El presente dictamen expone la evaluación de la eficacia y seguridad de lanreotida comparado con la mejor terapia de soporte para el tratamiento de tumor neuroendocrino (TNE) primario gastrointestinal, estadio clínico IV, grado 2, sin tratamiento previo / This opinion exposes the evaluation of the efficacy and safety of lanreotide compared to the best supportive therapy for the treatment of primary gastrointestinal neuroendocrine tumor (NET), clinical stage IV, grade 2, without previous treatment

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de lanreotida comparado con la mejor terapia de soporte para el tratamiento de tumor neuroendocrino (TNE) primario gastrointestinal, estadio clínico IV, grado 2, sin tratamiento previo. Los tumores neuroendocrinos (TNE) son un grupo heterogéneo de neoplasias que surgen de las células del sistema endocrino y el nervioso. No se han identificado datos epidemiológicos locales. No obstante, en los Estados Unidos se ha observado un crecimiento gradual en la incidencia, de 1.9 a 5.2/100 000 personas por año, a lo largo de las últimas tres décadas. Los TNE del tracto gastrointestinal (TNE-GI) representan aproximadamente dos tercios de todos los casos de TNE y son el segundo tipo de tumor gastrointestinal más común. La primera línea de tratamiento para los pacientes con TNE localizados, es la cirugía. Sin embargo, en casos avanzados (cuando se presentan las metástasis), el tratamiento es paliativo y limitado al control de la progresión de la enfermedad. En el contexto de EsSalud, actualmente no se cuenta con un tratamiento que permita el control de la progresión de enfermedad de estos pacientes. Así, especialistas locales consideran que lanreotida podría brindar un beneficio en el control del crecimiento y progresión tumoral para dichos pacientes. Lanreotida (Somatuline® Depot) es un octapéptido cíclico sintético análogo a la somatostatina natural. Lanreotida ha sido aprobado por la FDA y EMA para el tratamiento de pacientes con tumores neuroendocrinos gastroenteroprancreáticos (TNE-GEP). METODOLOGÍA: La búsqueda de la literatura se realizó con el objetivo de identificar evidencia sobre la eficacia y seguridad de lanreotida comparado con placebo para el tratamiento de tumor neuroendocrino primario gastrointestinal estadio clínico IV, grado 2, sin tratamiento previo. La búsqueda de la evidencia se realizó en las bases de datos bibliográficas: PubMed, Scopus y OVID. Adicionalmente, se revisó la evidencia generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como The National Institute for Health and Care Excellence (NICE), The National Comprehensive Cancer Network (NCCN), The Guidelines International Network (G-I-N), el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), The Canadian Agency for Drugs and Technologies in Health (CADTH), Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Quality and Efficiency in Health Care (IQWiG), The European Society for Medical Oncology (ESMO), European Medicines Agency (EMA), y Scottish Medicines Consortium (SMC). Finalmente, se realizó una búsqueda manual en el portal clinicaltrials.gov del National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que no hayan sido publicados aún. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de la lanreotida para el tratamiento de pacientes con tumores neuroendocrinos gastrointestinales. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: En el presente documento, se evaluó la mejor evidencia científica disponible hasta la actualidad en relación con la eficacia y seguridad de lanreotida para el tratamiento en pacientes adultos con diagnóstico de tumor neuroendocrino primario gastrointestinal estadio clínico IV, grado 2, sin tratamiento previo.  