFS), ALK TKI safety and overall survival (OS) were assessed. Uni- and multivariate PFS and OS analyses were performed. RESULTS: Crizotinib, ceritinib, and alectinib were administered in 94 and 100%, 35 and 31%, 38 and 52% of patients in groups A and B, respectively. The median PFS (months) was 5.4 (95% CI, 3.4-12.4) and 5.6 (95% CI, 2.5-14.7) with crizotinib (log-rank 0.0009, p = 0.9), 4.7 (95% CI, 1.0-11.5) and 23.0 (95% CI, 0.8-27.7) with ceritinib (log-rank 0.44, p = 0.5), and 21.2 (95% CI, 1.2 to not reached, NR) and 5.6 (95% CI, 0.5 to NR) with alectinib (log-rank 0.53, p = 0.5) in groups A and B, respectively. The median OS (months) comprised 29.8 (95% CI, 21.0 to NR) and 25.1 (95% CI, 10.8-53.6) in groups A and B, respectively (log-rank 0.57, p = 0.4). Age affected neither PFS nor OS. 19 and 37%, 50 and 40%, and 0 and 0% of patients in groups A and B, treated with crizotinib, ceritinib, and alectinib, respectively, developed high-grade adverse events. The treatment discontinuation rate was 9 and 21%, 16 and 60%, 0 and 0% with crizotinib, ceritinib, and alectinib in groups A and B, respectively. CONCLUSIONS: In the elderly, crizotinib, ceritinib, and alectinib treatments are associated with similar efficacy but different safety profiles; alectinib is associated with a lower rate of high-grade adverse events and a lower treatment discontinuation rate.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Carbazóis/efeitos adversos , Carbazóis/uso terapêutico , Crizotinibe/efeitos adversos , Crizotinibe/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Sulfonas/efeitos adversos , Sulfonas/uso terapêutico , Adulto Jovem
8.
J Thromb Thrombolysis ; 47(1): 121-128, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30255420

RESUMO

Anticoagulation is often used in superior vena cava syndrome (SVCS) associated with cancer (i.e malignant SVCS), even without thrombosis, but its effect on outcomes has not been reported. We aimed to determine factors and outcomes associated with thrombosis and anticoagulation in malignant SVCS. Patients with malignant SVCS diagnosed on computerized tomography (CT) were retrospectively included, indexed at diagnosis and followed for 6 months using medical records. The cohort included 183 patients with malignant SVCS of which 153 (84%) were symptomatic. Thirty of the 127 patients (24%) with a reviewable baseline CT had thrombosis of the SVC or tributaries at diagnosis. Patients with baseline thrombosis more often had symptomatic SVCS (p < 0.01). 70% (21/30) of patients with thrombosis and 52% (49/97) of those without thrombosis at baseline received anticoagulation, most often at therapeutic doses. Thrombosis occurred in 5/39 patients with anticoagulation (13%) compared to 2/18 (11%) of those without, during follow-up (p = 0.85). Anticoagulation was associated with a reduction in risk of SVC stent placement during follow-up that did not reach statistical significance (HR 0.47, 95% CI 0.2-1.13, p = 0.09). Major bleeding occurred in 7 (4%) patients, six of whom received anticoagulation (four therapeutic and two intermediate dose). Neither thrombosis nor anticoagulation affected survival. Anticoagulation is commonly used as primary prevention but its benefit remains to be proven. The role of reduced-dose anticoagulation in non-thrombotic malignant SVCS should be prospectively assessed.


Assuntos
Anticoagulantes/uso terapêutico , Neoplasias , Síndrome da Veia Cava Superior/terapia , Trombose/prevenção & controle , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Stents , Síndrome da Veia Cava Superior/tratamento farmacológico , Síndrome da Veia Cava Superior/mortalidade , Síndrome da Veia Cava Superior/cirurgia , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do Tratamento
9.
Lung Cancer ; 124: 117-124, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30268448

