RESUMO
BACKGROUND: Advanced (Stage IV) prostate and renal cancer have poor prognosis, and several therapies have been developed, but many are very costly. This study investigated drug regimens used in patients with untreated Stage IV prostate cancer and renal cell carcinoma and calculated the monthly cost of each. METHODS: We surveyed first-line drugs administered to patients with untreated Stage IV prostate cancer and renal cancer at Japan Clinical Oncology Group affiliated centers from April 2022 to March 2023. Drug costs were calculated according to drug prices in September 2023. Individual drug costs were calculated or converted to 28-day costs. RESULTS: A total of 700 patients with untreated Stage IV prostate cancer were surveyed. Androgen deprivation therapy + androgen receptor signaling inhibitor was the most common regimen (56%). The cost of androgen deprivation therapy + androgen receptor signaling inhibitor was 10.6-30.8-fold compared with conventional treatments. A total of 137 patients with Stage IV renal cancer were surveyed. Among them, 91% of patients received immune-oncology drug-based regimen. All patients received treatments with a monthly cost of ≥500 000 Japanese yen, and 80.4% of patients received treatments with a monthly cost of ≥1 million Japanese yen, of combination treatments. The cost of immune-oncology drug-based regimen was 1.2-3.1-fold that of TKI alone. CONCLUSION: To the best of our knowledge, this is the first report of a survey of first-line drug therapy in untreated Stage IV prostate cancer and renal cell carcinoma stratified by age and treatment costs. Our results show that most Japanese patients received state-of-the-art, effective treatments with high financial burden.
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Carcinoma de Células Renais , Neoplasias Renais , Neoplasias da Próstata , Humanos , Masculino , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/economia , Carcinoma de Células Renais/patologia , Japão , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/economia , Neoplasias Renais/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/economia , Neoplasias da Próstata/patologia , Idoso , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Idoso de 80 Anos ou mais , Custos de Medicamentos/estatística & dados numéricos , Inquéritos e Questionários , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Androgênios/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economiaRESUMO
INTRODUCTION: Cabozantinib is one of the preferred treatment options in the latest metastatic renal cell carcinoma (mRCC) guidelines. Cabozantinib is also associated with high drug expenses irrespective of the used dose, because a flat-prizing model has been implemented. In addition, concomitant intake with a high-fat meal increases its bioavailability on average by 57%. Combined with the long terminal half-life of cabozantinib (99 h), this creates possibilities to extend the dosing interval to reduce drug expenses whilst maintaining equivalent exposure. OBJECTIVES: The primary objective was to evaluate the population pharmacokinetic (POPPK) model of cabozantinib developed for its registration using real-world patients' therapeutic drug monitoring (TDM) data. The secondary objective was to design, simulate, and evaluate alternative dose regimens with the aim to reduce drug expenses whilst maintaining comparable exposure. METHODS: Retrospective TDM data from mRCC patients treated with cabozantinib were obtained. The data were evaluated using the published Food and Drug Administration (FDA) cabozantinib POPPK model, a two-compartment disposition model with a dual (fast and slow) lagged first-order absorption process derived from FDA registration documents, as a basis. Subsequently, simulations of alternative drug expenses saving regimens were evaluated. RESULTS: Twenty-seven mRCC patients with 75 pharmacokinetic observations were included. Patients were treated for a median of 75 days with a median dose of 40 mg. Model evaluation results showed that the cabozantinib TDM concentrations were adequately predicted by the published FDA cabozantinib POPPK model, except for a slightly higher clearance (CL) of 3.11 L/h compared to the reported value (2.23 L/h). The simulation study indicated that an alternative dose regimen that consists of taking 60 mg of cabozantinib for 2 days and then skipping 1 day results in comparable average exposure when compared with a 40 mg daily dose, both without food interaction, while saving 33.3% of the total drug expenses per month. The food effect of a high-fat meal was also taken into account when simulating other alternative dose regimens; 40 mg every 72 h combined with a high-fat meal resulted in comparable exposure when compared with a 20 mg daily dose fasted, while saving 66.7% in drug expenses. CONCLUSIONS: In this study, the optimized cabozantinib POPPK model resulted in adequate prediction of real-world cabozantinib pharmacokinetic data. Alternative dosing regimens with and without using known food interactions were proposed that resulted in potential strategies to significantly reduce cabozantinib drug expenses.
