RESUMO
Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.
Assuntos
Neoplasias Encefálicas , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Encefálicas/terapia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Terapia Combinada , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/terapiaRESUMO
BACKGROUND: The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown. METHODS: In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization. RESULTS: Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P = 0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing. CONCLUSIONS: Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Prognóstico , Método Duplo-Cego , Análise de SobrevidaRESUMO
BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Nefrectomia , Nivolumabe , Humanos , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , Nivolumabe/efeitos adversos , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/mortalidade , Masculino , Feminino , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Pessoa de Meia-Idade , Idoso , Canadá , Quimioterapia Adjuvante , Estadiamento de Neoplasias , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagemRESUMO
BACKGROUND: Existing data on the impact of Hispanic ethnicity on outcomes for patients with renal cell carcinoma (RCC) is mixed. The authors investigated outcomes of Hispanic and non-Hispanic White (NHW) patients with advanced RCC receiving systemic therapy at large academic cancer centers using the International Metastatic Renal Cell Carcinoma Database (IMDC). METHODS: Eligible patients included non-Black Hispanic and NHW patients with locally advanced or metastatic RCC initiating systemic therapy. Overall survival (OS) and time to first-line treatment failure (TTF) were calculated using the Kaplan-Meier method. The effect of ethnicity on OS and TTF were estimated by Cox regression hazard ratios (HRs). RESULTS: A total of 1563 patients (181 Hispanic and 1382 NHW) (mostly males [73.8%] with clear cell RCC [81.5%] treated with tyrosine kinase inhibitor [TKI] monotherapy [69.9%]) were included. IMDC risk groups were similar between groups. Hispanic patients were younger at initial diagnosis (median 57 vs. 59 years, p = .015) and less likely to have greater than one metastatic site (60.8% vs. 76.8%, p < .001) or bone metastases (23.8% vs. 33.4%, p = .009). Median OS and TTF was 38.0 months (95% confidence interval [CI], 28.1-59.2) versus 35.7 months (95% CI, 31.9-39.2) and 7.8 months (95% CI, 6.2-9.0) versus 7.5 months (95% CI, 6.9-8.1), respectively, in Hispanic versus NHW patients. In multivariable Cox regression analysis, no statistically significant differences were observed in OS (adjusted hazard ratio [HR], 1.07; 95% CI, 0.86-1.31, p = .56) or TTF (adjusted HR, 1.06; 95% CI, 0.89-1.26, p = .50). CONCLUSIONS: The authors did not observe statistically significant differences in OS or TTF between Hispanic and NHW patients with advanced RCC. Receiving treatment at tertiary cancer centers may mitigate observed disparities in cancer outcomes.
Assuntos
Carcinoma de Células Renais , Hispânico ou Latino , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/etnologia , Carcinoma de Células Renais/mortalidade , Masculino , Hispânico ou Latino/estatística & dados numéricos , Feminino , Pessoa de Meia-Idade , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Neoplasias Renais/etnologia , Idoso , População Branca/estatística & dados numéricos , Bases de Dados Factuais , Resultado do Tratamento , Adulto , Estimativa de Kaplan-MeierRESUMO
BACKGROUND: Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens. MATERIALS AND METHODS: Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively. Patients with mRCC who received either dual ICI therapy or ICI with VEGF-TKI in the first-line setting were included and were categorized as current, former, or nonsmokers. The primary outcomes were OS, time to treatment failure (TTF), and objective response rate (ORR). OS and TTF were compared between groups using the log-rank test and multivariable Cox regression models. ORR was assessed between the 3 groups using a multivariable logistic regression model. RESULTS: A total of 989 eligible patients were included in the analysis, with 438 (44.3%) nonsmokers, 415 (42%) former, and 136 (13.7%) current smokers. Former smokers were older and included more males, while other baseline characteristics were comparable between groups. Median follow-up for OS was 21.2 months. In the univariate analysis, a significant difference between groups was observed for OS (Pâ =â .027) but not for TTF (Pâ =â .9), with current smokers having the worse 2-year OS rate (62.8% vs 70.8% and 73.1% in never and former smokers, respectively). After adjusting for potential confounders, no significant differences in OS or TTF were observed among the 3 groups. However, former smokers demonstrated a higher ORR compared to never smokers (OR 1.45, Pâ =â .02). CONCLUSION: Smoking status does not appear to independently influence the clinical outcomes to first-line ICI-based regimens in patients with mRCC. Nonetheless, patient counseling on tobacco cessation remains a crucial aspect of managing patients with mRCC, as it significantly reduces all-cause mortality.
