RESUMO
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.
Assuntos
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
The treatment paradigm for advanced and metastatic renal cell carcinoma (mRCC) has evolved rapidly since the arrival of targeted therapies and novel immunotherapies. mRCC was previously treated only with cytokines. However, discoveries of mutations affecting the von Hippel-Lindau tumor suppressor gene (leading to increased expression of VEGF and hypoxia inducible factor/HIF-1) and of deregulations in the phosphatidylinositol-3 kinase/AKT/mTOR pathway (resulting in tumor angiogenesis, cell proliferation, and tumor growth) have led to the development of numerous targeted therapies. The U.S. Food and Drug Administration (FDA) has thus approved a total of nine targeted therapies since 2005, including VEGF tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, sorafenib, and lenvatinib), a monoclonal antibody targeting VEGF (bevacizumab), mTOR inhibitors (temsirolimus and everolimus), and a multityrosine kinase inhibitor (cabozantinib). Furthermore, the development of immune checkpoint inhibitors has again shifted the mRCC therapeutic landscape with the FDA's approval of nivolumab. Herein, we discuss the unprecedented changes in the field of clear cell histology mRCC in both the first-line and salvage settings, and we also discuss future therapies and recommend a treatment paradigm on sequencing of these agents.
Assuntos
Carcinoma de Células Renais/terapia , Neovascularização Patológica/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/uso terapêutico , Metástase Neoplásica , Proteínas de Neoplasias/genética , Neovascularização Patológica/epidemiologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Pirróis/uso terapêutico , Quinolinas/uso terapêutico , Sorafenibe , Sunitinibe , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
INTRODUCTION/BACKGROUND: Targeted therapy has become the mainstay of treatment for mRCC. The efficacy of this therapy in the older population is poorly understood. PATIENTS AND METHODS: Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Patient characteristics, data on second-line therapy, and outcomes including treatment duration and overall survival, were evaluated using summary statistics and multivariate analysis. RESULTS: All patients (n = 1381) were treated with front-line targeted therapy; 144 (10%) were 75 years old or older. Six patients (4%) were favorable risk, 99 patients (69%) intermediate risk, and 39 patients (27%) poor risk according to Heng Journal of Clinical Oncology 2009 prognostic factors. The initial treatment for those ≥ 75 years of age was sunitinib (n = 98), sorafenib (n = 35), bevacizumab (n = 7), and AZD217 (n = 4). Twenty-three percent of older patients and 39% of the younger patients went on to receive second-line therapy (P < .0001). The overall response rate, median treatment duration, and overall survival for the older versus younger group were 18% versus 25% (P = .0975), 5.5 months versus 7.5 months (P = .1388), and 16.8 months versus 19.7 months (P = .3321), respectively. When adjusted for poor prognostic factors, age 75 years and older was not found to be associated with poorer overall survival (hazard ratio [HR], 1.002; 95% confidence interval [CI], 0.781-1.285) or shorter treatment duration (HR, 1.018; 95% CI, 0.827-1.252). The retrospective study design was the primary limitation. CONCLUSION: The use of advanced age as a selection criterion for targeted therapy requires further study, with data suggesting no clinically meaningful differences in overall response rate, treatment duration, and overall survival between older and younger age groups.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Bevacizumab , Carcinoma de Células Renais/mortalidade , Bases de Dados Factuais , Feminino , Humanos , Indóis/efeitos adversos , Indóis/uso terapêutico , Neoplasias Renais/mortalidade , Masculino , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Quinazolinas/efeitos adversos , Quinazolinas/uso terapêutico , Estudos Retrospectivos , Sorafenibe , Sunitinibe , Resultado do TratamentoRESUMO
Cabozantinib/XL184 (Exelexis, Inc.) has demonstrated remarkable responses in kidney cancer. Preclinical results revealed VEGF, KIT and MET inhibition in a variety of solid tumors such as thyroid, ovarian, renal, lung, liver and prostate cancers. A phase II trial demonstrated efficacy in renal cancer with a 28 % objective response rate, stable disease rate of 62 % and median progression free survival of 14.7 months. Predominant toxicities of fatigue and diarrhea were noted. Dramatic responses in bone metastases (three of four patients) make the agent especially valuable for palliation in a disease, where presence of bone metastases is a predictor of worse survival. Cabozantinib is an emerging novel agent with promising activity in advanced kidney cancer. Randomized trials are planned in comparison with standard VEGF inhibitor therapy. Defining the role of MET overexpression would help patient selection and enrich and enhance the future evaluation of this targeted novel agent.