A la fecha, la búsqueda de la literatura científica identificó tres GPC, dos ETS, y un ECA fase III con dos publicaciones. Las tres GPC (NCCN, Singh et al, Alberta Health Services) recomiendan el uso de lanreotida como tratamiento en pacientes con TNE. Dentro de la evidencia empleada incluyen al único ECA, CLARINET (Caplin et al. 2014). Sin embargo, las GPC de NCCN y Singh et al, concuerdan en que la evidencia es de baja calidad, es decir brindan resultados imprecisos y con un alto riesgo de sesgo. Y los autores de las tres GPC reportaron tener conflicto de interés por haber recibido honorarios de la empresa farmacéutica Ipsen. La ETS de CADTH no brinda ninguna recomendación sobre el uso de lanreotida en la población de interés. Sólo determina que la evidencia demuestra que lanreotida tiene un efecto antiproliferativo y que es efectivo para el control de síntomas. La ETS realizada por el Ministerio de Salud de Chile, aprobó el uso de lanreotida como tratamiento de alto costo en pacientes con TNE. Esto teniendo en cuenta que el medicamento contaba con una aprobación de la FDA para la población a evaluar, no tenía ninguna orden de restricción de uso. El ECA de doble ciego realizado por Caplin et al. en el 2014, evalúa la eficacia y seguridad de lanreotida comparado con placebo en pacientes con tumores neuroendocrinos avanzados, bien o moderadamente diferenciados, no funcionales, receptores de somatostatina positivos, de grado 1 o 2 y con registro de la progresión de la enfermedad. En total participaron 204 sujetos, de los cuales 101 recibieron lanreotida (120 mg) y 103 recibieron placebo cada 28 días durante 96 semanas. Del total de participantes, el 42.2 % de los pacientes enrolados tenían TNE de origen en el intestino medio y posterior (población de interés del presente dictamen). En el subgrupo de pacientes con tumores primarios en el intestino medio el HR fue de 0.35 (IC 95 %: 0.16-0.80), y en el grupo de intestino posterior el HR fue de 1.47 (IC 95 %: 0.16-13.24). Sin embargo, los autores usaron el modelo estratificado de riesgos proporcionales de Cox, pese a que no se cumple el supuesto de proporcionalidad de riesgos (entrecruzamiento de curvas de K-M). De esta manera, los resultados no son precisos y son difíciles de interpretar. Además, en el grupo de intestino posterior los intervalos de confianza son demasiado amplios, evidenciando la falta de precisión de los datos (HR: 1.47; IC 95 %: 0.16-13.24). Los análisis de la SLP en los subgrupos son considerados exploratorios ya que no fueron considerados en el cálculo de tamaño de muestra. Además, la SLP, pese a ser un desenlace planteado en la pregunta PICO, no se ha demostrado que sea un desenlace de relevancia clínica desde la perspectiva del paciente. No se encontraron diferencias en la sobrevida global ni en la calidad de vida entre lanreotida y el uso de placebo en pacientes con TNE. Sobre el desenlace de valores de cromogranina A, se encontró incertidumbre sobre su valor predictivo en desenlaces de relevancia clínica como la SG o calidad de vida, debido a la baja calidad de la evidencia que evalúa esta asociación. Los eventos adversos serios fueron reportados por el 24.8 % de pacientes del grupo de lanreotida y 31.1 % en el grupo de placebo, sin presentar diferencias significativas en el riesgo relativo de tener un evento adverso serio entre lanreotida y placebo. Por su parte, los eventos adversos serios relacionados al tratamiento fueron 3/101 y 1/103, respectivamente. A la fecha, con la evidencia disponible, no existen argumentos técnicos que respalden un beneficio neto a favor del uso de lanreotida en pacientes con TNE gastrointestinal, sobre desenlaces clínicamente relevantes como la SG, calidad de vida, control de síntomas neuroendocrinos y seguridad. Los resultados en la SLP y cromogranina A, si bien mostraron diferencia a favor de lanreotida, no han demostrado que sean predictores de desenlaces de relevancia clínica como la SG y calidad de vida. En tal sentido, no se justificaría la inversión de recursos en un medicamento que no ha demostrado tener beneficios adicionales aun frente a placebo. Por lo expuesto, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación ­ IETSI no aprueba el uso de lanreotida como terapia en pacientes adultos con diagnóstico de tumor neuroendocrino primario gastrointestinal estadio clínico IV, grado 2, sin tratamiento previo.

