RESUMEN
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.
RESUMEN
BACKGROUND: Nivolumab plus cabozantinib (NIVO + CABO) was approved for first-line treatment of advanced renal cell carcinoma (aRCC) based on superiority versus sunitinib (SUN) in the phase III CheckMate 9ER trial (18.1 months median survival follow-up per database lock date); efficacy benefit was maintained with an extended 32.9 months of median survival follow-up. We report updated efficacy and safety after 44.0 months of median survival follow-up in intent-to-treat (ITT) patients and additional subgroup analyses, including outcomes by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score. PATIENTS AND METHODS: Patients with treatment-naïve aRCC received NIVO 240 mg every 2 weeks plus CABO 40 mg once daily or SUN 50 mg for 4 weeks (6-week cycles), until disease progression/unacceptable toxicity (maximum NIVO treatment, 2 years). Primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were overall survival (OS), objective response rate (ORR) per BICR, and safety and tolerability. RESULTS: Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN [16.6 versus 8.4 months; hazard ratio (HR) 0.59; 95% confidence interval (CI) 0.49-0.71]; median OS favoured NIVO + CABO versus SUN (49.5 versus 35.5 months; HR 0.70; 95% CI 0.56-0.87). ORR (95% CI) was higher with NIVO + CABO versus SUN [56% (50% to 62%) versus 28% (23% to 33%)]; 13% versus 5% of patients achieved complete response, and median duration of response was 22.1 months versus 16.1 months, respectively. PFS and OS favoured NIVO + CABO over SUN across intermediate, poor and intermediate/poor IMDC risk subgroups; higher ORR and complete response rates were seen with NIVO + CABO versus SUN regardless of IMDC risk subgroup. Any-grade (grade ≥3) treatment-related adverse events occurred in 97% (67%) versus 93% (55%) of patients treated with NIVO + CABO versus SUN. CONCLUSIONS: After extended follow-up, NIVO + CABO maintained survival and response benefits; safety remained consistent with previous follow-ups. These results continue to support NIVO + CABO as a first-line treatment for aRCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03141177.
Asunto(s)
Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renales , Neoplasias Renales , Nivolumab , Piridinas , Sunitinib , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Sunitinib/uso terapéutico , Sunitinib/farmacología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Masculino , Anilidas/uso terapéutico , Anilidas/farmacología , Femenino , Persona de Mediana Edad , Nivolumab/uso terapéutico , Nivolumab/farmacología , Piridinas/uso terapéutico , Piridinas/farmacología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Adulto , Estudios de Seguimiento , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.
Asunto(s)
Acetato de Abiraterona , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Prednisona , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Proteína BRCA1/genética , Reparación del ADN por Recombinación , Resultado del Tratamiento , Proteína BRCA2/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
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.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Anticuerpos Monoclonales Humanizados , Axitinib , Carcinoma de Células Renales/tratamiento farmacológico , Humanos , Neoplasias Renales/tratamiento farmacológico , Sunitinib/uso terapéuticoAsunto(s)
Melfalán , Mieloma Múltiple , Adulto , Humanos , Mieloma Múltiple/tratamiento farmacológico , Obesidad , Trasplante AutólogoRESUMEN
BACKGROUND: Radium-223 prolongs overall survival and delays symptomatic skeletal events (SSEs) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. The approved radium-223 regimen is 55 kBq/kg every 4 weeks (q4w) for six cycles (standard dose). We investigated different radium-223 regimens in patients with mCRPC. PATIENTS AND METHODS: Patients were randomised 1 : 1 : 1 to radium-223 standard-dose, high-dose (88 kBq/kg q4w for six cycles) or extended-schedule arms (55 kBq/kg q4w for 12 cycles). The primary end point, SSE-free survival (SSE-FS), was compared in patients treated with a high- versus standard-dose regimen, or with a standard dose in an extended (>6 to 12 cycles) versus standard schedule (six cycles). RESULTS: A total of 391 patients were randomised; baseline characteristics were balanced between arms. On-treatment SSEs developed in 37/130 (28%), 42/130 (32%) and 48/131 (37%) patients in the standard-dose, high-dose and extended-schedule arms, respectively. There was no statistically significant difference in SSE-FS in the high- versus standard-dose arms [median 12.9 months versus 12.3 months; hazard ratio (HR) 1.06, 80% confidence interval (CI) 0.88-1.27, P = 0.70], and in the extended- versus standard-schedule arms (median 10.8 months versus 13.2 months; HR 1.26, 80% CI 0.94-1.69, P = 0.31). Overall survival in the three treatment arms was similar. As many as 370 (95%) patients received treatment (median of six cycles) in each arm. Grade ≥3 treatment-emergent adverse events (TEAEs) affected 34% of patients in the standard-dose, 48% in the high-dose and 53% in the extended-schedule arm, causing permanent discontinuation in 9%, 16% and 17% of patients, respectively. CONCLUSION: Radium-223 high-dose or extended-schedule regimens resulted in no change in SSE-FS or other efficacy end points and were associated with more grade ≥3 TEAEs. The extended-schedule regimen (beyond six doses) could not be implemented in a large proportion of patients due to disease progression. Therefore, the standard-dose schedule remains one of the standard therapies for patients with symptomatic mCRPC. TRIAL REGISTRATION: ClinicalTrials.govNCT02023697.
