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INTRODUCTION: Enzalutamide (Enza) is an effective treatment for metastatic castrate-resistant prostate cancer (mCPRC). However, Enza is not cost-effective (CE) at willingness to pay (WTP) thresholds from $0-$125 000/quality adjusted life years (QALYs) and is therefore a strain on valuable health care dollars. Metformin (Met) is inexpensive (~$8.00/month) and is thought to improve prostate cancer specific and overall survival compared to those not taking Met. We hypothesized that there must be an added effect Met could provide that would make Enza CE thereby alleviating this financial strain on government health care budgets. MATERIALS AND METHODS: We constructed a Markov model and performed a threshold analysis to narrow in on the added effect needed to make such a combination therapy cost-effective at various WTP thresholds. RESULTS: At a WTP threshold of $50 000/QALY Enza + Met is unlikely to be CE unless it increases Enza's efficacy by more than 30%. At a WTP threshold of $100 000, Enza + Met could be CE barring Met adds 18.73% to the efficacy of Enza. CONCLUSIONS: Enza + Met is unlikely to be CE at WTP thresholds less than $100 000/QALY; these results make sense because a therapy that is not CE at these WTP thresholds by itself is unlikely to be CE with an adjuvant therapy that keep a patient on such a treatment for even longer. Finally, our model suggests that the mCRPC setting is not the optimal place to trial adding Met as the relative costs are high and utility values low.
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Antineoplásicos/uso terapêutico , Metformina/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antineoplásicos/economia , Benzamidas , Análise Custo-Benefício , Quimioterapia Combinada/economia , Humanos , Masculino , Cadeias de Markov , Metformina/economia , Nitrilas , Feniltioidantoína/economia , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/economia , Neoplasias de Próstata Resistentes à Castração/secundário , Neoplasias de Próstata Resistentes à Castração/terapia , Resultado do TratamentoRESUMO
BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
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Adenocarcinoma/tratamento farmacológico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Administração Oral , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Benzamidas , Progressão da Doença , Método Duplo-Cego , Humanos , Masculino , Metástase Neoplásica/diagnóstico por imagem , Nitrilas , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Radiografia , Receptores Androgênicos , Análise de SobrevidaRESUMO
BACKGROUND: Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence. METHODS: Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization. RESULTS: A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events. CONCLUSIONS: Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.).
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Antagonistas de Androgênios/administração & dosagem , Anilidas/administração & dosagem , Hormônio Liberador de Gonadotropina/análogos & derivados , Gosserrelina/administração & dosagem , Nitrilas/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Qualidade de Vida , Compostos de Tosil/administração & dosagem , Idoso , Anilidas/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Intervalos de Confiança , Esquema de Medicação , Seguimentos , Hormônio Liberador de Gonadotropina/uso terapêutico , Gosserrelina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Nitrilas/efeitos adversos , Ereção Peniana/efeitos dos fármacos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Análise de Sobrevida , Compostos de Tosil/efeitos adversosRESUMO
Purpose Preclinical evidence suggests dichloroacetate (DCA) can reverse the Warburg effect and inhibit growth in cancer models. This phase 1 study was undertaken to assess the safety, recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile of oral DCA in patients with advanced solid tumors. Patients and Methods Twenty-four patients with advanced solid malignancies were enrolled using a standard 3 + 3 protocol at a starting dose of 6.25 mg/kg twice daily (BID). Treatment on 28 days cycles was continued until progression, toxicity, or consent withdrawal. PK samples were collected on days 1 and 15 of cycle 1, and day 1 of subsequent cycles. PET imaging ((18) F-FDG uptake) was investigated as a potential biomarker of response. Results Twenty-three evaluable patients were treated with DCA at two doses: 6.25 mg/kg and 12.5 mg/kg BID (median of 2 cycles each). No DLTs occurred in the 6.25 mg/kg BID cohort so the dose was escalated. Three of seven patients had DLTs (fatigue, vomiting, diarrhea) at 12.5 mg/kg BID. Thirteen additional patients were treated at 6.25 mg/kg BID. Most toxicities were grade 1-2 with the most common being fatigue, neuropathy and nausea. No responses were observed and eight patients had stable disease. The DCA PK profile in cancer patients was consistent with previously published data. There was high variability in PK values and neuropathy among patients. Progressive increase in DCA trough levels and a trend towards decreased (18) F-FDG uptake with length of DCA therapy was observed. Conclusions The RP2D of oral DCA is 6.25 mg/kg BID. Toxicities will require careful monitoring in future trials.