Upfront surgery of small intestinal neuroendocrine tumors. Time to reconsider?

Small intestinal neuroendocrine tumors (SI-NETs) may demonstrate a widely variable clinical behavior but usually it is indolent. In cases with localized disease, locoregional resective surgery (LRS) is generally indicated with a curative intent. LRS of SI-NETs is also the recommended treatment when symptoms are present, regardless of the disease stage. Concerning asymptomatic patients with distant metastases, prophylactic LRS has been traditionally suggested to avoid possible future complications. Even the current European Neuroendocrine Tumor Society guidelines emphasize a possible effect of LRS in Stage IV SI-NETs with unresectable liver metastases. On the contrary, the 2017 National Comprehensive Cancer Network Guidelines on carcinoid tumors do not support the resection of a small, asymptomatic, relatively stable primary tumor in the presence of unresectable metastatic disease. Furthermore, a recent study revealed no survival advantage for asymptomatic patients with distant-stage disease who underwent upfront LRS. At the aforementioned paper, it was suggested that delayed surgery as needed was comparable with the upfront surgical approach in terms of postoperative morbidity and mortality, the length of the hospital stay and the rate of incisional hernia repairs but was associated with fewer reoperations for bowel obstruction. On the other hand, it is also important to note that some patients might benefit from a prophylactic surgical approach and our attention should focus on identifying this patient population.

Randomized Embolization Trial for NeuroEndocrine Tumor Metastases to the Liver (RETNET): study protocol for a randomized controlled trial.

BACKGROUND: Neuroendocrine tumors (NETs) are the second most common gastrointestinal malignancy after colon cancer. Up to 90% of patients with NETs develop liver metastases, which are a major determinant of symptoms and survival. Current guidelines recommend embolotherapy for progressive or symptomatic NET liver metastases, but the optimal technique among bland embolization, lipiodol chemoembolization, and drug-eluting bead chemoembolization remains unknown and controversial. METHODS/DESIGN: A prospective, open-label, multicenter randomized controlled trial will be conducted in patients with progressive or symptomatic unresectable NET liver metastases. Patients will be randomized to treatment with bland embolization, lipiodol chemoembolization, or drug-eluting microsphere chemoembolization, with 60 enrollees per arm. The primary endpoint will be hepatic progression-free survival (HPFS) following initial embolotherapy by RECIST criteria. The sample size is powered to detect an HR of 1.78 for HPFS following chemoembolization compared with bland embolization, which was estimated on the basis of existing retrospective studies. Secondary endpoints include overall progression-free survival, duration of symptom control, quality of life, rate of adverse events, and interval between embolotherapy cycles. Interim safety analyses will be performed at 10 and 30 patients per arm. DISCUSSION: The RETNET trial is a prospective, multicenter randomized controlled trial designed to determine the optimal embolotherapy technique for NET liver metastases. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02724540 . Registered on March 31, 2016.

Preoperative Fluorouracil, Doxorubicin, and Streptozocin for the Treatment of Pancreatic Neuroendocrine Liver Metastases.

INTRODUCTION: While preoperative chemotherapy is frequently utilized before resection of non-neuroendocrine liver metastases, patients with resectable neuroendocrine liver metastases typically undergo surgery first. FAS is a cytotoxic chemotherapy regimen that is associated with substantial response rates in locally advanced and metastatic pancreatic neuroendocrine tumors. METHODS: All patients who underwent R0/R1 resection of pancreatic neuroendocrine liver metastases at a single institution between 1998 and 2015 were included. The outcomes of patients treated with preoperative FAS were compared with those of patients who were not. RESULTS: Of the 67 patients included, 27 (40.3%) received preoperative FAS, whereas 40 (59.7%) did not. Despite being associated with higher rates of synchronous disease, lymph node metastases, and larger tumor size, patients who received preoperative FAS had similar overall survival [overall survival (OS), 108.2 months (95% confidence interval (CI) 78.0-136.0) vs. 107.0 months (95% CI 78.0-136.0), p = 0.64] and recurrence-free survival [RFS, 25.1 months (95% CI 23.2-27.0) vs. 18.0 months (95% CI 13.8-22.2), p = 0.16] as patients who did not. Among patients who presented with synchronous liver metastases (n = 46), the median OS [97.3 months (95% CI 65.9-128.6) vs. 65.0 months (95% CI 28.1-101.9), p = 0.001] and RFS [24.8 months (95% CI 22.6-26.9) vs. 12.1 months (2.2-22.0), p = 0.003] were significantly greater among patients who received preoperative FAS compared with those who did not. CONCLUSIONS: The use of FAS before liver resection is associated with improved OS compared with surgery alone among patients with advanced synchronous pancreatic neuroendocrine liver metastases.

Optimal Lymphadenectomy in Small Bowel Neuroendocrine Tumors: Analysis of the NCDB.

