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BACKGROUND: Nivolumab+ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years median follow-up from CheckMate 214. PATIENTS AND METHODS: Patients with aRCC (N=1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. Endpoints included OS, and independent radiology review committee-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients. RESULTS: With 8 years (99.1 months) median follow-up, the HR (95% CI) for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all IMDC risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). Median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1-not estimable (NE) versus 19.8-33.2; ITT], 82.8 versus 19.8 months [54.1-NE versus 16.4-26.4; I/P], and 61.5 versus 33.2 months [27.8-NE versus 24.8-51.4; FAV]). Incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time. CONCLUSIONS: Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC.
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PURPOSE: Germ cell tumours are the most common cancer of male adolescents and young adults (AYA, age 18-39). Men in this age group have been healthy much of their lives, and a diagnosis of cancer can cause significant psychosocial distress. We therefore sought to examine the psychosocial needs of patients with germ cell tumour and determine whether needs vary based on age (AYA vs non-AYA). We hypothesized that AYA experience more anxiety and distress in emotional, practical and physical domains. METHODS: We evaluated the responses of all patients referred to British Columbia (BC) Cancer who completed a pre-consultation health assessment form. This is a validated screening questionnaire for distress, subclinical/clinical symptoms of depression and anxiety and includes the Canadian Problem Checklist domains of emotional, informational, practical, spiritual, social/family and physical concerns. RESULTS: Data were collected for 349 patients (2011-2015). Patient population was predominantly AYA (n = 227) with median age 33 (range 18-83). The top 3 AYA concerns were financial, work/school, frustration and anger. AYA patients more commonly scored positive for symptoms of subclinical/clinical anxiety than non-AYA (39.4% vs. 27.9%, p = 0.028). Those AYA patients with subclinical/clinical anxiety symptoms experienced more fears and worries, concerns regarding work/school, lack of understanding of their disease, finances and frustration and anger. CONCLUSIONS: The results of this study indicate that AYA with testicular cancer have unique needs and experience more self-reported anxiety symptoms with emotional, informational and practical concerns. This is valuable information to stakeholders for allocation of resources to address cancer survivorship amongst these patients.
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Neoplasias de Células Germinales y Embrionarias/psicología , Medición de Resultados Informados por el Paciente , Estrés Psicológico/psicología , Adolescente , Adulto , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
BACKGROUND: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis. PATIENTS AND METHODS: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population. RESULTS: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]. CONCLUSION: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature. CLINICAL TRIAL NUMBER: NCT02684006.
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Carcinoma de Células Renales , Neoplasias Renales , Anticuerpos Monoclonales Humanizados , Axitinib , Carcinoma de Células Renales/tratamiento farmacológico , Humanos , Neoplasias Renales/tratamiento farmacológico , Sunitinib/uso terapéuticoRESUMEN
Background The IND.226 study was a phase Ib study to determine the recommended phase II dose of durvalumab + tremelimumab in combination with standard platinum-doublet chemotherapy. Sequential administration of multiple agents increases total chair time adding costs overall and inconvenience for patients. This cohort of the IND.226 study evaluated the safety and tolerability of durvalumab + tremelimumab given either sequentially (SEQ) or concurrently (CON). Methods Patients with advanced solid tumours were enrolled and randomised to either SEQ tremelimumab 75 mg IV over 1 h followed by durvalumab 1500 mg IV over 1 h q4wks on the same day, or CON administration over 1 h. The serum pharmacokinetic profile of SEQ versus CON of durvalumab and tremelimumab administration was also evaluated. Results 14 patients either received SEQ (n = 7pts) or CON (n = 7 pts). There were no infusion related reactions. Drug related adverse events (AEs) were mainly low grade and manageable, and comparable in frequency between SEQ/CON- fatigue (43%/57%), rash (43%/43%), pruritus (43%/29%) and nausea (14%/29%). One patient in each cohort discontinued treatment due to toxicity. The PK profiles of durvalumab and tremelimumab were similar between CON and SEQ, and to historical reference data. Conclusions Concurrent administration of durvalumab and tremelimumab over 1 h is safe with a comparable PK profile to sequential administration.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/sangre , Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/sangre , Antineoplásicos Inmunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/sangre , Inhibidores de Puntos de Control Inmunológico/farmacocinética , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/metabolismoRESUMEN
BACKGROUND: Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer. PATIENTS AND METHODS: Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated. RESULTS: Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response. CONCLUSIONS: Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway. CLINICALTRIALSGOV ID: NCT00487786.
