RESUMEN
BACKGROUND/AIMS: The phase III placebo-controlled RADIANT-2 trial investigated the efficacy of everolimus plus octreotide long-acting repeatable (LAR) in patients with advanced neuroendocrine tumors (NET) associated with carcinoid syndrome. Here we report a secondary analysis based on the previous somatostatin analogue (SSA) exposure status of patients enrolled in RADIANT-2. METHODS: Patients were randomly assigned to receive oral everolimus 10 mg/day plus octreotide LAR 30 mg intramuscularly (i.m.) or to receive matching placebo plus octreotide LAR 30 mg i.m. every 28 days. SSA treatment before study enrollment was permitted. Patient characteristics and progression-free survival (PFS) were analyzed by treatment arm and previous SSA exposure status. RESULTS: Of the 429 patients enrolled in RADIANT-2, 339 were previously exposed to SSA (95% received octreotide); 173 of 339 patients were in the everolimus plus octreotide LAR arm. All patients had a protocol-specified history of secretory symptoms, but analysis by type showed that more patients who previously received SSA therapy had a history of flushing symptoms (77%), diarrhea (86%), or both (63%) compared with SSA-naive patients (62, 62, and 24%, respectively). Patients who received everolimus plus octreotide LAR had longer median PFS regardless of previous SSA exposure (with: PFS 14.3 months, 95% confidence interval, CI, 12.0-20.1; without: 25.2 months, 95% CI, 12.0-not reached) compared with patients who received placebo plus octreotide LAR (with: 11.1 months, 95% CI, 8.4-14.6; without: 13.6 months, 95% CI, 8.2-22.7). CONCLUSION: Everolimus in combination with octreotide improves PFS in patients with advanced NET associated with carcinoid syndrome, regardless of previous SSA exposure.
Asunto(s)
Everolimus/uso terapéutico , Tumores Neuroendocrinos/tratamiento farmacológico , Octreótido/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Quimioterapia Combinada , Everolimus/administración & dosificación , Everolimus/efectos adversos , Femenino , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Octreótido/administración & dosificación , Octreótido/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Peptide receptor radionuclide therapy (PRRT) is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic neuroendocrine tumors (GEPNETs) patients. Most studies report objective response rates in 15-35% of patients. Also, outcome in terms of progression free survival (PFS) and overall survival compares very favorably with that for somatostatin analogs, chemotherapy, or new, 'targeted' therapies. They also compare favorably to PFS data for liver-directed therapies. Two decades after the introduction of PRRT, there is a growing need for randomized controlled trials comparing PRRT to 'standard' treatment, that is treatment with agents that have proven benefit when tested in randomized trials. Combining PRRT with liver-directed therapies or with targeted therapies could improve treatment results. The question to be answered, however, is whether a combination of therapies performed within a limited time-span from one another results in a better PFS than a strategy in which other therapies are reserved until after (renewed) tumor progression. Randomized clinical trials comparing PRRT with other treatment modalities should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs.
Asunto(s)
Tumores Neuroendocrinos/tratamiento farmacológico , Radioisótopos/uso terapéutico , Receptores de Péptidos/uso terapéutico , Animales , Humanos , Neoplasias Intestinales/diagnóstico , Neoplasias Intestinales/tratamiento farmacológico , Neoplasias Intestinales/mortalidad , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/mortalidad , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Radiofármacos/uso terapéutico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Tasa de Supervivencia/tendenciasRESUMEN
BACKGROUND: Staging for pancreatic neuroendocrine tumors (PNET) considers tumor size and lymph node (LN) status; however, correlation with survival remains unclear. METHODS: A single-institution database of patients with resected PNET was analyzed. RESULTS: Of the 150 patients, incidentally discovered PNET was the most common presentation (42%). One hundred thirteen patients (75%) had LN data, 32 (28%) with positive LN (LN+). Procedure and tumor size did not predict LN+. Perineural invasion (P = .016) and lymphovascular (P < .001) invasion, however, were more common in LN+. Multivariate analysis showed poor/moderate differentiation predicted LN+. Median follow-up was 52 months and median overall survival was 225 months. Fifty-two patients (35%) developed recurrence and median disease-free survival (DFS) was 74 months. Only poor/moderate differentiation affected DFS. CONCLUSIONS: PNET has an unclear prognosis based on variables factored into stage. In this study, tumor size did not predict LN+; furthermore, LN+ did not impact overall survival or DFS. Tumor differentiation appears to be more important in determining prognosis.