RESUMO

OBJECTIVES: Efficacy of immune check-point inhibitors (ICPi) in NSCLC with rare targetable drivers (RTDs) is largely unknown. MATERIALS AND METHODS: Consecutive patients with NSCLC and RTDs (non-EGFR/ALK, n-82) were selected from the Davidoff Cancer Center database. ORR, PFS, OS with ICPi, OS since advanced disease diagnosis, TMB, MSI, and PD-L1 expression were analyzed; uni- and multivariate PFS and OS analyses were done. OS with ICPi was compared between the RTD cohort and the non-selected NSCLC cohort (n-278). RESULTS: Of 50 tumors tested, 32%, 38%, and 30% were associated with ≥50%, 1-49% and <1% PD-L1 expression, respectively. Median TMB (n-48) comprised 4 muts/Mb (0-57); TMB ≥ 10 muts/Mb was seen in 19% of tumors. Both TMB and PD-L1 expression varied across different RTDs. All the 47 tumors were MSI stable. ORR with ICPi (n-44) was 16%, median PFS was 3.2 months (95% CI, 2.6-5.0), median OS was 16.2 months (95% CI, 8.4-NR). No correlation was seen between OS with ICPi and PD-L1 expression (p > 0.4), TMB (p > 0.8), or RTD type (p > 0.3). In the multivariate analysis, ECOG PS (p-0.005), targeted agents exposure (p-0.005), and ICPi exposure (p-0.04) were the only variables which correlated with OS since advanced disease diagnosis. Median OS since advanced disease diagnosis comprised 32 months (95% CI, 19.9-44.9) and 13 months (95% CI, 6.6-15.9) for patients who were and were not exposed to ICPi, respectively (log-rank test-6.3; p-0.01). In the inter-cohort comparison, for patients matched for ECOG PS (0/1), median OS with ICPi comprised 17.5 months (95% CI, 8.1-NR) and 8.6 months (95% CI, 6.7-NR) for RTD and non-selected patients, respectively (log-rank test-2.4, p-0.1). CONCLUSION: In NSCLC with RTD, ICPi have favorable efficacy and independent impact on OS. NSCLC with RTD is associated with MSI stable status and variable levels of PD-L1 expression and TMB; their predictive value remains to be determined.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Coortes , Feminino , Humanos , Israel/epidemiologia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Análise de Sobrevida , Resultado do Tratamento
10.
Thorac Cancer ; 9(11): 1470-1475, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30240138

RESUMO

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare disease and management of localized disease is controversial. Radiotherapy has been shown to be useful after extrapleural pneumonectomy (EPP), as well as with less aggressive surgery. As no reports of the treatment of this disease have ever been published from Israel, we report our experience with MPM and intensity-modulated radiotherapy (IMRT). METHODS: The complete medical records of patients treated for MPM at the Rabin Medical Center from 1 August 2007 to 31 March 2016 were reviewed. Twenty-seven patients were treated with IMRT, either post-EPP or without EPP. Patients received 54 Gy in 2 Gy fractions using the restricted field IMRT technique. Chemotherapy was administered sequentially in 26% of patients. Patients were followed up from the date of diagnosis to death or treatment failure. RESULTS: Seventy-eight percent of patients had the epithelioid subtype. Nearly all patients were male (85%) and 90% of non-surgical patients were administered chemotherapy compared to 56% of post-EPP patients. All patients completed therapy and only 16% had grade 1-2 radiation pneumonitis, with no incidence of grade 3 or higher. The median follow-up was 22 months and the mean overall survival was 34.9 months. The mean time to progression following radiation therapy was 26.7 months. The mean time to local and distant failure was 19 and 16 months, respectively. CONCLUSIONS: IMRT for localized pleural mesothelioma is a tolerable and effective therapy both post-EPP or without surgery. These results suggest that future investigation in this area is required.


Assuntos
Neoplasias Pulmonares/radioterapia , Mesotelioma/radioterapia , Neoplasias Pleurais/radioterapia , Radioterapia de Intensidade Modulada/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Resultado do Tratamento
11.
J Thorac Oncol ; 13(11): 1705-1716, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30121392

