Paola Tomassetti

Everolimus for Advanced Pancreatic Neuroendocrine Tumors

BACKGROUND Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

Comparison between 68Ga-DOTA-NOC and 18F-DOPA PET for the detection of gastro-entero-pancreatic and lung neuro-endocrine tumours

Purpose18F-FDG positron emission tomography (PET) value for the assessment of neuro-endocrine tumours (NET) is limited. Preliminary studies indicate that 18F-DOPA and 68Ga-DOTA-NOC are more accurate for disease assessment and 68Ga-DOTA peptides provide additional data on receptor status that are crucial for targeted radionuclide therapy. At present, there are no comparative studies investigating their role in NET.AimThe aim of this study was to compare 68Ga-DOTA-NOC and 18F-DOPA for the evaluation of gastro-entero-pancreatic and lung neuro-endocrine tumours.Materials and methodsThirteen patients with biopsy-proven NET (gastro-entero-pancreatic or pulmonary) were prospectively enrolled and scheduled for 18F-DOPA and 68Ga-DOTA-NOC PET. PET results obtained with both tracers were compared with each other, with other conventional diagnostic procedures (CT, ultrasound) and with follow-up (clinical, imaging).ResultsThe most common primary tumour site was the pancreas (8/13) followed by the ileum (2/13), the lung (2/13) and the duodenum (1/13). The carcinoma was well differentiated in 10/13 and poorly differentiated in 3/13 cases. 68Ga-DOTA-NOC PET was positive, showing at least one lesion, in 13/13 cases while 18F-DOPA PET was positive in 9/13. On a lesions basis, 68Ga-DOTA-NOC identified more lesions than 18F-DOPA (71 vs 45), especially at liver, lung and lymph node level. 68Ga-DOTA-NOC correctly identified the primary site in six of eight non-operated cases (in five cases, the primary was surgically removed before PET), while 18F-DOPA identified the primary only in two of eight cases.ConclusionsAlthough the patients studied are few and heterogeneous, our data show that 68Ga-DOTA-NOC is accurate for the detection of gastro-entero-pancreatic and lung neuro-endocrine tumours in either the primary or metastatic site and that it offers several advantages over 18F-DOPA.

68Ga-DOTANOC PET/CT clinical impact in patients with neuroendocrine tumors.

Several authors reported the superiority of 68Ga-DOTANOC PET/CT to conventional imaging (CI) for the assessment of neuroendocrine tumors (NET). However, the detection of a higher number of lesions is not necessarily followed by a modification of disease stage or therapeutic approach. The aim of this study was to assess the impact of 68Ga-DOTANOC PET/CT on the clinical management of NET patients. Methods: The study included 90 patients with pathologic confirmation of NET, CT performed within a month of 68Ga-DOTANOC PET/CT, and a follow-up period of at least 1 y. PET/CT results were compared with CI results. As a standard of reference to finally evaluate PET results, clinical and imaging follow-up data were used. To assess the clinical impact of PET findings, all referring physicians were contacted after PET and asked about how patients were managed. Stage or therapy modifications were independently recorded, and the overall impact was evaluated patient by patient if PET results either affected therapy or caused a change in disease stage. Results: Considering PET/CT and CI concordant cases (47/90 [52.2%]), PET findings affected the therapeutic management in 17 of 47 (36.2%) patients. Although PET did not result in modification of disease stage, 68Ga-DOTANOC detected a higher lesion number in most patients. PET/CT and CI findings were discordant in 42 of 90 (46.7%) patients: PET resulted in a modification of stage in 12 patients (28.6%) and affected the treatment plan in 32 patients (76.2%). PET and CT were both equivocal in 1 patient (1/90). Considering all cases, 68Ga-DOTANOC PET/CT affected either stage or therapy in 50 of 90 (55.5%) patients. The most frequent impact on management (27 patients) was the initiation or continuance of peptide receptor radionuclide therapy, followed by the initiation or continuance of somatostatin analog medical treatment (7 patients) and referral to surgery (6 patients). PET prevented unnecessary surgery in 6 patients and excluded from treatment with somatostatin analogs 2 patients with NET lesions that did not express somatostatin receptors. Less frequent impacts on management included the initiation of radiotherapy (1 patient), further diagnostic investigation (1 patient), and liver transplantation (1 patient). Conclusion: 68Ga-DOTANOC PET/CT either affected stage or caused a therapy modification in more than half the patients, thus confirming the clinical role of PET in the management of NET.

ENETS Consensus Guidelines for the Management of Patients with Gastroduodenal Neoplasms

a Department of Digestive and Liver Disease, Ospedale Sant’Andrea, Rome , Italy; b Department of Oncology, Royal Free University UFR Bichat-Beaujon-Louis Mourier, Colombes , France; c Digestive Oncology, University Hospital Gasthuisberg/Leuven, Leuven , Belgium; d Institute of Pathology, Catholic University – Policlinic A. Gemelli, Rome , Italy; e Department of Endocrinology, Medical University of Silesia, Katowice , Poland; f Department of Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen , Denmark; g Department of Pathology, Tohoku University Graduate School of Medicine, Sendai , Japan; h Department of Internal Medicine and Gastroenterology, St. Orsola Hospital, University of Bologna, Bologna , Italy; i Institut Catala d’Oncologia (IDIBELL), Barcelona , Spain; j Department of Gastroenterology, Beaujon Hospital, Clichy , France

Chromogranin A: Is It a Useful Marker of Neuroendocrine Tumors?