Asunto(s)
Neoplasias Óseas , Neoplasias de la Próstata Resistentes a la Castración , Radio (Elemento) , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/radioterapia , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Radioisótopos , Radio (Elemento)/efectos adversosRESUMEN
BACKGROUND: Novel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045. PATIENTS AND METHODS: Adult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR. RESULTS: A total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy. CONCLUSIONS: Long-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02256436.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Urológicas/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Docetaxel/administración & dosificación , Estudios de Seguimiento , Humanos , Recurrencia Local de Neoplasia/patología , Paclitaxel/administración & dosificación , Pronóstico , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tasa de Supervivencia , Neoplasias Urológicas/patología , Vinblastina/administración & dosificación , Vinblastina/análogos & derivadosRESUMEN
e-TC is an online intervention designed to address common psychosocial concerns of testicular cancer survivors. It aims to reduce anxiety, depression and fear of cancer recurrence by providing evidence-based information and psychological intervention. This paper details the development and pilot testing of e-TC. During pilot testing, 25 men (with varying psychological profiles) who had completed treatment for testicular cancer, 6 months to 5 years ago (which had not recurred), used e-TC over a 10-week period and provided quantitative and qualitative feedback on the feasibility and acceptability of the programme. Six men also completed a qualitative interview to provide detailed feedback on their experiences using e-TC. Fourteen men (56%) completed at least 80% of the programme. Participants reported a high level of satisfaction with the programme. Men's limited time was a barrier to programme use and completion, and participants suggested that men with a more recent diagnosis and a higher level of distress may be more likely to engage with the programme. e-TC appears to be a feasible and acceptable online intervention for survivors of testicular cancer. Findings from this study are currently being used to refine e-TC and guide the design of a larger efficacy study.
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Ansiedad/terapia , Supervivientes de Cáncer/psicología , Terapia Cognitivo-Conductual/métodos , Depresión/terapia , Estrés Psicológico/terapia , Neoplasias Testiculares/psicología , Adulto , Ansiedad/psicología , Depresión/psicología , Estudios de Factibilidad , Humanos , Internet , Masculino , Persona de Mediana Edad , Aceptación de la Atención de Salud , Proyectos Piloto , Estrés Psicológico/psicología , Terapia Asistida por Computador/métodosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ensayos Clínicos Fase II como Asunto , Estudios Multicéntricos como Asunto , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias Urogenitales/tratamiento farmacológico , Australia/epidemiología , Bleomicina/administración & dosificación , Cisplatino/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/epidemiología , Nueva Zelanda/epidemiología , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/epidemiología , Factores de Tiempo , Resultado del Tratamiento , Neoplasias Urogenitales/diagnóstico , Neoplasias Urogenitales/epidemiologíaRESUMEN
BACKGROUND/AIM: The utility of pulmonary function testing (PFT) to detect bleomycin-induced pneumonitis is controversial. We describe its impact on bleomycin dosing in a phase 2 trial of accelerated BEP (bleomycin, etoposide, cisplatin) for advanced germ cell tumours. METHODS: There were 12 planned weekly bleomycin doses for intermediate-risk and poor-risk disease and nine for good-risk disease. Clinical assessments, chest X-ray, diffusing capacity of lung for carbon monoxide (DLCO) and forced vital capacity (FVC) were performed bi-weekly. Bleomycin was ceased for predefined clinical/radiological evidence of pulmonary toxicity and a >25% reduction in DLCO or FVC. We determined doses planned, received and omitted and patients receiving all, ≥two-thirds, two-thirds of planned bleomycin doses. RESULTS: Of 43 eligible patients, 30% had lung metastases. Of 471, 375 (80%) of planned bleomycin doses were received, and 30% received Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación
, Bleomicina/administración & dosificación
, Neoplasias Pulmonares/epidemiología
, Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico
, Neoplasias Testiculares/tratamiento farmacológico
, Adolescente
, Adulto
, Antibióticos Antineoplásicos/efectos adversos
, Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación
, Australia
, Bleomicina/efectos adversos
, Monóxido de Carbono/análisis
, Cisplatino/administración & dosificación
, Relación Dosis-Respuesta a Droga
, Etopósido/administración & dosificación
, Femenino
, Humanos
, Neoplasias Pulmonares/secundario
, Masculino
, Neoplasias de Células Germinales y Embrionarias/patología
, Pronóstico
, Radiografía Torácica
, Pruebas de Función Respiratoria
, Neoplasias Testiculares/patología
, Capacidad Vital
, Adulto Joven
RESUMEN
BACKGROUND: Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). METHODS: Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. RESULTS: The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). CONCLUSIONS: We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Metilación de ADN , ADN de Neoplasias/genética , Epigenómica , Gutatión-S-Transferasa pi/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Islas de CpG , ADN de Neoplasias/sangre , Estudios de Seguimiento , Gutatión-S-Transferasa pi/sangre , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Reacción en Cadena de la Polimerasa , Pronóstico , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Tasa de Supervivencia , Estudios de Validación como AsuntoRESUMEN
BACKGROUND: Docetaxel is the first-line chemotherapy for castration-resistant prostate cancer (CRPC). However, response rates are â¼50% and determined quite late in the treatment schedule, thus non-responders are subjected to unnecessary toxicity. The potential of circulating microRNAs as early biomarkers of docetaxel response in CRPC patients was investigated in this study. METHODS: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. RESULTS: Fourteen microRNAs were associated with serum prostate-specific antigen (PSA) response or overall survival, according to Mann-Whitney U or log-rank tests. Non-responders to docetaxel and patients with shorter survival generally had high pre-docetaxel levels of miR-200 family members or decreased/unchanged post-docetaxel levels of miR-17 family members. Multivariate Cox regression with bootstrapping validation showed that pre-docetaxel miR-200b levels, post-docetaxel change in miR-20a levels, pre-docetaxel haemoglobin levels and visceral metastasis were independent predictors of overall survival when modelled together. CONCLUSIONS: Our study suggests that circulating microRNAs are potential early predictors of docetaxel chemotherapy outcome, and warrant further investigation in clinical trials.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Biomarcadores de Tumor/sangre , Resistencia a Antineoplásicos/genética , MicroARNs/sangre , Neoplasias de la Próstata/tratamiento farmacológico , ARN Neoplásico/sangre , Taxoides/uso terapéutico , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral/efectos de los fármacos , Docetaxel , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Curva ROC , Factores de Riesgo , Taxoides/farmacología , Resultado del TratamientoRESUMEN
Interpatient variability in the pharmacokinetics (PK) of sunitinib is high. Single nucleotide polymorphisms (SNPs) in PK candidate genes have been associated with the efficacy and toxicity of sunitinib, but whether these SNPs truly affect the PK of sunitinib remains to be elucidated. This multicenter study involving 114 patients investigated whether these SNPs and haplotypes in genes encoding metabolizing enzymes or efflux transporters are associated with the clearance of sunitinib and its active metabolite SU12662. SNPs were tested as covariates in a population PK model. From univariate analysis, we found that the SNPs in CYP3A4, CYP3A5, and ABCB1 were associated with the clearance of both sunitinib and SU12662. In multivariate analysis, CYP3A4*22 was found to be eliminated last with an effect size of -22.5% on clearance. Observed effect sizes are below the interindividual variability in clearance and are therefore too limited to directly guide individual dosing of sunitinib.