RESUMO

INTRODUCTION: Next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) enables noninvasive genomic analysis of NSCLC patients. Although plasma-detected genomic alterations (GAs) have been shown to predict targeted therapy response, evidence of durability of response is lacking or limited to small cohorts as is the impact of cfDNA NGS results on clinical decisions. METHODS: This retrospective study of stage IIIB/IV NSCLC patients between the years 2014 and 2017 in Israel used cfDNA NGS (Guardant360; Guardant Health, Inc., Redwood City, California) to identify targetable GAs. RESULTS: We consecutively tested 116 NSCLC patients, 41.4% before first-line therapy (group A), 34.5% upon progression on chemotherapy or immunotherapy (group B1), and 24.1% upon progression on EGFR tyrosine kinase inhibitors (group B2). Targetable GAs were found in 31% of group A (15 of 48 patients), 32.5% in group B1 (13 of 40 patients) and 71% in group B2 (20 of 28 patients). Treatment decision was changed to targeted therapy in 23% (11 of 48 patients), 25% (10 of 40 patients) and 32% (9 of 28 patients), respectively (total cohort 26%; 30/116). Objective response rate (Response Evaluation Criteria in Solid Tumors) was 43% (12 of 28 patients) including one complete response, partial response in 39% (11 of 28 patients), stable disease in 32% (9 of 28 patients), and progressive disease in 25% (7 of 28 patients). Disease control rate was 75% for 5 months median treatment duration. CONCLUSIONS: Comprehensive cfDNA testing impacted clinical decisions in one-quarter to one-third of initial and subsequent lines of treatment in advanced NSCLC patients. This retrospective study extends previous reports by showing that responses based on cfDNA are durable and change treatment decisions at initial presentation and at progression.


Assuntos
DNA Tumoral Circulante/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
12.
J Thorac Oncol ; 13(8): 1128-1137, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29723688

RESUMO

INTRODUCTION: The efficacy of immune checkpoint inhibitors (ICPi) in BRAF mutant NSCLC is unknown. METHODS: Multi-institutional retrospective chart review identified 39 patients with BRAF mutant NSCLC. The patients were divided into two groups: V600E (group A, n = 21) and non-V600E (group B, n = 18). Programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB) and microsatellite instability status were assessed in 29 (74%), 11 (28%), and 12 (31%) patients, respectively. Objective response rate, progression-free survival (PFS) with ICPi, and overall survival were analyzed. RESULTS: High (≥50%), intermediate (1-49%), and no (<1%) PD-L1 expression was observed in 8 of 19 (42%), 6 of 19 (32%), 5 of 19 (26%), and 5 of 10 (50%), 1 of 10 (10%), and 4 of 10 (40%) cases in groups A and B, respectively. Two tumors in group A showed high TMB (25%); none were microsatellite instability status-high. Twenty-two patients (group A, n = 12; group B, n = 10) received ICPi. Objective response rate with ICPi was 25% and 33% in groups A and B, respectively (p = 1.0). Median PFS with ICPi was 3.7 months (95% confidence interval [CI]: 1.6-6.6), and 4.1 months (95% CI: 0.1-19.6) in groups A and B, respectively (log-rank test = 0.81, p = 0.37). Neither BRAF mutation type nor PD-L1 expression affected the response probability/PFS. Median overall survival was not reached (95% CI: 13-NR) and comprised 21.1 months (95% CI: 1.8-NR) for patients who were and were not exposed to ICPi, respectively (log-rank test = 5.58, p = 0.018). CONCLUSIONS: BRAF mutant NSCLC is associated with high level of PD-L1 expression, low/intermediate TMB and microsatellite-stable status. ICPi have favorable activity both in BRAF V600E and BRAF non-V600E mutant NSCLC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/biossíntese , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Nivolumabe/administração & dosagem , Estudos Retrospectivos , Carga Tumoral
13.
Target Oncol ; 13(2): 217-226, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29353436

