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1.
BMJ Case Rep ; 14(1)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462020

RESUMO

A 49-year-old Asian Indian woman, with a previous history of biopsy proven stage IV primary lung adenocarcinoma with metastasis to liver, bones and central nervous system, presented with 1-month history of photopsia in right eye. She was on oral erlotinib since 6 months. Dilated fundus examination of right eye revealed a solitary dome-shaped brownish elevated lesion of approximately 1-disc diameter along the inferotemporal midperiphery with surrounding areas of hypopigmentation. Based on multimodal imaging, a diagnosis of resolved solitary unilateral choroidal metastasis from lung carcinoma in the right eye was made. In view of inactive and regressed choroidal metastasis, no intervention was mandated.


Assuntos
Adenocarcinoma/secundário , Antineoplásicos/uso terapêutico , Neoplasias da Coroide/secundário , Cloridrato de Erlotinib/uso terapêutico , Genes erbB-1 , Achados Incidentais , Neoplasias Pulmonares/patologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Sequência de Bases , Biomarcadores Tumorais/genética , Neoplasias da Coroide/diagnóstico , Neoplasias da Coroide/tratamento farmacológico , Neoplasias da Coroide/genética , Éxons , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Deleção de Sequência
2.
Anticancer Res ; 40(10): 5757-5764, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988903

RESUMO

BACKGROUND/AIM: To describe real clinical outcomes in patients with non-small cell lung cancer who have uncommon epidermal growth factor receptor (EGFR) mutations. MATERIALS AND METHODS: We performed a retrospective chart review from 15 medical institutes that cover a population of three million people from April 2008 to March 2019. RESULTS: There were 102 patients with uncommon EGFR mutation. Progression-free survival (PFS) tended to be longer in patients receiving afatinib compared with first-generation EGFR tyrosine kinase inhibitors. PFS in patients treated with afatinib or osimertinib was significantly longer than in patients treated with gefitinib or erlotinib (p=0.030). Multivariate analysis also revealed the contribution of afatinib or osimertinib to increased survival. In patients with exon 20 insertions, chemotherapy was efficacious. CONCLUSION: In treating patients with uncommon EGFR mutations, our results indicate longer-term survival might be achieved with second-generation or later TKIs and cytotoxic chemotherapeutic drugs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/uso terapêutico , Adulto , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão
3.
J Cancer Res Ther ; 16(4): 950-954, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930150

RESUMO

Despite recent advances in treatment with multidrug chemotherapy regimens, outcomes of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain very poor. Treatment with targeted therapies has shown marginal benefits due to intrinsic or acquired resistance. Actionable mutations, while detected infrequently in patients with PDAC, are becoming increasingly used in personalized medicine. Here, we describe an epidermal growth factor receptor (EGFR)-activating mutation (E746_T751>VP) to erlotinib, a first-generation tyrosine kinase inhibitor (TKI), in a patient with metastatic PDAC. After an initial partial response to erlotinib for 12 months, the patient's disease progressed with emergence of the EGFR A647T mutation. Certainly, the patient also progressed after switching therapy to a third-generation EGFR TKI (osimertinib). This case illustrates the posttreatment evolution of EGFR A647T-mediated resistance to the first- and third-generation TKIs. To our knowledge, this is the first case to report the aforementioned activating and resistance-mediated mutations. In summary, genomic analysis performed in this patient with PDAC on the tumor biopsy and peripheral blood provided tools to understand mechanisms of response and resistance to targeted therapy with EFGR TKIs.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico
4.
PLoS One ; 15(8): e0237790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810185