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Diazepam/administración & dosificación , Proteínas de Choque Térmico HSP27/antagonistas & inhibidores , Oligonucleótidos Antisentido/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Diazepam/efectos adversos , Diazepam/farmacocinética , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico , Humanos , Masculino , Persona de Mediana Edad , Chaperonas Moleculares , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/patología , Oligonucleótidos Antisentido/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
BACKGROUND: Several reports suggest that vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in Asian vs non-Asian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterised. METHODS: A multicentre, retrospective, cohort study using Asian and non-Asian centres which collected data on ethnicity, dose reductions and outcomes using the International mRCC Database Consortium. RESULTS: This study included 1024 (464 Asian, 560 non-Asian) patients with a 29.4 months median follow-up. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% P=0.1197). When adjusted for risk groups, there was no difference in overall or progression-free survival between non-Asians and Asians. Patients with dose reductions due to toxicity had longer treatment durations and overall survival than those who did not in both non-Asian (10.6 vs 5.0 months, P<0.0001; 22.6 vs 16.1 months, P=0.0016, respectively) and Asian populations (8.9 vs 5.4 months, P=0.0028; 28.0 vs 18.7 months, P=0.0069, respectively). CONCLUSIONS: Adjusting for risk groups, there appears to be no difference in outcome between Asian vs non-Asian patients with mRCC treated with VEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations due to longer treatment durations, but direct comparisons are needed.
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Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/etnología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/etnología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/efectos adversos , Pueblo Asiatico , Carcinoma de Células Renales/patología , Estudios de Cohortes , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. PATIENTS AND METHODS: mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). RESULTS: Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). CONCLUSIONS: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Determinación de la Elegibilidad , Humanos , Indazoles , Indoles/administración & dosificación , Estimación de Kaplan-Meier , Estado de Ejecución de Karnofsky , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Persona de Mediana Edad , Terapia Molecular Dirigida , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Sorafenib , Sulfonamidas/administración & dosificación , Sunitinib , Resultado del TratamientoRESUMEN
In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377-1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478-496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497-513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, â¼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.
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Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/terapia , Europa (Continente) , Estudios de Seguimiento , Humanos , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Tasa de SupervivenciaRESUMEN
Matuzumab is a humanized IgG1 EGFR monoclonal antibody. This phase I study investigated the tolerability, safety and pharmacokinetics (PK) of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer (NSCLC). Six dose levels/schedules of matuzumab were explored in combination with paclitaxel. Dose was escalated from 100 mg to 1,600 mg on a modified Fibonacci scheme according to the incidence of dose-limiting toxicity (DLT) over the first two cycles. DLT was assessed in patients who completed the first two treatment cycles or who stopped treatment because of a DLT during those cycles. Patients with non-progressive disease could then continue to receive study treatment for up to 6 months. The safety population comprised 44 patients, with DLT evaluable in 33. The maximum tolerated dose was not reached, with only one DLT reported at the 1,600 mg 3-weekly dose level. The most frequent grade 3/4 adverse events across all cycles were dyspnea (23 %) and neutropenia (11 %). Matuzumab exhibited non-linear PK, with accumulation after escalation and repeated dosing. Tumor growth control was seen in 15/44 (34 %) patients, including 5/9 (56 %) at the 800 mg weekly dose level. Matuzumab combined with paclitaxel was generally well tolerated in patients with advanced NSCLC. There was some evidence of anticancer activity in relation to the matuzumab 800 mg weekly dose.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Receptores ErbB/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversosRESUMEN
BACKGROUND: The purpose of the study was to assess the safety, tolerability, recommended phase II dose (RPTD), and preliminary antitumor activity of the combination of carboplatin-paclitaxel (Taxol)-temsirolimus. MATERIALS AND METHODS: Patients with solid malignancies suitable for carboplatin-paclitaxel (CP) chemotherapy and two or less prior lines of chemotherapy received 15, 20, or 25 mg of temsirolimus per week with CP given every 21 days. Thirty-eight eligible patients were entered into six dose levels with the first two levels administering temsirolimus on days 8 and 15 and the subsequent four dose levels switching to days 1 and 8 temsirolimus administration. RESULTS: Days 8 and 15 administration of temsirolimus was not feasible due to myelosuppression on day 15. CP on day 1 with temsirolimus on days 1 and 8 was well tolerated. Dose-limiting toxicity (DLT) was grade 4 thrombocytopenia (n=2) and grade 3 fatigue (n=1). Relative dose intensities for carboplatin, paclitaxel, and temsirolimus at the RPTD were 92%, 82%, and 56%, respectively. Non-DLT treatment-related adverse events occurring in >20% of patients included fatigue, mucositis, alopecia, neuropathy, nausea, neutropenia, thrombocytopenia, and infection. Grade 3/4 non-hematological toxicity was rare. Partial responses (PRs) and disease stabilization were seen in 46% and 49% of patients, respectively. Nine of 11 (82%) endometrial cancer patients had objective PRs. CONCLUSION: Carboplatin-paclitaxel-temsirolimus is well tolerated and the RPTD is carboplatin area under the curve 5 mg/ml/min, paclitaxel 175 mg/m2, both given on day 1 with temsirolimus 25 mg on days 1 and 8.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sirolimus/análogos & derivadosRESUMEN
BACKGROUND: A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria. METHODS: Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. RESULTS: One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors. CONCLUSIONS: Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.
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Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Resistencia a Antineoplásicos , Neoplasias Renales/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Bencenosulfonatos/farmacología , Bencenosulfonatos/uso terapéutico , Bevacizumab , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Everolimus , Femenino , Humanos , Indoles/farmacología , Indoles/uso terapéutico , Estimación de Kaplan-Meier , Neoplasias Renales/mortalidad , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/farmacología , Piridinas/uso terapéutico , Pirroles/farmacología , Pirroles/uso terapéutico , Factores de Riesgo , Sirolimus/análogos & derivados , Sirolimus/farmacología , Sirolimus/uso terapéutico , Sorafenib , Sunitinib , Resultado del TratamientoRESUMEN
BACKGROUND: 2-¹8fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) has been recommended in international guidelines in the evaluation of postchemotherapy seminoma residuals. Our trial was designed to validate these recommendations in a larger group of patients. PATIENTS AND METHODS: FDG-PET studies in patients with metastatic seminoma and residual masses after platinum-containing chemotherapy were correlated with either the histology of the resected lesion(s) or the clinical outcome. RESULTS: One hundred and seventy seven FDG-PET results were contributed. Of 127 eligible PET studies, 69% were true negative, 11% true positive, 6% false negative, and 15% false positive. We compared PET scans carried out before and after a cut-off level of 6 weeks after the end of the last chemotherapy cycle. PET sensitivity, specificity, negative predictive value (NPV), and positive predictive value were 50%, 77%, 91%, and 25%, respectively, before the cut-off and 82%, 90%, 95%, and 69% after the cut-off. PET accuracy significantly improved from 73% before to 88% after the cut-off (P=0.032). CONCLUSION: Our study confirms the high specificity, sensitivity, and NPV of FDG-PET for evaluating postchemotherapy seminoma residuals. When carried out at an adequate time point, FDG-PET remains a valuable tool for clinical decision-making in this clinical setting and spares patients unnecessary therapy.