Asunto(s)
Antineoplásicos/farmacocinética , Indoles/metabolismo , Indoles/farmacocinética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirroles/metabolismo , Pirroles/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/metabolismo , Citocromo P-450 CYP3A/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , SunitinibRESUMEN
BACKGROUND: This Australian single-arm, multicenter, phase II trial evaluated feasibility, tolerability and activity of accelerated bleomycin, etoposide and cisplatin (BEP) as first-line chemotherapy for metastatic germ cell tumours. PATIENTS AND METHODS: Patients were planned to receive cisplatin 20 mg/m(2) and etoposide 100 mg/m(2) days 1-5, and pegfilgrastim 6 mg day 6, all repeated every 2 weeks for four cycles (three cycles for good prognosis). Bleomycin was given at 30 000 IU weekly to a total of 12 doses (9 doses for good prognosis). Primary end point was feasibility, defined as the proportion of patients able to complete the etoposide and cisplatin components of BEP and be eligible to receive a fourth cycle of BEP by day 50. RESULTS: Twelve poor, 16 intermediate and 15 good prognosis (n = 43) eligible patients were enrolled. Two patients aged >40 years were ineligible and excluded from analyses. The regimen was feasible in 86%, not feasible in 7% and not assessable in 7% of patients. Most common grade 3/4 adverse events were non-neutropenic infection (16%) and febrile neutropenia (12%). Complete response (CR) to chemotherapy and surgery was achieved in 33% poor-prognosis, 81% intermediate-prognosis and 100% good-prognosis patients. At median follow-up of 27 months (range 6-42), the 2-year progression-free survival was 50% for poor-prognosis, 94% for intermediate-prognosis and 92% for good-prognosis patients. CONCLUSION: Accelerated BEP is feasible and tolerable. Efficacy data appear to be promising. This trial and a similar UK study provide the rationale for a randomised trial comparing accelerated versus standard BEP. Australian New Zealand Clinical Trials Registry Registration number. ACTRN 12607000294459.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias Testiculares/tratamiento farmacológico , Adolescente , Adulto , Bleomicina/administración & dosificación , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/secundario , Pronóstico , Neoplasias Testiculares/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: We assess the prognostic value of chemotherapy-induced leukopenia and sensory neuropathy in the CALYPSO trial patients treated with carboplatin-paclitaxel (CP) or carboplatin-liposomal doxorubicin (CPLD). METHODS: We performed a landmark analysis at first month after randomisation to correlate leukopenia (nadir white blood cell <4.0 × 10(9) per litre or severe infection) during cycle 1 of chemotherapy with progression-free survival (PFS). Using time-dependent proportional-hazards models, we also investigated the association between neuropathy and PFS. RESULTS: Of 608 patients with nadir blood and did not receive growth factors, 72% (CP=70%, CPLD=73%) had leukopenia. Leukopenia was prognostic for PFS in those receiving CP (adjusted hazard ratio (aHR) 0.66, P=0.01). Carboplatin-liposomal doxorubicin was more effective than CP in patients without leukopenia (aHR 0.51, P=0.001), but not those experiencing leukopenia (aHR 0.93, P=0.54; interaction P=0.008).Of 949 patients, 32% (CP=62%, CPLD=28%) reported neuropathy during landmark. Neuropathy was prognostic for PFS in the CP group only (aHR 0.77, P=0.02). Carboplatin-liposomal doxorubicin appeared to be more effective than CP among patients without neuropathy (aHR 0.70, P<0.0001), but not those with neuropathy (aHR 0.96, P=0.81; interaction P=0.15). CONCLUSION: First-cycle leukopenia and neuropathy were prognostic for patients treated with CP. Efficacy of CP treatment was similar to CPLD in patients who developed leukopenia. These findings support further research to understand the mechanisms of treatment-related toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/efectos adversos , Doxorrubicina/administración & dosificación , Leucopenia/inducido químicamente , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/efectos adversos , Adulto , Anciano , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Masculino , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Pronóstico , RecurrenciaRESUMEN
The bioavailability of orally administered imatinib is >90%, although the drug is monocationic under the acidic conditions in the duodenum. In vitro, we found that imatinib is transported by the intestinal uptake carrier organic anion transporting polypeptide (OATP1A2) and that this process is sensitive to pH, rosuvastatin, and genetic variants. However, in a study in patients with cancer, imatinib absorption was not associated with OATP1A2 variants and was unaffected by rosuvastatin. These findings highlight the importance of verifying in a clinical setting the drug-transporter interactions observed in in vitro tests.