BACKGROUND: Current National Comprehensive Cancer Network guidelines for resectable small bowel neuroendocrine tumors (NETs) recommend regional lymphadenectomy. However, no consensus exists on the optimal nodal harvest. METHODS: The National Cancer Database was queried for patients with resectable small bowel NETs (1998-2013). Patients with metastatic disease and missing lymph node harvest data were excluded. We performed logistic regression of factors determining nodal positivity and multivariable survival analyses. RESULTS: Of 11,852 patients, 81.8% underwent lymphadenectomy. 79.3% were node positive (N+) and 46.9% of patients had tumors < 1 cm. Independent predictors of N+ were large tumor size, ileal location, and neuroendocrine carcinoma histology. Logistic regression found no difference between observed and expected proportions of N+ patients with lymphadenectomy greater than or equal to eight nodes. Lower metastatic node ratio predicted improved survival on multivariable analysis and is associated with high-volume institutions. CONCLUSION: Small bowel NETs have high rates of nodal metastasis, even in patients with small tumors, and many patients do not undergo lymphadenectomy despite the clear benefit. Lymphadenectomy of eight nodes is optimal to identify N+ patients. Additionally, minimizing metastatic node ratio with complete regional lymphadenectomy is associated with improved survival in these patients.

Primary hepatic neuroendocrine tumor with multiple liver metastases: A case report with review of the literature.

We herein present a case involving a 41-year-old woman in whom ultrasound examination revealed multiple liver hemangiomas more than 3 years ago. Follow-up ultrasound examination revealed that the masses had significantly increased; the largest was located in the right lobe (about 8.2 cm × 7.4 cm × 6.0 cm). Abdominal multidetector computed tomography revealed multiple well-circumscribed, heterogeneous, hypodense masses (largest, 6.4 cm × 6.3 cm × 5.0 cm) with significant contrast enhancement during the arterial and portal phases and with contrast wash-out and peripheral enhancement during the delayed phases. Magnetic resonance images demonstrated multiple well-circumscribed, heterogeneous, hypointense hepatic masses with significant contrast enhancement (largest, 6.4 cm × 6.5 cm × 5.1 cm); multiple enlarged porta lymph nodes; and multiple slightly enlarged retroperitoneal lymph nodes. Histological and immunohistochemical examination of the right mass biopsy specimen suggested a malignant neoplasm that had originated from a neuroendocrine cell type (grade 2 well-differentiated neuroendocrine carcinoma). After performing a systemic examination to exclude metastasis from an extrahepatic primary site, we considered that the masses had arisen from a primary hepatic neuroendocrine tumor with multiple liver metastases. The patient underwent transcatheter arterial chemoembolization using a combination of oxaliplatin (150 mg) mixed with one bottle of gelatin sponge particles (560-710 µm) and lipiodol (6 mL). Primary neuroendocrine tumors of the liver are extremely rare. This case is interesting because of the rarity of this neoplasm and previous misdiagnosis as multiple liver hemangiomas. Previously reported cases in the literature are also reviewed.

The value of preoperative imaging in small bowel neuroendocrine tumors.

BACKGROUND: Neuroendocrine tumors of the small bowel (SBNETs) are a rare but important subgroup of malignancies. Since 30 % of SBNETs present with metastatic disease, often with an occult primary, preoperative imaging is critical for determining who will benefit most from abdominal exploration. We set out to evaluate the usefulness of the two most commonly performed imaging modalities in predicting the extent of disease found at exploration in patients with SBNETs. METHODS: A retrospective chart review was performed on patients with SBNETs resected at 1 institution. Data from preoperative computed tomography (CT) scans were reviewed to determine whether the primary tumor, nodal, or liver metastases were seen, then compared with intraoperative findings. Results of preoperative somatostatin receptor scintigraphy (SRS) were similarly examined. RESULTS: A total of 62 patients with SBNETs were included. Of these patients, 42 of 62 (68 %) had distant metastases and 48 of 62 (77 %) had nodal metastases at exploration. A total of 56 patients had preoperative CT scans and 47 had SRS. Using CT, a primary tumor was localized to the small bowel in 27 of 56 (48 %) and nodal metastases seen in 33 of 56 (79 %) of cases. SRS found intra-abdominal uptake in 35 of 47 cases (74 %). CONCLUSIONS: CT and SRS are complementary in making the diagnosis of SBNET, with CT giving more precise anatomical detail, while SRS helps to confirm that lesions are NETs and is useful for identifying occult extrahepatic sites of metastatic disease. However, 10-15 % of SBNETs were not identified by either test preoperatively, and therefore surgical exploration still plays an important role in making the diagnosis in these patients.