Asunto(s)
Tumores Neuroendocrinos/patología , Pancreatectomía , Neoplasias Pancreáticas/patología , Pancreaticoduodenectomía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/cirugía , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs is a novel method of treatment in patients with metastatic neuroendocrine tumors (NETs). For the first time in the United States, we present preliminary results of the treatment with Lutetium (177)(Lu) DOTATATE in patients with progressive NETs. METHODS: Thirty-seven patients with grade 1 and grade 2 disseminated and progressive gastroenteropancreatic NET were enrolled in a nonrandomized, phase 2 clinical trial. Repeated cycles of 200 mCi (7.4 GBq; ±10%) were administered up to the cumulative dose of 800 mCi (29.6 GBq; ±10%). RESULTS: Among 32 evaluable patients, partial response and minimal response to treatment were seen in 28% and 3%, respectively, and stable disease was seen in 41% of patients. A total of 28% had progressive disease. A response to treatment was significantly associated with lower burden of disease in the liver. No significant acute or delayed hematologic or kidney toxicity was observed. An impressive improvement of performance status and quality of life were seen after Lu-DOTATATE therapy. CONCLUSIONS: Treatment with multiple cycles of (177)Lu-DOTATATE peptide receptor radionuclide therapy is well tolerated. This treatment results in control of the disease in most patients, whereas systemic toxicities are limited and reversible. Quality of life is also improved.
Asunto(s)
Neoplasias del Sistema Digestivo/radioterapia , Tumores Neuroendocrinos/radioterapia , Octreótido/análogos & derivados , Compuestos Organometálicos/uso terapéutico , Radiofármacos/uso terapéutico , Receptores de Somatostatina/metabolismo , Adulto , Anciano , Neoplasias del Sistema Digestivo/metabolismo , Neoplasias del Sistema Digestivo/mortalidad , Neoplasias del Sistema Digestivo/patología , Progresión de la Enfermedad , Fraccionamiento de la Dosis de Radiación , Femenino , Fluorodesoxiglucosa F18 , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Imagen Multimodal , Clasificación del Tumor , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/secundario , Octreótido/efectos adversos , Octreótido/uso terapéutico , Compuestos Organometálicos/efectos adversos , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Calidad de Vida , Radiofármacos/efectos adversos , Texas , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
PURPOSE: The American Joint Committee on Cancer (AJCC) staging manual has introduced a TNM staging classification for jejunal-ileal (midgut) neuroendocrine tumors (NETs). This classification has not been validated in a population consisting solely of midgut NETs. The purpose of this study was to test the prognostic validity of the classification in such a population. METHODS: Patients with jejunal and ileocecal NETs who were treated at the Moffitt Cancer Center between 2000 and 2010 were assigned stages (I through IV). Kaplan-Meier analyses for overall survival (OS) were performed on the basis of TNM stage and pathologic grade. Multivariate modeling was performed using Cox proportional hazards regression. RESULTS: We identified 691 patients with jejunal-ileocecal NETs. The AJCC classification in aggregate was highly prognostic for OS (P < .001). Five-year OS rates for stages I through IV were 100%, 100%, 91%, and 72%, respectively. The survival difference between stages III and IV was significant (P < .001); the difference between stages I/II versus III was not statistically significant (P = .1). Among patients with stage IIIB tumors, 5-year survival rates were 95% for resectable tumors versus 78% for unresectable mesenteric tumors (P = .02). A proliferative threshold of five mitoses per 10 high-power fields (HPF) was of greater prognostic value than a threshold of two mitoses per 10 HPF for discriminating between low- and intermediate-grade tumors. CONCLUSION: Stage I and II midgut NETs are associated with identical survival rates. Stage IIIB tumors are heterogeneous, with significant differences in survival observed between resectable mesenteric lymph nodes versus unresectable masses in the root of the mesentery. A higher mitotic cutoff of five per 10 HPF may lead to improved prognostic differentiation between low- and intermediate-grade tumors. Revisions to the current AJCC staging and grading classification may be warranted.
