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Health disparities present a barrier to successful oncology treatment. The potential for precision oncology to reduce health disparities has not previously been analyzed. We performed a retrospective analysis of 12,627 patients from six major cancer centers whose tumors underwent genomic testing at Caris Life Sciences between 2010-2020. Kaplan-Meier and Cox regression were used to describe and analyze overall survival (OS). Molecular and demographic features of the cohort were analyzed by Chi-square and analysis of variance (ANOVA) tests. Black patients composed 25% of the cohort and White patients 63%. Among this molecularly-tested cohort, there were minimal outcome differences based on race, geographic location, or poverty level. When analyzing the interaction of age, race, and sex, racial-based disparities were noted primarily for young non-White women in the study cohort, but were more pronounced for men and women of all ages in the broader patient population within the SEER database. Mutations in five genes-APC, EGFR, STK11, TP53, and KRAS-were found to affect OS among our cohort and their prevalence varied by race in specific tumor types. Real-world outcomes data in mutation-defined cohorts also provided additional context to previously reported therapeutic response trends. Our study shows that patients who undergo molecular testing display reduced racial health disparities compared to the general population, while persistent racial disparities are influenced by age and sex. Genomic-driven racial disparities should be examined at a tumor lineage-specific level. Increased access to molecular testing for all eligible patients may play a role in improving health equity.
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BACKGROUND: Pembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe the landscape of frameshift mutations (FSs) and evaluated their role as a predictive biomarker to ICI in a clinical cohort of patients. METHODS: Comprehensive genomic profiling was performed on a cohort of solid tumor samples examining at least 324 genes. The clinical cohort included patients with metastatic solid malignancies who received ICI monotherapy and had tumor sequencing. Progression-free survival (PFS), overall survival, and objective response rates (ORR) were compared between the groups. RESULTS: We analyzed 246,252 microsatellite stable (MSS) and 4561 samples with microsatellite instability across solid tumors. Histologies were divided into groups according to TMB and FS. MSS distribution: TMB-L (<10 mut/Mb)/FS-A (absent FS) (N=111,065, 45%), TMB-H (≥10 mut/Mb)/FS-A (N=15,313, 6%), TMB-L/FS-P (present ≥1 FS) (N=98,389, 40%) and TMB-H/FS-P (N=21,485, 9%). FSs were predominantly identified in the p53 pathway. In the clinical cohort, 212 patients were included. Groups: TMB-L/FS-A (N=80, 38%), TMB-H/FS-A (N=36, 17%), TMB-L/FS-P (N=57, 27%), TMB-H/FS-P (N=39, 18%). FSs were associated with a higher ORR to ICI, 23.8% vs 12.8% (p=0.02). TMB-L/FS-P had superior median PFS (5.1 months) vs TMB-L/FS-A (3.6 months, p<0.01). The 12-month PFS probability was 34% for TMB-L/FS-P vs 17.1% for TMB-L/FS-A. CONCLUSIONS: FSs are found in 47% of patients with MSS/TMB-L solid tumors in a pan-cancer cohort. FS may complement TMB in predicting immunotherapy responses, particularly for tumors with low TMB.
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Segunda Neoplasia Primária , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Mutação da Fase de Leitura , Neoplasias/tratamento farmacológico , Neoplasias/genética , ImunoterapiaRESUMO
Current first-line standard therapy for metastatic non-small cell lung cancer without driver mutations involves chemotherapy and immunotherapy combination. Prior to the advent of immune checkpoint inhibition, REVEL, a randomized phase III trial demonstrated improved progression-free and overall survival with ramucirumab and docetaxel (ram+doc) in patients who failed platinum-based first-line therapy. Long-term outcomes related to second-line ramucirumab and docetaxel after first-line immunotherapy exposure remain unknown. We analyzed outcomes for 35 patients from our center whom received ramucirumab and docetaxel following disease progression on chemotherapy and immunotherapy combination. Median progression-free survival among patients who received ram+doc after exposure to immunotherapy was 6.6 months (95% CI = 5.5 to 14.9 months; p<0.0001), and median overall survival was 20.9 months (95% CI = 13.4 months to infinity; p<0.0001). These outcomes suggest that there may a synergistic benefit to combining chemotherapy with anti-angiogenic therapy after immunotherapy exposure. Future analyses should be evaluated prospectively and among a larger patient subset.
