Metastatic Pancreatic Endocrine Tumors Research Articles

Bevacizumab combined with 5-FU/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial) – A phase II non-randomised trial

Aim of the studyNeuroendocrine tumours are highly vascular neoplasms known to overexpress vascular endothelial growth factor (VEGF) and its receptor. Bevacizumab, an inhibitor of VEGF, was assessed in combination with chemotherapy in pancreatic neuroendocrine tumour (P-NET). Patients and methodsBETTER was a multicentre, open-label, non-randomised, two-group phase II trial. Patients with progressive metastatic, well-differentiated P-NET received a minimum of 6month treatment of bevacizumab at 7.5mg/kg IV on d1 q3w with 5-FU at 400mg/m2/day and streptozocin at 500mg/m2/day IV from d1 to d5 every 42days. The primary end-point was progression-free survival (PFS); secondary end-points were overall survival (OS), overall response rate, safety and quality of life. ResultsA total of 34 patients were included. Median age was 55years, 65% of patients were men, 97% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and 97% had a Ki-67 proliferative index of <15%. After a maximum of 24month follow-up per patient, the median PFS assessed by investigators was 23.7months [95% confidence interval (CI): 13.1; not reached], 19 (56%) patients had a partial response and 15 (44%) had stable disease as best response. OS rate at 24months was 88%. The most frequently reported grade 3–4 adverse events were hypertension (21% patients), abdominal pain (12%) and thromboembolic events (9%). ConclusionBevacizumab with 5-FU/streptozocin in the treatment of pancreatic NETs seems to be feasible with a PFS of 23.7months, which deserves further attention. No unexpected toxicity was observed.

Extended surgery for advanced pancreatic endocrine tumours

Pancreatic endocrine tumours are often diagnosed at an advanced stage with hepatic metastasis. This study investigated whether extended resections for advanced malignant pancreatic endocrine tumours influenced disease-free and disease-specific survival. Patients who had curative resection of pancreatic endocrine tumours were analysed retrospectively for disease-free and disease-specific survival, with a focus on the role of extended surgical resection. Forty-one patients were included in the analysis, 13 of whom underwent extended surgical resection in addition to pancreatic resection. This included partial liver resection in nine patients, portal vein resection in three, partial gastric resection in five and liver transplantation in three patients. There were no deaths in hospital or within 30 days. Median follow-up was 40 (range 2-239) months. Thirty-five, 24 and 13 patients survived more than 1, 3 and 5 years respectively. Patients who underwent extended resection had similar disease-specific survival to those who had pancreatic resection alone (hazard ratio (HR) 1·50, 95 per cent confidence interval (c.i.) 0·35 to 6·35; P = 0·581) but with a higher frequency of complications (odds ratio (OR) 4·28, 95 per cent c.i. 1·04 to 17·62; P = 0·044). Among patients with liver metastases, the mortality rate was higher in those in whom liver resection was not possible than in patients who had liver resection (HR 9·24, 1·00 to 85·18; P = 0·049). Patients who had liver resection had similar disease-specific survival to those without liver metastases (HR 0·84, 0·09 to 7·57; P = 0·877). Extended surgical resection for locally advanced and metastatic pancreatic endocrine tumours is feasible with encouraging disease-specific survival.

Metastatic Pancreatic Endocrine Tumor Presenting as Thoracic Spinal Cord Compression

A case report. The authors present a rare case of metastatic nonfunctioning neuroendocrine tumor of the pancreas presenting as thoracic spinal cord compression. Pancreatic endocrine tumors (PETs) are a slow-growing subset of pancreatic tumors. They can be classified as either functioning or nonfunctioning. To our knowledge, this is the second reported case of a PET presenting as spinal cord compression. The clinical course, radiologic features, pathology, and outcome of the metastasis of PET are reported. A 59-year-old woman presenting with a 2-week history of midthoracic back pain and early signs of myelopathy. A computed tomography scan and magnetic resonance imaging revealed multiple mildly enhancing lesions within T5, T7, T8, and L1 vertebral bodies with ventral epidural and bilateral T8-T9 neuroforaminal soft tissue extension causing severe spinal canal stenosis. A computed tomography-guided biopsy was inconclusive, and we performed a T7-T9 laminectomy with T8 bilateral transpedicular decompression and T6 to T10 pedicle screw fixation and posterolateral fusion with subtotal resection of the tumor. Pathology was consistent with low-grade neuroendocrine tumor. The patient recovered well, and an octreotide scan ultimately revealed an area of abnormal uptake within the body of the pancreas. We have reported a rare case of a metastatic PET presenting as spinal cord compression.