RESUMO

This study determined the frequency and factors associated with EGFR testing rates and erlotinib treatment as well as associated survival outcomes in patients with non small cell lung cancer in Kentucky. Data from the Kentucky Cancer Registry (KCR) linked with health claims from Medicaid, Medicare and private insurance groups were evaluated. EGFR testing and erlotinib prescribing were identified using ICD-9 procedure codes and national drug codes in claims, respectively. Logistic regression analysis was performed to determine factors associated with EGFR testing and erlotinib prescribing. Cox-regression analysis was performed to determine factors associated with survival. EGFR mutation testing rates rose from 0.1% to 10.6% over the evaluated period while erlotinib use ranged from 3.4% to 5.4%. Factors associated with no EGFR testing were older age, male gender, enrollment in Medicaid or Medicare, smoking, and geographic region. Factors associated with not receiving erlotinib included older age, male gender, enrollment in Medicare or Medicaid, and living in moderate to high poverty. Survival analysis demonstrated EGFR testing or erlotinib use was associated with a higher likelihood of survival. EGFR testing and erlotinib prescribing were slow to be implemented in our predominantly rural state. While population-level factors likely contributed, patient factors, including geographic location (areas with high poverty rates and rural regions) and insurance type, were associated with lack of use, highlighting rural disparities in the implementation of cancer precision medicine.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Testes Genéticos/estatística & dados numéricos , Neoplasias Pulmonares/tratamento farmacológico , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Análise Mutacional de DNA/economia , Análise Mutacional de DNA/estatística & dados numéricos , Prescrições de Medicamentos/economia , Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/economia , Uso de Medicamentos/estatística & dados numéricos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Testes Genéticos/economia , Disparidades em Assistência à Saúde/economia , Humanos , Kentucky/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Medicaid/economia , Medicaid/estatística & dados numéricos , Medicare/economia , Medicare/estatística & dados numéricos , Pessoa de Meia-Idade , Mutação , Pobreza/estatística & dados numéricos , Medicina de Precisão/economia , Medicina de Precisão/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Fatores Sexuais , Análise de Sobrevida , Estados Unidos , Adulto Jovem
5.
PLoS One ; 15(7): e0234818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32663210

RESUMO

BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors used to treat EGFR mutation positive non-small-cell lung cancer (NSCLC). Skin rash and diarrhea are well-known and common adverse events in patients receiving erlotinib, whereas other adverse events, including eye, liver, or renal disorders have not been evaluated adequately. This meta-analysis aimed to evaluate the ocular, hepatobiliary, and renal toxicities of erlotinib in patients with NSCLC cancers. METHODS: In total, sixty studies were assessed, and the results of the included studies were quantitatively integrated using meta-analysis. The incidence of ocular, hepatobiliary (alanine aminotransferase [ALT] and bilirubin elevations; other hepatic adverse events), and renal adverse events were estimated. Additionally, the erlotinib-treated groups and the control groups (placebo or other treatment) were compared with respect to ocular disorders and ALT elevation. The study protocol has been registered in the International Prospective Register for Systematic Reviews (PROSPERO) CRD42018093758. RESULTS: The overall incidence of ocular disorders was 3.30% (95% confidence interval [CI] 2.20%-5.00%). The incidence of ALT elevation, bilirubin elevation, and other hepatobiliary disorders was 6.40% (95% CI 3.90%-10.4%), 3.80% (95% CI 2.30%-6.10%), and 1.00% (95% 0.60%-1.80%), respectively. The incidence of renal disorder was 3.10% (95% CI 1.90%-5.00%). The risk of ocular toxicity in the erlotinib treatment group was significantly increased (risk ratio = 2.91; 95% CI 1.70-4.98) compared to that in the control group. ALT elevation was not significantly different between the two groups. CONCLUSION: Based on the results, careful monitoring of ocular toxicity in patients receiving erlotinib should be recommended and closer monitoring of hepatic toxicity should be also recommended in patients with liver-related risk factors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Cloridrato de Erlotinib/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Sistema Digestório/etiologia , Intervalo Livre de Doença , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Exantema/etiologia , Olho/efeitos dos fármacos , Oftalmopatias/etiologia , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Nefropatias/etiologia , Neoplasias Pulmonares/genética , Masculino , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
6.
Medicine (Baltimore) ; 99(23): e20510, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32501998