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Ácido Dicloroacético/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Adulto , Idoso , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Estudos de Coortes , Ácido Dicloroacético/efeitos adversos , Ácido Dicloroacético/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/metabolismoRESUMO
INTRODUCTION: High-dose chemotherapy with autologous stem-cell transplantation (HDC-ASCT) is standard therapy for metastatic germ cell tumors (mGCTs) in patients whose disease progresses during or after conventional chemotherapy. We conducted a retrospective review of HDC-ASCT in relapsed mGCT patients in the province of Alberta, Canada, over the past two decades. METHODS: Patients with mGCTs who received HDC-ASCT at two provincial cancer referral centers from 2000-2018 were identified from institutional databases. Baseline clinical and treatment characteristics were collected, as well as overall survival (OS ) and disease-free survival (DFS). Relevant prognostic variables were analyzed. RESULTS: Forty-three patients were identified. The median age was 28 years (range 19-56). A majority (95%) had non-seminoma histology and testis/retroperitoneal primary (84%). Twenty patients (47%) had poor-risk disease, as per The International Germ Cell Consensus Classification (IGCCC), at start of first-line chemotherapy. HDC-ASCT was used as second-line therapy in 65% of patients, and 58% of ASCT patients received tandem transplants. Median followup after ASCT was 22 months (range 2-181). At last followup, 42% of patients were alive without disease, including 3/7 (43%) of patients with primary mediastinal disease. Two-year and five-year DFS/OS ratios were 44%/65% and 38%/45%, respectively. Median OS and DFS for all patients were 30.0 months (13.3-46.6) and 8.0 months (0.9-15.1), respectively. CONCLUSIONS: We found that HDC-ASCT is an effective salvage therapy in mGCT, consistent with existing literature. Patients appeared to benefit regardless of primary site. Although limited by small sample size, we found a numerical difference in DFS and OS between second- and third-line HDC-ASCT and single vs. tandem ASCT.
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PURPOSE: The Alberta Prostate Cancer Research Initiative (APCaRI) Registry and Biorepository was established in 2014 by the APCaRI to facilitate the collection of clinical and patient-reported data, biospecimen, to measure prostate cancer outcomes and to support the development and clinical translation of innovative technologies to better diagnose and predict outcomes for patients with prostate cancer. PARTICIPANTS: Men suspected with prostate cancer and referred to Urology centres in Alberta were enrolled in the APCaRI 01 study, while men with a prior prostate cancer diagnosis participated in the APCaRI 03 study from 1 July 2014 to 30 June 2019. The APCaRI Registry and Biorepository links biospecimens and data from a wide representation of patients drawn from an Alberta population of more than 4 million. FINDINGS TO DATE: From 1 July 2014 to 30 June 2019, total APCaRI 01 and 03 study recruitment was 3754 men; 142 (4%) of these men withdrew in full, 65 men (2%) withdrew biospecimens and 123 men (3%) died of any cause. Over this same time, 8677 patient-reported outcome measure (PROM) surveys and 7368 biospecimens were collected and are available from the registry and biorepository, respectively. The data entry error rate was 0.8% and 0.95% for critical and non-critical values, respectively, and 1.8% for patient-reported surveys. FUTURE PLANS: The APCaRI Registry and Biorepository will collect longitudinal data and PROM surveys until 2024, patient outcomes up to 25 years after recruitment and biospecimen storage for up to 25 years. The APCaRI cohorts will continue to provide data and samples to researchers conducting retrospective studies. The richness of the data and biospecimens will complement many different research questions, ultimately to improve the quality of care for men with prostate cancer.