Pancreatic endocrine tumor with neoplastic venous thrombus and bilobar liver metastasis. A case report

We report the case of an asymptomatic 56-year-old woman with a metastatic pancreatic endocrine tumor, fortuitously discovered by abdominal imaging. A CT-scan showed a large mass in the pancreatic tail invading the spleen and stomach; in addition, there was neoplastic thrombus within the spleno-mesentericoportal venous confluence and bilobar liver metastases. Surgical resection was performed in two stages. The first procedure was an extended left pancreatectomy with venous thrombectomy and "clearance" of the left hepatic lobe. During the interval, embolization of the right portal vein was carried out. Right hepatectomy and radiofrequency destruction of residual metastases was then performed. On the basis of completeness of the resection and the histopathological data, the patient did not undergo any adjuvant therapy, in accordance with French guidelines. At 1 year of follow-up, there was no evidence of recurrence.

Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors

Somatostatin analogs were initially developed for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating data has supported their role as antiproliferative agents, capable of stabilizing tumor growth in patients with metastatic neuroendocrine malignancies, including carcinoid and pancreatic endocrine tumors. A phase III, randomized, placebo-controlled trial has now demonstrated that octreotide long-acting repeatable (LAR) 30 mg can significantly prolong time to tumor progression among patients with metastatic midgut NETs regardless of functional status, chromogranin A level or age. In addition to significantly lengthening time to tumor progression in the overall study population, subset analysis suggests that patients with low tumor burden are most likely to experience disease stabilization with octreotide LAR 30 mg, supporting the early use of octreotide LAR in patients with metastatic disease. Further research efforts are underway to evaluate the use of somatostatin analogs as antiproliferative agents in other types of gastroenteropancreatic-NETs. Ongoing studies are also evaluating novel somatostatin analogs and somatostatin analogs in combination with other anti-tumor therapies.

Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors

Liver biopsy of metastatic pancreatic endocrine tumors allows confirmation of the diagnosis and assessment of prognosis. However, sampling variability is a potential limitation. Our aim was to use the tissue microarray technique to assess the heterogeneity of three prognostic markers, ie, MIB-1 proliferation index, microvascular density and somatostatin receptor type 2, inside single or between synchronous or metachronous liver metastases of pancreatic endocrine tumors. Tissue microarrays were constructed, which included core biopsies taken from surgically resected liver metastases in 29 patients. MIB-1, microvascular density and somatostatin receptor type 2 were evaluated after immunostaining. The heterogeneity was highlighted by the calculation of the reproducibility of the values of two cores randomly selected among all the cores studied. For quantitative variables, it was assessed by the intraclass correlation coefficient and by a Bland–Altman approach. For qualitative variables, observed agreement and weighted κ were given. A total of 184 liver metastases were analyzed. For MIB-1, the intraclass correlation coefficients were 0.63, 0.69 and 0.67 and for microvascular density, the intraclass correlation coefficients were 0.48, 0.60 and 0.00, respectively, in single, synchronous and metachronous liver metastases. The variability increased for higher mean values of microvascular density. For somatostatin receptor type 2, the observed agreements were 91% (κ=0.81), 69% (κ=0.49) and 79% (κ=0.68) in single, synchronous and metachronous liver metastases, respectively. In conclusion, tissue microarray analysis identifies heterogeneity of protein expression in pancreatic endocrine metastases, which depends on the marker tested. The reproducibility is better for MIB-1 and somatostatin receptor type 2 than for microvascular density. Sampling variability should be taken into consideration as a potential limitation to the assessment of prognostic and therapeutic markers in biopsy samples from metastatic pancreatic endocrine tumors.

Selective Hepatic Artery Embolization for Treatment of Patients with Metastatic Carcinoid and Pancreatic Endocrine Tumors