Assuntos
Anilidas , Carcinoma de Células Renais , Neoplasias Renais , Piridinas , Humanos , Piridinas/farmacocinética , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Piridinas/economia , Anilidas/farmacocinética , Anilidas/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Modelos Biológicos , Monitoramento de Medicamentos/métodos , Adulto , Antineoplásicos/farmacocinética , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Custos de Medicamentos , Idoso de 80 Anos ou maisRESUMO
BACKGROUND AND OBJECTIVES: Despite significant progress in biomedical research, the rate of success in oncology drug development remains inferior to that of other therapeutic fields. Mechanistic models provide comprehensive understanding of the therapeutic effects of drugs, which is crucial for designing effective clinical trials. This study was performed to acquire a better understanding of PI3K-AKT-TOR pathway modulation and preclinical to clinical translational bridging for a specific compound, apitolisib (PI3K/mTOR inhibitor), by developing integrated mechanistic models. METHODS: Integrated pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy models were developed for xenografts bearing human renal cell adenocarcinoma and for patients with solid tumors (phase 1 studies) to characterize relationships between exposure of apitolisib, modulation of the phosphorylated Akt (pAkt) biomarker triggered by inhibition of the PI3K-AKT-mTOR pathway, and tumor response. RESULTS: Both clinical and preclinical integrated models show a steep sigmoid curve linking pAkt inhibition to tumor growth inhibition and quantified that a minimum of 35-45% pAkt modulation is required for tumor shrinkage in patients, based on platelet-rich plasma surrogate matrix and in xenografts based on tumor tissue matrix. Based on this relationship between targeted pAkt modulation and tumor shrinkage rate, it appeared that a constant pAkt inhibition of 61% and 65%, respectively, would be necessary to achieve tumor stasis in xenografts and patients. CONCLUSIONS: These results help when it comes to evaluating the translatability of the preclinical analysis to the clinical target, and provide information that will enhance the value of future preclinical translational dose-finding and dose-optimization studies to accelerate clinical drug development. TRIAL REGISTRY: ClinicalTrials.gov NCT00854152 and NCT00854126.
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Carcinoma de Células Renais , Neoplasias Renais , Inibidores de MTOR , Inibidores de Fosfoinositídeo-3 Quinase , Animais , Feminino , Humanos , Camundongos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias Renais/tratamento farmacológico , Inibidores de MTOR/uso terapêutico , Inibidores de MTOR/farmacologia , Inibidores de MTOR/farmacocinética , Neoplasias/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Estudos Retrospectivos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cancer remains a significant global health challenge, and despite remarkable advancements in therapeutic strategies, poor tolerability of drugs (causing dose reduction/interruptions) and/or the emergence of drug resistance are major obstacles to successful treatment outcomes. Metastatic renal cell carcinoma (mRCC) accounts for 2% of global cancer diagnoses and deaths. Despite the initial success of targeted therapies in mRCC, challenges remain to overcome drug resistance that limits the long-term efficacy of these treatments. Our analysis aim was to develop a semi-mechanistic longitudinal exposure-tumor growth inhibition model for patients with mRCC to characterize and compare everolimus (mTORC1) and apitolisib's (dual PI3K/mTORC1/2) ability to inhibit tumor growth, and quantitate each drug's efficacy decay caused by emergence of tumor resistance over time. Model-estimated on-treatment tumor growth rate constant was 1.7-fold higher for apitolisib compared to everolimus. Estimated half-life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib, suggesting a faster rate of tumor re-growth for apitolisib patients likely due to the emergence of resistance. Goodness-of-fit plots including visual predictive check indicated a good model fit and the model was able to capture individual tumor size-time profiles. Based on our knowledge, this is the first clinical report to quantitatively assess everolimus (mTORC1) and apitolisib (PI3K/mTORC1/2) efficacy decay in patients with mRCC. These results highlight the difference in overall efficacy of 2 drugs due to the quantified efficacy decay caused by emergence of resistance, and emphasize the importance of model-informed drug development for targeted cancer therapy.