RESUMO

BACKGROUND: Precision treatment of cancer uses biomarker-driven therapy to individualize and optimize patient care. OBJECTIVE: To evaluate real-life clinical experience with biomarker-driven therapy in metastatic gastric and esophageal cancer in Israel. PATIENTS AND METHODS: This multicenter retrospective cohort study included patients with metastatic gastric or esophageal cancer who were treated in the participating institutions and underwent biomarker-driven therapy. Treatment was considered to have a benefit if the ratio between the longest progression-free survival (PFS) post biomarker-driven therapy and the last PFS before the biomarker-driven therapy was ≥1.3. The null hypothesis was that ≤15% of patients gain such benefit. RESULTS: The analysis included 46 patients (61% men; median age, 58 years; 57% with poorly-differentiated tumors). At least one actionable (i.e., predictive of response to a specific therapy) biomarker was identified for each patient. Immunohistochemistry was performed on all samples and identified 1-8 (median: 3) biomarkers per patient (most commonly: low TS, high TOPO1, high TOP2A). Twenty-eight patients received therapy after the biomarker analysis (1-4 lines). In the 1st line after biomarker analysis, five patients (18%) achieved a partial response and five (18%) stable disease; the median (range) PFS was 129 (12-1155) days. Twenty-four patients were evaluable for PFS ratio analysis; in seven (29.2%), the ratio was ≥1.3. In a one-sided exact binomial test vs. the null hypothesis, p = 0.019; therefore, the null hypothesis was rejected. CONCLUSIONS: Our findings demonstrated that implementing biomarker-driven analysis is feasible and could provide clinical benefit for a considerable proportion (~30%) of patients with metastatic gastric or esophageal cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/terapia , Neoplasias Gástricas/terapia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Gástricas/patologia
14.
Lung Cancer ; 126: 217-223, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29254746

RESUMO

OBJECTIVES: Nivolumab has recently received regulatory approval as a 2nd-line treatment of non-small cell lung cancer (NSCLC). The data regarding its effectiveness and safety in real life setting is lacking. MATERIALS AND METHODS: 260 consecutive patients with advanced NSCLC treated with nivolumab at five Israeli cancer centers between January 2015 and March 2016 were evaluated for overall survival (OS) and toxicity. OS was analyzed by the Cox proportional-hazards regression model. Overall response rate (ORR) and progression-free survival (PFS) were assessed in 49 patients using RECIST, v.1.1. RESULTS: Median age was 67y (41-99); males 68%; smokers 76%; ECOG PS ≥2 46%; non-squamous/squamous/other/NR 70%/23%/6%/1%; brain metastases 21%; liver metastases 21%; treatment line: 1st/2nd/3rd+-line/NR 6%/64%/26%/4%. With median survival follow-up of 18.5 months (range, 12.0-26.9), 155 (60%) patients died; median OS comprised 5.9 months (95% CI 4.7-7.4). In univariate and multivariate analysis, the only variable which significantly correlated with OS was ECOG PS. Median OS of patients with ECOG PS 0/1 and ECOG PS ≥2 comprised 9.5 months (95% CI, 6.7-NR) and 3.5 months (95% CI, 2.6-4.5), respectively. For 49 patients evaluable for response (median follow-up of 8.4 months (range, 2-16.8), ORR was 35%, median PFS was 2.8 months (95% CI, 1.8-7.7), incidence of pseudo-progression was 9%. The nivolumab safety profile was in accordance with the literature data, except for febrile neutropenia and pericarditis (observed in 1 case each). CONCLUSION: In real life setting, the effectiveness of nivolumab is reasonable yet less prominent than it has been demonstrated in clinical trials. ECOG PS ≥2 is associated with poor prognosis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Israel , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento
15.
Harefuah ; 156(11): 686-691, 2017 11.
Artigo em Hebraico | MEDLINE | ID: mdl-29198084

RESUMO

BACKGROUND: In the last decade, important advances in understanding the lung cancer cellular signal pathways have led to the designing of targeted drugs that significantly prolong survival. Recent data shows that 64% of lung adenocarcinomas harbor at least one activating driver mutation, including treatable mutations such as RET, ERBB2 (HER-2) and ROS1 gene mutations, besides the regularly screened ALK and EGFR genes. Next-Generation Sequencing (NGS) reveals more clinically meaningful genomic alterations as compared to currently used diagnostic tests. However, the clinical impact of NGS testing merits further investigation. OBJECTIVES: To evaluate the impact of NGS-based tumor profiling on therapeutic decision making in the real life setting in advanced lung cancer patients. METHODS: The study population included 50 lung cancer patients who were treated at Davidoff Cancer Center, Rabin Medical Center in 2011-2015, and for whom a broad, hybrid capture-based NGS genomic profiling test was performed. The data was retrospectively collected from patient charts. RESULTS: 39 of 46 included patients (84.8%) had one or more driver alternations, and a targeted agent was administered according to alteration discovered in 21 of 46 cases (45.7%). 15 (37.5%) treated patients were exclusively detected by NGS. The most frequent drivers were EGFR (26.1%), KRAS (19.6%), ALK (13%), STK11 (10.9%) and RET (8.7%). Interestingly, 10 patients became EGFR and ALK positive by NGS after the previous standard local molecular testing was negative. CONCLUSIONS: Molecular testing using NGS can reveal a targetable genomic alteration in the vast majority of lung tumors. Its broad use for therapeutic decision making is essential since approximately half of the patients can benefit from customized treatment upon testing results. DISCUSSION: Although this topic needs to be further assessed in large randomized controlled trials, our positive results emphasize the importance of multiplex testing as a diagnostic test in advanced lung cancer patients. The implementation of NGS at Rabin Medical Center in the near future is highly anticipated.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Mutação , Genômica , Humanos
16.
Medicine (Baltimore) ; 96(4): e5951, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28121940