PURPOSE We evaluated the pattern of chromogranin A (CgA) plasma levels in a large number of patients with neuroendocrine tumors (NETs), in a series of patients with chronic atrophic gastritis (CAG) with and without enterochromaffin-like (ECL) cell hyperplasia, and in healthy participants (HPs). PATIENTS AND METHODS Two hundred thirty-eight patients with NETs, 42 patients with CAG with or without ECL cell hyperplasia, and 48 HPs were studied. All patients underwent a baseline visit, biochemical routine check-up, imaging techniques, endoscopy, and histologic determination. RESULTS CgA plasma levels were higher in patients with NETs compared with CAG patients or HPs (P < .001). In the NET group, we observed higher CgA levels in patients with diffuse disease compared with patients with local or hepatic disease (P < .001). CgA plasma levels were significantly higher in patients with Zollinger-Ellison syndrome compared with other types of endocrine tumors (P < .001). We found the best cutoff range between HPs and NET patients to be 18 to 19 U/L (sensitivity, 85.3%; specificity, 95.8%). Comparing all participants without neoplasia (HPs, CAG patients, and disease-free patients) and patients with endocrine tumors, the best cutoff range was 31 to 32 U/L (sensitivity, 75.3%; specificity, 84.2%). Setting the specificity at 95%, the cutoff range was 84 to 87 U/L (sensitivity, 55%). CONCLUSION Our study confirms the high specificity and sensitivity of CgA in diagnosing an endocrine tumor. It is necessary to use a cutoff range of 84 to 87 U/L to obtain a high specificity in diagnosing NETs, with the aim of excluding patients in whom the CgA was elevated as a result of other non-neoplastic diseases.

Metastatic and Locally Advanced Pancreatic Endocrine Carcinomas: Analysis of Factors Associated With Disease Progression

PURPOSE Knowledge of clinical course of pancreatic endocrine carcinomas (PECs) is poor. This study aimed to determine the time to progression of advanced PECs, and to identify predictors capable of selecting subgroups with higher risk of progression. PATIENTS AND METHODS In this multicenter retrospective analysis, patients with advanced PECs were enrolled. Staging was according to European Neuroendocrine Tumors Society guidelines. Grading was based on proliferation index using Ki67 immunohistochemistry. The primary end point was progression-free survival (PFS), which was assessed using the Kaplan-Meier method. The Cox regression proportional hazard model was used to identify predictors for tumor progression. RESULTS Two hundred two patients with PECs were enrolled, including 172 with well-differentiated and 30 with poorly differentiated endocrine carcinomas. There were 34 patients with stage III and 168 with stage IV tumors. G1 tumors were present in 19.7% of patients, whereas 60.1% of patients had G2 tumors, and the remaining 20.2% had G3 tumors. Disease progression occurred in 166 patients (82.2%), at a median interval of 10 months (interquartile range, 5 to 22) from diagnosis. Median PFS was 14 months. Different PFS were observed depending on G grade (P < .001) and tumor differentiation (P < .001) and in patients who did not receive any antitumor treatment (P = .002). The major risk factor for progression was the proliferation index Ki67 (hazard ratio, 1.02 for each increasing unit; P < .001). Overall 5-year survival was 44.1%. CONCLUSION The vast majority of patients with advanced PECs undergo disease progression. The major risk factor for progression is Ki67 index, which should lead physicians dealing with PECs to plan appropriate follow-up programs and therapeutic strategies.

Nonfunctioning Pancreatic Endocrine Tumors: A Multicenter Clinical Study

OBJECTIVES:Nonfunctioning pancreatic endocrine tumors (NFPTs) are rare neoplasms that have been the object of few studies that have involved only small numbers of patients. This study was carried out to obtain a comprehensive and up-to-date clinical picture of these tumors.METHODS:A total of 184 patients with NFPT admitted to three Italian hospitals in the last 15 yr were studied. The diagnosis of NFPT was confirmed histologically using conventional and immunohistochemical techniques. Data were obtained from the medical charts or directly from the patients.RESULTS:There were 85 men (46.2%) and 99 women (53.8%). The mean age at diagnosis was 55.2 yr (range 17–82 yr). The percentage of smokers and alcohol drinkers was similar to that in the general population. Seven patients (3.9%) had a family history of exocrine pancreatic carcinoma. In 120 cases (65.2%), the diagnosis was made after workup for pain or other symptoms, in the remaining 64 cases (34.8%), the tumor was discovered incidentally by ultrasound; in this group survival was significantly greater than it was for the symptomatic patients (p = 0.0043). Survival was also found to be improved by tumor resection (p < 0.0001), absence of metastases (p < 0.0001), and small tumor size (≤3 cm) (p < 0.0007).CONCLUSIONS:NFPTs were slightly more frequent in women and were diagnosed most often in middle-aged individuals. No risk factors other than a family history of exocrine pancreatic carcinoma were found. Tumor discovery while patients were still asymptomatic, tumor resection, absence of metastases, and tumor size ≤3 cm significantly prolonged survival.