Portal vein embolization using a Histoacryl/Lipiodol mixture before right liver resection.

PURPOSE: The purpose of this retrospective study was to evaluate the efficacy and safety of percutaneous transhepatic portal vein embolization (PVE) of the right liver lobe using Histoacryl/Lipiodol mixture to induce contralateral liver hypertrophy before right-sided (or extended right-sided) hepatectomy in patients with primarily unresectable liver tumors. METHODS: Twenty-one patients (9 females and 12 males) underwent PVE due to an insufficient future liver remnant; 17 showed liver metastases and 4 suffered from biliary cancer. Imaging was performed prior to and 4 weeks after PVE. Surgery was scheduled for 1 week after a CT or MRI control. The primary study end point was technical success, defined as complete angiographical occlusion of the portal vein. The secondary study end point was evaluation of liver hypertrophy by CT and MRI volumetry and transfer to operability. RESULTS: In all the patients, PVE could be performed with a Histoacryl/Lipiodol mixture (n = 20) or a Histoacryl/Lipiodol mixture with microcoils (n = 1). No procedure-related complications occurred. The volume of the left liver lobe increased significantly (p < 0.0001) by 28% from a mean of 549 ml to 709 ml. Eighteen of twenty-one patients (85.7%) could be transferred to surgery, and the intended resection could be performed as planned in 13/18 (72.3%) patients. CONCLUSION: Preoperative right-sided PVE using a Histoacryl/Lipiodol mixture is a safe technique and achieves a sufficient hypertrophy of the future liver remnant in the left liver lobe.

Pancreatic neuroendocrine tumors with involved surgical margins: prognostic factors and the role of adjuvant radiotherapy.

PURPOSE: Pancreatic neuroendocrine tumors (pNET) are rare neoplasms associated with poor outcomes without resection, and involved surgical margins are associated with a worse prognosis. The role of adjuvant radiotherapy (RT) in these patients has not been characterized. METHODS AND MATERIALS: We retrospectively evaluated 46 consecutive patients with positive or close (<1 mm) margins after pNET resection, treated from 1983 to 2010, 16 of whom received adjuvant RT. Median RT dose was 50.4 Gy in 1.8-Gy fractions; half the patients received concurrent chemotherapy with 5-fluorouracil or capecitabine. No patients received adjuvant chemotherapy. Cox multivariate analysis (MVA) was used to analyze factors associated with overall survival (OS). RESULTS: Median age at diagnosis was 56 years, and 52% of patients were female. Median tumor size was 38 mm, 57% of patients were node-positive, and 11% had a resected solitary liver metastasis. Patients who received RT were more likely to have larger tumors (median, 54 mm vs. 30 mm, respectively, p = 0.002) and node positivity (81% vs. 33%, respectively, p = 0.002) than those not receiving RT. Median follow-up was 39 months. Actuarial 5-year OS was 62% (95% confidence interval [CI], 41%-77%). In the group that did not receive RT, 3 patients (10%) experienced local recurrence (LR) and 5 patients (18%) developed new distant metastases, while in the RT group, 1 patient (6%) experienced LR and 5 patients (38%) developed distant metastases. Of all recurrences, 29% were LR. On MVA, male gender (adjusted hazard ratio [AHR] = 3.81; 95% CI, 1.21-11.92; p = 0.02) and increasing tumor size (AHR = 1.02; 95% CI, 1.01-1.04; p = 0.007) were associated with decreased OS. CONCLUSIONS: Long-term survival is common among patients with involved-margin pNET. Despite significantly worse pathologic features among patients receiving adjuvant RT, rates of LR between groups were similar, suggesting that RT might aid local control, and merits further evaluation.

Resected pancreatic neuroendocrine tumors: patterns of failure and disease-related outcomes with or without radiotherapy.

