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INTRODUCTION: The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC). METHODS AND MATERIALS: Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in March 2019. Outcomes included overall survival (OS). A survey of treating physicians assessed reasons for treatment initiations and discontinuations. RESULTS: Overall, 376 patients with mRCC initiated first-line therapy; 171 (45.5%) received pazopanib, 75 (19.9%) sunitinib, and 74 (19.7%) participated in a clinical trial. Median (95% confidence interval) OS was longest in the clinical trial group (50.3 [35.8-not reached] months) versus pazopanib (39.0 [29.7-50.9] months) and sunitinib 26.2 [19.9-61.5] months). Non-clear cell RCC (21.5% of patients) was associated with worse median OS than clear cell RCC (18.0 vs. 47.3 months). Differences in baseline characteristics, treatment starting dose, and relative dose exposure among treatment groups suggest selection bias. Survey results revealed a de-emphasis on quality of life, toxicity, and patient preference compared with efficacy in treatment selection. CONCLUSION: The MaRCC Registry gives insights into real-world first-line treatment selection, outcomes, and physician rationale regarding initial treatment selection prior to the immunotherapy era. Differences in outcomes between clinical trial and off-study patients reflect the difficulty in translating trial results to real-world patients, and emphasize the need to broaden clinical trial eligibility. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed regarding these endpoints.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/patologia , Feminino , Humanos , Imunoterapia , Indazóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Masculino , Estudos Prospectivos , Qualidade de Vida , Sistema de Registros , Estudos Retrospectivos , Sunitinibe/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: The management of Renal cell carcinoma (RCC) patients with liver metastases is challenging. Liver-directed therapy, such as Transarterial radioembolization (TARE), is a reasonable option for these patients; however, its safety and efficacy are not well characterized. This study evaluated the safety and efficacy of TARE in patients with liver-dominant metastatic RCC. MATERIALS AND METHODS: This is a retrospective, single-center study. Thirty-eight patients' medical records were reviewed who underwent TARE between January 1, 2009, and December 31, 2019, in a tertiary cancer center. Two were excluded from further analysis. Thirty-six patients received 51 TARE treatments. Median follow-up time was 18.2 months. Imaging data were evaluated using mRECIST or RECIST 1.1 criteria. Toxicities, treatment responses, liver progression-free survival (LPFS), and median overall survival (OS) were calculated. Univariate and multivariate analyses were conducted to reveal predictors of OS. RESULTS: Median OS from TARE was 19.3 months (95% CI, 22.6-47.4) and from diagnosis of liver metastases was 36.5 months (95% CI: 26.4-49.8). Mild, grade 1 or 2, biochemical toxicity developed in 27 patients (75%). Grade 3-4 toxicity was noted in two patients (5.5%). The objective response rate was 89%; the disease control rate was 94% (21 complete response, 11 partial response, two stable disease, and two progressive disease). Univariate and multivariate analyses showed longer survival in patients who had objective response, lower lung shunt fraction, and better baseline liver function. CONCLUSIONS: TARE is safe and effective and led to promising overall survival in patients with liver-dominant metastatic RCC. LEVEL OF EVIDENCE: Level 3, retrospective cohort study.