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OBJECTIVE: Human epidermal growth factor receptor 2 (HER2) overexpression occurs in up to 30% of breast cancer cases. Ado-trastuzumab emtansine (T-DM1) is approved to treat residual HER2-positive breast cancer after neoadjuvant therapy. The aim of this study was to determine the quality-adjusted time with symptoms or toxicity and without symptoms or toxicity (Q-TWiST) of T-DM1 compared to trastuzumab for residual invasive HER2-positive breast cancer. METHODS: The authors developed an analytical model extracting individual patient data and estimated invasive disease-free survival and overall survival over a 30-year time horizon. Only direct costs from adjuvant treatment were considered as well as relapse treatment from Brazilian and American payer perspectives. Heart events were considered for utility and cost analysis. RESULTS: The 30-year projection utilizing the Weibull method estimated a mean invasive disease-free survival of 16.4 years for T-DM1 and 10.4 for Trastuzumab, in addition to a mean overall survival of 18.1 and 15.4 years, respectively. We determined a Q-TWiST gain of 3,812 years for the T-DM1 arm when compared to trastuzumab and an Incremental cost-effectiveness ratio per Q-TWiST of US$ 11,467.65 in the United States and US$ 3,332.73 in Brazil. CONCLUSION: Ado-trastuzumab emtansine is cost-effective from both Brazilian and American perspectives.
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Neoplasias da Mama , Ado-Trastuzumab Emtansina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Análise Custo-Benefício , Feminino , Humanos , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Receptor ErbB-2/uso terapêutico , Trastuzumab/uso terapêutico , Estados UnidosRESUMO
Aim: This analysis aimed to evaluate the cost-effectiveness of pembrolizumab monotherapy as first-line treatment in advanced non-small-cell lung cancer patients with a programmed death ligand 1 (PD-L1) tumor proportion score ≥1% from a US payer perspective. Materials & methods: A partitioned survival model was developed using efficacy and safety data from the KEYNOTE-042 trial and projected over 20 years. Costs accounted for treatment, toxicity and disease management. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were reported. Results: Pembrolizumab resulted in an expected gain of 0.60 life years and 0.49 QALYs compared with platinum-based chemotherapy. The incremental cost-effectiveness ratio was US$130,155/QALY. Conclusion: Pembrolizumab is projected to be cost-effective compared with platinum-based chemotherapy as first-line treatment for advanced non-small-cell lung cancer with PD-L1 tumor proportion score ≥1%.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/análise , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais Humanizados/economia , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Carcinoma Pulmonar de Células não Pequenas/química , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Análise Custo-Benefício , Gerenciamento Clínico , Custos de Cuidados de Saúde , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/mortalidade , Anos de Vida Ajustados por Qualidade de VidaRESUMO
BACKGROUND: Treatment options are limited for patients with advanced hepatocellular carcinoma (HCC) that progresses after treatment with sorafenib. Cabozantinib, an oral small molecule inhibitor of multiple tyrosine kinase receptors, recently showed improved overall survival (OS) compared with placebo in sorafenib-pretreated patients with advanced HCC in the CELESTIAL trial. This study assessed the cost-effectiveness of cabozantinib for second-line treatment of patients with advanced HCC from a US healthcare system perspective. PATIENTS AND METHODS: Cost and utility data were extracted from the CELESTIAL trial and used to determine the cost-effectiveness of cabozantinib compared with placebo plus best supportive care. The main outcome of this study was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) gained by using cabozantinib compared with placebo plus best supportive care in sorafenib-pretreated HCC. RESULTS: In the base-case analysis using data from the CELESTIAL trial, the incremental QALY and ICER were 0.067 and $1,040,675 for cabozantinib compared with placebo and best supportive care. OS reported in the CELESTIAL trial (hazard ratio, 0.76; 95% CI, 0.63-0.92) had the strongest association with the ICER. In one-way sensitivity analyses, there were no scenarios in which cabozantinib was cost-effective. In a cost-threshold analysis, cabozantinib would have to be priced at least $50 per pill to be cost-effective considering a willingness to pay of $100,000 per QALY. Although the CELESTIAL trial demonstrated that cabozantinib improves OS compared with placebo in patients with HCC that progresses after treatment with sorafenib, our analysis shows that cabozantinib is not a cost-effective therapy in this scenario. CONCLUSIONS: At current costs, cabozantinib is not cost-effective for second-line therapy of HCC in the United States.