Assuntos
Carcinoma de Células Renais , Inibidores de Checkpoint Imunológico , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Masculino , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Feminino , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Fumar/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Paradigm shifts in kidney cancer management have led to higher health care spending. Here, total and per capita health care spending and primary drivers of change in health expenditures for kidney cancer in the United States between 1996 and 2016 are estimated. METHODS: Public databases developed by the Institute for Health Metrics and Evaluation for the Disease Expenditure Project were used. The prevalence of kidney cancer was estimated from the Global Burden of Disease Study. Changes in health care spending on kidney cancer were assessed by joinpoint regression and expressed as annual percent changes (APCs). RESULTS: In 2016, total health care spending on kidney cancer was $3.42 billion (95% CI, $2.91 billion to $3.89 billion) compared with $1.18 billion (95% CI, $1.07 billion to $1.31 billion) in 1996. Per capita spending had two inflection points in 2005 and 2008, close to the approval years of targeted therapies, which corresponded to APCs of +2.9% (95% CI, +2.3% to +3.6%; p < .001) per year, 1996-2005; +9.2% (95% CI, +3.4% to +15.2%; p = .004) per year, 2005-2008; and +3.1% (95% CI, +2.2% to +3.9%; p < .001) per year, 2008-2016. Inpatient care was the largest contributor to health expenditures, which accounted for $1.56 billion (95% CI, $1.19 billion to $1.95 billion) in 2016. Price and intensity of care was the primary driver of increased health expenditures, whereas service utilization was the primary driver of reduced health expenditures. CONCLUSIONS: Prevalence-adjusted health care spending on kidney cancer continues to rise in the United States, which is primarily attributable to inpatient care and driven by the price and intensity of care over time.
Assuntos
Gastos em Saúde , Neoplasias Renais , Humanos , Estados Unidos/epidemiologia , Hospitalização , Prevalência , Neoplasias Renais/epidemiologia , Neoplasias Renais/terapiaRESUMO
BACKGROUND: Active surveillance after orchiectomy is the preferred management in clinical stage I (CSI) germ-cell tumours (GCT) associated with a 15 to 30% relapse rate. PATIENTS AND METHODS: In the IGCCCG Update database, we compared the outcomes of gonadal disseminated GCT relapsing from initial CSI to outcomes of patients with de novo metastatic GCT. RESULTS: A total of 1014 seminoma (Sem) [298 (29.4%) relapsed from CSI, 716 (70.6%) de novo] and 3103 non-seminoma (NSem) [626 (20.2%) relapsed from CSI, 2477 (79.8%) de novo] were identified. Among Sem, no statistically significant differences in PFS and OS were found between patients relapsing from CSI and de novo metastatic disease [5-year progression-free survival (5y-PFS) 87.6% versus 88.5%; 5-year overall survival (5y-OS) 93.2% versus 96.1%). Among NSem, PFS and OS were higher overall in relapsing CSI patients (5y-PFS 84.6% versus 80.0%; 5y-OS 93.3% versus 88.7%), but there were no differences within the same IGCCCG prognostic groups (HR = 0.89; 95% CI: 0.70-1.12). Relapses in the intermediate or poor prognostic groups occurred in 11/298 (4%) Sem and 112/626 (18%) NSem. CONCLUSION: Relapsing CSI GCT patients expect similar survival compared to de novo metastatic patients of the same ICCCCG prognostic group. Intermediate and poor prognosis relapses from initial CSI expose patients to unnecessary toxicity from more intensive treatments.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Segunda Neoplasia Primária , Seminoma , Neoplasias Testiculares , Masculino , Humanos , Neoplasias Testiculares/cirurgia , Prognóstico , Intervalo Livre de Progressão , Seminoma/cirurgia , RecidivaRESUMO
BACKGROUND: Preserving health-related quality of life (HRQOL) is an important goal during renal cell carcinoma treatment. We report HRQOL outcomes from a phase II trial (NCT03173560). PATIENTS AND METHODS: HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of 2 different starting doses of lenvatinib (18 mg vs. 14 mg daily) in combination with everolimus (5 mg daily), following one prior vascular endothelial growth factor-targeted treatment. HRQOL was measured using 3 different instruments-FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L-which were all secondary endpoints. Change from baseline was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale. TTD for each treatment arm was estimated using the Kaplan-Meier method. RESULTS: Baseline characteristics of the 343 participants randomly assigned to 18 mg lenvatinib (n = 171) and 14 mg lenvatinib (n = 172) were well balanced. Least-squares mean estimates for change from baseline were favorable for the 18 mg group over the 14 mg group for the FKSI-DRS and most EORTC QLQ-C30 scales, but differences between treatments did not exceed the minimally important thresholds. Median TTD was longer among participants in the 18 mg group than those in the 14 mg group for most scales. CONCLUSIONS: Participants who received an 18 mg lenvatinib starting dose had favorable HRQOL scores and longer TTD on most scales compared with those who received a 14 mg starting dose.