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Glucosa-6-Fosfato/análogos & derivados , Tomografía de Emisión de Positrones , Radiofármacos , Seminoma/diagnóstico por imagen , Neoplasias Testiculares/diagnóstico por imagen , Humanos , Masculino , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: In this article, we report the evolution of treatment with increased use of active surveillance for stage I disease as well as risk-adapted chemotherapy for disseminated disease and associated outcomes of testicular seminoma in a contemporary population-based cohort. METHODS: All patients with histologically confirmed seminoma referred from 1999 to 2008 to the British Columbia Cancer Agency or Providence Cancer Center were retrospectively reviewed. Both institutions manage 90% of testicular cancers in their respective area. RESULTS: A total of 649 patients were included. Clinical stage (CS) distribution: CSI/II/III n=545/87/17. For CSI, there was a progressive and marked decrease in the utilization of prophylactic radiation (RT), and corresponding increase in the use of active surveillance. No deaths related to seminoma were reported in CSI patients. CSII or CSIII patients received RT or International Germ Cell Cancer Collaborative Group (IGCCCG) risk-appropriate chemotherapy with 101 of 104 patients being in long-term remission and 3 patients dying from treatment complications. For the entire seminoma population, <1% of patients died of seminoma or treatment after a median follow-up of 47 months (range 2-130 months). CONCLUSIONS: Progressive application of policies of active surveillance and earlier initiation of IGCCCG risk-adapted chemotherapy result in nearly universal control for all patients presenting with seminoma while reducing the burden of treatment.
Asunto(s)
Seminoma/terapia , Neoplasias Testiculares/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/administración & dosificación , Bleomicina/uso terapéutico , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Terapia Combinada , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Orquiectomía , Radioterapia Adyuvante , Estudios Retrospectivos , Seminoma/patología , Neoplasias Testiculares/patología , Resultado del Tratamiento , Espera VigilanteRESUMEN
BACKGROUND: The objective of the study was to investigate the activity of sunitinib in a cell line model and subsequently in patients with cisplatin-refractory or multiply relapsed germ cell tumors (GCT). METHODS: The effect of sunitinib on cell proliferation in cisplatin-sensitive and cisplatin-refractory GCT cell lines was evaluated after 48-h sunitinib exposure by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, and IC(50) (concentration that causes 50% inhibition of growth) doses were determined. Sunitinib was subsequently administered at a dose of 50 mg/day for 4 weeks followed by a 2-week break to 33 patients using a Simon two-stage design. RESULTS: Sunitinib demonstrated comparable dose-dependent growth inhibition in cisplatin-sensitive and cisplatin-resistant cell lines, with IC(50) between 3.0 and 3.8 µM. Patient characteristics were as follows: median of 2 (1-6) cisplatin-containing regimens; high-dose chemotherapy 67%; late relapse 33%; and cisplatin refractory or absolute cisplatin refractory 54%. Toxic effects included fatigue (39%), anorexia (21%), diarrhea (27%), mucositis (45%), nausea (33%), hand-foot syndrome (12%), dyspepsia (27%), and skin rash (18%). No unexpected side-effects were observed. Thirty -two of 33 patients were assessable for response. Three confirmed partial responses (PRs) and one unconfirmed PR were seen for a total response rate of 13%. Median progression-free survival (PFS) was 2 months, with a 6-month PFS rate of 11%. CONCLUSIONS: Sunitinib shows in vitro activity in cisplatin-resistant GCT cell lines. Modest clinical activity in heavily pretreated GCT patients was observed.