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Neoplasias da Próstata , Alberta/epidemiologia , Humanos , Masculino , Medidas de Resultados Relatados pelo Paciente , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Sistema de Registros , Estudos Retrospectivos , TecnologiaRESUMO
PURPOSE: We determined the associations between comorbidity, and overall survival and bladder cancer specific survival after radical cystectomy. MATERIALS AND METHODS: The Alberta Urology Institute Radical Cystectomy database is an ongoing multi-institutional computerized database containing data on all adult patients with a diagnosis of primary bladder cancer treated with radical cystectomy in Edmonton, Canada from April 1994 forward. The current study is an analysis of consecutive database patients treated between April 1994 and September 2007. Comorbidity information was obtained through a medical record review using the Adult Comorbidity Evaluation 27 instrument. The outcome measures were overall survival and bladder cancer specific survival. Cox proportional regression analysis was used to determine the associations between comorbidity, and overall survival and bladder cancer specific survival. RESULTS: Of the database patients 160 (34%), 225 (48%) and 83 (18%) had no/mild comorbidity, moderate comorbidity and severe comorbidity, respectively. Compared to patients with no or mild comorbidity, multivariate Cox proportional regression analyses that included age, adjuvant chemotherapy, surgeon procedure volume, pathological T stage, pathological lymph node status, total number of lymph nodes removed, surgical margin status and lymphovascular invasion showed that increased comorbidity was independently associated with overall survival (moderate HR 1.59, 95% CI 1.16-2.18, p = 0.004; severe HR 1.83, 95% CI 1.22-2.72, p = 0.003) and bladder cancer specific survival (moderate HR 1.50, 95% CI 1.04-2.15, p = 0.028; severe HR 1.65, 95% CI 1.04-2.62, p = 0.034). CONCLUSIONS: Increased comorbidity was independently associated with an increased risk of overall mortality and bladder cancer specific mortality after radical cystectomy.
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Causas de Morte , Comorbidade , Cistectomia/métodos , Invasividade Neoplásica/patologia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/cirurgia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alberta , Análise de Variância , Estudos de Coortes , Intervalos de Confiança , Cistectomia/mortalidade , Bases de Dados Factuais , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Probabilidade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Sociedades Médicas , Estatísticas não Paramétricas , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologiaRESUMO
BACKGROUND: Sunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient. MATERIALS AND METHODS: In a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria. RESULTS: The null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6-16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18-20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration. CONCLUSIONS: Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. CLINICALTRIALS. GOV IDENTIFIER: NCT01499121.
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Antineoplásicos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Neoplasias Renais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Sunitinibe/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/secundário , Carcinoma de Células Renais/secundário , Relação Dose-Resposta a Droga , Esquema de Medicação , Duração da Terapia , Estudos de Viabilidade , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Intervalo Livre de Progressão , Sunitinibe/farmacocinética , Sunitinibe/uso terapêutico , Taxa de SobrevidaRESUMO
BACKGROUND: Studies of cancer risk and molecular carcinogenesis suggest a role for inflammation in cancer development and progression. The authors sought to determine whether specific blood proteins associated with inflammation predict for outcomes in men with metastatic androgen-independent prostate cancer (AIPC) who are initiating docetaxel-based chemotherapy. METHODS: Baseline plasma samples were stored (-80 degrees C) from 160 of 250 patients enrolled in the AIPC Study of Calcitriol ENhancing Taxotere (ASCENT) trial, a randomized, placebo-controlled trial comparing weekly docetaxel plus high-dose calcitriol with weekly docetaxel. Multiplex immunoassays measured 16 cytokine, chemokine, cardiovascular, or inflammatory markers. The Cox proportional hazards model was used to assess associations between baseline biomarkers, clinical characteristics, and survival. Logistic regression was used for analyses of associations with prostate-specific antigen (PSA) decline. RESULTS: C-reactive protein (CRP) was found to be significantly predictive of a shorter overall survival (hazards ratio [HR] of 1.41 for each natural logarithm [ln] [CRP] increase; 95% confidence interval [95% CI], 1.20-1.65 [P < .0001]). When CRP (continuous) was entered into a multivariate model using 13 baseline clinical variables, only elevated CRP remained a significant predictor (P < .0001) of shorter overall survival. When categorized as normal (