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Carcinoma Hepatocelular , Carcinoma de Células Renais , Embolização Terapêutica , Neoplasias Renais , Neoplasias Hepáticas , Carcinoma Hepatocelular/terapia , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/radioterapia , Humanos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/terapia , Fígado , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/radioterapia , Estudos Retrospectivos , Resultado do Tratamento , Radioisótopos de Ítrio/uso terapêuticoRESUMO
BACKGROUND: Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy. OBJECTIVE: To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC. DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease. INTERVENTION: Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method. RESULTS AND LIMITATIONS: The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12-45). Median PFS was 9.2 mo (95% CI 5.5-not estimable), and median OS was 15.6 mo (95% CI 9.2-not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design. CONCLUSIONS: Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination. PATIENT SUMMARY: We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects. CLINICAL REGISTRATION: This trial is registered at ClinicalTrials.Gov as NCT02915783.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/efeitos adversos , Humanos , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia , QuinolinasRESUMO
BACKGROUND: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. METHODS: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. RESULTS: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. CONCLUSIONS: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento , Conduta ExpectanteRESUMO
BACKGROUND: Axitinib plus pembrolizumab showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) versus sunitinib in a randomised phase III trial in patients with advanced renal-cell carcinoma (RCC). We report long-term efficacy and safety of the axitinib/pembrolizumab from the phase I trial (NCT02133742), after 46-55 months from study initiation (data cut-off date, 23rd July 2019). METHODS: Fifty-two treatment-naïve patients with advanced RCC were treated with oral axitinib 5 mg twice daily and intravenous pembrolizumab 2 mg/kg every 3 weeks. PFS, duration of response (DoR) and OS were summarised using the Kaplan-Meier method. RESULTS: At a median follow-up of 42.7 months (95% confidence interval [CI]: 41.1-44.1), median OS was not reached; 38 (73.1%) patients were alive. The probability of being alive at 4 years was 66.8% (95% CI: 49.1-79.5). Median PFS in the overall population was 23.5 months (95% CI: 15.4-30.4). ORR was 73.1%; five patients had complete response. Median DoR was 22.1 months (95% CI: 15.1-34.5). Grade III/IV adverse events (AEs) were reported in 38 (73.1%) patients and 20 (38.5%) discontinued treatment because of AEs: 17 (32.7%) discontinued axitinib, 13 (25.0%) discontinued pembrolizumab, and 10 (19.2%) discontinued both drugs. Common AEs included diarrhoea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%) and dysphonia (48.1%). There were no new AE terms reported and no treatment-related deaths. CONCLUSIONS: In patients with advanced RCC with ~4 years of follow-up, combination axitinib/pembrolizumab continued to demonstrate clinical benefit, with no new safety signals.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Axitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Fatores de Tempo , Estados UnidosRESUMO
PURPOSE: Combined axitinib/pembrolizumab is approved for advanced renal cell carcinoma (aRCC). This exploratory analysis examined associations between angiogenic and immune-related biomarkers and outcomes following axitinib/pembrolizumab treatment. PATIENTS AND METHODS: Prospectively defined retrospective correlative exploratory analyses tested biospecimens from 52 treatment-naïve patients receiving axitinib and pembrolizumab (starting doses 5 mg twice daily and 2 mg/kg respectively, every 3 weeks). Tumor tissue, serum, and whole blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and end of treatment (EOT) for blood-based samples. Clinical outcomes were objective response rate (ORR) and progression-free survival (PFS). RESULTS: Higher baseline tumor levels of CD8 showed a trend toward longer PFS (HR 0.4; P = 0.091). Higher baseline serum levels of CXCL10 (P = 0.0197) and CEACAM1 (P = 0.085) showed a trend toward better ORR and longer PFS, respectively. Patients for whom IL6 was not detected at baseline had longer PFS versus patients for whom it was detected (HR 0.4; P = 0.028). At C2D1 and/or EOT, mainly immune-related biomarkers showed any association with better outcomes. The genes CA9 (P = 0.084), HIF1A (P = 0.064), and IFNG (P = 0.073) showed trending associations with ORR, and AKT3 (P = 0.0145), DDX58 (P = 0.0726), GZMA (P = 0.0666), LCN2 (NGAL; P = 0.0267), and PTPN11 (P = 0.0287) with PFS. CONCLUSIONS: With combined axitinib/pembrolizumab treatment in patients with aRCC, mostly immune-related biomarkers are associated with better treatment outcomes. This exploratory analysis has identified some candidate biomarkers to consider in future prospective testing.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Axitinibe/administração & dosagem , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos de Neoplasias/sangue , Axitinibe/efeitos adversos , Biomarcadores Tumorais/genética , Anidrase Carbônica IX/sangue , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Proteína DEAD-box 58/sangue , Relação Dose-Resposta a Droga , Feminino , Granzimas/sangue , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Interferon gama/sangue , Lipocalina-2/sangue , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neovascularização Patológica/sangue , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Intervalo Livre de Progressão , Proteína Tirosina Fosfatase não Receptora Tipo 11/sangue , Receptores Imunológicos/sangue , Resultado do TratamentoRESUMO
