Management of Diarrhea in Patients With Carcinoid Syndrome.

Neuroendocrine tumors (NETs) arise from enterochromaffin cells found in neuroendocrine tissues, with most occurring in the gastrointestinal tract. The global incidence of NETs has increased in the past 15 years, likely due to better diagnostic methods. Small-bowel NETs are frequently associated with carcinoid syndrome (CS). Carcinoid syndrome diarrhea occurs in 80% of CS patients and poses a substantial symptomatic and economic burden. Patients with CS diarrhea frequently suffer from diarrhea and flushing and report corresponding impairment in quality of life, requiring substantial changes in daily activities and lifestyle. Treatment paradigms range from surgical debulking to liver-directed therapies to treatment with somatostatin analogs, nonspecific anti-diarrheal agents, and a tryptophan hydroxylase inhibitor. Other causes of diarrhea, including steatorrhea, short bowel syndrome, and bile acid malabsorption, should be considered in NET patients with refractory diarrhea. More therapeutic options are needed for symptomatic management of patients with NETs, and better understanding of the pathophysiology can empower clinicians with improved patient care.

Is Multifocality an Indicator of Aggressive Behavior in Small Bowel Neuroendocrine Tumors?

OBJECTIVES: Many patients with small bowel neuroendocrine tumors (SBNETs) have multifocal tumors (MFTs), but the frequency of MFTs has varied widely across SBNET studies. It is also unclear whether patients with MFTs have more advanced disease or worse clinical course than do those with unifocal SBNETs. We set out to determine the frequency of multifocal and unifocal SBNETs and compare clinicopathologic factors, somatostatin receptor 2 expression, and survival. METHODS: Clinicopathologic variables from 179 patients with surgically managed SBNETs were collected. Statistical comparisons were made using Welch t-test, Wilcoxon test, and Fisher's exact test. Survival was assessed using the Kaplan-Meier method. Somatostatin receptor 2 expression was analyzed by quantitative polymerase chain reaction, and Ki-67 expression by immunohistochemistry. RESULTS: Multifocal tumors were found in 45% of patients with SBNETs. Clinicopathologic factors such as grade, TNM stage, presence of distant metastases, mean somatostatin receptor 2 expression, success of imaging modalities, and preoperative and postoperative hormone levels were not significantly different between multifocal and unifocal groups. Progression-free survival and overall survival were also not significantly affected by multifocality. CONCLUSIONS: Clinicopathologic features and survival of patients with MFTs and unifocal tumors are remarkably similar. Although the etiology of MFTs is unclear, patients with MFTs do not have a more aggressive clinical course than patients with unifocal SBNETs.

Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate in Patients With Somatostatin Receptor Expressing Neuroendocrine Tumors: Six Years' Assessment.

OBJECTIVES: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a promising treatment for patients with inoperable, well to moderately differentiated metastatic neuroendocrine tumors (NETs). In continuation of our novel study with the radionuclide lutetium Lu, we now present further results of Lu DOTATATE therapy in managing NETs and other somatostatin receptor-expressing tumors in a larger and more diverse patient group. PATIENTS AND METHODS: One hundred forty-four consecutive patients (85 men and 59 women; age range, 11-87 years; mean age, 58.5 years) with histologically confirmed NET were enrolled. One hundred forty-three patients received at least 1 cycle of treatment. Among them, 132 were deemed evaluable by having at least 1 cycle of treatment and a posttreatment MRI or CT scan for assessment based on modified Response Evaluation Criteria in Solid Tumors. Response to therapy was evaluated in terms of progression-free survival, overall survival, as well as radiologic, biochemical, and clinical responses. Further, analysis of symptoms was reviewed during therapy and also in subsequent follow-ups for safety evaluation. Renal, gastrointestinal (GI), hepatic, and hematological adverse events were evaluated using National Cancer Institute common toxicities criteria V4.03, through full blood panels, as well as consultation with patients for any symptoms and/or adverse events. RESULTS: As of July 2016, median progression-free survival was about to be reached. Of 28 patients who have completed Lu DOTATATE therapy (completion of 4 or more cycles of treatment and all designated follow-ups), no patient showed complete response (CR), 8 patients (28.57%) showed partial response (PR), 16 patients (57.14%) showed stable disease (SD), and progressive disease (PD) was observed in 4 patients (14.28%). The objective response rate (CR + PR) of this group was 28.57% (n = 8) with a cumulative disease control (CR + PR + SD) of 85.71% (n = 24).Among 132 evaluable patients, assessment of treatment response using modified Response Evaluation Criteria in Solid Tumors criteria revealed CR in none of the patients, PR in 12 patients (9.09%), SD in 66 patients (50%), whereas PD, which included patients who passed away, was observed in 54 patients (40.90%), yielding an objective response rate of 9.09% (n = 12) and a cumulative disease control rate of 59.09% (n = 78).Symptoms including abdominal pain, diarrhea, flushing, and fatigue improved in over 50% of the patients, whereas weight loss improved in 28.26% of the patients. No grade 3 or grade 4 renal toxicities were found, though eleven grade 3 and five grade 4 hematological as well as three grade 3 hepatotoxicities were reported. Grade 3 hematotoxicity lasted an average of 2.7 months, and grade 4 lasted for only 0.9 months, whereas grade 3 hepatotoxicity lasted an average of 3.1 months. CONCLUSIONS: Lu-octreotate peptide receptor radionuclide therapy has shown promising potential as a safe and effective targeted therapy in inoperable, well to moderately differentiated metastatic neuroendocrine cancers. The results of the multicenter randomized clinical trial conducted in United States and Europe are concordant with current study.

Peptide Receptor Radionuclide Therapy Outcomes in a North American Cohort With Metastatic Well-Differentiated Neuroendocrine Tumors.

OBJECTIVES: The objective of this study was to describe the outcomes of patients in the University of Iowa Neuroendocrine Tumor (NET) Database treated with peptide receptor radionuclide therapy (PRRT). METHODS: One hundred thirty-five patients from the University of Iowa NET Database who received PRRT were analyzed, their characteristics were described, and survival was calculated. RESULTS: The median age at diagnosis was 51 years, and 64% were men. The primary tumor was located in the small bowel (SBNET) in 37.8%, in the pancreas (PNET) in 26.0%, in the lung in 13.3%, in unknown primary in 9.6%, and in other sites in 13.3%. A radiographic response of any magnitude was observed in 65.8%, 11.1% had a mixed response, and 15.4% showed progression. The overall survival (OS) from the first PRRT was 40 months, and the median time to progression was 23.9 months. Higher pretreatment chromogranin A and pancreastatin levels predicted inferior OS. CONCLUSIONS: Peptide receptor radionuclide therapy resulted in a relatively long OS and time to progression in heavily pretreated North American patients with advanced NETs. Elevated pretreatment chromogranin A and pancreastatin predicted shorter OS after therapy. Peptide receptor radionuclide therapy is a valuable treatment option in patients with advanced NETs, especially SBNETS.