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Ambiente , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Piperazinas/metabolismo , Pirimidinas/metabolismo , Animales , Benzamidas , Transporte Biológico Activo/fisiología , Femenino , Células HeLa , Humanos , Mesilato de Imatinib , Piperazinas/antagonistas & inhibidores , Pirimidinas/antagonistas & inhibidores , Xenopus laevisRESUMEN
BACKGROUND: Androgen deprivation therapy (ADT) for prostate cancer treatment induces a metabolic syndrome, which may contribute to non-cancer-related morbidity and mortality. Metformin may abrogate these effects. Additionally, metformin has potential antineoplastic activity in various malignancies including prostate cancer. MATERIALS AND METHODS: A literature review using PubMed with the keywords: AMPK, androgen deprivation therapy, insulin resistance, metabolic syndrome, metformin and prostate cancer was undertaken. RESULTS: This overview will look at the current evidence linking ADT and metabolic syndrome while discussing ongoing clinical trials under way assessing the effectiveness of metformin in abrogating these effects. The potential antineoplastic activity of metformin, mediated by multiple proposed mechanisms based on evidence from preclinical and clinical studies, will also be elucidated in this review. CONCLUSIONS: Overall available data support the potential dual benefit of metformin on ADT-induced metabolic syndrome and in its antineoplastic activity in prostate cancer, justifying the need for ongoing clinical trials to confirm these effects as the evidence currently available for standard practice is lacking.
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Antineoplásicos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Neoplasias de la Próstata/terapia , Animales , Antineoplásicos/farmacología , Humanos , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Masculino , Síndrome Metabólico/etiología , Síndrome Metabólico/prevención & control , Metformina/farmacología , Neoplasias de la Próstata/complicaciones , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Metastases from prostate cancer occur largely in bone through a haematogenous route. Metastatic spread of prostate cancer to the leptomeninges was rarely seen in the past. However, there has been a recent increase in presentations of leptomeningeal spread from prostate cancer in our institutions. Between 2004 and 2006, four patients were diagnosed with metastatic prostate cancer with leptomeningeal metastases in our centres. All four patients had hormone refractory prostate cancer and had previously had chemotherapy. The median survival of these patients was approximately 15 months from the time of hormone refractoriness. The prognosis of leptomeningeal metastasis secondary to metastatic prostate cancer is poor, ranging from 2 to 7 months as seen in our series. New cases of leptomeningeal metastases seen in our series are hypothesized to be secondary to the use of effective modern systemic treatments. A parallel might be drawn with the increased rate of central nervous system metastases in breast cancer since the introduction of effective cytotoxic treatments and more recently targeted therapies. We suggest the clinicians to be aware of the potential change of natural history and pattern of progression in metastatic prostate cancer.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundario , Encéfalo/patología , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/secundario , Neoplasias de la Próstata/diagnóstico , Anciano , Hormonas/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
BACKGROUND: The aim of the study was to evaluate the effectiveness, safety, and clinical outcomes of erythropoietin therapy in the treatment of anaemic cancer subjects receiving chemotherapy and to examine hypochromic red blood cell measurement as an indicator of functional iron sufficiency and as a predictor of responsiveness or non-responsiveness to erythropoietin therapy. METHODS: Patients who had a non-myeloid malignancy, had Hb < or = 11.0 g/dL, had a life expectancy of more than 6 months, were 18 years or older, were receiving chemotherapy and would continue to be treated for at least 2 months were given s.c. epoetin alfa three times a week. RESULTS: Haemoglobin levels increased significantly at all time periods compared with baseline and the number of transfusions received decreased significantly at all time periods compared with baseline. Quality of life as measured by Functional Assessment of Cancer Therapy-Anaemia showed significant increases at months 2 and 4 and there were significant improvements in the fatigue subscale at both time points (P < 0.05). Significant improvements at end-point were observed for the physical, emotional and functional well-being, and additional concern subscales (all P < 0.05). Haematocrit and reticulocytes increased significantly at end-point compared with at baseline (haematocrit 33.4 vs 28.3%, P < 0.001; reticulocytes 105.8 vs 78.6 x 10(9)/dL, P = 0.005). The percentage of hypochromic red blood cells did not show predictive value for response to treatment status. CONCLUSION: Epoetin alfa improved haemoglobin levels and quality of life in anaemic cancer patients receiving chemotherapy.