BACKGROUND: Metastatic melanoma (mM) and renal cell carcinoma (mRCC) are often treated with anti-PD-1 based therapy, however not all patients respond and further therapies are needed. High dose interleukin-2 (HD IL-2) can lead to durable responses in a subset of mM and mRCC patients. The efficacy and toxicity of HD IL-2 therapy following anti-PD-1 or anti-PD-L1 therapy have not yet been explored. METHODS: Reports on mM and mRCC patients who had received HD IL-2 after PD-1 or PD-L1 inhibition were queried from the PROCLAIMSM database. Patient characteristics, toxicity and efficacy were analyzed. RESULTS: A total of 57 patients (40 mM, 17 mRCC) were treated with high dose IL-2 after PD-1 or PD-L1 inhibition and had data recorded in the PROCLAIM database. The best overall response rate to HD IL-2 was 22.5% for mM (4 complete response (CR), 5 partial responses (PRs)) and 24% for mRCC (2 CRs, 2 PRs). The toxicity related to HD IL-2 observed in these patients was similar to that observed in patients treated with HD IL-2 without prior checkpoint blockade. One patient who had received prior PD-L1 blockade developed drug induced pneumonitis with HD IL-2 requiring steroid therapy. CONCLUSION: In this retrospective analysis, HD IL-2 therapy displayed durable antitumor activity in mM and mRCC patients who progressed following treatment with PD-1 and PD-L1 inhibition. The toxicities were generally manageable and consistent with expectations from HD IL-2 but physicians should watch for immune related toxicities such as pneumonitis. This analysis supports the development of randomized prospective trials to assess the proper sequencing and combination of immune checkpoint blockade and cytokine therapy.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Interleucina-2/efeitos adversos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Intervalo Livre de Progressão , Adulto JovemRESUMO
Advanced bladder cancer patients have limited therapeutic options resulting in a median overall survival (OS) between 12 and 15 months. Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) has been used successfully in treating patients with metastatic melanoma, resulting in a median OS of 52 months. In this study, we investigated the feasibility of expanding TIL from the tumors of bladder cancer patients. Primary bladder tumors and lymph node (LN) metastases were collected. Tumor specimens were minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. Expanded TIL were phenotyped by flow cytometry and anti-tumor reactivity was assessed after co-culture with autologous tumor digest and IFN-gamma ELISA. Of the 28 transitional cell bladder or LN tumors collected, 14/20 (70%) primary tumors and all of the LN metastases demonstrated TIL expansion. Expanded TIL were predominantly CD3+ (median 63%, range 10-87%) with a median of 30% CD8 + T cells (range 5-70%). TIL secreted IFN-gamma in response to autologous tumor. Addition of agonisitic 4-1BB antibody improved TIL expansion from primary bladder tumors regardless of pre-treatment with chemotherapy. This study establishes the practical first step towards an autologous TIL therapy process for therapeutic testing in patients with bladder cancer.
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BACKGROUND: Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. METHODS: In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. FINDINGS: Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response). INTERPRETATION: The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). FUNDING: Pfizer Inc.
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Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Axitinibe/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Idoso , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Quimioterapia Adjuvante , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Nefrectomia , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Patients with prostate cancer receiving androgen deprivation therapy (ADT) are at risk of sleep disturbance; however, to the authors' knowledge, the mechanisms by which ADT may affect sleep are not well understood. The current study compared objective and subjective sleep disturbance in ADT recipients and controls and examined whether sleep disturbance in ADT recipients is attributable to the influence of ADT on hot flashes and nocturia. METHODS: Patients with prostate cancer were assessed before or within 1 month after the initiation of ADT as well as 6 months and 12 months later (78 patients). Patients with prostate cancer were treated with prostatectomy only (99 patients) and men with no history of cancer (108 men) were assessed at similar intervals. Participants self-reported their sleep disturbance (Insomnia Severity Index) and interference from hot flashes (Hot Flash Related Daily Interference Scale). One hundred participants also wore actigraphs for 3 days at the 6-month assessment to measure objective sleep disturbance and reported their nocturia frequency. RESULTS: ADT recipients reported worse sleep disturbance, higher rates of clinically significant sleep disturbance, and greater hot flash interference than controls (Ps≤.03). In cross-sectional analyses among those with actigraphy data, ADT recipients had greater objective sleep disturbance and more episodes of nocturia (Ps<.01). Cross-sectional mediation analyses demonstrated that the association between ADT and objectively and subjectively measured sleep disturbance was partly attributable to nocturia and hot flashes (Ps<.05). CONCLUSIONS: The results of the current study suggest that the association between ADT and sleep may be partly explained by nocturia and hot flash interference. Future studies should examine behavioral and pharmacologic interventions to address these symptoms among ADT recipients. Cancer 2018;124:499-506. © 2017 American Cancer Society.