Prognosis in patients with carcinoid and pancreatic endocrine tumors with diffuse, unresectable liver metastases is poor. Palliation is often difficult despite the use of somatostatin analogs, interferon alpha, or systemic chemotherapy. Several reviews have suggested that hepatic artery embolization, with or without intraarterial chemotherapy, can be used for control of symptoms and for cytoreduction in patients with liver dominant metastases. Between 2000 and 2002, 161 embolizations using polyvinyl alcohol or microspheres were performed on 84 patients with carcinoid or pancreatic endocrine tumors metastatic to the liver. A retrospective review was performed to evaluate symptomatic response, biochemical response, adverse effects, and duration of survival. Baseline and follow-up computed tomography scans were also assessed to determine radiographic response rates. Further analysis of survival was performed to assess the possible impact of various postembolization therapies. Eighty-four patients underwent bland hepatic artery embolizations during the study period. Among 55 symptomatic patients, 44 patients had fewer symptoms, and among 35 patients whose tumor markers were followed, 28 had a major biochemical response. Objective radiographic responses were observed in 11 of 23 patients. No deaths occurred during therapy, and major toxicities were rare. Median overall survival was 36 months from time of initial embolization. Hepatic artery embolization frequently results in clinical and radiographic responses in patients with unresectable liver metastases from carcinoid or pancreatic endocrine tumors. Morbidity is low when appropriate supportive care is provided. Hepatic artery embolization often results in regressions in patients with unresectable liver metastases from carcinoid or pancreatic endocrine tumors.

Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas

The epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of many tumors. To analyze the expression of EGFR and activated EGFR in well-differentiated neuroendocrine carcinomas including primary and metastatic gastrointestinal carcinoid tumors and pancreatic endocrine tumors (PET), we examined 58 gastrointestinal carcinoid tumors and 48 PET using immunohistochemistry, Western blotting, and RT-PCR. EGFR and activated EGFR (P-EGFR) were expressed by both gastrointestinal carcinoids and PET in primary and metastatic tumors, although a higher percentage of gastrointestinal carcinoid tumors expressed EGFR and activated EGFR. Western blotting detected a 170 kDa band for both EGFR and activated EGFR in three primary carcinoid tumors and two metastatic carcinoid tumors to the liver. RT-PCR analysis confirmed the expression of EGFR mRNA in both primary and metastatic carcinoid tumors. Patients with activated EGFR expression in their primary PET had a significantly worse prognosis compared to those who did not express activated-EGFR (P=0.043). These results indicate that gastrointestinal carcinoid tumors as well as PET express EGFR and activated EGFR, and that expression is more common in gastrointestinal carcinoid tumors compared to pancreatic endocrine tumors. These findings implicate the EGFR and P-EGFR signal transduction pathway in the pathogenesis of these neuroendocrine tumors and suggest that targeted therapy directed against the EGFR tyrosine kinase domain may be a useful therapeutic approach in patients with unresectable metastatic gastrointestinal carcinoid tumors and pancreatic endocrine tumors.

Liver abscess formation after hepatic chemoembolization for metastatic pancreatic neuroendocrine tumor

Hepatic chemoembolization is an effective treatment of unresectable hypervascular hepatic tumors, but history of bilioenteric anastomosis is a major risk factor for liver abscess due to the retrograde enteric bacterial contamination. We report a case of culture‐negative liver abscess developed after hepatic chemoembolization for a metastatic pancreatic endocrine tumor, and discuss the pathogenesis of liver abscess formation. We also present a potential pitfall for the prophylactic antibiotic therapy in a patient with a history of bilioenteric anastomosis. This is the first report of a culture‐negative liver abscess caused by hepatic chemoembolization for a metastatic pancreatic endocrine tumor.

Pancreatic endocrine tumour: a 22-year clinico-pathological experience with morphological, immunohistochemical observation and a review of the literature

The clinico-pathological features of 53 Chinese patients (27 males; 26 females) with pancreatic endocrine tumours were studied. The age range was from 14 to 78 years old (mean: 48 years) with the modal peak in the sixth decade for both sexes. Pancreatic endocrine tumours accounted for 14% of the primary pancreatic tumours operated on in Queen Mary Hospital. The autopsy incidence was 0.11%. Seventy-two per cent (38 cases) of the tumours were clinically functioning, comprising 33 insulinomas, three gastrinomas and two glucagonomas. A rare case of malignant gastrinoma associated with Cushing's syndrome was also documented. The functional tumours were seen in the younger patients. The calculated annual incidence of clinically significant tumours was approximately 0.2 per 100,000 population. There was no correlation between the site, functional status and histological patterns of the tumours. Seventy-two per cent of the tumours showed a trabecular pattern. Calcification was present in 5.7% (three cases); two such cases being gastrinomas. Amyloid was found in 25% of tumours, chiefly (92%) in the insulinomas. The main difficulty encountered in diagnosis was distinguishing between solid and cystic tumours of the pancreas. The incidence of malignancy was 15% and the histological features were poor predicative indicators of malignant potential. The metastatic pancreatic endocrine tumours were often detected in the liver and lymph nodes. Immunohistochemical stains showed evidence of multi-hormone production in 18% of cases and all tumours showed a positive reaction to at least one of the six markers, namely, neuron-specific enolase (NSE), chromogrannin (CG), synaptophysin (SYN), insulin (INS), glucagon (GLU) or somatostatin (SOM). The three panendocrine markers (NSE, SYN, CG) were satisfactory for initial screening of the endocrine nature of the tumours if used in combination, as 92% of tumours were positive for at least one of these three markers.