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Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Proteína C-Reativa/metabolismo , Calcitriol/uso terapêutico , Agonistas dos Canais de Cálcio/uso terapêutico , Neoplasias Hormônio-Dependentes/sangue , Neoplasias da Próstata/sangue , Taxoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Docetaxel , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/patologia , Placebos , Prognóstico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Taxa de SobrevidaRESUMO
BACKGROUND & AIMS: Recent research suggests that variations of skeletal muscle (SM) and fat predict the severity of chemotherapy-induced toxicities in patients with renal cell carcinoma (RCC). Cardio-toxicity has not been evaluated in this context. METHODS: In this study we considered 47 RCC patients who participated in randomized clinical trials of sorafenib or sunitinib (i.e., targeted therapy). To capture cardio-toxicity, multi gated acquisition (MUGA) scan-defined left ventricular ejection fraction (LVEF) tests (at least 3 tests over 1 year of treatment) were abstracted. Computed tomography (CT) cross-sectional images were analyzed before start of targeted therapy and at 1 year to define SM and fat at baseline and changes over time concurrent with MUGA-defined LVEF measurement. RESULTS: MUGA-defined cardio-toxicity (usually fall in LVEF >10% to an absolute LVEF<55%) occurred in 8/47 (17%) patients over 1 year of targeted therapy (all were male). Percentage of patients with high fat mass (baseline CT-defined total adipose tissue/indexed by height2 greater than the gender-specific median value) was higher among patients with cardio-toxicity versus patients without cardio-toxicity [7 (87.5%) versus 16 (41.0%); p = 0.02]. The percentage of SM loss in patients with cardio-toxicity was higher than the patients without cardio-toxicity [median of loss (%) -7 versus 0 respectively; p = 0.04]. CONCLUSION: Cardio-toxicity in RCC patients might be associated with high fat mass. This finding is distinct from prior observations that low body weight and sarcopenia associated with non-cardiac toxicities of targeted therapies. Concurrence of SM loss over time and development of cardio-toxicity is reported for the first time.
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Tecido Adiposo/diagnóstico por imagem , Composição Corporal , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Sorafenibe/toxicidade , Sunitinibe/toxicidade , Função Ventricular Esquerda/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sorafenibe/administração & dosagem , Sorafenibe/uso terapêutico , Sunitinibe/administração & dosagem , Sunitinibe/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Exercise has been shown to improve quality of life (QoL) in some cancer survivor groups, but it is unknown if the unique QoL issues faced by bladder cancer survivors are also amenable to an exercise intervention. This study provides the first data examining the association between exercise and QoL in bladder cancer survivors. METHODS: Bladder cancer survivors identified through a provincial cancer registry were mailed a survey that included the Godin Leisure Time Exercise Questionnaire, the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) scale, and the Fatigue Symptom Inventory. RESULTS: Of the 525 bladder cancer survivors (51% response rate) that completed the survey, 22.3% were meeting public health exercise guidelines in the past month, 16.0% were insufficiently active (i.e., some exercise but less than the guidelines), and 61.7% were completely sedentary. ANOVA indicated a general linear association between meeting guidelines and QoL, with those meeting guidelines reporting more favorable scores than completely sedentary survivors on the FACT-Bl (mean difference, 7.6; 95% confidence interval, 3.6-11.7; P < 0.001), the FACT (P = 0.001), the trial outcome index (P < 0.001), functional well-being (P < 0.001), additional concerns (P = 0.001), sexual functioning (P < 0.001), erectile function (P < 0.001), body image (P < 0.001), and various fatigue indicators (P < 0.05). Adjusting for key medical and demographic factors slightly attenuated the magnitude of the associations but did not alter the substantive conclusions. CONCLUSIONS: Exercise is positively associated with QoL in bladder cancer survivors, although few are meeting public health exercise guidelines. Studies testing the causal effects of exercise on QoL issues unique to this population are warranted.