Assuntos
Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Anilidas/efeitos adversos , Antineoplásicos/efeitos adversos , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Piridinas/efeitos adversosAssuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Humanos , Niacinamida/análogos & derivados , Compostos de Fenilureia , Radiografia , Sorafenibe , Sunitinibe , Resultado do TratamentoRESUMO
BACKGROUND: In recent years, JM-216/satraplatin (GPC Biotech, Inc.) has emerged as a novel oral platinum analogue with a better toxicity profile than cisplatin. Since satraplatin is more hydrophobic than cisplatin or oxaliplatin, it appears to demonstrate efficacy in cisplatin-resistant cell lines. The preclinical and clinical evaluation of satraplatin stimulated this review of the pharmacology and clinical trial data of this agent. METHODS: A literature review was conducted in the MEDLINE database from 1985 to present using the keywords 'satraplatin' or 'JM-216'. The abstracts regarding satraplatin reported at the 2007 - 2009 American Society of Clinical Oncology meetings were also reviewed. RESULTS/CONCLUSION: Satraplatin has a favorable toxicity profile, and appears to have clinical activity against a variety of malignancies such as breast, prostate and lung cancer. The oral route of administration and the intermittent schedule makes it very convenient for clinical use. Despite this, a FDA-approved indication has not yet been achieved. The only Phase III trial with satraplatin was conducted in pretreated metastatic castrate-resistant prostate cancer (CRPC), revealing an improvement in progression-free survival but no overall survival benefit. Future development would have to include designing trials in docetaxel-refractory metastatic CRPC, or in other malignancies where cisplatin is of benefit.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Administração Oral , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/fisiopatologia , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/farmacologiaRESUMO
PURPOSE: Sorafenib is an oral Raf kinase inhibitor, approved for the treatment of advanced renal cancer. Clinical investigation of the safety and feasibility of sorafenib therapy in patients with impaired renal function was performed in this study. MATERIALS AND METHODS: The protocol was approved by the Human Investigation Committee of Wayne State University. Medical records of patients with metastatic renal cancer at Wayne State University started on sorafenib between November 2005 to January 2007 were reviewed. Patients with a calculated creatinine clearance (CrCl) of 60 mL/min or less (chronic kidney disease stage 3 or greater per Kidney Disease Outcomes Quality Initiative guidelines) were deemed to have renal insufficiency. RESULTS: A total of 32 patients who met the selection criteria were analyzed. Fourteen of 32 (44%) patients had renal insufficiency (range, 32-60 mL/min). Median age was 71 years in patients with CrCl < or = 60 mL/min and 54 years in those with > 60 mL/min. Incidence of diarrhea (57% vs. 33%) and hand-foot syndrome (86% vs. 56%) were higher in the renal-dysfunction group. Dose interruptions and dose reductions were noted in 57% and 43% of patients with renal dysfunction versus 28% and 22% in those without. No significant differences were noted in response rate, progression-free survival or overall survival. CONCLUSION: Renal insufficiency is frequently observed in patients with advanced renal cancer. Sorafenib therapy can be safely delivered in patients with mild and moderate renal dysfunction, and efficacy appears to be maintained.
Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Rim/fisiopatologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzenossulfonatos/efeitos adversos , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , SorafenibeRESUMO
Dietary intake of lycopene and soy has been associated with a lower risk of prostate cancer. In vitro studies with lycopene and genistein, a soy isoflavone, have shown induction of apoptosis and inhibition of cell growth in androgen-sensitive (LNCaP) and androgen-independent (PC3 and VeCaP) prostate cancer cell lines. In a previous Phase II clinical trial in prostate cancer patients, we observed prostate-specific antigen (PSA) stabilization with soy isoflavone intake. In this Phase II clinical trial, we investigated the efficacy of lycopene alone or in combination with soy isoflavones on serum PSA levels in men with prostate cancer. To be eligible for the study, men with prostate cancer had to have rising serum PSA following local therapy or while on hormone therapy. Study population included 71 eligible patients who had 3 successive rising PSA levels or a minimum PSA of 10 ng/ml at 2 successive evaluations prior to starting therapy. Subjects were randomly assigned to receive a tomato extract capsule containing 15 mg of lycopene alone (n = 38) or together with a capsule containing 40 mg of a soy isoflavone mixture (n = 33) twice daily orally for a maximum of 6 mo. One patient on the lycopene arm did not receive therapy due to his inability to ingest the study pill. There was no decline in serum PSA in either group qualifying for a partial or complete response. However, 35 of 37 (95%) evaluable patients in the lycopene group and 22 of 33 (67%) evaluable patients in the lycopene plus soy isoflavone group achieved stable disease described as stabilization in serum PSA level. The data suggest that lycopene and soy isoflavones have activity in prostate cancer patients with PSA relapse disease and may delay progression of both hormone-refractory and hormone-sensitive prostate cancer. However, there may not be an additive effect between the 2 compounds when taken together. Future studies are warranted to further investigate the efficacy of lycopene and soy isoflavones in prostate cancer as well as the mechanism of potential negative interaction between them.
Assuntos
Carotenoides/uso terapêutico , Genisteína/uso terapêutico , Antígeno Prostático Específico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Carotenoides/efeitos adversos , Suplementos Nutricionais , Progressão da Doença , Quimioterapia Combinada , Genisteína/efeitos adversos , Humanos , Isoflavonas , Licopeno , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Antígeno Prostático Específico/efeitos dos fármacos , Glycine max , Resultado do TratamentoRESUMO
PURPOSE: Local failure continues to be a major problem in the management of pancreatic cancer. Delivery of adequate radiation doses to the pancreas is limited by radiation-sensitive normal structures in the upper abdomen. To overcome some of these restrictions, we have developed a regimen of intensity-modulated radiotherapy (IMRT) with concurrent capecitabine. METHODS AND MATERIAL: This is a retrospective analysis of the first 15 patients with adenocarcinoma of the pancreas treated on this regimen (7 as adjuvant therapy after curative resection and 8 patients for unresectable disease). Intensity-modulated radiotherapy was planned using the CORVUS system and delivered with a segmented multileaf collimator, using a 6-MV photon beam and 10 intensity steps. Two target volumes were entered: target 1 consisted of the gross tumor volume (in unresectable cases) or the tumor bed (in postsurgical cases); and target 2 consisted of the draining lymph nodes. Both targets were treated simultaneously in 25 daily fractions, 5 days a week. In the postoperative setting, the total dose to target 1 was 45-54 Gy (median, 54 Gy). For unresectable disease the dose was 54-55 Gy (median, 54 Gy). The total dose to target 2 was 45 Gy in all patients. Patients were treated with one of two six-field beam arrangements found to produce superior dose distributions. Capecitabine was given at 1,600 mg/m(2)/day in two divided doses, 5 days per week, concurrently with radiotherapy. In addition, most patients (73%) received gemcitabine-based chemotherapy. Systemic chemotherapy was given before, after, or both before and after chemoradiotherapy in 47%, 7%, and 20% of patients, respectively. Patients were evaluated on a weekly basis. RESULTS: Treatment was tolerated well. Grade 1/2 nausea/vomiting developed in 8 patients (53%) and Grade 1/2 hematologic toxicity developed in 9 patients (60%). Only 1 patient (7%) had Grade 3 toxicity, a gastric ulceration that responded to medical management. Nine patients (60%) had weight loss (median, 7 lbs; range, 3-12 lbs). The median follow-up time is 8.5 months (10.1 months in patients who are alive). In the resectable group there have been no deaths, and there has been 1 local relapse (14%). In the unresectable group there have been 2 deaths, and the 1-year actuarial survival rate is 69%. Two patients converted to resectability, 5 patients (62.5%) have persistent locoregional disease after chemoradiotherapy, and 1 patient (12%) is locally controlled without surgery. CONCLUSIONS: This regimen of IMRT with tumor-selective radiosensitization is well tolerated. The low toxicity profile compares favorably with that of protocols based on continuous-infusion 5-fluorouracil or gemcitabine, and the preliminary indications of efficacy are encouraging.