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Anilidas/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Análise Custo-Benefício , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Anilidas/efeitos adversos , Anilidas/economia , Antineoplásicos , Carcinoma Hepatocelular/economia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Tomada de Decisão Clínica/métodos , Ensaios Clínicos Fase III como Assunto , Simulação por Computador , Intervalo Livre de Doença , Custos de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/economia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Cadeias de Markov , Modelos Econômicos , Estadiamento de Neoplasias , Cuidados Paliativos/economia , Seleção de Pacientes , Placebos/administração & dosagem , Placebos/efeitos adversos , Placebos/economia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/economia , Piridinas/efeitos adversos , Piridinas/economia , Anos de Vida Ajustados por Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Sorafenibe/farmacologia , Sorafenibe/uso terapêuticoRESUMO
OBJECTIVE: To evaluate the cost-effectiveness of the addition of chemotherapy or abiraterone to androgen deprivation. METHODS: We developed an analytical model to determine the cost-effectiveness of the addition of docetaxel or abiraterone versus androgen deprivation therapy alone. Direct and indirect costs were included in the model. The effects were expressed in Quality-Adjusted Life Years adjusted for side effects. RESULTS: Compared to androgen deprivation therapy alone, the addition of chemotherapy and of abiraterone generated 0.492 and 0.999, respectively, in Quality-Adjusted Life Years. Abiraterone led to a Quality-Adjusted Life Years gain of 0.506 compared to docetaxel. The incremental costs per Quality-Adjusted Life Years were R$ 133.649,22 for docetaxel, R$ 330.828,70 for abiraterone and R$ 571.379,42 for abiraterone compared to docetaxel, respectively. CONCLUSION: The addition of chemotherapy to androgen deprivation therapy is more cost-effective than the addition of abiraterone to androgen deprivation therapy. However, discounts on abiraterone cost might improve cost-effectiveness.
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Antagonistas de Androgênios/economia , Androstenos/economia , Antineoplásicos Hormonais/economia , Análise Custo-Benefício/métodos , Docetaxel/economia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/economia , Antagonistas de Androgênios/uso terapêutico , Androstenos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brasil , Docetaxel/uso terapêutico , Humanos , Masculino , Placebos/economia , Placebos/uso terapêutico , Intervalo Livre de Progressão , Neoplasias da Próstata/mortalidade , Anos de Vida Ajustados por Qualidade de Vida , Valores de Referência , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do TratamentoAssuntos
Liderança , Oncologistas/educação , Humanos , Internacionalidade , Sociedades Médicas , Estados UnidosRESUMO
Lung cancer is one of the most incident types of cancer and a leading cause of cancer mortality in Brazil. We reviewed the current status of lung cancer by searching relevant data on prevention, diagnosis, and treatment in the country. This review highlights several issues that need to be addressed, including smoking control, patient lack of awareness, late diagnosis, and disparities in the access to cancer health care facilities in Brazil. We propose strategies to help overcome these limitations and challenge health care providers, as well as the society and governmental representatives, to work together and to take a step forward in fighting lung cancer.
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Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Brasil/epidemiologia , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Neoplasias Pulmonares/epidemiologia , Masculino , Fatores de Risco , Distribuição por Sexo , Fatores de TempoRESUMO
Introduction: Tyrosine kinase inhibition of the epidermal growth factor receptor (EGFR) is the standard in the first line treatment of patients with advanced non-small-cell lung cancer (NSCLC) harbouring EGFR activating mutations. Here we aim to discern efficacy and toxicity measures through a meta-analysis of published studies that could aid treatment selection. Materials And Methods: We performed a meta-analysis of the main randomized clinical trials evaluating the currently approved EGFR-TKIs in first-line of treatment of EGFR-positive advanced NSCLC. Cochrane guidelines were used for statistical analysis. Results: 3,179 patients were included. All EGFR TKIs showed improved outcomes with respect to ORR and PFS when compared to standard platinum-doublet chemotherapy. Comparative ORR for gefitinib, erlotinib and afatinib were 52.1%, 67.3% and 61.6% respectively. HRs for PFS were 0.62 (95% CI, 0.38-1.00) for gefitinib, 0.28 (95% CI, 0.17-0.45) for erlotinib and 0.40 (95% CI, 0.20-0.83) for afatinib. HRs for OS were not statistically significant for any agent. Conclusions: Our results suggest similar clinical efficacy and higher toxicity of Afatinib treatment. As this still remains the agent with best CSF penetration, we suggest its use is limited to patients presenting with brain metastasis. We suggest the use of Gefitinib in patients without CNS involvement. Faced with the impossibility to dose-reduce Gefitinib, Erlotinib represents a tolerable and effective alternative to Afatinib and Gefitinib if response to EGFR inhibition is considered still effective.