Asunto(s)
Antineoplásicos/uso terapéutico , Cisplatino/farmacología , Resistencia a Antineoplásicos , Indoles/uso terapéutico , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Pirroles/uso terapéutico , Neoplasias Testiculares/tratamiento farmacológico , Adulto , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia sin Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Indoles/farmacología , Concentración 50 Inhibidora , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/mortalidad , Pirroles/farmacología , Sunitinib , Neoplasias Testiculares/mortalidad , Resultado del Tratamiento , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante/métodos , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias Testiculares/tratamiento farmacológico , Humanos , MasculinoRESUMEN
BACKGROUND: With treatment leading to nearly uniform cure in clinical stage I nonseminomatous testicular cancer (CSI-NSGCT), diminishing treatment-related morbidity has become the primary concern. This study examined feasibility and outcome of active surveillance as treatment in an unselected CSI patient population. MATERIALS AND METHODS: All patients with CSI-NSGCT referred from 1998 to 2007 to the British Columbia Cancer Agency and the Oregon Testis Cancer Program were retrospectively reviewed. A total of 233 patients were identified, of which 223 chose active surveillance. RESULTS: Vascular invasion (VI) was absent, present and unknown in 66%, 27% and 7% of cases, respectively. Overall, 49% of patients had embryonal predominant disease. Fifty-nine patients (26%) relapsed, all but one with good prognosis disease. VI was present in 30 relapsed patients. Most patients relapsed within 2 years (88%). Only 7 of 223 patients (3%) relapsed beyond 2 years. All relapses were in long-term remission following chemotherapy with or without retroperitoneal lymph node dissection (RPLND). Only 17 of 223 patients (8%) required postorchiectomy surgery. Disease-specific survival is 100% after a median follow-up of 52 months (3-136). No patient has required second-line chemotherapy. CONCLUSIONS: Active surveillance for all CSI-NSGCT patients is associated with excellent outcomes comparable with the best results reported with primary RPLND or adjuvant chemotherapy. Nearly 75% of patients are spared any therapy after orchiectomy.
Asunto(s)
Neoplasias de Células Germinales y Embrionarias/cirugía , Orquiectomía/rehabilitación , Vigilancia de la Población/métodos , Neoplasias Testiculares/cirugía , Adolescente , Adulto , Quimioterapia Adyuvante/estadística & datos numéricos , Comorbilidad , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/epidemiología , Neoplasias de Células Germinales y Embrionarias/mortalidad , Orquiectomía/efectos adversos , Orquiectomía/estadística & datos numéricos , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/epidemiología , Recurrencia , Estudios Retrospectivos , Riesgo , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/epidemiología , Neoplasias Testiculares/mortalidad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: This study investigated the safety, pharmacokinetics (PK) and clinical antitumor activity of ABT-751, a novel sulfonamide antimitotic and vascular disrupting agent, in combination with docetaxel (Taxotere) in patients with castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Patients received docetaxel (60-75 mg/m(2)) i.v. on day 1 and ABT-751 (100-200 mg) orally daily for 14 days, repeated every 3 weeks for up to 10 times on four escalating dose levels (DLs). RESULTS: Thirty-two patients received a median of 8.5 treatment cycles (range 1-10). One of six patients on DL 3 (D 60 mg/m(2) + A 200 mg) and 4 (D 75 mg/m(2) + A 200 mg) experienced dose-limiting toxicity, and both DLs were expanded. Overall, severe adverse events occurred more commonly on DL 4 than 3 (47% versus 18% of patients). PK data for docetaxel and ABT-751 were similar to reported literature. Best post-treatment prostate-specific antigen decline of > or =50% occurred in 60% and objective responses occurred in 45% of patients. Median overall survival was 24 months (95% confidence interval 8.3-37.7 months). CONCLUSIONS: The combination of ABT-751 and docetaxel is safe and active in CRPC. Based on the cumulative safety analysis, the recommended phase II dose of ABT-751 is 200 mg daily with docetaxel 60 mg/m(2) for this patient population.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Castración , Neoplasias de la Próstata/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Taxoides/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante/efectos adversos , Progresión de la Enfermedad , Docetaxel , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Sulfonamidas/efectos adversos , Taxoides/efectos adversos , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Targeted therapy has greatly changed the way in which metastatic renal cell carcinoma (RCC) is treated. Agents that inhibit the vascular endothelial growth factor and mammalian target of rapamycin pathways that otherwise lead to angiogenesis have now become the standard of care. Much research into the sequence and combination of these agents is ongoing, and new anti-angiogenic agents are being developed. This overview covers the standard treatment of metastatic rcc with targeted therapy, immunotherapy, and surgery. Future directions and ongoing clinical trials are also discussed.