RESUMO

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is the primary treatment option for patients with non-small cell lung cancer (NSCLC). However, one of the major adverse effects associated with this therapy is skin toxicity, which impacts the patient's quality of life. This study aimed to describe the severities and locations of skin toxicity, and to analyze their association with the quality of life in patients with advanced NSCLC who received EGFR-TKI therapy as first-line treatment.This cross-sectional and correlation study was conducted at a tertiary medical center in northern Taiwan between July 2015 and March 2016. Skin toxicity was assessed and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). The Skindex-16 scale was used to measure the skin disease-related quality of life.A total of 146 NSCLC patients who received EGFR-TKI therapy within the first 3 months of diagnosis were included in this study; 93.2% of these patients experienced skin toxicities. Approximately 70% of the patients developed xerosis and pruritus, while 50% had papulopustular eruptions and paronychia. The mean skin symptom impact score was 5.38 (standard deviation = 2.65). The skin-related quality of life varied widely among the participants but remained acceptable (mean score = 13.96, standard deviation = 16.55). Skin symptoms correlated significantly with poor quality of life (r = 0.50, P < .001). Younger patients and those treated with afatinib were the most affected, reporting the poorest quality of life. Patients who required EGFR-TKI dose reduction had experienced more severe skin symptoms than had patients who did not require it (7.35 vs 5.01, P < .001).Skin toxicity related to EGFR-TKI treatment impacts the quality of life in patients with NSCLC. During the treatment period, skin assessment and tailored management should be incorporated into the daily care plan.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/normas , Pele/efeitos dos fármacos , Afatinib/efeitos adversos , Afatinib/normas , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/psicologia , Correlação de Dados , Estudos Transversais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/psicologia , Cloridrato de Erlotinib/efeitos adversos , Cloridrato de Erlotinib/normas , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/efeitos adversos , Gefitinibe/normas , Gefitinibe/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Qualidade de Vida/psicologia , Pele/fisiopatologia , Inquéritos e Questionários , Taiwan/epidemiologia
7.
J Cancer Res Ther ; 16(1): 132-138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362623

RESUMO

Context: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are considered to be effective treatments for advanced NSCLC patients with sensitizing EGFR mutations. There are many complex and rare mutations in the EGFR gene. The efficacy of the first-generation EGFR-TKI (erlotinib) is unknown for tumors harboring rare EGFR mutations. Aims: The purpose of this study was to investigate the clinical significance of rare EGFR mutations in EGFR-TKI-naive patients and the efficacy of erlotinib. Settings and Design: Istanbul University, Istanbul Medical Faculty, Department of Medical Oncology, Istanbul/Turkey, and retrospective observational study. Subjects and Methods: We retrospectively analyzed 117 non-small cell lung cancer (NSCLC) patients with EGFR mutations who had not previously used EGFR-TKIs. Exons 18-21 of EGFR were analyzed by polymerase chain reaction and subjected to direct sequencing methods. Statistical Analysis Used: Survival estimates were calculated by the Kaplan-Meier method using SPSS 25 software (IBM SPSS, Chicago, USA). Results: Of 117 patients who had EGFR mutations, 23 patients had rare and complex EGFR mutations. Only 9 of them were treated with erlotinib. Three patients (3.5%) with exon 20 mutations received erlotinib. Two with EGFR-p. Q787Q (SNP ID, rs10251977; c.2361G>A) synonymous mutation in exon 20 were responsive to erlotinib therapy in the second-line setting after first-line chemotherapy. To the best of our knowledge, the present two cases are the first to be reported with lung adenocarcinoma with EGFR-p. Q787Q synonymous mutation responding to erlotinib. Conclusion: NSCLC patients harboring rare EGFR mutations generally did not show consistent or favorable responses to EGFR-TKI. We suggest that this rare synonymous mutation (EGFR-p. Q787Q) is a sensitive EGFR mutation in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/patologia , Mutação , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Turquia
8.
Clin Exp Metastasis ; 37(3): 391-399, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32356218

RESUMO

Brain metastases (BMs) are frequently occurred in lung adenocarcinoma with driver mutation. There is a need to explore multi-discipline treatments and prognostic factors in those patients with most frequent driver mutations: EGFR mutation and ALK fusion. In the retrospective study, different therapies and prognostic factors were compared between EGFR and ALK-driven lung adenocarcinoma with BMs. 516 patients with EGFR mutation and 76 with ALK fusion were screened for this study, 303 (58.7%) and 34 (44.7%) had BM respectively. In multivariate analyses, the pretreatment factors including delayed BMs and asymptomatic BMs, treatment strategies including the first-generation tyrosine kinase inhibitor (TKI) and cranial radiotherapy (RT) treatment, were associated with much better OS in EGFR mutation patients. Moreover, we found EGFR-mutation patients receiving erlotinib would achieve better survival than those receiving gefitinib (P = 0.032). However, BM patients with ALK fusion treated by only the first generation TKI (HR = 0.23, P = 0.036) or cranial RT (HR = 0.12, P = 0.003), had better OS. After balancing of baseline characteristics of the two groups, there was no significant difference in the survival between BM patients with EGFR mutation and ALK fusion. And only cranial RT was associated with better survival in those patients (HR = 0.52, P < 0.001). In the BM patients of lung adenocarcinoma with driver mutation, TKI underlie the therapy strategies, but cranial RT still plays an important role while receiving the first generation TKI.