Assuntos
Antineoplásicos , Carcinoma de Células Renais , Resistencia a Medicamentos Antineoplásicos , Everolimo , Neoplasias Renais , Alvo Mecanístico do Complexo 1 de Rapamicina , Inibidores de Fosfoinositídeo-3 Quinase , Everolimo/uso terapêutico , Everolimo/farmacologia , Everolimo/administração & dosagem , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Modelos Biológicos , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Masculino , Feminino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The objective of our study was to integrate the efficacy results of post-nephrectomy adjuvant therapies in renal cell carcinoma (RCC) patients with risk of recurrence, and attempt to determine the optimal intervention choice. METHODS: We performed standard meta-analysis procedures in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed, Embase, and Cochrane Library databases were searched from inception to 22 September 2022. Randomized controlled trials reporting overall survival (OS) or disease-free survival (DFS) of adjuvant therapies, including immune checkpoint inhibitors (ICIs) and targeted therapies, in adult post-nephrectomy RCC patients were eligible for inclusion. RESULTS: Seven studies involving 7548 participants were included in our analyses. In contrast with placebo, DFS benefit with ICIs was only observed in female RCC patients and RCC patients with high programmed death-ligand 1 (PD-L1) expression (≥ 1%), sarcomatoid features, and M0 intermediate-high risk. Network meta-analyses demonstrated that pembrolizumab exhibited both DFS and OS benefit compared with placebo, sunitinib, sorafenib, and girentuximab, and only DFS benefit compared with atezolizumab and nivolumab plus ipilimumab. CONCLUSIONS: Our results suggest that post-nephrectomy RCC patients with sarcomatoid differentiation and high PD-L1 expression were more responsive to ICIs. Furthermore, pembrolizumab monotherapy exhibited superior DFS and OS results over other adjuvant therapies.
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Carcinoma de Células Renais , Neoplasias Renais , Nefrectomia , Humanos , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Taxa de Sobrevida , Quimioterapia Adjuvante , Inibidores de Checkpoint Imunológico/uso terapêutico , Prognóstico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Terapia CombinadaRESUMO
OBJECTIVE: The current analysis aimed to evaluate the economic benefit of toripalimab plus axitinib for previously untreated RCC patients from the Chinese healthcare system perspective. METHODS: The partitioned survival model was developed to simulate 3-week patients' transition in 20-year time horizon to evaluate the cost-effectiveness of toripalimab plus axitinib compared with sunitinib for advanced RCC. Survival data were gathered from the RENOTORCH trial, and cost and utility inputs were obtained from the database and published literature. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were the model outputs. Subgroup analyses and sensitivity analyses were conducted to increase the comprehensiveness and estimate the robustness of the model results. RESULTS: In the base-case analysis, compared with sunitinib, toripalimab plus axitinib could bring additional 1.19 LYs and 0.65 QALYs, with the marginal cost of $41,499.23, resulting in the ICER of $64,337.49/QALY, which is higher than the WTP threshold. And ICERs were always beyond the WTP threshold of all subgroups. Sensitivity analyses demonstrated the model results were robust. CONCLUSIONS: Toripalimab plus axitinib was unlikely to be the cost-effective first-line therapy for patients with previously untreated advanced RCC compared with sunitinib from the Chinese healthcare system perspective.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Axitinibe , Carcinoma de Células Renais , Análise Custo-Benefício , Neoplasias Renais , Modelos Econômicos , Anos de Vida Ajustados por Qualidade de Vida , Sunitinibe , Humanos , Axitinibe/administração & dosagem , Axitinibe/economia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/economia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/economia , China , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/economia , Sunitinibe/administração & dosagem , Sunitinibe/economia , Análise de Custo-EfetividadeRESUMO
This study delves into the potential therapeutic benefits of Fufang Sanling Granules for kidney cancer, focusing on their active components and the underlying mechanisms of their interaction with cancer-related targets. By constructing a drug-active component-target network based on eight herbs, key active compounds such as kaempferol, quercetin, and linolenic acid were identified, suggesting their pivotal roles in modulating immune responses and cellular signaling pathways relevant to cancer progression. The research further identified 51 central drug-disease genes through comprehensive bioinformatics analyses, implicating their involvement in crucial biological processes and pathways. A novel risk score model, encompassing six genes with significant prognostic value for renal cancer, was established and validated, showcasing its effectiveness in predicting patient outcomes through mutation analysis and survival studies. The model's predictive power was further confirmed by its ability to stratify patients into distinct risk groups with significant survival differences, highlighting its potential as a prognostic tool. Additionally, the study explored the relationship between gene expression within the identified black module and the risk score, uncovering significant associations with the extracellular matrix and immune infiltration patterns. This reveals the complex interplay between the tumor microenvironment and cancer progression. The integration of the risk score with clinical parameters through a nomogram significantly improved the model's predictive accuracy, offering a more comprehensive tool for predicting kidney cancer prognosis. In summary, by combining detailed molecular analyses with clinical insights, this study presents a robust framework for understanding the therapeutic potential of Fufang Sanling Granules in kidney cancer. It not only sheds light on the active components and their interactions with cancer-related genes but also introduces a reliable risk score model, paving the way for personalized treatment strategies and improved patient management in the future.