PURPOSE: Pancreatic neuroendocrine tumors (NET) are rare and have better disease-related outcomes compared with pancreatic adenocarcinoma. Surgical resection remains the standard of care, although many patients present with locally advanced or metastatic disease. Little is known regarding the use of radiotherapy in the prevention of local recurrence after resection. To better define the role of radiotherapy, we performed an analysis of resected patients at our institution. METHODS: Between 1994 and 2009, 33 patients with NET of the pancreatic head and neck underwent treatment with curative intent at Duke University Medical Center. Sixteen patients were treated with surgical resection alone while an additional 17 underwent resection with adjuvant or neoadjuvant radiation therapy, usually with concurrent fluoropyrimidine-based chemotherapy (CMT). Median radiation dose was 50.4 Gy and median follow-up 28 months. RESULTS: Thirteen patients (39%) experienced treatment failure. Eleven of the initial failures were distant, one was local only and one was local and distant. Two-year overall survival was 77% for all patients. Two-year local control for all patients was 87%: 85% for the CMT group and 90% for the surgery alone group (p = 0.38). Two-year distant metastasis-free survival was 56% for all patients: 46% and 69% for the CMT and surgery patients, respectively (p = 0.10). CONCLUSIONS: The primary mode of failure is distant which often results in mortality, with local failure occurring much less commonly. The role of radiotherapy in the adjuvant management of NET remains unclear.

[Fulminant duodenal bleeding as first manifestation of a neuroendocrine carcinoma of the pancreatic head]. / Fulminante Duodenalblutung als Erstmanifestation eines neuroendokrinen Pankreaskopfkarzinoms.

CASE REPORT: A 73-year-old male patient presented with upper gastrointestinal bleeding. The reason was an arterial hemorrhage from a duodenal tumor that could only be stopped by an angiographic intervention. In the further staging, there was evidence for a neuroendocrine carcinoma of the pancreatic head with infiltration of the duodenum and hepatic metastases. Due to good differentiation (G1) a systemic biotherapy with octreotide LAR was induced. After recurrent bleeding with arrosion of a branch of the superior mesenteric artery, a duodenum-preserving pancreatic head resection was performed. Afterwards, the systemic therapy was changed to a palliative chemotherapy with streptozotocin and 5-fluorouracil due to local progression of the disease and a Ki-67 index of 4% in the primary tumor. CONCLUSION: In about 0.7% of patients with neuroendocrine tumors, the lesion is located in the pancreas. At this site these entities are very heterogeneous. The majority are nonfunctional tumors without secretion of bioactive substances and the associated symptoms. About 60% of the patients present with advanced metastasized disease. The therapy depends on the local spread and histological grading as well as symptoms of the patient. The only curative option represents surgical resection. However, even in a palliative situation, there can be benefit for the patient in case of a tumor mass reduction of > 90%. Alternative therapies in the palliative situation are somatostatin analogs, a classic systemic chemotherapy, or locoregional interventional procedures.

[Liver chemoembolization: an update]. / Le point sur la chimioembolisation hépatique.

Percutaneous intraarterial techniques for treatment of liver tumors are continuously under development. New therapeutic methods are available (such as microsphere-encapsulated chemotherapy or yttrium 90 microspheres) and presently under evaluation. These methods enlarge the field of indications, i.e. in metastasis from colorectal cancer. Hepatocellular carcinoma and metastasis from neuroendocrine tumours are the main pathologies favourably responding to "conventional" chemoembolization. Thank to controlled studies and meta-analysis performed along the last ten years, curative-palliative-as well as adjuvant-indications for chemoembolization in hepatocellular carcinoma are now wellestablished.

The role of cytoreductive hepatic surgery as an adjunct to the management of metastatic neuroendocrine carcinomas.