Rapid and Sustained Relief from the Symptoms of Carcinoid Syndrome: Results from an Open 6-Month Study of the 28-Day Prolonged-Release Formulation of Lanreotide

This 6-month, open, non-controlled, multicenter, dose-titration study evaluated the efficacy and safety of 28-day prolonged-release (PR) lanreotide in the treatment of carcinoid syndrome. Eligible patients had a carcinoid tumor with ≧3 stools/day and/or ≧1 moderate/severe flushing episodes/day. Six treatments of 28-day PR lanreotide were administered by deep subcutaneous injection. The dose for the first two injections was 90 mg. Subsequent doses could be titrated (60, 90, 120 mg) according to symptom response. Seventy-one patients were treated. Flushing decreased from a mean of 3.0 at baseline to 2.3 on day 1, and 2.0 on day 2, with a daily mean of 2.1 for the first week post-treatment (p < 0.05). Diarrhea decreased from a mean of 5.0 at baseline to 4.3 on day 1 (p < 0.05), and 4.5 on day 2, with a daily mean of 4.4 for the first week post-treatment (p < 0.001). Symptom frequency decreased further after the second and third injections, and reached a plateau after the fourth injection. By month 6, flushing and diarrhea had significantly decreased from baseline by a mean of 1.3 and 1.1 episodes/day, respectively (both p ≤ 0.001); 65% of patients with flushing as the target symptom and 18% of diarrhea-target patients achieved ≧50% reduction from baseline. Median urinary 5-hydroxyindoleacetic acid and chromogranin A levels decreased by 24 and 38%, respectively. Treatment was well tolerated. 28-day PR lanreotide was effective in reducing the symptoms and biochemical markers associated with carcinoid syndrome.

Fecal elastase 1 determination in chronic pancreatitis

This study assessed the diagnostic accuracy offecal elastase 1 in chronic pancreatitis. Fifty-threehealthy subjects, 44 patients with chronic pancreatitis(22 severe, 13 moderate, and 9 mild), and 43 patients with nonpancreatic digestive diseasewere studied. Elastase 1 concentration was determined ona small sample of feces using a commercially availablekit. Fecal chymotrypsin was also measured. With a cutoff level of 190 μg/g, all healthycontrols except one (98.1%), and the majority ofpatients with nonpancreatic digestive diseases (40 of43; 93.0%) had elastase values above this limit. Amongthe 44 patients with chronic pancreatitis, 34(77.3%) had pathological values: all 22 (100%) withsevere disease, 10 of 13 (76.9%) with moderate diseaseand 2 of 9 (22.2%) with mild disease. Chymotrypsinvalues were pathological in 25 of 44 (56.8%) patientswith chronic pancreatitis: 17 of 22 (77.2%) with severepancreatitis, 7 of 13 (53.8%) with moderatepancreatitis, and 1 of 9 (11.1%) with mild disease. The specificity was 95.8% for elastase 1 and 85.4%for chymotrypsin. The difference both in sensitivity andspecificity of the two enzymes was statisticallysignificant (P < 0.05). Fecal elastase 1 has a high sensitivity, superior to that of fecalchymotrypsin, in the diagnosis of chronic pancreatitis.For its simplicity and rapidity, it could represent thetubeless test of choice in chronicpancreatitis.

Chromogranin A as a marker of neuroendocrine neoplasia: An Italian Multicenter Study

Elevated circulating chromogranin A (CgA) levels are found in neuroendocrine tumors (NETs), but the diagnostic usefulness of this marker is still debatable. To assess the role of CgA for the diagnosis of gastroenteropancreatic (GEP) NETs and the identification of metastatic patients, an Italian multicenter observational study has been performed. CgA was evaluated in 202 GEP NET patients by IRMA and ELISA. The cutoffs for diagnosis and presence of metastases were identified by receiver-operating characteristic (ROC) curve. We found good correlation between IRMA and ELISA. The ROC analysis identified a cutoff of 53 ng/ml for IRMA and 16 U/l for ELISA as discriminating between controls and patients with active disease (sensitivity 71.3 and 84%; specificity 71 and 85% respectively). Metastases were present in 123 patients, having significantly higher CgA levels than patients without metastases. ROC analysis identified a cutoff of 146 ng/ml for IRMA and 67.3 U/l for ELISA as discriminating between patients with and without metastases (sensitivity 57 and 63.3%; specificity 55.6 and 71.4% respectively). For pancreatic NETs positive and negative predictive values were 84 and 78% respectively (90% specificity and 68% sensitivity). We found lower CgA levels in patients with extensive metastatic spread than in those with liver metastases only. These data assess the role of CgA evaluation in GEP NETs, and demonstrate that higher CgA levels associate with metastatic disease, confirming that CgA levels can provide a helpful practical biochemical marker for the clinical management of NETs, but with low sensitivity and specificity.