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ABSTRACT Lung cancer is one of the most incident types of cancer and a leading cause of cancer mortality in Brazil. We reviewed the current status of lung cancer by searching relevant data on prevention, diagnosis, and treatment in the country. This review highlights several issues that need to be addressed, including smoking control, patient lack of awareness, late diagnosis, and disparities in the access to cancer health care facilities in Brazil. We propose strategies to help overcome these limitations and challenge health care providers, as well as the society and governmental representatives, to work together and to take a step forward in fighting lung cancer.
RESUMO O câncer de pulmão é um dos tipos de câncer com maior incidência e uma das principais causas de mortalidade por câncer no Brasil. Revisamos a situação atual do câncer de pulmão por meio de pesquisa de dados relevantes a respeito de prevenção, diagnóstico e tratamento no país. Esta revisão mostra várias questões que precisam de atenção, tais como controle do tabagismo, educação dos pacientes, desconhecimento por parte dos pacientes, diagnóstico tardio e desigualdade de acesso ao tratamento de câncer no Brasil. Propomos estratégias para ajudar a superar essas limitações e desafiamos os profissionais de saúde, a sociedade e os representantes do governo a trabalhar em conjunto e dar um passo à frente na luta contra o câncer de pulmão.
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Humanos , Masculino , Feminino , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Fatores de Tempo , Brasil/epidemiologia , Fatores de Risco , Distribuição por Sexo , Acessibilidade aos Serviços de Saúde , Neoplasias Pulmonares/epidemiologiaRESUMO
Lung cancer is the leading cause of cancer-related deaths in the world. Immune checkpoint inhibitors (ICI) stimulate cytotoxic lymphocyte activity against tumour cells. These agents are available for the treatment of non-small cell lung cancer (NSCLC) after failure of platinum-based therapy. One recent study has demonstrated that ICI monotherapy was superior to platinum-based chemotherapy for first-line treatment. Nevertheless, this benefit was only for a minority of the population (30%) whose tumour programmed death receptor ligand-1 (PD-L1) expression was above 50%. Therefore, several strategies are under investigation. One option for patients with PD-L1 expression lower than 50% may be the combination of ICI with platinum-based chemotherapy or with ICIs against different targets. However, all of these combinations are at an early stage of investigation and may be very expensive or toxic, producing several harmful adverse events.
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OBJECTIVE: To assess the cost-effectiveness of chemohormonal therapy in patients with metastatic hormone-sensitive and non-metastatic high-risk prostate cancer. METHODS: An analytical decision model was developed to determine the cost-effectiveness of chemohormonal therapy versus androgen deprivation therapy alone in patients with metastatic hormone-sensitive prostate cancer and patients with non-metastatic high-risk prostate cancer. The cost-effectiveness in metastatic patients with a high-volume disease was assessed separately. The model used data from randomized clinical trials and drug acquisition costs in Brazil. In addition, the costs of post-progression therapies have been included in this model. The benefits to health are expressed as the quality-adjusted life-years, and the incremental cost-effectiveness ratios were calculated. RESULTS: Chemohormonal therapy may be associated with improved quality-adjusted life-years for all patient. The improvement was more than six times greater for patients with high-volume metastatic disease. In these patients, the incremental cost-effectiveness ratios were up to 74% lower than the incremental cost-effectiveness ratios of patients with non-metastatic disease. CONCLUSION: Chemohormonal therapy has been more cost-effective in patients with high-volume metastatic disease.