RESUMO

RATIONALE: Pseudoprogression, that is, initial tumor growth followed by subsequent tumor regression, has been well described for immunomodulation therapy in melanoma patients. This phenomenon is not well defined in lung cancer. Nivolumab, an anti-PD-1 monoclonal antibody, was recently approved for nonsmall cell lung cancer (NSCLC) as a second-line therapy. PATIENT CONCERNS AND DIAGNOSIS: We present a patient with squamous NSCLC, suffering from multiple bone and subcutaneous metastases. INTERVENTIONS: The patient was treated with nivolumab. OUTCOMES: A subcutaneous lesion in her upper back grew substantially after the first cycle of nivolumab, and later regressed, with marked improvement in all cancer sites. LESSONS: Such pseudoprogression may serve to predict subsequent clinical response.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Idoso , Neoplasias Ósseas/secundário , Carcinoma de Células Escamosas/secundário , Evolução Fatal , Feminino , Humanos , Neoplasias Pulmonares/patologia , Nivolumabe , Neoplasias de Tecidos Moles/secundário
17.
Clin Lung Cancer ; 18(4): e223-e232, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28082048

RESUMO

BACKGROUND: RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B-RET and CCDC6-RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET-rearranged LADC are still being delineated. MATERIALS AND METHODS: We present a series of 14 patients with RET-rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy. RESULTS: A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B-RET and CCDC6-RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B-RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6-RET and KIF5B-RET fusions showed pronounced and durable responses to platinum-based chemotherapy that lasted for 8 to 15 months. Two patients' tumors showed programmed cell death ligand 1-positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months. CONCLUSION: RET-rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anilidas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Platina/uso terapêutico , Piridinas/uso terapêutico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adulto , Idoso , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ret/genética , Análise de Sobrevida , Fatores de Transcrição/genética , Resultado do Tratamento
18.
J Thorac Oncol ; 12(2): 258-268, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27865871

RESUMO

INTRODUCTION: Targeted therapy significantly prolongs survival in lung adenocarcinoma. Current diagnostic guidelines include only EGFR and anaplastic lymphoma receptor tyrosine kinase gene (ALK) testing. Next-generation sequencing (NGS) reveals more actionable genomic alterations than do standard diagnostic methods. Data on the influence of hybrid capture (HC)-based NGS on treatment are limited, and we investigated its impact on treatment decisions and clinical outcomes. METHODS: This retrospective study included patients with advanced lung cancer on whom HC-based NGS was performed between November 2011 and October 2015. Demographic and clinicopathologic characteristics, treatments, and outcome data were collected. RESULTS: A total of 101 patients were included (median age 63 years [53% females, 45% never-smokers, and 85% with adenocarcinoma]). HC-based NGS was performed upfront and after EGFR/ALK testing yielded negative or inconclusive results in 15% and 85% of patients, respectively. In 51.5% of patients, HC-based NGS was performed before first-line therapy, and in 48.5%, it was performed after treatment failure. HC-based NGS identified clinically actionable genomic alterations in 50% of patients, most frequently in EGFR (18%), Ret proto-oncogene (RET) (9%), ALK (8%), Mesenchymal-epithelial transition factor (MET) receptor tyrosine kinase gene (6%), and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) (5%). In 15 patients, it identified EGFR/ALK aberrations after negative results of prior standard testing. Treatment strategy was changed for 43 patients (42.6%). The overall response rate in these patients was 65% (complete response 14.7%, partial response 50%). Median survival was not reached. Immunotherapy was administered in 33 patients, mostly without an actionable driver, with a presenting disease control rate of 32%, and with an association with tumor mutation burden. CONCLUSIONS: HC-based NGS influenced treatment decisions in close to half of the patients with lung adenocarcinoma and was associated with an overall response rate of 65%, which may translate into a survival benefit.