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Medicamentos de Ervas Chinesas , Neoplasias Renais , Humanos , Neoplasias Renais/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/imunologia , Prognóstico , Medicamentos de Ervas Chinesas/uso terapêutico , Variação Genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genéticaRESUMO
Vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitors (VEGFR-TKIs) are often used for treatment of several types of cancer; however, they are associated with an increased risk of proteinuria, sometimes leading to treatment discontinuation. We searched PubMed and Scopus to identify clinical studies examining the incidence and risk factors for proteinuria caused by VEGFR-TKIs in patients with renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. The global incidence of proteinuria ranged from 6% to 34% for all grades of proteinuria, and from 1% to 10% for grade ≥3 proteinuria. The incidence of proteinuria did not differ significantly by cancer type, but in all three cancer types, there was a trend toward a higher incidence of proteinuria with lenvatinib than with other VEGFR-TKIs. In terms of risk factors, the incidence of proteinuria was significantly higher among Asians (including Japanese) compared with non-Asian populations. Other risk factors included diabetes mellitus, hypertension, and previous nephrectomy. When grade 3/4 proteinuria occurs, patients should be treated according to the criteria for dose reduction or withdrawal specified for each drug. For grade 2 proteinuria, treatment should be continued when the benefits outweigh the risks. Referral to a nephrologist should be considered for symptoms related to decreased renal function or when proteinuria has not improved after medication withdrawal. These management practices should be implemented universally, regardless of the cancer type.
Assuntos
Carcinoma Hepatocelular , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Hepáticas , Proteinúria , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/complicações , Incidência , Neoplasias Renais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Prevalência , Proteinúria/epidemiologia , Quinolinas/uso terapêutico , Quinolinas/efeitos adversos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fatores de Risco , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/epidemiologia , /uso terapêuticoRESUMO
OBJECTIVE: Surgical treatment of unilateral Wilms tumor (WT) in children is controversial. In this study, we aimed to evaluate the survival and prognosis of radical nephrectomy (RN) and nephron-sparing surgery (NSS) in children with unilateral WT receiving adjuvant chemotherapy. PATIENTS AND METHODS: Data on pediatric patients with WT were collected from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2019. Multivariate logistic regression was used to analyze factors influencing the choice of surgical strategy. Cox proportional hazard models were used to assess factors associated with overall survival. RESULTS: We included 1,825 patients with unilateral WT (<14 years) who received adjuvant chemotherapy and surgery. Between 2000 and 2019, the percentage of patients treated with NSS increased from 4% in 2000 to 8% in 2019. There was no significant difference in 10-year overall survival between the two surgical strategies [NSS vs. RN, 93.26% (95% CI, 86.88%-100%) vs. 92.17% (95% CI, 90.75%-93.61%), p=0.98]. Patients with unilateral WTs ≤4 cm were more likely to be treated with NSS. There was no survival benefit for patients treated with RN compared with that for those treated with NSS (HR, 0.74; 95% CI, 0.29-1.86; p=0.5). CONCLUSIONS: The use of NSS in children with unilateral WT has increased over the last two decades. Tumor size is an important influencing factor for the surgical application of NSS. Patients who underwent NSS had an equivalent OS compared with the overall group of patients with unilateral tumors who received RN.