Assuntos
Adenocarcinoma de Pulmão/terapia , Neoplasias Encefálicas/terapia , Irradiação Craniana , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Quimiorradioterapia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Estudos Retrospectivos , Adulto Jovem
9.
PLoS One ; 15(4): e0231413, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32267879

RESUMO

INTRODUCTION: Comparison of the effectiveness and cost-effectiveness of three first-line EGFR-tyrosine kinase inhibitors (TKIs) would improve patients' clinical benefits and save costs. Using real-world data, this study attempted to directly compare the effectiveness and cost-effectiveness of first-line afatinib, erlotinib, and gefitinib. METHODS: During May 2011-December 2017, all patients with non-small cell lung cancer (NSCLC) visiting a tertiary center were invited to fill out the EuroQol five-dimension (EQ-5D) questionnaires and World Health Organization Quality of Life, brief version (WHOQOL-BREF), and received follow-ups for survival and direct medical costs. A total of 379 patients with EGFR mutation-positive advanced NSCLC under first-line TKIs were enrolled for analysis. After propensity score matching for the patients receiving afatinib (n = 48), erlotinib (n = 48), and gefitinib (n = 96), we conducted the study from the payers' perspective with a lifelong time horizon. RESULTS: Patients receiving afatinib had the worst lifetime psychometric scores, whereas the differences in quality-adjusted life expectancy (QALE) were modest. Considering 3 treatments together, afatinib was dominated by erlotinib. Erlotinib had an incremental cost-effectiveness of US$17,960/life year and US$12,782/QALY compared with gefitinib. Acceptability curves showed that erlotinib had 58.6% and 78.9% probabilities of being cost-effective given a threshold of 1 Taiwanese per capita GDP per life year and QALY, respectively. CONCLUSION: Erlotinib appeared to be cost-effective. Lifetime psychometric scores may provide additional information for effectiveness evaluation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Análise Custo-Benefício , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Afatinib/uso terapêutico , Idoso , Carcinoma Pulmonar de Células não Pequenas/economia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Expectativa de Vida , Neoplasias Pulmonares/economia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pontuação de Propensão , Qualidade de Vida , Taxa de Sobrevida , Taiwan , Centros de Atenção Terciária
10.
JAMA Netw Open ; 3(3): e200452, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32134464

RESUMO

Importance: The Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database may provide insights into the comparative effectiveness of oncological treatments for elderly individuals who are underrepresented in clinical trials. Objective: To evaluate the suitability of SEER-Medicare data for assessing the effectiveness of adding a drug to an existing treatment regimen on the overall survival of elderly patients with cancer. Design, Setting, and Participants: This comparative effectiveness study analyzed SEER-Medicare data from 9549 individuals who received a new diagnosis of stage II colorectal cancer (2008-2012) and 940 patients who received a new diagnosis of advanced pancreatic adenocarcinoma (2007-2012), with follow-up to December 31, 2013 (SEER-Medicare data released in 2015). Two (hypothetical) target trials were designed and emulated based on 2 existing randomized clinical trials: (1) adjuvant fluorouracil after curative surgery for individuals with stage II colorectal cancer and (2) erlotinib added to gemcitabine for individuals with advanced pancreatic adenocarcinoma. Data were analyzed January 2018 to March 2019. Exposures: The following treatment strategies were compared: (1) fluorouracil initiation vs no initiation within 3 months of tumor resection and (2) erlotinib initiation vs no initiation within 12 weeks of gemcitabine initiation. Main Outcomes and Measures: All-cause mortality within 60 months of baseline for the fluorouracil trial and within 72 weeks for the erlotinib trial. Results: Compared with 3293 individuals in the existing fluorouracil trial, 9549 eligible individuals included in the present analyses were more likely to have colon cancer (8565 [90%] vs 2291 [71%]) and were older (median [interquartile range], 79 [73-84] vs 63 [56-68] years). The 5-year risk difference for initiation vs noninitiation of fluorouracil after surgery was -3.8% (95% CI, -14.8% to 12.6%), and the mortality hazard ratio (HR) was 0.95 (95% CI, 0.85-1.04). Compared with 569 individuals in the existing erlotinib trial, 940 eligible patients included in the present analysis were older (median [range], 74 [66-93] vs 64 [36-92] years) and more likely to be male (547 [58%] vs 298 [52%]). The 1-year risk difference for initiation vs noninitiation of erlotinib was 4.7% (95% CI, -9.4% to 18.0%), and the corresponding mortality HR was 1.04 (95% CI, 0.86-1.42). In naive analyses, the mortality HR estimate was 1.14 (95% CI, 0.95-1.36) for the fluorouracil emulation and 0.68 (95% CI, 0.54-0.87) for the erlotinib emulation. Conclusions and Relevance: The present estimates were similar to those from randomized clinical trials that studied adding the same cancer drugs to existing regimens. The published HR was 1.02 (95% CI, 0.70-1.48) in the fluorouracil trial for individuals aged 70 or older and 0.96 (95% CI, 0.74-1.24) in the erlotinib trial for individuals aged 65 years or older. The SEER-Medicare database may be adequate for studying the real-world effectiveness of adding a drug to treatment regimens used for elderly individuals with cancer.


Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Neoplasias do Colo/mortalidade , Neoplasias do Colo/terapia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias do Colo/patologia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , Fluoruracila/uso terapêutico , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Programa de SEER , Taxa de Sobrevida , Estados Unidos
11.
Z Gastroenterol ; 58(4): 332-340, 2020 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-32052394

RESUMO

Metastatic pancreatic cancer has the worst prognosis of all cancers. With nab-Paclitaxel/gemcitabine, FOLFIRINOX, and gemcitabine/erlotinib, several treatment options are available which improve the patient's overall survival. Especially for patients who develop rash under erlotinib treatment can benefit from gemcitabine/erlotinib combination therapy. This non-interventional study (NIS ML21284) investigated the effectiveness and tolerability of gemcitabine/erlotinib therapy in the treatment routine of metastatic pancreatic cancer, in particular, in the context of the occurrence of a rash.Between 2007 and 2010, the treatment data of 433 patients in 98 centres were documented. All parameters recorded were assessed descriptively.Treatment with gemcitabine/erlotinib resulted in both a significant increased median overall survival of the patient subgroup with rash grade ≥ 1 (9.90; 95 % confidence interval [CI], 8.19 to 11.05 vs. 6.48 months; 95 % CI, 5.66 to 7.40, p = 0.0010) and median progression-free survival (5.43, 95 % CI, 4.90 to 6.12 vs. 3.98 months, 95 % CI, 3.52 to 5.03, p = 0.0131). The overall response rate of patients treated with gemcitabine/erlotinib, who had developed rash grade ≥ 1, was 5.9 % higher compared to patients without rash (31.7 % vs. 25.8 %).In conclusion, these results from the daily treatment routine of metastatic pancreatic cancer underline the importance of combined gemcitabine/erlotinib therapy for a subgroup of patients who develop a rash in the course of erlotinib treatment.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina/uso terapêutico , Humanos , Resultado do Tratamento
12.
J Med Econ ; 23(1): 48-53, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31314630

RESUMO

Aims: To assess healthcare resource utilization (HCRU) and costs in patients with non-small cell lung cancer treated with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors afatinib or erlotinib as first-line treatment.Materials and methods: This retrospective analysis used data from three large administrative claims databases in the US: Truven MarketScan, IMS PharMetrics Plus, and Optum Clinformatics Data Mart. Patients with diagnosis codes of lung cancer treated with afatinib or erlotinib were included in the sample. Treatment cohorts were matched on baseline characteristics using propensity scores to account for potential selection bias. HCRU and healthcare costs were compared between the matched afatinib and erlotinib cohorts.Results: In total, 3,152 patients met the study inclusion criteria; propensity score matching of the afatinib and erlotinib patients yielded 525 matched pairs with well-balanced baseline characteristics. The afatinib cohort had significantly fewer patients with ≥1 inpatient visits (40.4% vs 52.2%, p = 0.0001) and outpatient emergency room (ER) visits (45.7% vs 54.1%, p = 0.0066). Per patient per month (PPPM) visits were significantly different between afatinib compared to erlotinib for inpatient visits (0.1 vs 0.2, p = 0.0152), other outpatient visits PPPM (2.6 vs 3.0, p = 0.022) and outpatient office visits (2.0 vs 1.7, p = 0.0059). Although costs of outpatient office ($1,624 vs $1,070; p = 0.0086) and pharmacy ($6,709 vs $5,932; p < 0.0001) visits were higher for afatinib vs erlotinib, total costs did not differ significantly between cohorts ($14,972 vs $14,412; p = 0.4415).Limitations: Retrospective claims data can be subject to coding errors or data omissions; patients were required to have continuous health plan enrolment; EGFR mutation status was not confirmed.Conclusions: Patients treated with afatinib as first-line monotherapy experienced fewer inpatient stays and ER visits compared with erlotinib. Total costs were not significantly different between the two treatment cohorts.