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Antagonistas de Receptores de Andrógenos/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Análise Custo-Benefício , Neoplasias da Próstata/economia , Anos de Vida Ajustados por Qualidade de Vida , Taxoides/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Docetaxel , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Resultado do TratamentoRESUMO
OBJECTIVE:: To assess aspects related to cancer in indigenous population. METHODS:: This is a retrospective study developed in a public university hospital. We included patients with 18 or more years of age, diagnosed with solid tumors, and followed between 2005 and 2015. Clinical features were assessed by descriptive statistics, and survival was evaluated by Kaplan-Meier curves and multivariate Cox regression. RESULTS:: Fifty patients were included. The cancer incidence was 15.73 per 100,000. The mean age at diagnosis was 54 years and most patients were female (58%). Cancer of the cervix (28%) and prostate (16%) were the most common. The mean time between the onset of symptoms and the diagnosis was 9 months and from diagnosis to the treatment was 3.4 months. Disease diagnosed at stage IV (17%) had worse overall survival (HR: 11.4; p<0.05). The 5-year survival rate ranged from 88% for prostate cancer to 0% for lung cancer. All 5-year survival rates were lower as compared to other populations. CONCLUSION:: The most prevalent cancer sites were cervix and prostate. Disease stage and primary site were prognostic factors. OBJETIVO:: Avaliar os aspectos relacionados a câncer em populações indígenas. MÉTODOS:: Estudo retrospectivo conduzido em um hospital universitário público. Foram incluídos pacientes com 18 anos ou mais, diagnosticados com tumores sólidos e acompanhados entre 2005 e 2015. Os aspectos clínicos foram avaliados por meio de estatística descritiva, e a sobrevida foi avaliada por meio de curvas de Kaplan-Meier e regressão multivariada de Cox. RESULTADOS:: Foram incluídos 50 pacientes. A incidência de câncer foi 15,73 por 100 mil. A média de idade ao diagnóstico foi 54 anos, e a maioria era do sexo feminino (58%). O câncer de colo uterino (28%) e o de próstata (16%) foram os mais frequentes. O tempo médio entre o início dos sintomas e o diagnóstico foi 9 meses, e entre o diagnóstico e o tratamento, de 3,4 meses. Doença diagnosticada no estágio IV (17%) resultou em pior sobrevida global (HR: 11,4; p<0,05). A sobrevida em 5 anos variou de 88% para o câncer de próstata a 0% para pulmão. Todas as taxas de sobrevida em 5 anos foram menores em comparação a outras populações. CONCLUSÃO:: Os locais mais frequentes de neoplasia foram colo de útero e próstata. O estágio da doença e o sítio primário foram fatores prognósticos.
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Indígenas Sul-Americanos/estatística & dados numéricos , Neoplasias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Atenção à Saúde/estatística & dados numéricos , Feminino , Serviços de Saúde do Indígena/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/etnologia , Neoplasias/terapia , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/etnologia , Neoplasias do Colo do Útero/patologia , Adulto JovemRESUMO
AIM: Concomitant chemoradiotherapy (with cisplatin or carboplatin) is an option of definitive treatment for squamous head and neck cancer. We aimed to perform a meta-analysis comparing those two platinum agents. MATERIALS & METHODS: We carried out a systematic search on English literature between 1990 and 17 April 2015 according to the Cochrane review guidelines. RESULTS: Five of 60 studies fulfilled inclusion criteria with 491 patients. There was no difference in response rate. Cisplatin tends to be more active systemically than carboplatin, without statistically significance; 5-year survival rate: 30 and 27%, respectively (p = 0.33). CONCLUSION: Despite the trend to improved outcomes in using cisplatin, carboplatin is also active and can be a reasonable option to treat patients.
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Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Neoplasias de Cabeça e Pescoço/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Recidiva Local de Neoplasia , Resultado do TratamentoRESUMO
Worldwide, there are enormous inequities in cancer control that cause poor outcomes among patients with cancer who live in low- and middle-income countries (LMICs). One of the biggest challenges that oncology faces today is how to increase patient access to expensive, but life-saving, therapies in LMICs. Access to cancer medications in LMICs is a major problem, especially in recent years, as the costs of these therapies continue to rise exponentially. One mechanism available to LMICs to improve access to cancer medications allows a country to pursue a compulsory license for a given drug. Here, we will review how the legal framework in the World Trade Organization's Trade-Related Aspects of Intellectual Property Rights Agreement and the Doha Declaration supports countries to circumvent patent laws and acquire compulsory licenses for essential medicines. We will also discuss the current and future role of compulsory licenses in oncology and how compulsory licenses may improve access to cancer drugs in LMICs.
