RESUMEN
PURPOSE: Mutations in the RET proto-oncogene and vascular endothelial growth factor receptor (VEGFR) activity are critical in the pathogenesis of medullary thyroid cancer (MTC). Sorafenib, a multikinase inhibitor targeting Ret and VEGFR, showed antitumor activity in preclinical studies of MTC. PATIENTS AND METHODS: In this phase II trial of sorafenib in patients with advanced MTC, the primary end point was objective response. Secondary end points included toxicity assessment and response correlation with tumor markers, functional imaging, and RET mutations. Using a two-stage design, 16 or 25 patients were to be enrolled onto arms A (hereditary) and B (sporadic). Patients received sorafenib 400 mg orally twice daily. RESULTS: Of 16 patients treated in arm B, one achieved partial response (PR; 6.3%; 95% CI, 0.2% to 30.2%), 14 had stable disease (SD; 87.5%; 95% CI, 61.7% to 99.5%), and one was nonevaluable. In a post hoc analysis of 10 arm B patients with progressive disease (PD) before study, one patient had PR of 21+ months, four patients had SD >or= 15 months, four patients had SD Asunto(s)
Bencenosulfonatos/uso terapéutico
, Carcinoma Medular/tratamiento farmacológico
, Inhibidores de Proteínas Quinasas/uso terapéutico
, Piridinas/uso terapéutico
, Neoplasias de la Tiroides/tratamiento farmacológico
, Administración Oral
, Adulto
, Anciano
, Bencenosulfonatos/administración & dosificación
, Bencenosulfonatos/efectos adversos
, Biomarcadores de Tumor/metabolismo
, Carcinoma Medular/enzimología
, Carcinoma Medular/genética
, Carcinoma Medular/mortalidad
, Carcinoma Medular/secundario
, Supervivencia sin Enfermedad
, Femenino
, Humanos
, Estimación de Kaplan-Meier
, Imagen por Resonancia Magnética
, Masculino
, Persona de Mediana Edad
, Mutación
, Niacinamida/análogos & derivados
, Compuestos de Fenilurea
, Tomografía de Emisión de Positrones
, Inhibidores de Proteínas Quinasas/administración & dosificación
, Inhibidores de Proteínas Quinasas/efectos adversos
, Proto-Oncogenes Mas
, Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores
, Proteínas Proto-Oncogénicas c-ret/genética
, Piridinas/administración & dosificación
, Piridinas/efectos adversos
, Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
, Sorafenib
, Neoplasias de la Tiroides/enzimología
, Neoplasias de la Tiroides/genética
, Neoplasias de la Tiroides/mortalidad
, Neoplasias de la Tiroides/patología
, Factores de Tiempo
, Tomografía Computarizada por Rayos X
, Resultado del Tratamiento
, Estados Unidos
, Adulto Joven
RESUMEN
PURPOSE: Based on the pivotal role of Ras-Raf-MAP-ERK signaling and vascular endothelial growth factor (VEGF) in papillary thyroid cancer (PTC), we conducted a phase II clinical trial of sorafenib targeting RAF and VEGF receptor kinases in PTC. PATIENTS AND METHODS: The primary end point was the objective response rate. Secondary end points included response correlation with serum thyroglobulin (Tg); functional imaging; tumor genotype; and signaling inhibition in tumor biopsies. Using a Simon minimax two-stage design, 16 or 25 chemotherapy-naïve metastatic PTC patients were to be enrolled in arm A (accessible tumor for biopsy). Arm B patients had other subtypes of thyroid carcinoma or prior chemotherapy, and did not require tumor biopsies. Patients received 400 mg orally twice per day of sorafenib. Response was assessed every 2 months using RECIST (Response Evaluation Criteria in Solid Tumors). RESULTS: Of 41 PTC patients, six patients had a partial response (PR; 15%; 95% CI, 6 to 29) and 23 patients (56%; 95% CI, 40 to 72) had stable disease longer than 6 months. Median duration of PR was 7.5 months (range, 6 to 14). Median progression-free survival was 15 months (95% CI, 10 to 27.5). In 14 (78%) of 18 Tg-assessable PTC patients, Tg declined more than 25%. Common grade 3 adverse events included hand-foot skin reaction, musculoskeletal pain, and fatigue. BRAF mutation was detected in 17 (77%) of 22 PTCs analyzed. Four of 10 paired tumor biopsies from PTC patients showed a reduction in levels of vascular endothelial growth factor receptor phosphorylation, ERK phosphorylation, and in VEGF expression during sorafenib therapy. No PRs were noted among non-PTC patients. CONCLUSION: Sorafenib is reasonably well-tolerated therapy with clinical and biologic antitumor activity in metastatic PTC.
Asunto(s)
Adenocarcinoma Papilar/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Piridinas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Adenocarcinoma Papilar/mortalidad , Adenocarcinoma Papilar/patología , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Sorafenib , Tiroglobulina/sangre , Tiroglobulina/efectos de los fármacos , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patologíaRESUMEN
BACKGROUND: Radiofrequency ablation (RFA) is gaining acceptance as a treatment modality for several tumor types. However, its use in patients with breast carcinoma remains investigational. The current study was undertaken to determine the feasibility of treating small breast malignancies with RFA and to evaluate the postablation magnetic resonance imaging scans (MRI) and histologic findings. METHODS: Patients with core-needle biopsy-proven invasive carcinoma (< 2 cm in greatest dimension) underwent ultrasound-guided RFA under local anesthesia. Surgical excision was undertaken 1-3 weeks later. All patients had breast MRI scans performed before ablation and repeated within 24 hours of surgery. RESULTS: Ten patients completed the treatment and experienced minimal or no discomfort. The mean tumor size was 1.2 cm (range, 0.8-1.6 cm). The mean time required for ablation was 13.8 minutes (range, 7-21 minutes). There were no treatment-related complications other than minimal breast ecchymosis. A pre-RFA MRI scan showed enhancing tumors in 9 of 10 (90%) patients. A post-RFA MRI scan revealed no residual lesion enhancement in 8 of these 9 patients (89%), and the zone of ablation was demonstrated in all patients. One patient had residual enhancement anteriorly consistent with residual tumor, which was confirmed histologically. Evaluation of the remaining ablated lesions revealed a spectrum of changes ranging from no residual tumor to coagulation necrosis with recognizable malignant cells. Immunostains for cytokeratin 8/18 were negative in these recognizable malignant cells. CONCLUSIONS: RFA of small breast malignancies can be performed under local anesthesia in an office-based setting. A postablation MRI scan appears to predict histologic findings, although tumor viability needs to be assessed in a long-term study.