BACKGROUND: Patients with metastatic neuroendocrine cancers to the liver often present with disabling endocrinopathies and pain associated with bulky disease. Quality of life for these patients is poor and can require long-term therapy with somatostatin analogs for control of their symptoms. Alternative therapies to decrease tumor burden and subsequent hormone release have been investigated. Of these, cytoreductive surgery was found to have the most consistent and profound impact on symptom regression and overall survival. METHODS: Several cases are reported that illustrate an aggressive multimodality approach in the treatment of metastatic neuroendocrine cancers to the liver. The literature is reviewed and the role of cytoreductive surgery in the management of hepatic neuroendocrine metastases is discussed. RESULTS: Cytoreductive surgery can be performed safely with minimal morbidity and mortality. Regression of symptoms occurs in the majority of patients and survival is prolonged. CONCLUSIONS: Surgical intervention as part of an aggressive multimodality treatment plan results in improved outcomes for patients with advanced hepatic metastases of neuroendocrine origin. Future directions may include earlier surgical intervention with adjuvant therapies reserved for aggressive recurrent disease.

Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA(0),Tyr3]octreotate.

Medical treatment and chemotherapy are seldom successful in achieving objective tumour reduction in patients with metastatic neuroendocrine tumours. Treatment with the radiolabelled somatostatin analogue [(90)Y-DOTA(0),Tyr(3)]octreotide may result in partial remissions in 10-25% of patients. The newer analogue [DOTA(0),Tyr(3)]octreotate (octreotate) has a ninefold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA(0),Tyr(3)]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide (177)Lu, it has proved very successful in achieving tumour regression in animal models. The effects of (177)Lu-octreotate therapy were studied in 35 patients with neuroendocrine gastro-entero-pancreatic (GEP) tumours who underwent follow-up for 3-6 months after receiving their final dose. Patients were treated with doses of 100, 150 or 200 mCi (177)Lu-octreotate, to a final cumulative dose of 600-800 mCi, with treatment intervals of 6-9 weeks. Nausea and vomiting within the first 24 h after administration were present in 30% and 14% of the administrations, respectively. WHO toxicity grade 3 anaemia, leucocytopenia and thrombocytopenia occurred after 0%, 1% and 1% of the administrations, respectively. Serum creatinine and creatinine clearance did not change significantly. The effects of the therapy on tumour size were evaluable in 34 patients. Three months after the final administration, complete remission was found in one patient (3%), partial remission in 12 (35%), stable disease in 14 (41%) and progressive disease in seven (21%), including three patients who died during the treatment period. Tumour response was positively correlated with a high uptake on the octreoscan, limited hepatic tumour mass and a high Karnofsky Performance Score. Because of the limited efficacy of alternative therapies, many physicians currently adopt an expectant attitude when dealing with patients with metastatic GEP tumours. However, in view of the high success rate of therapy with (177)Lu-octreotate and the absence of serious side-effects, we advocate its use in patients with GEP tumours without waiting for tumour progression.

[Liver metastases--primary or multimodal therapy?]. / Lebermetastasen--primäre oder multimodale Therapie?

Multimodal therapeutic concepts for the treatment of liver metastasis are currently undergoing evaluation--prompted by the fact that few patients have lasting benefit from resection alone. Thus, for example, in practice, virtually only metastases from colorectal carcinoma or neuroendocrine tumors can be referred to surgical treatment, and, of these, only 20-25% are technically resectable. Furthermore, even after an R0 resection, recurrent disease subsequently develops in 60-75% of the cases. In primarily non-resectable colorectal liver metastases, prior systemic treatment with 5-FU/folinic acid and oxaliplatin can result in partial or complete remission in 50-60% of cases and, depending on patient selection criteria, a secondary R0 resection rendered possible in 14-38%. Theoretical oncological considerations suggest that neoadjuvant treatment should be applied in the case of resectable liver metastases too. The question of whether the prognosis is then improved compared with resection alone is currently being investigated in a prospective multicentre study conducted by the EORTC. The value of adjuvant therapy administered with the aim of lowering the risk of recurrence following "curative" resection of liver metastases is presently not considered to have been adequately demonstrated. With regard to the efficacy of regional chemotherapy, the results of two prospective randomized studies are contradictory. Nor can the multimodal approach decisively improve the outcome of non-radical resection of metastatic lesions. This means that primary or secondary resection with a margin of clearance continues to represent the gold standard for the treatment of colorectal liver metastases. Neoadjuvant or adjuvant chemotherapy--where applicable with the additional use of various methods of thermal ablation (cryotherapy, laser therapy, high-frequency thermotherapy)--should be restricted to clinical trials.