RESUMEN
The aim of this post hoc analysis of the VELOUR study (ClinicalTrials.gov NCT00561470) was to investigate the treatment effect of adding aflibercept to second-line infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) in patients with metastatic colorectal cancer (mCRC) who had failed any prior oxaliplatin-containing regimen. Adjuvant rapid relapsers (ARR), who were enrolled directly following relapse during or within 6 months of completion of oxaliplatin-containing adjuvant chemotherapy (N = 124, including 17 patients who also received bevacizumab as part of their adjuvant therapy), were excluded from the original VELOUR intention-to-treat (ITT) population (N = 1226). After exclusion of the ARR, overall survival (OS) in the ITT minus ARR (ITT-ARR) population (N = 1102) was longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm [hazard ratio (HR) 0.78, 95 % confidence interval (CI) 0.68-0.90; median survival difference 1.87 months]. In the subgroup of patients assigned to the prior bevacizumab stratum at randomization, OS was numerically longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm (HR 0.81; 95 % CI 0.63-1.04; median survival difference 2.14 months). Comparison of the post hoc analysis results with the primary analysis from VELOUR suggests that the inclusion of the directly enrolled ARR may have understated the aflibercept treatment benefit for both bevacizumab-pretreated and bevacizumab-naïve patients in the strictly second-line setting although no definitive conclusion may be inferred. The benefit associated with the addition of aflibercept to second-line FOLFIRI in patients with mCRC was observed whatever the timing of first-line disease progression. There were no unexpected safety concerns.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Compuestos Organoplatinos/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Camptotecina/administración & dosificación , Camptotecina/farmacología , Camptotecina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Método Doble Ciego , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/administración & dosificación , Leucovorina/farmacología , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/farmacología , Oxaliplatino , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/farmacología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. PATIENTS AND METHODS: In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. RESULTS: KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. CONCLUSION: This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Regulación Neoplásica de la Expresión Génica , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Panitumumab , Valor Predictivo de las Pruebas , Estudios Prospectivos , Proteínas Proto-Oncogénicas p21(ras) , Resultado del TratamientoRESUMEN
PURPOSE: A recent study identified a prognostic model for survival in metastatic colorectal cancer patients which included WBC count, alkaline phosphatase (AP), number of metastatic sites, and patients' self-reported social functioning. The aim of this research is to validate this model on data from an independent sample. PATIENTS AND METHODS: This validation study is based on a prospective randomized controlled trial in patients with metastatic colorectal cancer conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Chronotherapy Group. Overall, 564 patients in 10 countries were enrolled. For the purpose of this independent validation, patients with health-related quality of life (HRQOL) baseline data were analyzed. HRQOL was assessed using the EORTC Quality of Life Questionnaire C30 (QLQ-C30). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. RESULTS: The previous model with an additional adjustment, by stratification for sex, was replicated and its parameters were confirmed to independently predict survival: WBC count with an hazard ratio (HR) of 1.31 (95% CI, 1.021 to 1.698; P = .034); AP with an HR of 1.53 (95% CI, 1.188 to 1.979; P = .001); number of sites involved with an HR of 1.90 (95% CI, 1.531 to 2.364; P < .0001); and patients' self-reported social functioning with an HR of 0.94 (95% CI, 0.905 to 0.976; P = .001). The latter translates into a 6% increase in the likelihood of an earlier death for every 10-point decrease in the social functioning scale of the EORTC QLQ-C30. CONCLUSION: This study provides confirmatory evidence of the independent prognostic value of patients' self-reported social functioning in patients with advanced colorectal cancer.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Autoevaluación (Psicología) , Adenocarcinoma/patología , Adenocarcinoma/psicología , Adulto , Anciano , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/psicología , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Participación del Paciente , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Calidad de Vida , Reproducibilidad de los ResultadosRESUMEN
AIMS: This report describes three patients suffering from nodular regenerative hyperplasia (NRH). METHODS: These patients have received six, 16 and 20 cycles of neoadjuvant 5-fluorouracil and oxaliplatin-based chemotherapy before planned extended hepatectomy. Two patients underwent uneventful portal vein embolization to hypertrophy the future remnant liver. RESULTS: At the end of chemotherapy, liver function tests deteriorated and portal hypertension appeared in two patients, including ascites, splenomegaly and oesophageal varices. Liver biopsy was performed through a percutaneous (two patients) or a transjugular approach (one patient) and allowed the diagnosis of NRH, which was considered to be a contraindication for major liver resection in all three patients, associated with extrahepatic disease progression in one patient. All patients died from neoplastic disease progression despite further chemotherapy at 6, 17 and 31 months following the diagnosis of NRH. One patient developed liver failure and ascites at the time of death. CONCLUSIONS: Physicians should be aware of the potential occurrence and therapeutic impact of NRH in patients suffering from CRLM and treated by neoadjuvant 5FU-oxaliplatin-based chemotherapy before major liver surgery.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Regeneración Hepática/efectos de los fármacos , Hígado/efectos de los fármacos , Anciano , Quimioterapia Adyuvante/efectos adversos , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Contraindicaciones , Progresión de la Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Hepatectomía , Humanos , Hiperplasia , Hígado/patología , Hígado/cirugía , Hepatopatías/diagnóstico , Hepatopatías/mortalidad , Hepatopatías/patología , Hepatopatías/terapia , Pruebas de Función Hepática , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and anticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer. PATIENTS AND METHODS: For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chronoFLO4) would improve survival by 10% compared with conventional 2-day delivery of the same drugs (FOLFOX2). Patients were treated every 2 weeks with intrapatient dose escalation. RESULTS: Baseline characteristics were similar in both arms for the 564 patients (36 institutions, 10 countries). Median survival was 19.6 months (95% confidence limit [CL] = 18.2, 21.2) with chronoFLO4 and 18.7 months with FOLFOX2 (95% CL = 17.7, 21.0; P = .55). The main dose-limiting toxicities were diarrhea for chronoFLO4 and neutropenia for FOLFOX2. The analysis of survival predictors showed that sex was the single most important factor (P = .001). In women, the risk of an earlier death with chronoFLO4 was increased by 38% compared with FOLFOX2, with median survival times of 16.3 and 19.1 months (P = .03), respectively. In men, the risk of death was decreased by 25% with chronoFLO4 compared with FOLFOX2, with median survival times of 21.4 and 18.3 months (P = .02), respectively. CONCLUSION: Both regimens achieved similar median survival times more than 18 months with an acceptable toxicity. The chronomodulated schedule produced a survival advantage over FOLFOX in men. The strong sex dependency of optimal scheduling of fluorouracil, leucovorin, and oxaliplatin calls for translational investigations of determinants related to the patient's molecular clock.