Assuntos
Afatinib/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Afatinib/economia , Idoso , Receptores ErbB/genética , Cloridrato de Erlotinib/economia , Feminino , Gastos em Saúde/estatística & dados numéricos , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Humanos , Revisão da Utilização de Seguros , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/economia , Estudos Retrospectivos , Estados Unidos , Adulto Jovem
13.
N Engl J Med ; 382(1): 41-50, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31751012

RESUMO

BACKGROUND: Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported. METHODS: In this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib (80 mg once daily) or one of two other EGFR-TKIs (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily, with patients receiving these drugs combined in a single comparator group). Overall survival was a secondary end point. RESULTS: The median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group. CONCLUSIONS: Among patients with previously untreated advanced NSCLC with an EGFR mutation, those who received osimertinib had longer overall survival than those who received a comparator EGFR-TKI. The safety profile for osimertinib was similar to that of the comparator EGFR-TKIs, despite a longer duration of exposure in the osimertinib group. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.).


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/efeitos adversos , Idoso , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Método Duplo-Cego , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/efeitos adversos
14.
Cancer Res ; 80(4): 709-718, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31806641

RESUMO

The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting mTOR as a robust target for therapy. Inhibitors of mTOR have had limited success clinically, however, in part because their mechanism of action is cytostatic rather than cytotoxic. Here, we tested three distinct mTOR kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation of glioblastoma cells, whereas PP242 uniquely induced apoptosis. Apoptosis induced by PP242 resulted from off-target cooperative inhibition of JAK2 and protein kinase C alpha (PKCα). Induction of apoptosis was also decreased by additional on-target inhibition of mTOR, due to induction of autophagy. As EGFR inhibitors can block PKCα, EGFR inhibitors erlotinib and osimertinib were tested separately in combination with the JAK2 inhibitor AZD1480. Combination therapy induced apoptosis of glioblastoma tumors in both flank and in patient-derived orthotopic xenograft models, providing a preclinical rationale to test analogous combinations in patients. SIGNIFICANCE: These findings identify PKCα and JAK2 as targets that drive apoptosis in glioblastoma, potentially representing a clinically translatable approach for glioblastoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Feminino , Glioblastoma/patologia , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Camundongos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Proteína Quinase C-alfa/antagonistas & inibidores , Proteína Quinase C-alfa/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Oncogene ; 39(10): 2140-2155, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31819169

RESUMO

Endocytosis is an essential component of cell motility, which facilitates the malignant behavior of cancer. Sorting nexin (SNX) family members are associated with tumor progression. However, the role and mechanism of SNX5 in hepatocellular carcinoma (HCC) progression remain largely unknown. In this study, we investigated the clinical significance and possible involvement of SNX5 in the progression of HCC. Here, we showed that SNX5 was upregulated in tumors compared with adjacent nontumorous tissues in HCC patients. The upregulation of SNX5 in HCC was associated with vascular invasion, intrahepatic metastasis, and poor prognosis. The overexpression of SNX5 promoted HCC cell proliferation, migration, invasion, and metastasis, whereas silencing SNX5 expression resulted in decreased cell proliferation, migration, and invasion. Knockdown of SNX5 significantly inhibited HCC cell proliferation by inducing G1/S transition arrest. Mechanistically, we demonstrated that SNX5 promoted cell proliferation, migration, and invasion via the activation of the EGFR-ERK1/2 pathway by blocking EGF-mediated EGFR internalization. We found that SNX5 interacted with EGFR in HCC cells. Moreover, SNX5-induced cell proliferation, migration, and invasion were partially reversed by the knockdown of EGFR or by ERK1/2 inhibitors. In addition, we demonstrated that SNX5 knockdown sensitized HCC cells to tyrosine kinase inhibitors, including erlotinib and sorafenib. Taken together, our results indicate that SNX5 promotes HCC cell proliferation and metastasis via inhibiting the endocytosis and degradation of EGFR, thereby activating the ERK1/2 signaling pathway. Our work also suggests that SNX5 is a potential therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Sistema de Sinalização das MAP Quinases , Inibidores de Proteínas Quinases/uso terapêutico , Nexinas de Classificação/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/fisiopatologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Nexinas de Classificação/metabolismo
16.
Pancreatology ; 20(1): 101-109, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31787526