Asunto(s)
Neoplasias Intestinales/mortalidad , Neoplasias Intestinales/patología , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Adulto , Comités Consultivos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Neoplasias Intestinales/complicaciones , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Estadificación de Neoplasias , Tumores Neuroendocrinos/complicaciones , Pronóstico , Reproducibilidad de los Resultados , Medición de Riesgo , Estados Unidos/epidemiologíaRESUMEN
Pasireotide (SOM230) is a novel multireceptor-targeted somatostatin (sst) analog with high binding affinity for sst receptor subtype 1, 2, 3 (sst(1,2,3)) and sst(5). Because of this binding profile, pasireotide may offer symptom control in patients with neuroendocrine tumors (NETs) and carcinoid syndrome no longer responsive to octreotide LAR. This was a phase II, open-label, multicenter study of pasireotide in patients with advanced NET whose symptoms of carcinoid syndrome (diarrhea/flushing) were inadequately controlled by octreotide LAR. Patients received s.c. pasireotide 150âµg twice daily (bid), escalated to a maximum dose of 1200âµg bid until a clinical response was achieved. Forty-four patients were evaluated for efficacy and 45 for tolerability. Pasireotide 600-900âµg s.c. bid effectively controlled the symptoms of diarrhea and flushing in 27% of patients. Evaluation of tumor response in 23 patients showed 13 with stable disease and ten with progressive disease at study end. The most common drug-related adverse events were nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%) and most were of mild or moderate severity. Pasireotide 600-900âµg s.c. bid was effective and generally well tolerated in controlling the symptoms of carcinoid syndrome in 27% of patients with advanced NET refractory or resistant to octreotide LAR therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Diarrea/tratamiento farmacológico , Rubor/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Tumores Neuroendocrinos/tratamiento farmacológico , Somatostatina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Resistencia a Antineoplásicos , Femenino , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Octreótido/uso terapéutico , Calidad de Vida , Somatostatina/administración & dosificación , Somatostatina/efectos adversos , Somatostatina/farmacocinética , Resultado del TratamientoRESUMEN
BACKGROUND: The risk of metastatic spread among patients with early-stage pancreatic neuroendocrine tumors has not been well established. The authors sought to evaluate whether the new TNM staging systems proposed by the American Joint Committee on Cancer (AJCC) and European Neuroendocrine Tumor Society (ENETS) are prognostic for relapse-free survival (RFS) after surgical resection. METHODS: Patients with surgically resected localized or locally advanced pancreatic NETs treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I-III) based on the AJCC and ENETS classifications. RFS and overall survival were measured using Kaplan-Meier methodology, with log-rank testing for evaluation of the 2 tumor staging systems. Multivariate analysis was performed controlling for tumor grade, location, surgery type, functional hormonal status, and incidental diagnosis. RESULTS: The authors identified 123 patients with nonmetastatic, surgically resected pancreatic NETs. When using the AJCC classification, 5-year RFS rates for stages I through III were 78%, 53%, and 33%, respectively (P < 0.01). Using the ENETS classification, 5-year RFS rates for stages I to III were 100%, 70%, and 53% (P < 0.18). When excluding patients who were referred after their metastatic recurrence, the 5-year RFS rates for stages I to III were 90%, 73%, and 66% according to the AJCC classification, and 100%, 84%, and 75% according to the ENETS classification. Recurrence rates peaked at approximately 2 years after surgery. CONCLUSIONS: The AJCC and ENETS TNM classifications for pancreatic NETs are prognostic for recurrence-free survival and can be adopted in clinical practice.