Assuntos
Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Everolimo/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Qualidade de Vida , Fator A de Crescimento do Endotélio Vascular , Antineoplásicos/administração & dosagemRESUMO
BACKGROUND: Risk stratification tools for patients with advanced melanoma (AM) treated with immune checkpoint inhibitors (ICI) are lacking. We identified a new prognostic model associated with overall survival (OS). PATIENTS AND METHODS: A total of 318 treatment naïve patients with AM receiving ICI were collected from a multi-centre retrospective cohort study. LASSO Cox regression identified independent prognostic factors associated with OS. Model validation was carried out on 500 iterations of bootstrapped samples. Harrel's C-index was calculated and internally validated to outline the model's discriminatory performance. External validation was carried out in 142 advanced melanoma patients receiving ICI in later lines. RESULTS: High white blood cell count (WBC), high lactate dehydrogenase (LDH), low albumin, Eastern Cooperative Oncology Group (ECOG) performance status ≥1, and the presence of liver metastases were included in the model. Patients were parsed into 3 risk groups: favorable (0-1 factors) OS of 52.9 months, intermediate (2-3 factors) OS 13.0 months, and poor (≥4 factors) OS 2.7 months. The C-index of the model from the discovery cohort was 0.69. External validation in later-lines (N = 142) of therapy demonstrated a c-index of 0.65. CONCLUSIONS: Liver metastases, low albumin, high LDH, high WBC, and ECOG≥1 can be combined into a prognostic model for AM patients treated with ICI.
Assuntos
Neoplasias Hepáticas , Melanoma , Humanos , Prognóstico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Estudos Retrospectivos , Melanoma/patologia , AlbuminasRESUMO
PURPOSE: Clinical trials have demonstrated higher complete response rates in the immuno-oncology-based combination arms than in the tyrosine kinase inhibitor arms in patients with metastatic renal cell carcinoma. We aimed to characterize real-world patients who experienced complete response to the contemporary first-line therapies. MATERIALS AND METHODS: Using the International Metastatic Renal Cell Carcinoma Database Consortium, response-evaluable patients who received frontline immuno-oncology-based combination therapy or tyrosine kinase inhibitor monotherapy were analyzed. Baseline characteristics of patients and post-landmark overall survival were compared based on best overall response, as per RECIST 1.1. RESULTS: A total of 52 (4.6%) of 1,126 and 223 (3.0%) of 7,557 patients experienced complete response to immuno-oncology-based and tyrosine kinase inhibitor therapies, respectively (P = .005). An adjusted odds ratio for complete response achieved by immuno-oncology-based combination therapy (vs tyrosine kinase inhibitor monotherapy) was 1.56 (95% CI 1.11-2.17; P = .009). Among patients who experienced complete response, the immuno-oncology-based cohort had a higher proportion of non-clear cell histology (15.9% and 4.7%; P = .016), sarcomatoid dedifferentiation (29.8% and 13.5%; P = .014), and multiple sites of metastases (80.4% and 50.0%; P < .001) than the tyrosine kinase inhibitor cohort. Complete response was independently associated with post-landmark overall survival benefit in both the immuno-oncology-based and tyrosine kinase inhibitor cohorts, giving respective adjusted hazard ratios of 0.17 (95% CI 0.04-0.72; P = .016) and 0.28 (95% CI 0.21-0.38; P < .001). CONCLUSIONS: The complete response rate was not as high in the real-world population as in the clinical trial population. Among those who experienced complete response, several adverse clinicopathological features were more frequently observed in the immuno-oncology-based cohort than in the tyrosine kinase inhibitor cohort. Complete response was an indicator of favorable overall survival.