Assuntos
Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Sistemas de Apoio a Decisões Clínicas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Mutação , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sequência de DNA/métodos , Adulto Jovem
19.
Clin Lung Cancer ; 18(2): 156-161, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27913214

RESUMO

BACKGROUND: Patients with lung cancer are at increased risk for venous thromboembolism (VTE), particularly those receiving chemotherapy. It is estimated that 8% to 15% of patients with advanced non-small-cell lung cancer (NSCLC) experience a VTE in the course of their disease. The incidence in patients with specific molecular subtypes of NSCLC is unknown. We undertook this review to determine the incidence of VTE in patients with ALK (anaplastic lymphoma kinase)-rearranged NSCLC. PATIENTS AND METHODS: We identified all patients with ALK-rearranged NSCLC diagnosed and/or treated at the Princess Margaret Cancer Centre (PM CC) in Canada between July 2012 and January 2015. Retrospective data were extracted from electronic medical records. We then included a validation cohort comprising all consecutive patients with ALK-rearranged NSCLC treated in 2 tertiary centers in Israel. RESULTS: Within the PM CC cohort, of 55 patients with ALK-rearranged NSCLC, at a median follow-up of 22 months, 23 (42%) experienced VTE. Patients with VTE were more likely to be white (P = .006). The occurrence of VTE was associated with a trend toward worse prognosis (overall survival hazard ratio = 2.88, P = .059). Within the validation cohort (n = 43), the VTE rate was 28% at a median follow-up of 13 months. Combining the cohorts (n = 98), the VTE rate was 36%. Patients with VTE were younger (age 52 vs. 58 years, P = .04) and had a worse Eastern Cooperative Oncology Group performance status (P = .04). VTE was associated with shorter overall survival (hazard ratio = 5.71, P = .01). CONCLUSION: The rate of VTE in our ALK-rearranged cohort was 3- to 5-fold higher than previously reported for the general NSCLC population. This warrants confirmation in larger cohorts.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Receptores Proteína Tirosina Quinases/genética , Tromboembolia Venosa/epidemiologia , Adulto , Idoso , Quinase do Linfoma Anaplásico , Canadá/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prevalência , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Tromboembolia Venosa/genética
20.
Lung Cancer ; 98: 114-117, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27393516

RESUMO

Central nervous system (CNS) metastases occur in 30% of patients with advanced non-small cell lung cancer (NSCLC). Localized treatments targeting CNS metastases result in delays in systemic therapy administration and are associated with neurocognitive impairment. Nivolumab is an immune check-point inhibitor that is approved as a second-line treatment of NSCLC. Data regarding the intracranial activity of nivolumab is lacking. We retrospectively reviewed the efficacy and safety of nivolumab in five patients with advanced NSCLC and new/progressing intracranial metastases. Intracranial response was assessed by magnetic resonance imaging (MRI) using mRECIST v. 1.1 criteria. All patients had parenchymal brain metastases; two patients had leptomeningeal carcinomatosis diagnosed according to radiological criteria. All patients were asymptomatic and did not require corticosteroids or immediate local therapy. We observed one complete and one partial response in the brain. Stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved in one additional patient. Two patients progressed in the CNS. Time-to-response comprised 5 weeks and 9 weeks; both responses are still ongoing at the time of the report (24+ and 28+ weeks since start of treatment). Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS metastases-related grade≥3 adverse events were observed. Nivolumab might have intracranial activity and favorable safety profile in patients with CNS metastases secondary to NSCLC. Nivolumab CNS activity warrants further evaluation.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias Encefálicas/diagnóstico por imagem , Progressão da Doença , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Nivolumabe , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Resultado do Tratamento
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