Asunto(s)
Estadificación de Neoplasias/clasificación , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hallazgos Incidentales , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/patología , Tumores Neuroendocrinos/cirugía , Neoplasias Pancreáticas/cirugía , Pronóstico , Sociedades Médicas , Adulto JovenRESUMEN
BACKGROUND: Palladin is a metastasis-associated gene regulating cell motility. The expression of palladin protein in pancreatic neuroendocrine tumors (PET) and carcinomas (PECA) is not known. MATERIALS AND METHODS: A tissue microarray (TMA) of well-differentiated (WD) PETs/PECAs (AJCC 2010) and non-neoplastic, histologically normal pancreatic tissue/islets (HNPIs) was immunostained with palladin antibody and quantified using the Allred score. The results were correlated with the presence or absence of liver metastases. RESULTS: The retrospective study included 19 males and 19 females of age 27-79 years (mean 54). Tumor size was 0.9-11.5 cm (mean 3.8). Palladin expression was cytoplasmic and/or membranous. The tumors with high palladin expression were associated with liver metastasis (p<0.0001). All 14 primary PECA with hepatic metastases (MP-PECAs) exhibited palladin expression whereas 14 out of 24 (58%) clinically-localized primary PET (CLP-PETs) expressed palladin (p<0.01) with median Allred scores of 5 (range 3-7) and 2 (range 0-6) respectively (p<0.0001). The mean Allred score for the HNPIs in the MP-PECAs (N=6) was higher (4.2) as compared to that in the CLP-PETs (2.5,N=11) (p=0.23). CONCLUSION: Palladin may identify primary pancreatic endocrine neoplasms with a propensity to metastasize to the liver.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Proteínas del Citoesqueleto/metabolismo , Neoplasias Hepáticas/secundario , Neoplasias Pancreáticas/patología , Fosfoproteínas/metabolismo , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
PURPOSE: The American Joint Committee on Cancer (AJCC) staging manual (seventh edition) has introduced its first TNM staging classification for pancreatic neuroendocrine tumors (NETs) derived from the staging algorithm for exocrine pancreatic adenocarcinomas. This classification has not yet been validated. METHODS: Patients with pancreatic NETs treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I to IV) based on the new AJCC classification. Kaplan-Meier analyses for overall survival (OS) were performed based on age, race, histologic grade, incidental diagnosis, and TNM staging (European Neuroendocrine Tumors Society [ENETS] v AJCC) using log-rank tests. Survival time was measured from time of initial diagnosis to date of last contact or date of death. Multivariate modeling was performed using Cox proportional hazards regression. Weighted Cohen's κ coefficient was computed to evaluate the agreement of ENETS and AJCC classifications. RESULTS: We identified 425 patients with pancreatic NETs. On the basis of histopathologic grade, 5-year survival rates for low-, intermediate-, and high-grade tumors were 75%, 62%, and 7%, respectively (P < .001). When using the ENETS classification, 5-year OS rates for stages I, II, III, and IV were 100%, 88%, 85%, and 57%, respectively (P < .001). Subsequently, using the AJCC classification, 5-year OS rates for stages I, II, III, and IV were 92%, 84%, 81%, and 57%, respectively (P < .001). Both the novel AJCC classification and the ENETS classification were highly prognostic for survival. CONCLUSION: The AJCC TNM classification for pancreatic NETs is prognostic for OS and can be adopted in clinical practice.
Asunto(s)
Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Adolescente , Adulto , Comités Consultivos , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Femenino , Gastrinoma/mortalidad , Gastrinoma/patología , Glucagonoma/mortalidad , Glucagonoma/patología , Humanos , Hallazgos Incidentales , Insulinoma/mortalidad , Insulinoma/patología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Tumores Neuroendocrinos/clasificación , Neoplasias Pancreáticas/clasificación , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de Riesgo , Estados Unidos/epidemiología , Vipoma/mortalidad , Vipoma/patologíaRESUMEN
BACKGROUND: Treatment options for metastatic gastroenteropancreatic neuroendocrine tumors (NETs) have evolved in recent years. The somatostatin analogs octreotide and lanreotide have long been used for management of symptoms such as flushing and diarrhea associated with hormonally active NETs. New evidence demonstrates that these agents can also inhibit tumor growth. Other novel agents targeting the VEGF and mTOR pathways have recently been investigated in multicenter phase III studies. METHODS: The authors review the recent literature on treatments for metastatic gastroenteropancreatic NETs and summarize new therapeutic developments. RESULTS: Novel agents targeting somatostatin receptors and the VEGF and mTOR pathways are capable of significantly prolonging progression-free survival in certain NET subtypes. New temozolomide-based chemotherapy regimens have demonstrated considerable activity in pancreatic NETs. Liver-targeted therapies, including surgical resection, radiofrequency ablation, and hepatic artery embolization, are effective options for patients whose metastases are predominantly confined to the liver. Embolization of (90)Y-embedded spheres (radioembolization) represents a novel approach to managing liver metastases. CONCLUSIONS: Treatment options are expanding rapidly for patients with metastatic gastroenteropancreatic NETs, driven largely by randomized, collaborative clinical trials. Future clinical trials should compare the efficacy of emerging therapies and evaluate combination vs sequential approaches.