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Neoplasias Renais , Tumor de Wilms , Humanos , Criança , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Estudos Transversais , Estudos Retrospectivos , Néfrons/cirurgia , Néfrons/patologia , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/cirurgia , Nefrectomia/efeitos adversos , Nefrectomia/métodosRESUMO
OBJECTIVES: The purpose of this study is to examine the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy (NIVO + IPI) compared with the sunitinib (SUN) therapy for Japanese patients with advanced renal cell carcinoma from the perspective of a Japanese health insurance payer. METHODS: A lifetime horizon was applied, and 2% per annum was set as the discount rate. The threshold was set as $ 75 000 per quality-adjusted life-year (QALY) gained. For the analytical method, we used a partitioned survival analysis model to estimate the incremental cost-effectiveness ratio (ICER), which is calculated by dividing incremental costs by incremental QALYs. Progression-free survival, progressive disease, and death were set as health states. Additionally, cost parameters and utility weights were set as key parameters. We set the intermediate/poor-risk population as the base case. Scenario analysis was conducted for the intention-to-treat population and the favorable risk population. Furthermore, one-way sensitivity analysis and probabilistic sensitivity analysis were conducted for each population. RESULTS: In the base-case analysis, the QALYs of NIVO + IPI and SUN were 4.32 and 2.99, respectively. NIVO + IPI conferred 1.34 additional QALYs. Meanwhile, the total costs in the NIVO + IPI and SUN were $692 288 and $475 481, respectively. As a result, the ICER of NIVO + IPI compared with SUN was estimated to be $162 243 per QALY gained. The parameter that greatly affected the ICER was the utility weight of progression-free survival in NIVO + IPI. CONCLUSIONS: NIVO + IPI for advanced renal cell carcinoma seems to be not cost-effective compared with the SUN in the Japanese healthcare system.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/patologia , Nivolumabe/uso terapêutico , Nivolumabe/efeitos adversos , Ipilimumab/uso terapêutico , Ipilimumab/efeitos adversos , Japão , Análise de Custo-Efetividade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/etiologia , Neoplasias Renais/patologiaRESUMO
OBJECTIVES: To characterise the restrictiveness of eligibility criteria in contemporary renal cell carcinoma (RCC) trials, using recommendations from the American Society of Clinical Oncology (ASCO)-Friends of Cancer Research (FCR) initiative. METHODS: vPhase I-III trials assessing systemic therapies in patients with RCC starting between 30 June 2012 and 30 June 2022 were identified. Eligibility criteria regarding brain metastases, prior or concurrent malignancies, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, and human immunodeficiency virus (HIV) infection were identified and stratified into three groups: exclusion, conditional inclusion, and not reported. Descriptive statistics were used to determine the frequency of eligibility criteria. Fisher's exact test or chi-square test were used to calculate their associations with certain trial characteristics. RESULTS: A total of 423 RCC trials were initially identified of which 112 (26.5%) had sufficient accessible information. Exclusion of patients with HIV infection, HBV/HCV infection, brain metastases, and prior or concurrent malignancies were reported in 74.1%, 53.6%, 33.0%, and 8.0% of trials, respectively. In the context of HIV and HBV/HCV infection, patients were largely excluded from trials evaluating immunotherapy (94.4% and 77.8%, respectively). In addition, brain metastases were excluded in trials assessing targeted therapy (36.4%), combined therapy (33.3%), and immunotherapy (22.2%). Exclusion of patients with prior or concurrent malignancies was less frequently reported, accounting for 9.1%, 8.3%, and 5.6% targeted therapy, combined therapy and immunotherapy trials, respectively. CONCLUSION: A substantial proportion of RCC trials utilise restrictive eligibility criteria, excluding patients with fairly prevalent comorbidities. Implementing the ASCO-FCR recommendations will ensure resulting data are more inclusive and aligned with patient populations in the real-world.
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Neoplasias Encefálicas , Carcinoma de Células Renais , Infecções por HIV , Hepatite C , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Hepatite C/tratamento farmacológico , Neoplasias Renais/tratamento farmacológicoRESUMO
OBJECTIVE: We aimed to assess the relative importance of attributes and the willingness to pay for pharmacological therapies among patients with renal cell carcinoma in China. METHODS: Patients with renal cell carcinoma completed a D-efficient-designed, discrete-choice experiment online survey that presented a series of ten trade-off questions and one examining scenario. Based on the literature review and consultations with patients with renal cell carcinoma and clinicians, each question included a pair of hypothetical renal cell carcinoma medication profiles characterized by seven attributes including progression-free survival, objective response rate, medication regimen, fatigue, gastrointestinal reaction, hand-foot syndrome, and monthly out-of-pocket costs. Relative importance and willingness to pay were calculated using coefficients estimated by mixed logit regression in the main analysis. Subgroup analyses were conducted considering the heterogeneity of the participants, based on sex, education level, and income level, using conditional logit regression. RESULTS: The analysis incorporated responses from 182 Chinese respondents. Except for the medication regimen, all attributes were statistically significant. Progression-free survival was the most important attribute, followed by objective response rate, monthly out-of-pocket costs, fatigue, gastrointestinal reaction, and hand-foot syndrome. Patients were willing to pay ï¿¥2010.51 ($298.30), ï¿¥494.93 ($73.43) for 1 unit improvement of progression-free survival, and objective response rate, andï¿¥7558.93 ($1121.50), ï¿¥6927.24 ($1027.78) to avoid experiencing fatigue and gastrointestinal reaction, respectively. Differences in preferences and willingness to pay were found according to patients' gender, income, and education level. CONCLUSIONS: In China, patients with renal cell carcinoma preferred medications with better efficacy (objective response rate and progression-free survival) and lower out-of-pocket costs. Heterogeneity can be found in preferences and willingness to pay based on patients' gender, income, and education levels.