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Antagonistas de Androgênios/efeitos adversos , Fogachos/epidemiologia , Noctúria/epidemiologia , Neoplasias da Próstata/tratamento farmacológico , Transtornos do Sono-Vigília/epidemiologia , Idoso , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , ProstatectomiaRESUMO
OBJECTIVES: The adverse sexual effects of androgen deprivation therapy (ADT) on men with prostate cancer have been well described. Less well known is the relative degree of sexual dysfunction and bother associated with ADT compared to other primary treatment modalities such as radical prostatectomy. We sought to describe the trajectory and relative magnitude of changes in sexual function and bother in men on ADT and to examine demographic and clinical predictors of ADT's adverse sexual effects. METHODS: Prostate cancer patients treated with ADT (n = 60) completed assessments of sexual function and sexual bother 3 times during a 1-year period after the initiation of ADT. Prostate cancer patients treated with radical prostatectomy only and not receiving ADT (n = 85) and men with no history of cancer (n = 86) matched on age and education completed assessments at similar intervals. RESULTS: Androgen deprivation therapy recipients reported worsening sexual function and increasing bother over time compared to controls. Effect sizes for the differences in sexual function were large to very large, and for bother were small to very large. Age younger than 83 years predicted relatively poorer sexual function, and age younger than 78 years predicted greater sexual bother at 12 months in men on ADT compared to men not on ADT. CONCLUSIONS: Most men on ADT for prostate cancer will never return to baseline levels of sexual function. Interventions focused on sexual bother over function and designed to help couples build and maintain satisfying relationship intimacy are likely to more positively affect men's psychological well-being while on ADT than medical or sexual aids targeting sexual dysfunction.
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Antagonistas de Androgênios/efeitos adversos , Neoplasias da Próstata/tratamento farmacológico , Comportamento Sexual/psicologia , Disfunções Sexuais Fisiológicas/induzido quimicamente , Adaptação Psicológica , Idoso , Antagonistas de Androgênios/uso terapêutico , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/psicologia , Qualidade de Vida/psicologia , Comportamento Sexual/estatística & dados numéricos , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Parceiros Sexuais/psicologiaRESUMO
Squamous penile cancer may be localized to the phallus, metastatic to regional lymph nodes, or metastatic to distant lymph nodes or other organs. In the clinical situation of regional lymph node metastasis, a multimodality approach can have a big impact on outcomes. In particular, use of systemic chemotherapy as a neoadjuvant treatment is discussed, with several examples illustrating instances of regression and of resistance, and contrasting with adjuvant timing for use of chemotherapy. Radiation with coordinated combined chemotherapy is another complementary, locally directed approach that can be considered for men with squamous penile cancer with regional lymph node spread. The randomized trial InPACT (International Penile Cancer Adjuvant Chemotherapy Trial, NCT02305654) will enroll some of the squamous penile cancer patients with clinically node positive disease.
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IMPORTANCE: The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval. OBJECTIVE: To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC. DESIGN, SETTING, AND PARTICIPANTS: This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein. INTERVENTION: Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES: Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1). RESULTS: A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis). CONCLUSIONS AND RELEVANCE: Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01693562.