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Resultado do Tratamento , Modelos de Riscos Proporcionais , Imunoterapia , Estudos Retrospectivos , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: The COVID-19 pandemic is suspected to have affected cancer care and outcomes among patients in Canada. In this study, we evaluated the impact of the state of emergency period during the COVID-19 pandemic (Mar. 17 to June 15, 2020) on cancer diagnoses, stage at diagnosis and 1-year survival in Alberta. METHODS: We included new diagnoses of the 10 most prevalent cancer types from Jan. 1, 2018, to Dec. 31, 2020. We followed patients up to Dec. 31, 2021. We used interrupted time series analysis to examine the impact of the first COVID-19-related state of emergency in Alberta on the number of cancer diagnoses. We used multivariable Cox regression to compare 1-year survival of the patients who received a diagnosis during 2020 after the state of emergency with those who received a diagnosis during 2018 and 2019. We also performed stage-specific analyses. RESULTS: We observed significant reductions in diagnoses of breast cancer (incidence rate ratio [IRR] 0.67, 95% confidence interval [CI] 0.59-0.76), prostate cancer (IRR 0.64, 95% CI 0.56-0.73) and colorectal cancer (IRR 0.64, 95% CI 0.56- 0.74) and melanoma (IRR 0.57, 95% CI 0.47-0.69) during the state of emergency period compared with the period before it. These decreases largely occurred among early-stage rather than late-stage diagnoses. Patients who received a diagnosis of colorectal cancer, non-Hodgkin lymphoma and uterine cancer in 2020 had lower 1-year survival than those diagnosed in 2018; no other cancer sites had lower survival. INTERPRETATION: The results from our analyses suggest that health care disruptions during the COVID-19 pandemic in Alberta considerably affected cancer outcomes. Given that the largest impact was observed among early-stage cancers and those with organized screening programs, additional system capacity may be needed to mitigate future impact.
Assuntos
Neoplasias da Mama , COVID-19 , Neoplasias Colorretais , Masculino , Humanos , Alberta , PandemiasRESUMO
The first-in-class, small molecule HIF-2α inhibitor, belzutifan, has demonstrated promising antitumor activity in previously treated patients with clear cell renal cell carcinoma (RCC). HIF-2α also regulates VEGF expression and is involved in resistance to anti-VEGF therapy. This study describes the rationale and design for a randomized, phase III study evaluating efficacy and safety of belzutifan plus the tyrosine kinase inhibitor (TKI) lenvatinib versus the TKI cabozantinib in patients with advanced RCC progressing after anti-PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy. Considering the unmet need for effective and tolerable treatment of advanced RCC following immune checkpoint inhibitors, belzutifan plus lenvatinib may have a positive benefit/risk profile. Clinical Trial Registration: NCT04586231 (ClinicalTrials.gov).
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Antígeno B7-H1 , Inibidores de Proteínas Quinases/efeitos adversos , Fatores de Transcrição Hélice-Alça-Hélice BásicosRESUMO
BACKGROUND: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. METHODS: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. FINDINGS: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. INTERPRETATION: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. FUNDING: National Institutes of Health and National Cancer Institute.
Assuntos
Anilidas/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Sunitinibe/administração & dosagem , Idoso , Anilidas/efeitos adversos , Canadá , Carcinoma de Células Renais/mortalidade , Crizotinibe/administração & dosagem , Crizotinibe/efeitos adversos , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/efeitos dos fármacos , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Piridinas/efeitos adversos , Sunitinibe/efeitos adversos , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Estados UnidosRESUMO
BACKGROUND: Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown. METHODS: Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups. RESULTS: Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of life was similar between both groups. After adjustment with propensity score matching, CM use was also associated with longer overall survival in patients with lung cancer (adjusted hazard ratio 0.80, 95%CI, 0.68-0.94, P =.0054). However, several key control variables like EGFR status were not available. CONCLUSION: One in 5 patients in phase III clinical trials report using CM. CM was not associated with worse cancer-specific outcomes. However, CM users had more favorable baseline prognostic factors, and likely other confounders that may have contributed to improved outcomes observed in the lung cohort. Physicians should monitor for CM use and potential interactions with clinical trial drugs.