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Carcinoma de Células Renais , Síndrome Mão-Pé , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , China , Gastos em Saúde , Neoplasias Renais/tratamento farmacológico , Masculino , FemininoRESUMO
BACKGROUND AND OBJECTIVE: Metastatic renal cell carcinoma (mRCC) patients have been reported to have better outcomes when treated with immunotherapies (IO) compared to targeted therapies (TT). This study aims to evaluate the impact of first-line systemic therapies on survival of mRCC patients with or without sarcomatoid features using real-world data. METHODS: Metastatic RCC patients of International mRCC Database Consortium (IMDC) intermediate or high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system. Patients were classified by initial treatment: (1) targeted therapy (TT) used alone or (2) immunotherapy (IO)-based systemic therapies used in combination of either IO-IO or IO-TT. The inverse probability of treatment weighting using propensity scores was used to balance for covariates. Cox proportional hazard models were used to assess the impact of initial treatment received on overall survival (OS). KEY FINDINGS AND LIMITATIONS: Of the 1202 eligible patients, 791 were treated with TT and 411 with IO combinations. Of the patients, 76% were male, and the majority (91%) had a nephrectomy before systemic therapy. In nonsarcomatoid patients (639 TT and 320 IO patients), treatment with IO was associated with improved OS compared with patients treated with TT (median of 72 vs 48 mo, hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.50-0.80, objective response rate [ORR] of 38.5% for IO and 23.5% for TT). In sarcomatoid patients (152 TT and 91 IO patients), treatment with IO was associated with improved OS (median of 48 vs 18 mo, HR 0.41, 95% CI 0.26-0.64, ORR of 49.5% for IO and 13.8% for TT). Similar results were observed in patients with synchronous metastatic disease only. CONCLUSIONS AND CLINICAL IMPLICATIONS: IO treatment was associated with improved survival in mRCC patients. The magnitude of benefit is increased in patients with sarcomatoid mRCC, consequently, identifying the sarcomatoid status early on could help healthcare providers make a better treatment decision. PATIENT SUMMARY: Metastatic renal cell carcinoma (mRCC) patients of International mRCC Database Consortium intermediate and high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system (CKCis). In this study, treatment with immunotherapy was associated to an improved survival and response rates for mRCC patients with and without sarcomatoid features. The magnitude of benefit is increased in patients with sarcomatoid mRCC.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/patologia , Masculino , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Neoplasias Renais/mortalidade , Neoplasias Renais/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Imunoterapia , Estudos Retrospectivos , Taxa de Sobrevida , Terapia de Alvo MolecularRESUMO
OBJECTIVE: Nivolumab plus ipilimumab (NIVO + IPI) and pembrolizumab plus axitinib (PEM + AXI) have demonstrated significant clinical benefits as first-line (1 L) treatments for intermediate/poor-risk advanced renal cell carcinoma (aRCC) patients. This study aimed to assess the cost-effectiveness of NIVO + IPI versus PEM + AXI from a Brazilian private healthcare system perspective, utilizing a novel approach to estimate comparative efficacy between the treatments. METHODS: A three-state partitioned survival model (progression-free, progressed, and death) was developed to estimate costs, life-years (LYs), quality-adjusted LYs (QALYs), and the incremental cost-utility ratio (ICUR) over a 40-year time horizon. In the absence of head-to-head comparisons between NIVO + IPI and PEM + AXI, clinical data for NIVO + IPI was obtained from CheckMate 214 (NCT02231749) and for PEM + AXI from KEYNOTE-426 (NCT02853331). A matching-adjusted indirect comparison was conducted to account for the imbalance of treatment effect modifiers between the trials. Patient characteristics, resource use, health state utilities, and costs were based on Brazilian-specific sources. Costs and health outcomes were both discounted by 5% annually in line with Brazilian guidelines. The robustness of the results was evaluated through extensive sensitivity analysis and scenario analyses. RESULTS: When comparing the matched versus unmatched OS, PFS, and TTD curves there was no noteworthy difference. NIVO + IPI was associated with cost savings (R$ 350,232), higher LYs (5.54 vs. 4.61), and QALYs (4.74 vs. 3.76) versus PEM + AXI, resulting in NIVO + IPI dominating PEM + AXI. Key model drivers were the treatment duration for PEM, NIVO, and AXI. NIVO + IPI remained dominant in all scenario analyses, which indicated that model results were robust to alternative modelling inputs or assumptions. CONCLUSIONS: This analysis shows that NIVO + IPI is estimated to be a life-extending and potentially cost-saving 1 L treatment option when compared with PEM + AXI for intermediate/poor-risk a RCC patients in the Brazilian private healthcare system.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Nivolumabe/uso terapêutico , Ipilimumab/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Axitinibe/uso terapêutico , Prognóstico , Análise Custo-Benefício , Brasil , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Atenção à Saúde , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologiaRESUMO