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Exercício Físico/psicologia , Qualidade de Vida , Sobreviventes/psicologia , Neoplasias da Bexiga Urinária/psicologia , Idoso , Análise de Variância , Fadiga/etiologia , Feminino , Humanos , Masculino , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: Clinical trial data has shown pazopanib to be non-inferior in overall survival (OS) compared to sunitinib as first-line treatment for metastatic renal cell carcinoma (mRCC). The purpose of this study was to evaluate outcomes and compare dose-modifying toxicities of mRCC patients treated with suntinib or pazopanib in the real-world setting. METHODS: Data were collected on mRCC patients using the prospective Canadian Kidney Cancer Information System (CKCis) database from January 2011 to November 2015. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. RESULTS: We identified 670 patients treated with sunitinib (n=577) and pazopanib (n=93). There were no significant differences in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (p=0.807). Patients treated with sunitinib had improved OS compared with pazopanib (median 31.7 vs. 20.6 months, p=0.028; adjusted hazard ratio [aHR] 0.60; 95% confidence interval [CI] 0.38-0.94). Time to treatment failure (TTF) was numerically, but not statistically, improved with sunitinib (medians 11.0 vs. 8.4 months, p=0.130; aHR 0.87; 95% CI 0.59-1.28). Outcomes with individualized dosing on sunitinib were unavailable for this analysis. Patients treated with sunitinib had a higher incidence of mucositis, hand-foot syndrome, and gastroesophageal reflux disease; patients treated with pazopanib had a higher incidence of hepatotoxicity. CONCLUSIONS: In Canadian patients with mRCC, treatment with sunitinib appears to be associated with an improved OS compared to pazopanib in the first-line setting. Patient selection factors and the contemporary practice of individualized dosing with sunitinib may contribute to these real-world outcomes and warrant further investigation.
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BACKGROUND: Bone metastases are a common cause of morbidity in patients with prostate carcinoma. We studied the effect of a new bisphosphonate, zoledronic acid, which blocks bone destruction, on skeletal complications in prostate cancer patients with bone metastases. METHODS: Patients with hormone-refractory prostate cancer and a history of bone metastases were randomly assigned to a double-blind treatment regimen of intravenous zoledronic acid at 4 mg (N = 214), zoledronic acid at 8 mg (subsequently reduced to 4 mg; 8/4) (N = 221), or placebo (N = 208) every 3 weeks for 15 months. Proportions of patients with skeletal-related events, time to the first skeletal-related event, skeletal morbidity rate, pain and analgesic scores, disease progression, and safety were assessed. All statistical tests were two-sided. RESULTS: Approximately 38% of patients who received zoledronic acid at 4 mg, 28% who received zoledronic acid at 8/4 mg, and 31% who received placebo completed the study. A greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2%; difference = -11.0%, 95% confidence interval [CI] = -20.3% to -1.8%; P =.021) or those who received zoledronic acid at 8/4 mg (38.5%; difference versus placebo = -5.8%, 95% CI = -15.1% to 3.6%; P =.222). Median time to first skeletal-related event was 321 days for patients who received placebo, was not reached for patients who received zoledronic acid at 4 mg (P =.011 versus placebo), and was 363 days for those who received zoledronic acid at 8/4 mg (P =.491 versus placebo). Compared with urinary markers in patients who received placebo, urinary markers of bone resorption were statistically significantly decreased in patients who received zoledronic acid at either dose (P =.001). Pain and analgesic scores increased more in patients who received placebo than in patients who received zoledronic acid, but there were no differences in disease progression, performance status, or quality-of-life scores among the groups. Zoledronic acid at 4 mg given as a 15-minute infusion was well tolerated, but the 8-mg dose was associated with renal function deterioration. CONCLUSION: Zoledronic acid at 4 mg reduced skeletal-related events in prostate cancer patients with bone metastases.
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Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores/análise , Densidade Óssea/efeitos dos fármacos , Neoplasias Ósseas/complicações , Reabsorção Óssea/metabolismo , Difosfonatos/administração & dosagem , Difosfonatos/efeitos adversos , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Infusões Intravenosas , Masculino , Qualidade de Vida , Resultado do Tratamento , Ácido ZoledrônicoRESUMO
Avascular necrosis (AVN) is the final common pathway resulting from insufficient blood supply to bone, commonly the femoral head. There are many postulated etiologies of non-traumatic AVN, including corticosteroids, bisphosphonates, and radiotherapy (RT). However, it is unclear whether there is a dose threshold for the development of RT-induced AVN. In this case report, we describe a patient with prostate cancer metastatic to bone diagnosed with AVN after receiving single-fraction palliative RT to the left femoral head. Potential contributing factors are discussed, along with a review of other reported cases. At present, the RT dose threshold below which there is no risk for AVN is unknown, and therefore detrimental impact from the RT cannot be excluded. Given the possibility that RT-induced AVN is a stochastic effect, it is important to be aware of the possibility of this diagnosis in any patient with a painful hip who has received RT to the femoral head.