Assuntos
Ensaios Clínicos Fase III como Assunto , Terapias Complementares , Metástase Neoplásica , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Terapias Complementares/efeitos adversos , Terapias Complementares/estatística & dados numéricos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Metástase Neoplásica/terapia , Qualidade de Vida , Estudos RetrospectivosRESUMO
LESSONS LEARNED: The primary endpoint of this phase II study that evaluated the efficacy and safety of the investigational compound, AGS-16C3F, versus axitinib in previously treated patients with metastatic renal cell carcinoma (mRCC) was not met. Median progression-free survival, the primary endpoint, was 2.9 months with AGS-16C3F and 5.7 months with axitinib (HR, 1.676; 95% CI, 1.107-2.537; p = .015), per investigator assessment The safety profile for each study drug was as expected, with the most commonly reported adverse events being fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. These results provide a benchmark for axitinib use in heavily pretreated patients with mRCC. BACKGROUND: AGS-16C3F is a novel antibody-drug conjugate that targets cell-surface ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) and is conjugated to a microtubule disruptive agent. Here we present findings from a phase II study of AGS-16C3F versus axitinib in metastatic renal cell carcinoma (mRCC). METHODS: Patients with mRCC of any histology and disease progression during or after their last treatment regimen were randomized 1:1 to intravenous AGS-16C3F 1.8 mg/kg every 3 weeks or oral axitinib 5 mg twice daily (starting dose). The primary objective was investigator-assessed progression-free survival (PFS) of AGS-16C3F versus axitinib (RECIST version 1.1). RESULTS: In the total population (N = 133), 63% (n = 84) of patients had completed the study at data cutoff (August 21, 2019). Median PFS was 2.9 months with AGS-16C3F and 5.7 months with axitinib (hazard ratio [HR], 1.676; 95% confidence interval [CI], 1.107-2.537; p = .015). There were no significant differences between arms in secondary efficacy endpoints, including overall survival (13.1 months, AGS-16C3F and 15.4 months, axitinib; HR, 1.079; 95% CI, 0.681-1.707; p = .747). In the safety population (n = 131), the most commonly reported adverse events were fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. The incidence of diarrhea was lower in the AGS-16C3F arm than in the axitinib arm (17% vs. 48%), and ocular toxicities were more frequent in the AGS-16C3F arm than in the axitinib arm (44% vs. 26%). CONCLUSION: The investigational compound, AGS-16C3F, did not meet the primary endpoint of this trial. These study results provide a benchmark for axitinib use in heavily pretreated patients with mRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Anticorpos Monoclonais Humanizados , Axitinibe , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Resultado do TratamentoRESUMO
PURPOSE: The time between radiographic identification of a renal tumor and surgery can be concerning for patients and clinicians due to fears of tumor progression while awaiting treatment. This study aimed to evaluate the association between surgical wait time and oncologic outcomes for patients with renal cell carcinoma. MATERIALS AND METHODS: The Canadian Kidney Cancer Information System is a multi-institutional prospective cohort initiated in January 2011. Patients with clinical stage T1b or greater renal cell carcinoma diagnosed between January 2011 and December 2019 were included in this analysis. Outcomes of interest were pathological up staging, cancer recurrence, cancer specific survival and overall survival. Time to recurrence and death were estimated using Kaplan-Meier estimates and associations were determined using Cox proportional hazards models. RESULTS: A total of 1,769 patients satisfied the study criteria. Median wait times were 54 days (IQR 29-86) for the overall cohort and 81 days (IQR 49-127) for cT1b tumors (1,166 patients), 45 days (IQR 27-71) for cT2 tumors (672 cases) and 35 days (IQR 18-61) for cT3/4 tumors (563). Adjusting for comorbidity, tumor size, grade, histological subtype, margin status and pathological stage, there was no association between prolonged wait time and cancer recurrence or death. CONCLUSIONS: In the context of current surgeon triaging practices surgical wait times up to 24 weeks were not associated with adverse oncologic outcomes after 2 years of followup.
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Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Recidiva Local de Neoplasia/epidemiologia , Nefrectomia/estatística & dados numéricos , Tempo para o Tratamento/estatística & dados numéricos , Idoso , Canadá/epidemiologia , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Rim/diagnóstico por imagem , Rim/patologia , Rim/cirurgia , Neoplasias Renais/diagnóstico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Nefrectomia/normas , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Radiografia/estatística & dados numéricos , Fatores de Tempo , Tempo para o Tratamento/normas , Triagem/normas , Triagem/estatística & dados numéricosRESUMO
This systematic review aims to gather primary data from cancer institutions that have implemented changes to cancer service provision amid the COVID-19 outbreak to inform future intervention and health care facility response strategies. A comprehensive literature search was done on Global Health Medline and EMBASE using pertinent key words and MeSH terms relating to COVID-19 and Cancer service provision. A total of 72 articles were selected for inclusion in this systematic review. Following the narrative synthesis that was conducted of the literature, 6 core themes that encompassed common cancer service intervention adopted by institutions were identified: (1) Testing and Tracking, (2) Outreach and Communication, (3) Protection, (4) Social Distancing (5) Treatment Management, (6) Service Restructuring. Since cancer patients are a high-risk population amid the COVID-19 pandemic, these areas of targeted intervention can be used to inform necessary actions in institutions facing similar risks, based on previous learning from numerous cancer centers globally.