Aim: Network meta-analyses (NMAs) increasingly feature time-varying hazards to account for non-proportional hazards between different drug classes. This paper outlines an algorithm for selecting clinically plausible fractional polynomial NMA models. Methods: The NMA of four immune checkpoint inhibitors (ICIs) + tyrosine kinase inhibitors (TKIs) and one TKI therapy for renal cell carcinoma (RCC) served as case study. Overall survival (OS) and progression free survival (PFS) data were reconstructed from the literature, 46 models were fitted. The algorithm entailed a-priori face validity criteria for survival and hazards, based on clinical expert input, and predictive accuracy against trial data. Selected models were compared with statistically best-fitting models. Results: Three valid PFS and two OS models were identified. All models overestimated PFS, the OS model featured crossing ICI + TKI versus TKI curves as per expert opinion. Conventionally selected models showed implausible survival. Conclusion: The selection algorithm considering face validity, predictive accuracy, and expert opinion improved the clinical plausibility of first-line RCC survival models.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Metanálise em Rede , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Renais/tratamento farmacológicoRESUMO
INTRODUCTION: Pembrolizumab was recently approved as an adjuvant treatment of renal cell carcinoma (RCC), based on prolonged disease-free survival compared to placebo in the phase III KEYNOTE-564 trial. The objective of this study was to evaluate the cost-effectiveness of pembrolizumab as monotherapy in the adjuvant treatment of RCC post-nephrectomy, from a US health sector perspective. PATIENTS AND METHODS: A Markov model with 4 health states (disease-free, locoregional recurrence, distant metastases, and death) was developed to compare the cost and effectiveness of pembrolizumab versus routine surveillance or sunitinib. Transition probabilities were estimated using patient-level KEYNOTE-564 data (cutoff: June 14, 2021), a retrospective study, and published literature. Costs of adjuvant and subsequent treatments, adverse events, disease management, and terminal care were estimated in 2022 US$. Utilities were based on EQ-5D-5L data collected in KEYNOTE-564. Outcomes included costs, life-years (LYs), and quality-adjusted LYs (QALYs). Robustness was assessed through one-way and probabilistic sensitivity analyses. RESULTS: Total cost per patient was $549,353 for pembrolizumab, $505,094 for routine surveillance, and $602,065 for sunitinib. Over a lifetime, pembrolizumab provided gains of 0.96 QALYs (1.00 LYs) compared to routine surveillance, yielding an incremental cost-effectiveness ratio of $46,327/QALY. Pembrolizumab dominated sunitinib with 0.89 QALYs (0.91 LYs) gained while saving costs. At a $150,000/QALY threshold, pembrolizumab was cost-effective versus both routine surveillance and sunitinib in 84.2% of probabilistic simulations. CONCLUSION: Pembrolizumab is projected to be cost-effective as an adjuvant RCC treatment versus routine surveillance or sunitinib based on a typical willingness-to-pay threshold.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Estados Unidos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Análise de Custo-Efetividade , Sunitinibe/uso terapêutico , Estudos Retrospectivos , Análise Custo-Benefício , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Nefrectomia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Disparities in metastatic renal cell carcinoma (mRCC) outcomes persist in the era of oral anticancer agents (OAAs) and immunotherapies (IOs). We examined variation in the utilization of mRCC systemic therapies among US Medicare beneficiaries from 2015 to 2019. Logistic regression models evaluated the association between therapy receipt and demographic covariates including patient race, ethnicity, and sex. In total, 15 407 patients met study criteria. After multivariable adjustment, non-Hispanic Black race and ethnicity was associated with reduced IO (adjusted relative risk ratio [aRRR] = 0.76, 95% confidence interval [CI] = 0.61 to 0.95; P = .015) and OAA receipt (aRRR = 0.76, 95% CI = 0.64 to 0.90; P = .002) compared with non-Hispanic White race and ethnicity. Female sex was associated with reduced IO (aRRR = 0.73, 95% CI = 0.66 to 0.81; P < .001) and OAA receipt (aRRR = 0.74, 95% CI = 0.68 to 0.81; P < .001) compared with male sex. Thus, disparities by race, ethnicity, and sex were observed in mRCC systemic therapy utilization for Medicare beneficiaries from 2015 to 2019.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Masculino , Feminino , Idoso , Estados Unidos/epidemiologia , Carcinoma de Células Renais/tratamento farmacológico , Medicare , Neoplasias Renais/tratamento farmacológico , Etnicidade , BrancosRESUMO