RESUMO
PURPOSE: Androgen deprivation therapy is a common treatment in men with prostate cancer that may cause fatigue, functional decline, increased body fatness, and loss of lean body tissue. These physical changes can negatively affect health-related quality of life. Resistance exercise may help to counter some of these side effects by reducing fatigue, elevating mood, building muscle mass, and reducing body fat. METHODS: In a two-site study, 155 men with prostate cancer who were scheduled to receive androgen deprivation therapy for at least 3 months after recruitment were randomly assigned to an intervention group that participated in a resistance exercise program three times per week for 12 weeks (82 men) or to a waiting list control group (73 men). The primary outcomes were fatigue and disease-specific quality of life as assessed by self-reported questionnaires after 12 weeks. Secondary outcomes were muscular fitness and body composition. RESULTS: Men assigned to resistance exercise had less interference from fatigue on activities of daily living (P =.002) and higher quality of life (P =.001) than men in the control group. Men in the intervention group demonstrated higher levels of upper body (P =.009) and lower body (P <.001) muscular fitness than men in the control group. The 12-week resistance exercise intervention did not improve body composition as measured by changes in body weight, body mass index, waist circumference, or subcutaneous skinfolds. CONCLUSION: Resistance exercise reduces fatigue and improves quality of life and muscular fitness in men with prostate cancer receiving androgen deprivation therapy. This form of exercise can be an important component of supportive care for these patients.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Terapia por Exercício , Fadiga/etiologia , Neoplasias da Próstata/complicações , Neoplasias da Próstata/tratamento farmacológico , Qualidade de Vida , Levantamento de Peso , Atividades Cotidianas , Idoso , Índice de Massa Corporal , Peso Corporal , Fadiga/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético , Aptidão Física , Resultado do TratamentoRESUMO
PURPOSE: Protein kinase C (PKC)-alpha and Raf-1 are important elements of proliferative signal transduction pathways in both normal and malignant cells. Abrogation of either Raf-1 or PKC-alpha function can both inhibit cellular proliferation and induce apoptosis in several experimental cancer models including prostate cancer cell lines. ISIS 3521 and ISIS 5132 are antisense phosphorothioate oligonucleotides that inhibit PKC-alpha and Raf-1 expression, respectively, and induce a broad spectrum of antiproliferative and antitumor effects in several human tumor cell lines. In Phase I evaluation both ISIS 3521 and ISIS 5132 could be safely administered on 21-day i.v. infusion schedules and demonstrated preliminary evidence of antitumor activity. On the basis of these findings, a randomized Phase II study of ISIS 3521 and ISIS 5132 was performed in two comparable cohorts of patients who had chemotherapy-naïve, hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Patients with documented evidence of metastatic HRPC and a prostate-specific antigen (PSA) value > or =20 ng/ml were randomized to receive treatment with either ISIS 3521 or ISIS 5132 as a continuous i.v. infusion for 21 days repeated every 4 weeks. Patients were stratified according to the presence or absence of bidimensionally measurable disease at the time of randomization. The principal endpoints included PSA response, objective response in patients with bidimensionally measurable disease, and treatment failure defined as new or worsening symptoms; a fall in performance status of 2 levels; new or objective progression of disease; or a rise in PSA for 12 weeks without symptom improvement. Plasma samples were collected to assess individual steady-state concentrations and to relate this pharmacokinetic parameter to observed toxicities and responses. RESULTS: Thirty-one patients were randomized in this study; 15 patients received 43 courses of ISIS 3521 and 16 patients received 48 courses of ISIS 5132. The most common toxicities observed were mild to moderate (grade 1 or 2) fatigue and lethargy in 21% and 56% of patients treated with ISIS 3521 and ISIS 5132, respectively. Although no objective or PSA responses were observed in any patient treated with ISIS 3521 or ISIS 5132, persistent stable disease was observed in 3 patients for 5 or more months, and in 5 patients the PSA values did not rise >25% for 120 days or longer. CONCLUSIONS: The antisense oligonucleotides ISIS 3521 and ISIS 5132, at these doses and on this schedule, do not possess clinically significant single-agent antitumor activity in HRPC. Protracted stable disease in some patients may indicate a cytostatic effect. Additional work is required to define the optimal role of PKC-alpha or Raf-1 inhibition in the treatment of HRPC.