Asunto(s)
Neoplasias Gastrointestinales/terapia , Hígado/efectos de los fármacos , Tumores Neuroendocrinos/terapia , Neoplasias Pancreáticas/terapia , Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Gastrointestinales/patología , Humanos , Interferón-alfa/uso terapéutico , Metástasis de la Neoplasia , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Somatostatina/análogos & derivadosRESUMEN
OBJECTIVES: Using gene expression profiling on frozen primary pancreatic endocrine tumors (PETs), we discovered RUNX1T1 as a leading candidate progression gene. This study was designed (1) to validate the differential expression of RUNX1T1 protein on independent test sets of metastatic and nonmetastatic PETs and (2) to determine if RUNX1T1 underexpression in primary tumors was predictive of liver metastases. METHODS: Immunohistochemical expression of RUNX1T1 protein was quantified using Allred scores on archival metastatic (n = 13) and nonmetastatic (n = 24) primary adult PET tissues using custom-designed tissue microarrays. Wilcoxon rank sum/Fisher exact tests and receiver operating characteristic curves were used in the data analysis. RESULTS: Median RUNX1T1 scores were 2 (2-7) and 6 (3-8) in metastatic versus nonmetastatic primaries (P < 0.0001). Eleven of 13 metastatic and 1 of 24 nonmetastatic primaries exhibited RUNX1T1-scores of 4 or less (P < 0.0001). Low RUNX1T1 expression was highly associated with hepatic metastases (P < 0.0001), whereas conventional histological criteria (Ki-67 index, mitotic rate, necrosis) were weakly associated with metastases (P = 0.08-0.15). Considering RUNX1T1 expression (Allred) score of 4 or less to be predictive, the sensitivity to predict hepatic metastases was 85%, with a specificity of 96%. CONCLUSIONS: RUNX1T1 protein is underexpressed in well-differentiated metastatic primary PETs relative to nonmetastatic primaries and emerges as a promising novel biomarker for prediction of liver metastases.
Asunto(s)
Neoplasias Hepáticas/metabolismo , Tumores Neuroendocrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción/metabolismo , Adulto , Anciano , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Pronóstico , Proteómica/métodos , Proteínas Proto-Oncogénicas/genética , Proteína 1 Compañera de Translocación de RUNX1 , Análisis de Matrices Tisulares , Factores de Transcripción/genéticaRESUMEN
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare tumors that arise from the diffuse neuroendocrine system. This heterogeneous group of tumors was often considered a single entity. This belied their biological diversity, and the biggest advance in understanding these tumors over the past decades has been in understanding this diversity. Diagnosis of these tumors has been aided by advances in pathological diagnosis and classification and tumor imaging with endoscopic ultrasound and somatostatin receptor fusion imaging. Genetic and molecular advances have identified molecular targets in the treatment of these tumors. Surgery remains the mainstay of treatment, amply supported by interventional radiological techniques, including embolization. Treatment of metastatic disease has improved significantly with the addition of several new agents, including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and yttrium-90-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and lutetium-177-DOTA octreotate. Despite significant advances in the understanding and management of GEP-NETs, the survival of patients remains largely unchanged and there remains a need for the development of national and international research collaborations to spearhead future efforts.
Asunto(s)
Neoplasias del Sistema Digestivo/diagnóstico , Neoplasias del Sistema Digestivo/terapia , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/terapia , Biomarcadores de Tumor/análisis , Neoplasias del Sistema Digestivo/epidemiología , Neoplasias del Sistema Digestivo/genética , Humanos , Tumores Neuroendocrinos/epidemiología , Tumores Neuroendocrinos/genética , Estados UnidosRESUMEN
Extrapulmonary poorly differentiated neuroendocrine carcinomas can originate in the gastrointestinal tract, bladder, cervix, and prostate. These high-grade malignancies are characterized by aggressive histological features (high mitotic rate, extensive necrosis, and nuclear atypia) and a poor clinical prognosis. They are infrequently associated with secretory hormonal syndromes (such as the carcinoid syndrome) and rarely express somatostatin receptors.Most poorly differentiated neuroendocrine carcinomas are locally advanced or metastatic at presentation. First-line systemic chemotherapy with a platinum agent (cisplatin or carboplatin) and etoposide is recommended for most patients with metastatic-stage disease; however, response durations are often short. Sequential or concurrent chemoradiation is recommended for patients with loco-regional disease. In patients with localized tumors undergoing surgical resection, adjuvant treatment (chemotherapy with or without radiation) is warranted in most cases.