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COVID-19/epidemiologia , Institutos de Câncer/organização & administração , Neoplasias/diagnóstico , Neoplasias/terapia , Comunicação , Humanos , Controle de Infecções/organização & administração , Pandemias , Distanciamento Físico , SARS-CoV-2RESUMO
BACKGROUND: International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium (IMDC) risk groups are important when considering therapeutic options for first-line treatment. MATERIALS AND METHODS: Adult patients with clear cell mRCC initiating first-line sunitinib between 2010 and 2018 were included in this retrospective database study. Median time to treatment discontinuation (TTD) and overall survival (OS) were estimated using Kaplan-Meier analysis. Outcomes were stratified by IMDC risk groups and evaluated for those in the combined intermediate and poor risk group and separately for those in the intermediate risk group with one versus two risk factors. RESULTS: Among 1,769 patients treated with first-line sunitinib, 318 (18%) had favorable, 1,031 (58%) had intermediate, and 420 (24%) had poor IMDC risk. Across the three risk groups, patients had similar age, gender, and sunitinib initiation year. Median TTD was 15.0, 8.5, and 4.2 months in the favorable, intermediate, and poor risk groups, respectively, and 7.1 months in the combined intermediate and poor risk group. Median OS was 52.1, 31.5, and 9.8 months in the favorable, intermediate, and poor risk groups, respectively, and 23.2 months in the combined intermediate and poor risk group. Median OS (35.1 vs. 21.9 months) and TTD (10.3 vs. 6.6 months) were significantly different between intermediate risk patients with one versus two risk factors. CONCLUSION: This real-world study found a median OS of 52 months for patients with favorable IMDC risk treated with first-line sunitinib, setting a new benchmark on clinical outcomes of clear cell mRCC. Analysis of intermediate risk group by one or two risk factors demonstrated distinct clinical outcomes. IMPLICATIONS FOR PRACTICE: This analysis offers a contemporary benchmark for overall survival (median, 52.1 months; 95% confidence interval, 43.4-61.2) among patients with clear cell metastatic renal cell carcinoma who were treated with sunitinib as first-line therapy in a real-world setting and classified as favorable risk according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification. This study demonstrates that clinical outcomes differ between IMDC risk groups as well as within the intermediate risk group based on the number of risk factors, thus warranting further consideration of risk group when counseling patients about therapeutic options and designing clinical trials.
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Carcinoma de Células Renais , Neoplasias Renais , Adulto , Carcinoma de Células Renais/tratamento farmacológico , Intervalo Livre de Doença , Humanos , Neoplasias Renais/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Sunitinibe/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). MATERIALS AND METHODS: To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. RESULTS: Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. CONCLUSION: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic. IMPLICATIONS FOR PRACTICE: Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity.
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COVID-19/epidemiologia , Institutos de Câncer/estatística & dados numéricos , Neoplasias Embrionárias de Células Germinativas/terapia , COVID-19/prevenção & controle , Canadá/epidemiologia , Institutos de Câncer/tendências , Europa (Continente)/epidemiologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Oncologistas/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Padrões de Prática Médica/tendências , SARS-CoV-2 , Inquéritos e Questionários , Telemedicina/tendênciasRESUMO
This bibliometric analysis aims to identify publications and highlight the key areas that have shaped modern clinical practices for aortic valve replacement (AVR). In this paper, the top 100 most cited manuscripts for AVR are analyzed. The Thomson Reuters Web of Science database was searched using the terms "aortic valve replacement," "AVR," "sAVR," "tAVR," or "TAVI." The results were ranked by citation number and the top 100 articles were further analyzed by evaluating the subject, author, journal, year of publication, institution, and country of origin. Thirty-thousand and eight hundred eligible papers were examined, with an accumulation of 81 851 citations in total and a mean citation of 819 per manuscript (ranged: 344-4180). The New England Journal of Medicine had the most manuscripts whereas Circulation had the most citations. The number of citations has also significantly increased for articles published after 2000.The most cited manuscript highlighting the management of valvular heart disease, was written by Baumgartner et al By providing the most influential references, this work serves as a comprehensive guide to topics of interest in the field of AVR.