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Neoplasias Abdominais/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Abdominais/química , Neoplasias Abdominais/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/análise , Carcinoma de Células de Transição/química , Carcinoma de Células de Transição/secundário , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/química , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Critérios de Avaliação de Resposta em Tumores Sólidos , Retratamento , Taxa de SobrevidaRESUMO
BACKGROUND: Targeting the vascular endothelial growth factor (VEGF) pathway has improved outcomes in metastatic renal cell carcinoma (RCC); however, resistance inevitably occurs. CD105 (endoglin) is an angiogenic pathway that is strongly upregulated after VEGF inhibition, potentially contributing to resistance. The authors tested whether TRC105, a monoclonal antibody against endoglin, impacted disease control in patients with previously treated RCC who were receiving bevacizumab. METHODS: Eligible patients with metastatic RCC who had previously received 1 to 4 prior lines of therapy, including VEGF-targeted agents, were randomized 1:1 to receive bevacizumab 10 mg/kg intravenously every 2 weeks (arm A) or the same plus TRC105 10 mg/kg intravenously every 2 weeks (arm B). The primary endpoint was progression-free survival (PFS) at 12 and 24 weeks. Correlative studies included serum transforming growth factor ß (TGFß) and CD105 levels as well as tissue immunostaining for TGFß receptors. RESULTS: Fifty-nine patients were enrolled (28 on arm A and 31 on arm B), and 1 patient on each arm had a confirmed partial response. The median PFS for bevacizumab alone was 4.6 months compared with 2.8 for bevacizumab plus TRC105 (P = .09). Grade ≥ 3 toxicities occurred in 16 patients (57%) who received bevacizumab compared with 19 (61%) who received bevacizumab plus TRC105 (P = .9). Baseline serum TGFß levels below the median (<10.6 ng/mL) were associated with longer median PFS (5.6 vs 2.1 months; P = .014). CONCLUSIONS: TRC105 failed to improve PFS when added to bevacizumab. TGFß warrants further study as a biomarker in RCC. Cancer 2017;123:4566-4573. © 2017 American Cancer Society.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Papilar/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Bevacizumab/administração & dosagem , Carcinoma Papilar/secundário , Carcinoma de Células Renais/secundário , Feminino , Seguimentos , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaRESUMO
OBJECTIVE: We conducted a retrospective analysis of two clinical trials in treatment-naïve patients (n = 402) with advanced renal cell carcinoma (RCC) treated with axitinib. Our objective was to compare duration of treatment (DT) and clinical outcome in patients who achieved DT >18 months (longer DT) versus ≤18 months (shorter DT). PATIENTS AND METHODS: DT, objective response rate (ORR), tumor shrinkage, and overall survival (OS) were summarized for patients with longer and shorter DT. RESULTS: Overall, 152 patients (37.8%) had longer DT and 250 (62.2%) had shorter DT (median, 34.7 vs. 6.5 months, respectively). ORR in all 402 patients with advanced RCC was 43.5%. ORR was 75% for longer DT versus 24.4% for shorter DT (p < 0.0001). More patients with longer DT versus shorter DT had ≥10% tumor shrinkage at first scan (74.8% vs. 55.3%; p = 0.0001) and maximum on-study tumor shrinkage was greater in longer-DT versus shorter-DT group (-51.8% vs. -22.1%; p < 0.0001). Median OS was 32.6 months in the overall population while in the patients with longer DT the median was not reached. Treatment-related adverse events (AEs) grade ≥3 were more frequent in longer-DT versus shorter-DT and included hypertension (25.7% vs. 18.8%), diarrhea (15.1% vs. 4.4%), and weight decrease (11.2% vs. 3.2%); however, these AEs decreased over time in both groups. Eastern Cooperative Oncology Group performance status 0, favorable hematology values, no bone or liver metastases, and baseline tumor burden below the overall median were associated with longer DT. CONCLUSIONS: Longer duration (>18 months) of axitinib treatment was associated with increased frequency of early tumor shrinkage, greater magnitude of tumor shrinkage, and a favorable OS.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Axitinibe , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Imidazóis/farmacologia , Indazóis/farmacologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Estudos Retrospectivos , Análise de Sobrevida , Carga Tumoral , Adulto JovemRESUMO