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Oligodesoxirribonucleotídeos Antissenso/farmacocinética , Oligonucleotídeos Antissenso/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Tionucleotídeos/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Divisão Celular , Humanos , Isoenzimas/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Oligodesoxirribonucleotídeos Antissenso/toxicidade , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Proteína Quinase C-alfa , Proteínas Proto-Oncogênicas c-raf/metabolismo , Distribuição Aleatória , Transdução de Sinais , Tionucleotídeos/toxicidade , Resultado do TratamentoRESUMO
PURPOSE: Incel (biricodar, VX-710) restores drug sensitivity to P-glycoprotein and multidrug resistance-associated protein-1-expressing cells. This Phase I/II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus doxorubicin in patients with inoperable, locally advanced or metastatic, anthracycline-resistant/refractory, soft tissue sarcoma. EXPERIMENTAL DESIGN: In Phase I, i.v. bolus doxorubicin at 60, 75, or 67.5 mg/m(2) was administered 8 h after initiation of a 72-h continuous i.v. (CIV) infusion of VX-710 (120 mg/m(2)/h) to cohorts of patients to establish a maximum tolerated dose. For efficacy evaluations in Phase II, eligible patients had inoperable, locally advanced or metastatic, anthracycline-resistant/refractory soft tissue sarcoma; < or =225 mg/m(2) cumulative prior doxorubicin; and adequate hematological, liver, and kidney function. Cycles were repeated every 3 weeks. RESULTS: Fourteen patients were enrolled in Phase I. Myelosuppression was the dose-limiting toxicity with 75 and then 67.5 mg/m(2) doxorubicin, and the maximum tolerated dose was established at 60 mg/m(2) with VX-710, 120 mg/m(2)/h, 72-h CIV. VX-710 had no apparent effect on doxorubicin pharmacokinetics. Twenty-nine patients enrolled in Phase II were treated with VX-710, 120 mg/m(2)/h 72-h CIV, and 60 mg/m(2) doxorubicin. Among 26 evaluable patients, minimal activity was noted among 11 patients with gastrointestinal stromal tumors (GISTs); however, in 15 patients with anthracycline-resistant sarcomas of other histologies, 2 achieved partial responses and 7 patients had disease stabilization with an overall median progression-free interval of 3.4 months. CONCLUSION: Anthracycline resistance in GISTs appears to be independent of P-glycoprotein or multidrug resistance-associated protein-1 resistance mechanisms. However, the combination of VX-710 and doxorubicin resulted in objective responses or disease stabilization in patients with strictly defined anthracycline-refractory non-GIST sarcomas, which warrants further evaluation.
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Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
OBJECTIVE: We evaluate the impact of surveillance programs on the outcome of men with clinical stage 1 NSGCT following orchidectomy. PATIENTS AND METHODS: A retrospective review of 197 patients with a minimum of 2 years follow-up at seven cancer centres was conducted. Histological characteristics of the primary tumor were recorded for each patient. Surveillance protocols consisted of clinical assessments, chest X-rays, serum beta HCG (bHCG), alpha feto-protein (aFP), and abdominopelvic CT. All clinic visits and test completions were tracked. In accordance with each centre's specific surveillance protocol, patient compliance was defined as missing no more than two assessments/year. RESULTS: Overall 5 year survival was 100%. With a median follow-up of 54 months (range: 11-164 months), the relapse rate at 5 years was 29%. The median time to relapse was 6 months (range: 2-135 months). Ninety percent of relapses occurred within 18 months and only two patients relapsed after 5 years. On univariate analysis, only the presence of lymphovascular invasion was predictive of relapse. The first indicator of relapse was: CT alone, 36%; elevated bHCG or aFP, 29%; CXR, 10%; or clinical exam, 7%. Either CT, tumor markers, or CXR detected 90% of all relapses. Although differences in the frequency of assessments between the centres existed, no significant differences occurred in rates of relapse or survival (p>0.07). The mean rate of compliance with clinic visit (which included CXR and tumor markers) was 78% (range: 68.4-94.2%). The mean rate of compliance with CT scanning, was 64.3% (range: 32.2-100%). In the centre with the protocol requiring the least frequent visits, the rates of compliance were observed to be highest. CONCLUSIONS: Surveillance remains an effective means of managing stage 1 NSGCT despite variability in protocols and in patients compliance. An abnormal CT was the most frequent identifier of disease relapse, and in combination with tumor markers and CXR, 90% of relapses were detected within 2 years of orchiectomy. Modifications of surveillance protocols to less frequent assessments may be possible and should be subject to prospective evaluation.