RESUMO

BACKGROUND/OBJECTIVES: Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients. METHODS: Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers. RESULTS: Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2-7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels. CONCLUSIONS: Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.


Assuntos
Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Eur J Cancer ; 125: 49-57, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31838405

RESUMO

BACKGROUND: In the FLAURA trial, osimertinib demonstrated superior progression-free survival and a favorable toxicity profile to erlotinib or gefitinib as initial therapy in patients with EGFR-mutated advanced non-small-cell lung cancer. Patient-reported outcomes from FLAURA are discussed here. METHODS: Patients (N = 556) completed the EORTC QLQ-LC13 weekly for 6 weeks, then every 3 weeks, and the QLQ-C30 every 6 weeks. Prespecified key symptoms were cough, dyspnea, chest pain, appetite loss, and fatigue. Score changes from baseline to randomized treatment discontinuation were assessed using a mixed-effects model. A ≥10-point change was considered clinically relevant. Odds of improvement and time to deterioration were investigated. QLQ-C30 functioning scores were assessed post hoc. RESULTS: Questionnaire completion rates were >70% at most time points. Baseline mean scores were similar in the osimertinib and erlotinib/gefitinib arms. Scores improved in both arms, but none reached clinical relevance at 5% significance level. A statistically significant difference favoring osimertinib for chest pain was not clinically relevant (-6.84 vs -3.88; p = 0.021). Odds of improvement and time to deterioration were similar between treatments. In post hoc analyses, improvements favored osimertinib for emotional functioning (8.79 vs 4.91; p = 0.004) and social functioning (7.66 vs 1.74; p < 0.001). Cognitive functioning remained stable with osimertinib but deteriorated with erlotinib/gefitinib (0.03 vs -3.91; p = 0.005). CONCLUSIONS: Key symptoms improved from baseline in both treatment arms in FLAURA. Key symptom improvements that were both statistically significant and clinically relevant were not observed in favor of either treatment arm. CLINICAL TRIAL REGISTRATION: NCT02296125.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Cloridrato de Erlotinib/farmacologia , Feminino , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/patologia , Masculino
18.
Cancer ; 126(6): 1339-1350, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31821539

RESUMO

BACKGROUND: Osimertinib (AZD9291), a third-generation, mutation-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), is an approved drug for patients who have non-small cell lung cancer (NSCLC) with activating EGFR mutations or those harboring a resistant T790M mutation. Unfortunately, all patients eventually relapse and develop resistance to osimertinib. The current study addressed whether ERK inhibition exerts effects similar to those produced by MEK inhibition in overcoming acquired resistance to osimertinib. METHODS: Drug effects on cell and tumor growth were assessed by measuring cell number alterations and colony formation in vitro and with xenografts in nude mice in vivo. Apoptosis was assessed with annexin V/flow cytometry and protein cleavage. Protein alterations in cells were detected with Western blot analysis. Gene overexpression and knockout were achieved with lentiviral infection and CRISPR/Cas9, respectively. RESULTS: The combination of osimertinib with an ERK inhibitor synergistically decreased the survival of osimertinib-resistant cell lines with enhanced induction of apoptosis and effectively inhibited the growth of osimertinib-resistant xenografts in nude mice. Moreover, the combination of an MEK or ERK inhibitor with a first-generation (eg, erlotinib) or second-generation (eg, afatinib) EGFR-TKI also very effectively inhibited the growth of osimertinib-resistant cells in vitro and of tumors in vivo, although these cell lines were cross-resistant to first-generation or second-generation EGFR-TKIs. CONCLUSIONS: The current findings emphasize the importance of targeting MEK/ERK signaling in maintaining the long-term benefit of osimertinib through overcoming acquired resistance to osimertinib, warranting further investigation of this therapeutic strategy to improve the therapeutic efficacy of osimertinib in the clinic.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Afatinib/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Quimioterapia Combinada , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/uso terapêutico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Nus , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Sci Rep ; 9(1): 18793, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31827134