Asunto(s)
Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/terapia , HumanosRESUMEN
PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Sirolimus/análogos & derivados , Administración Oral , Adulto , Anciano , Cromogranina A/sangre , Supervivencia sin Enfermedad , Everolimus , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/mortalidad , Octreótido/administración & dosificación , Octreótido/efectos adversos , Neoplasias Pancreáticas/mortalidad , Fosfopiruvato Hidratasa/sangre , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sirolimus/farmacocinética , Insuficiencia del TratamientoRESUMEN
Management of liver metastasis from neuroendocrine tumors routinely includes an interventional radiologist. Hepatic artery embolization, either bland (transarterial embolization) or with chemotherapy (transarterial chemoembolization), has been shown to improve response rates in neuroendocrine metastases to the liver. Radiofrequency ablation, cryotherapy, and percutaneous alcohol ablation are important adjuncts or alternative treatments to surgical debulking. In this article, the authors examine important techniques in the armamentarium of the interventional radiologist.
Asunto(s)
Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Tumores Neuroendocrinos/terapia , Radiología Intervencionista , Ablación por Catéter , Quimioembolización Terapéutica , Criocirugía , Embolización Terapéutica , Etanol/administración & dosificación , Arteria Hepática , Humanos , Inyecciones , Láseres de Estado Sólido , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/secundario , Radiofármacos/uso terapéutico , Solventes/administración & dosificación , Radioisótopos de Itrio/uso terapéuticoAsunto(s)
Tumor Carcinoide/terapia , Neoplasias Hepáticas/terapia , Síndrome Carcinoide Maligno/terapia , Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Tumor Carcinoide/irrigación sanguínea , Tumor Carcinoide/secundario , Quimioembolización Terapéutica , Ensayos Clínicos como Asunto , Procedimientos Quirúrgicos del Sistema Digestivo , Arteria Hepática , Humanos , Interferones/uso terapéutico , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/secundario , Síndrome Carcinoide Maligno/patología , Radiofármacos/uso terapéutico , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Pancreatectomy for ductal adenocarcinoma has been performed with increasing frequency since the late 1980s as postoperative mortality decreased and long-term survival became more common. However, the belief persists among some clinicians that pancreatectomy offers little survival benefit. This report reviews our institutional experience with pancreatectomy for pancreatic adenocarcinoma and provides a critical overview of the controversies regarding the benefits of surgical intervention for patients who are candidates for curative resection. METHODS: We determined the survival of 142 patients who underwent pancreatectomy for ductal adenocarcinoma with curative intent (stage IA-IIB) at Moffitt Cancer Center during the last two decades by using data obtained from review of the medical record, the Moffitt Cancer Registry, and the Social Security Death Index. Histologic diagnosis was confirmed by expert review of stained sections cut from fixed surgical specimens. RESULTS: In the 137 patients who survived at least 30 days after surgery, the median survival was 21.2 months after resection, with Kaplan-Meier 3- and 5-year disease-specific survival rates of 36% and 32%, respectively. One patient has survived without evidence of recurrent disease for more than 15 years after pancreatectomy. Survival for patients greater than 75 year of age did not differ from that of younger patients. The postoperative mortality rate was 1.5% during the most recent years of highest operative volume (2003 to 2006) and 3.5% for the entire patient cohort. CONCLUSIONS: Review of our 20-year experience with resection of pancreatic adenocarcinoma indicates that pancreatectomy with curative intent offers a real chance of long-term survival to patients with this highly lethal disease for which there is no other curative modality.
Asunto(s)
Adenocarcinoma/cirugía , Pancreatectomía , Neoplasias Pancreáticas/cirugía , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Pancreaticoduodenectomía , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) comprise a heterogeneous group of neoplasms for which treatment is variable, depending on the clinical stage. Despite this diversity, surgery remains the gold standard in the management of PNETs. This paper discusses whether aggressive surgical intervention is indicated for PNETs and investigates what prognostic factors may assist in predicting which patients with invasive disease will benefit most from surgical intervention. METHODS: A review was conducted of large surgical series reported in the English literature over the last 10 years as they pertain to current surgical intervention in PNETs and of prognostic factors related to surgical outcome and survival. RESULTS: Improved survival can be achieved with aggressive surgical management of PNETs. The presence of hepatic metastases is not a contraindication to surgical resection of the primary PNET. Results of series that reported prognostic factors are heterogeneous. CONCLUSIONS: Aggressive surgical resection for selected individuals with PNETs can be performed safely and may improve both symptomatic disease and overall survival. Consideration for resection of primary PNETs should be given to patients with treatable hepatic metastases. Prognostic indices such as tumor differentiation and ability to achieve R0/R1 resection have been linked to survival outcome in PNETs and should be considered when planning aggressive surgical management for this disease.