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Neoplasias Embrionárias de Células Germinativas/cirurgia , Orquiectomia , Cooperação do Paciente , Neoplasias Testiculares/cirurgia , Canadá , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/patologia , Vigilância da População , Estudos Retrospectivos , Neoplasias Testiculares/patologia , Resultado do TratamentoRESUMO
OBJECTIVE: To examine predictors of adherence in a randomized controlled trial of resistance exercise training (RET) in prostate cancer survivors receiving androgen deprivation therapy. STUDY DESIGN AND SETTING: A randomized controlled trial conducted at fitness centers in Ottawa and Edmonton, Canada. Prostate cancer survivors (n=155) completed measures of social cognitive variables, quality of life (QOL), behavior, and fitness before being randomized to either an exercise (n=82) or control (n=73) group. The exercise group was asked to perform supervised RET three times per week for 12 weeks. RESULTS: The exercise group attended 28.2 of the 36 (78.3%) RET sessions. Univariate analyses revealed eight different significant (Ps <.05) predictors of exercise adherence including exercise stage of change, intention, age, QOL, fatigue, subjective norm, leg-press test, and perceived behavioral control. A multivariate analysis indicated that there were three independent predictors of adherence that explained 20.4% of the variance: exercise stage of change (beta=0.26; P=.013), age (beta=-0.22; P=.037), and intention (beta=0.19; P=.073). CONCLUSION: Exercise adherence in the trial was very good but not optimal. Adherence was predicted by variables from many different categories including social cognitive, QOL, behavioral, fitness, and demographic. These findings may have important implications for maximizing adherence during clinical trials of exercise in prostate cancer survivors.
Assuntos
Terapia por Exercício , Cooperação do Paciente , Neoplasias da Próstata/terapia , Fatores Etários , Antagonistas de Androgênios/uso terapêutico , Atitude , Humanos , Masculino , Análise Multivariada , Estudos Prospectivos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/psicologiaRESUMO
INTRODUCTION: Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) for muscle invasive urothelial carcinoma of the bladder improves survival. This study was undertaken to determine the rate of neoadjuvant gemcitabine and cisplatin use prior to RC and to assess its effect on the pathologic response rates and cancer-specific survival (CSS) and overall survival (OS). METHODS: This retrospective chart review examined all patients having a RC between January 1, 2007 and June 30, 2011. We collected patient demographics, pre-treatment clinical stage, type of chemotherapy, post-RC pathologic data and survival data. RESULTS: A total of 251 RC were performed of which 160 were for stage cT2-T4 urothelial carcinoma of the bladder. Of the 160 patients, 91 (57%) received neoadjuvant gemcitabine and cisplatin (GC) and 69 (43%) went straight to RC. Patients receiving neoadjuvant GC had a greater chance of achieving a pathologically lower stage compared to the untreated population: pT0 at 21% vs. 3%; non-invasive cancer at 37% vs. 10%; and organ-confined cancer at 60% vs. 33% (p < 0.001). Survival correlated with pathological stage: ≤pT3a patients had a median OS and CSS of 48.8 and 51.2 months compared to an OS and a CSS in ≥pT3b patients of 21.8 and 28.1 months, respectively (p < 0.0001). CONCLUSIONS: Neoadjuvant chemotherapy for urothelial carcinoma of the bladder is more frequently administered at our institution compared to the published literature. We have found that neoadjuvant chemotherapy increases the rate of down-staging, which is associated with a reduced the risk of death from urothelial carcinoma of the bladder.