PURPOSE: To evaluate safety and efficacy of transarterial hepatic radioembolization treatment of patients with liver-dominant metastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: From July 2010 to December 2014, 18 patients with liver-dominant metastatic RCC were treated with yttrium-90 glass microsphere radioembolization. Retrospective review of medical records and imaging studies was performed to evaluate toxicities, treatment response, and overall survival. The median follow-up period from radioembolization treatment was 17.8 months (range, 3-54.4 months). RESULTS: Median overall survival from RCC diagnosis was 64 months (95% confidence interval [CI], 0-144.1 months), from diagnosis of liver metastasis was 29 months (95% CI, 7.2-50.8 months), and from radioembolization treatment was 22.8 months (95% CI, 13.2-32.3 months). After treatment, 10 patients reported grade 1 clinical toxicities, and 8 patients had grade 1 or 2 biochemical toxicities. The best radiographic responses of 17 patients who underwent contrast-enhanced cross-sectional imaging showed complete response in 16 patients and partial response in 1 patient evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. The last available imaging of these 17 patients demonstrated complete response in 14 patients, partial response in 1 patient, and progression of disease in 2 patients. Images of a patient who underwent noncontrast CT showed stable disease as best response and stable disease on the last available imaging evaluated by RECIST. CONCLUSIONS: Radioembolization is safe and effective and led to improved hepatic disease control and overall survival in patients with liver-dominant metastatic RCC.
Assuntos
Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/terapia , Embolização Terapêutica/métodos , Neoplasias Renais/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Compostos Radiofarmacêuticos/administração & dosagem , Radioisótopos de Ítrio/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/mortalidade , Embolização Terapêutica/efeitos adversos , Embolização Terapêutica/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Radioisótopos de Ítrio/efeitos adversosRESUMO
PURPOSE: Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesis-generating prospective mRCC trial. EXPERIMENTAL DESIGN: Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated lymphocytes, PD-L1 expression (Dako immunohistochemistry; ≥5% vs. <5% tumor membrane staining), tumor gene expression (Affymetrix U219), serum chemokines, and safety were assessed. RESULTS: In 91 treated patients, median overall survival [95% confidence interval (CI)] was 16.4 months [10.1 to not reached (NR)] for nivolumab 0.3 mg/kg, NR for 2 mg/kg, 25.2 months (12.0 to NR) for 10 mg/kg, and NR for treatment-naïve patients. Median percent change from baseline in tumor-associated lymphocytes was 69% (CD3+), 180% (CD4+), and 117% (CD8+). Of 56 baseline biopsies, 32% had ≥5% PD-L1 expression, and there was no consistent change from baseline to on-treatment biopsies. Transcriptional changes in tumors on treatment included upregulation of IFNγ-stimulated genes (e.g., CXCL9). Median increases in chemokine levels from baseline to C2D8 were 101% (CXCL9) and 37% (CXCL10) in peripheral blood. No new safety signals were identified. CONCLUSIONS: Immunomodulatory effects of PD-1 inhibition were demonstrated through multiple lines of evidence across nivolumab doses. Biomarker changes from baseline reflect nivolumab pharmacodynamics in the tumor microenvironment. These data may inform potential combinations. Clin Cancer Res; 22(22); 5461-71. ©2016 AACR.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Fatores Imunológicos/imunologia , Fatores Imunológicos/uso terapêutico , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Quimiocina CXCL10/imunologia , Quimiocina CXCL9/imunologia , Everolimo/imunologia , Everolimo/uso terapêutico , Feminino , Humanos , Interferon gama/imunologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Nivolumabe , Estudos Prospectivos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