Immune checkpoint inhibitors (ICIs) target programmed cell death (PD) 1 receptor and its ligand PD-L1, and have become an integral part of treatment regimens in many cancers including lung cancer, renal cell carcinoma, melanoma, and more. Cancer is associated with a significantly increased risk of venous thromboembolism compared to non-cancer patients, and the risks increase further with anticancer therapies including ICIs. Cancer-associated thrombosis can lead to hospitalizations, delayed cancer treatment, and mortality. While thrombosis was not reported as a major complication in initial clinical trials leading to the approval of ICIs, emerging evidence from post-marketing studies revealed concerning risks of thrombosis in patients receiving ICIs. However, results remained heterogenous given differences in study designs and populations. Recent studies also showed that C-reactive protein dynamics might be an easily accessible biomarker for thrombosis and disease response in this population. In addition, early findings indicated that a commonly used anticoagulant for cancer-associated thrombosis, factor Xa inhibitors, might have potential synergistic antitumor effects when combined with ICIs. Herein we will review the current literature on the incidence, risk factors, and management of thrombosis in patients with cancer receiving ICIs. We aim to provide valuable information for clinicians in managing these patients.
Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Renais , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Incidência , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1 , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1 , Fatores de Risco , Neoplasias Renais/tratamento farmacológicoRESUMO
BACKGROUND: There is a lack of consensus regarding the optimal method of assessing health-related quality of life (HR-QOL) among patients with metastatic renal cell carcinoma (mRCC). This study explored the perceived relevance of items that make up the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), as judged by patients with mRCC. METHODS: This was a multinational cross-sectional survey. Eligible patients responded to a questionnaire composed of 18 items that assessed the perceived relevance of each item in the FKSI-19 questionnaire. Open-ended questions assessed additional issues deemed relevant by patients. Responses were grouped as relevant (scores 2-5) or nonrelevant (score 1). Descriptive statistics were collated, and open-ended questions were analyzed and categorized into descriptive categories. Spearman correlation statistics were used to test the association between relevance and clinical characteristics. RESULTS: A total of 151 patients were included (gender: 78.1 M, 21.9F; median age: 64; treatment: 38.4 immunotherapy, 29.8 targeted therapy, 13.9 immuno-TKI combination therapy) in the study. The most relevant questions evaluated fatigue (77.5), lack of energy (72.2), and worry that their condition will get worse (71.5). Most patients rated blood in urine (15.2), fevers (16.6), and lack of appetite (23.2) as least relevant. Qualitative analysis of open-ended questions revealed several themes, including emotional and physical symptoms, ability to live independently, effectiveness of treatment, family, spirituality, and financial toxicity. CONCLUSION: There is a need to refine widely used HR-QOL measures that are employed among patients diagnosed with mRCC treated with contemporary therapies. Guidance was provided for the inclusion of more relevant items to patients' cancer journey.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Pessoa de Meia-Idade , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Qualidade de Vida , Estudos Transversais , Inquéritos e Questionários , RimRESUMO
BACKGROUND: Renal cell carcinoma (RCC) is the seventh most common neoplasm in high-income countries. New clinical pathways have been developed to deal with this tumor, which includes costly drugs that pose an economic threat to the sustainability of healthcare services. This study provides an estimate of the direct costs of care for patients with RCC by stage of disease (early vs. advanced) at diagnosis, and disease management phase along the pathway recommended by local and international guidelines. MATERIALS AND METHODS: Considering the clinical pathway for RCC adopted in the Veneto region (north-east Italy) and the latest guidelines, we developed a very detailed "whole-disease" model that covers the probabilities of all potentially necessary diagnostic and therapeutic actions involved in the management of RCC. Based on the cost of each procedure according to the Veneto Regional Authority's official reimbursement tariffs, we estimated the total and average per-patient costs by stage of disease (early or advanced) and phase of its management. RESULTS: In the first year after diagnosis, the mean expected cost of a patient with RCC is 12,991 if it is localized or locally-advanced and reaches 40,586 if it is advanced. For early disease, the main cost is incurred by surgery, whereas medical therapy (first and second line) and supportive care become increasingly important for metastatic disease. CONCLUSION: It is crucially important to examine the direct costs of care for RCC, and to predict the burden on healthcare services of new oncological therapies and treatments, as the findings could be useful for policy-makers planning the allocation of resources.