Prospective study of aggressive resection of metastatic pancreatic endocrine tumors.

Because metastatic pancreatic endocrine tumors (MPET) have a poor prognosis, 17 patients with potentially resectable MPET were prospectively studied to define the efficacy of aggressive resection. Patients underwent resection when the full extent of MPET was deemed operable after imaging studies were obtained. Two patients underwent three reoperations for recurrent tumor. MPET were completely excised in 16 of 20 cases by major resections of liver, viscera, and nodes, with no operative mortality. Survival was 87% at 2 years and 79% at 5 years with mean follow-up of 3.2 years. Median imaging disease-free interval was 1.8 years, and four of 17 patients remain biochemically cured. After aggressive resection patients with MPET limited in extent had higher survival than patients with extensive MPET (p < 0.019). In a nonrandomized cohort of 25 patients with inoperable tumor, survival was 60% at 2 years and 28% at 5 years. In select patients MPET can be resected safely with a favorable outcome; most patients will experience recurrence, but some may be cured. Resection of extensive MPET does not appear to improve survival. Resection of limited MPET should be considered as life-extending and potentially curative therapy.

RESISTANCE OF METASTATIC PANCREATIC ENDOCRINE TUMOURS AFTER LONG‐TERM TREATMENT WITH THE SOMATOSTATIN ANALOGUE OCTREOTIDE (SMS 201–995)

Ten patients with metastatic pancreatic endocrine tumours were treated with the long-acting somatostatin analogue octreotide (SMS 201-995). Three patients showed no response, clinically or biochemically, and treatment was therefore withdrawn. The seven remaining patients continued treatment for a median period of 28 months (range 13-54 months). Treatment was initially effective, symptoms improved and the concentrations of tumour-related hormones were reduced. Worsening of symptoms and rising levels of tumour-related hormone concentrations occurred a median of 5 months (range 1-6 months) after the start of therapy and were initially reversed by increasing the dose of octreotide over a median of 10 months (range 6-16 months). However, after a median of 13 months (range 5-34 months) at the maximum dosage, symptoms recurred and were no longer responsive to a further increase in dosage of octreotide or other therapeutic measures. All patients died within a period of 5 months once this resistant phase of their illness had been reached.

Octreotide (SMS 201-995) in the Treatment of Metastatic Glucagonoma: Report of One Case and Review of the Literature

We report 1 patient with a necrolytic migratory erythema, a high plasma glucagon concentration and a metastatic pancreatic endocrine tumor who has now been treated effectively for 33 months with the somatostatin analogue octreotide (SMS 201-995) (400 micrograms/day). The results of SMS 201-995 in the treatment of glucagonoma syndrome are reviewed.

Octreotide: reduces hormone concentrations and improves clinical symptoms in patients with metastatic pancreatic endocrine tumours

Octreotide: reduces hormone concentrations and improves clinical symptoms in patients with metastatic pancreatic endocrine tumours

Remission of symptoms during long term treatment of metastatic pancreatic endocrine tumours with long acting somatostatin analogue.

Five patients with metastatic pancreatic endocrine tumours injected a long acting somatostatin analogue (SMS 201-995) 50 micrograms subcutaneously every 12 hours and were followed up for three to six months. Treatment aimed at controlling excess secretion of hormone by the tumours thereby bringing symptomatic relief. Four patients showed a significant reduction in tumour related hormone concentrations but in none did values return to normal. All five patients, however, noted definite symptomatic improvement and in one this was dramatic (disappearance of life threatening diarrhoea and correction of metabolic acidosis and hypokalaemia within 48 hours). Mild worsening of symptoms and increasing fasting tumour related hormone concentrations after three to six months of treatment were reversed by doubling the 12 hourly dose. The treatment was well tolerated and had no deleterious effect on fasting blood glucose concentrations. This somatostatin analogue seems a promising non-invasive treatment for metastatic pancreatic endocrine tumours.