BACKGROUND: In a randomized phase II trial in metastatic renal cell carcinoma (mRCC), objective response rate was significantly higher with axitinib versus placebo titration (54% vs. 34%; 1-sided P = .019). PATIENTS AND METHODS: Treatment-naive patients with mRCC (n = 213) received axitinib 5 mg twice per day (b.i.d.) for 4 weeks. Patients meeting dose titration criteria were randomized to receive axitinib 5 mg b.i.d. with axitinib or placebo titration (n = 56 each); 91 patients ineligible for randomization continued axitinib 5 mg b.i.d.; 10 discontinued before randomization. RESULTS: Median overall survival (95% confidence interval [CI]) was 42.7 months (24.7-not estimable) with axitinib titration versus 30.4 months (23.7-45.0) with placebo titration (stratified hazard ratio, 0.785; 95% CI, 0.485-1.272; 1-sided P = .162), and 41.6 months (95% CI, 33.0-not estimable) in nonrandomized patients. Safety data were consistent with previous reports. CONCLUSION: Median overall survival was numerically longer in patients with first-line mRCC who received axitinib versus placebo titration. No new safety signal was observed after long-term axitinib treatment in first-line mRCC.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/uso terapêutico , Axitinibe , Intervalo Livre de Doença , Interação do Duplo Vínculo , Esquema de Medicação , Feminino , Humanos , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Although fatigue is a common problem for men with prostate cancer undergoing androgen deprivation therapy (ADT), there has been little systematic research on this issue. The present study examined changes in fatigue among prostate cancer patients receiving ADT compared to controls and predictors of heightened fatigue in ADT patients. METHODS: Prostate cancer patients treated with ADT (ADT+ group, n = 60) completed assessments of fatigue prior to or just after ADT initiation (baseline) and 6 and 12 months later. Prostate cancer patients treated with prostatectomy only (ADT- group, n = 85) and men without cancer (CA- group, n = 86) matched on age and education completed assessments at similar intervals. RESULTS: Group-by-time interactions for fatigue severity, interference, and duration were observed when comparing the ADT+ group to the controls. Groups did not differ at baseline; however, the ADT+ group reported worse fatigue at 6 and 12 months. The same pattern was observed for changes in the prevalence of clinically meaningful fatigue and the extent of clinically meaningful change in fatigue. Within the ADT+ group, higher baseline comorbidity scores were associated with greater increases in fatigue interference, and higher baseline Gleason scores were associated with greater increases in fatigue duration. CONCLUSIONS: Prostate cancer patients receiving ADT demonstrate a trajectory of worsened fatigue during the first 12 months following treatment initiation relative to the controls. Greater comorbidities and higher Gleason scores at baseline appear to be risk factors for heightened fatigue during the first year following ADT initiation. Results highlight important time points for implementation of interventions aimed at fatigue reduction.
Assuntos
Antagonistas de Androgênios/efeitos adversos , Fadiga/induzido quimicamente , Neoplasias da Próstata/tratamento farmacológico , Qualidade de Vida/psicologia , Idoso , Humanos , Masculino , Fatores de RiscoRESUMO
PURPOSE: Neoadjuvant chemotherapy (NAC) can downstage invasive bladder cancers prior to radical cystectomy (RC) and improve overall survival. However, the optimal management in patients with persistent non-organ confined disease (pT3-T4 and/or pN+) following RC has not been completely defined. The aim of this study was to describe outcomes associated with the use of adjuvant chemotherapy (AC) in patients with residual non-organ confined cancer at RC following NAC. MATERIALS AND METHODS: Using data from a high-volume referral institution, pT3-T4 and/or pN+ patients who received NAC and then also RC were identified. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed with Kaplan-Meier analysis. RESULTS: From 2001 to 2013, 161 patients received NAC and then RC. Eighty-eight pT3-T4 and/or pN+ patients were identified. Twenty-nine (33 %) received AC. Adjuvant chemotherapy in the majority of patients was carboplatin-based (16), followed by cisplatin (8) and other, mainly taxane-containing regimens (5). The median RFS was 17.5 months in the AC and 13.7 months in the non-AC group (p = 0.78). AC remained an insignificant predictor for RFS after adjusting for pT, pN and margin status (HR 0.89, 95 % CI 0.48-1.68]). CSS was 23 and 22 months (p = 0.65) and remained insignificant after adjusting for pathologic confounders. CONCLUSIONS: In our current study population, adjuvant conventional cytotoxic chemotherapy was not associated with significant improvements in RFS or CSS. The choice of AC regimens, and incorporation of newer treatments, may be the key for improving outcomes in this high-risk patient group.