RESUMO

Epidermal growth factor receptor (EGFR) targeted therapies have shown limited efficacy in head and neck squamous cell carcinoma (HNSCC) patients despite its overexpression. Identifying molecular mechanisms associated with acquired resistance to EGFR-TKIs such as erlotinib remains an unmet need and a therapeutic challenge. In this study, we employed an integrated multi-omics approach to delineate mechanisms associated with acquired resistance to erlotinib by carrying out whole exome sequencing, quantitative proteomic and phosphoproteomic profiling. We observed amplification of several genes including AXL kinase and transcription factor YAP1 resulting in protein overexpression. We also observed expression of constitutively active mutant MAP2K1 (p.K57E) in erlotinib resistant SCC-R cells. An integrated analysis of genomic, proteomic and phosphoproteomic data revealed alterations in MAPK pathway and its downstream targets in SCC-R cells. We demonstrate that erlotinib-resistant cells are sensitive to MAPK pathway inhibition. This study revealed multiple genetic, proteomic and phosphoproteomic alterations associated with erlotinib resistant SCC-R cells. Our data indicates that therapeutic targeting of MAPK pathway is an effective strategy for treating erlotinib-resistant HNSCC tumors.


Assuntos
Antineoplásicos/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , MAP Quinase Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal , Genômica , Humanos , Redes e Vias Metabólicas , Fenótipo , Proteômica , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , Sequenciamento Completo do Genoma
20.
Math Biosci Eng ; 16(6): 7921-7933, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31698647

RESUMO

Background: An increasing number of patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and develop progressive disease after receiving conventional treatments. In recent years, several novel therapies have been approved for later lines of therapy of previously treated NSCLC. Erlotinib, an EGFR tyrosine kinase inhibitor, was recommended as the second-line therapy for pre-treated patients. However, the use of erlotinib has been reported to represent different clinical effects and adverse effects. Objectives: The current study was aim to investigate the efficacy and safety of erlotinib versus chemotherapy in pre-treated patients with advanced NSCLC. Methods: Electronic databases were searched for eligible literatures updated on June 2018. Randomized-controlled trials assessing the efficacy and safety of erlotinib in pre-treated NSCLC were included, of which the main outcomes were ORR (objective response rate), PFS (progression-free survival), OS (overall survival) and AEs (adverse events). All the data were pooled with the corresponding 95% confidence interval using RevMan software. Sensitivity analyses and heterogeneity were quantitatively evaluated. Results: A total of 11 randomized controlled trials were included in this analysis. The group of erlotinib did not achieved benefit in progression-free survival (OR = 0.61, 95%CI = 0.33-1.12, P = 0.11), overall survival (OR = 0.98, 95%CI = 0.84-1.15, P = 0.81) as well with the objective response rate (OR = 0.77, 95%CI = 0.36-1.63, P = 0.49), respectively. In the results of subgroup analysis among the patients with EGFR wild-type, there is also no significant differences in overall survival with erlotinib (OR = 0.90, 95%CI = 0.78-1.04, P = 0.15) and progression-free survival (OR = 0.33, 95%CI = 0.09-1.18, P = 0.09). The most common treatment-related adverse events in the erlotinib group is rash (OR = 5.79, 95%CI = 2.12-15.77, P = 0.0006), and neutropenia (OR = 0.02, 95%CI = 0.01-0.10, P ≤ 0.00001) is more found in the control group. In addition, fatigue (P = 0.09) and diarrhea (P = 0.52), the difference between the two groups had no statistical significance. Conclusions: There was no significant difference noted with regard to efficacy and safety between erlotinib vs. chemotherapy as the later-line therapy for previously treated patients with NSCLC, even with subgroup patients who have wild-type EGFR tumors. While, erlotinib might increase the risk of rash, and decrease the risk of neutropenia, compared with the chemotherapy. Further research is needed to develop a database of all EGFR mutations and their individual impact on the differing treatments.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptores ErbB/genética , Cloridrato de Erlotinib/efeitos adversos , Exantema/induzido quimicamente , Humanos , Mutação , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Razão de Chances , Segurança do Paciente , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico
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