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Bevacizumab may improve outcomes of patients with breast cancer, but the absence of an established biomarker hampers patient selection and researchers´ ability to demonstrate a clear survival benefit. Its putative target, circulating VEGF-A, emerged as the main candidate and we sought to identify the relationship between VEGF-A levels and outcomes through systematic review. We searched electronic databases and meeting proceedings for randomized controlled trials (RCTs) comparing the addition of bevacizumab to standard chemotherapy for breast cancer. RCTs were included if outcomes were presented separately according to VEGF-A plasma levels. Random-effects model were applied to calculate the pooled hazard ratios for progression-free survival, event-free survival (EFS), comprising disease recurrence, progression or any-cause death, and overall survival (OS), with respective confidence intervals (95 % CI). High and low VEGF-A levels subgroups followed each trial definition, and results were compared using the interaction test. Heterogeneity was calculated using χ (2) test (I (2)). Three trials enrolled a total of 3748 patients. 1713 patients had baseline VEGF-A levels in plasma available for assessment and were included. One trial added bevacizumab in the adjuvant setting (N = 2591) and two on first-line metastatic disease with taxane-based therapy (N = 1160) There was no interaction between VEGF-A levels and study setting (adjuvant vs. first line therapy). Bevacizumab improved PFS of patients with above median VEGF-A plasma levels (HR 0.56; 95 % CI 0.43-0.73; P < 0.001; I (2) = 0 %), but not of those with below median VEGF-A levels (HR 0.89; 95 % CI 0.68-1.15; P = 0.37; I (2) = 0 %), with relevant differences between these two groups, P-for interaction = 0.02. The same happened with EFS (VEGF-A above median HR 0.62; 95 % CI 0.39-0.79; P < 0.001; I (2) = 11 %; below median HR 0.89; 95 % CI 0.71-1.14; P = 0.98; I (2) = 17 %; P-for interaction = 0.03). OS data were not available. VEGF-A level is a reasonable candidate biomarker for bevacizumab in the treatment of breast cancer. Further studies have to confirm its surrogacy in overall survival and in other scenarios including other anti-angiogenic therapies.
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Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/sangue , Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Humanos , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Based on improved clinical outcomes in randomized controlled clinical trials (RCTs) the FDA and EMA have approved bevacizumab with interferon, sunitinib, and pazopanib in the first-line treatment of low to intermediate risk metastatic clear cell renal cell carcinoma (mRCC). However, there is little comparative data to help in choosing the most effective drug among these agents. METHODS: We performed an indirect comparative effectiveness analysis of the pivotal RCTs of bevacizumab with interferon, sunitinib, or pazopanib compared to one another or interferon alone in first-line treatment of metastatic or advanced RCC. Endpoints of interest were overall survival (OS), progression free survival (PFS), and response rate (RR). Adverse events were also examined. RESULTS: The meta-estimate of the hazard ratio (95% confidence interval) for OS for bevacizumab with interferon vs. interferon alone was 0.86 (0.76-0.97), for sunitinib vs. interferon alone was 0.82 (0.67-1.00), for pazopanib vs. interferon alone was 0.74 (0.57-0.97), for sunitinib vs. bevacizumab with interferon was 0.95 (0.75-1.20), for pazopanib vs. bevacizumab with interferon was 0.86 (0.64-1.16), and for pazopanib vs. sunitinib was 0.91 (0.76-1.08). Similarly, bevacizumab with interferon, sunitinib, or pazopanib had better PFS and RR than interferon alone. Sunitinib and pazopanib had better RR than bevacizumab with interferon and there was suggestive evidence pazopanib may outperform sunitinib in terms of RR. CONCLUSIONS: Bevacizumab with interferon, sunitinib, and pazopanib are adequate first-line options in treatment of mRCC. Interferon alone should not be considered an optimal first-line treatment.