Systemic Therapy of Advanced Well-differentiated Small Bowel Neuroendocrine Tumors Progressive on Somatostatin Analogues.

OPINION STATEMENT: Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors whose management requires a nuanced and multi-disciplinary approach in order to control symptoms, halt tumor growth, and improve survival outcomes. Of late, the treatment landscape of NENs has advanced considerably as a result of several pivotal clinical trials, which have established somatostatin analogues as first-line therapy for advanced, metastatic, well-differentiated neuroendocrine tumors (NETs). However, an evolving classification system as well as an increased understanding of distinct clinical, molecular, and biologic features contribute to complexity in management. In particular, there remains limited randomized prospective data in the somatostatin analogue (SSA)-refractory setting for patients with primary tumors that originate in the small bowel. For well-differentiated small bowel neuroendocrine tumors (SBNETs), treatment beyond SSAs includes radionuclide therapy, targeted agents, liver-directed therapy, and to a lesser extent, cytotoxic chemotherapy. In the current era, selection of these agents is largely based on expert opinion in the context of patient and tumor characteristics without definitive data on the preferred order of agents to administer. In this review, we aim to describe the treatment landscape of metastatic SBNETs beyond SSAs and provide an overview of novel treatments which are currently under clinical evaluation.

Capecitabine-Temozolomide in Advanced Grade 2 and Grade 3 Neuroendocrine Neoplasms: Benefits of Chemotherapy in Neuroendocrine Neoplasms with Significant 18FDG Uptake.

INTRODUCTION: Capecitabine-temozolomide (CAPTEM) chemotherapy, alone or with concurrent peptide receptor radionuclide therapy (PRRT), has activity in advanced WHO grade 2 and grade 3 neuroendocrine neoplasms (NENs). The objective of this study was to evaluate the activity of the CAPTEM in patients with grade 2 and grade 3 NENs and identify prognostic factors. MATERIALS AND METHODS: A retrospective analysis of patients with metastatic grade 2 and grade 3 NENs, who were having baseline significant dual uptake on 68Ga-DOTATATE/18F-fluorodeoxyglucose (FDG)-PET-CT scan and treated with CAPTEM chemotherapy between January 2014 and December 2019 at Tata Memorial Hospital, was conducted. The clinical variables and survival data were collected. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. RESULTS: A total of 68 patients received the CAPTEM regimen, of whom 29 patients (43%) received CAPTEM alone and 39 patients (57%) received concurrent PRRT. The primary sites were pancreas in 32 (47%) and small intestine in 12 (18%) patients. Mean Ki-67 index was 12.6% (range: 3-50). Forty-five patients (65%) were treatment naïve. There were no significant differences in baseline clinical variables between patients treated with CAPTEM alone or with CAPTEM-PRRT. Both regimens were well tolerated. With a median follow-up of 22.1 months, the median PFS for the entire cohort was 27.5 months. There was no statistical difference in the median PFS between patients receiving CAPTEM alone or CAPTEM-PRRT (33.7 vs. 22 months; p = 0.199). A Ki-67 index of >5% predicted for inferior PFS on multivariate analysis (24 versus 73.8 months; p = 0.04; hazard ratio -3.77; 95% confidence interval: 1.07-13.26). CONCLUSION: CAPTEM, alone or concurrent with PRRT, has a significant activity in grade 2 and grade 3 NENs with dual SSTR and 18FDG expression. A Ki-67 index >5% predicts strongly for inferior outcomes and should be further explored as a prognostic cutoff in grade 2 NENs. Early initiation of CAPTEM should be considered in this group of tumors with significant baseline 18FDG expression.

Management of metastatic pheochromocytomas and paragangliomas: when and what.

Recently, the treatment landscape for metastatic pheochromocytomas and paragangliomas (MPPGL) has seen both progress and setbacks. We provide an up-to-date review of the multimodality management of MPPGL and discuss novel opportunities and current challenges in the treatment landscape. Given the unique clinical presentation of MPPGL, we discuss the management of hormone-related clinical sequelae and traditional modalities of therapy. Advances in the understanding of the molecular biology of these diverse tumors have enabled novel strategies such as augmenting DNA damage by targeted delivery of radionuclides such as 131I and 177Lu, abrogating tumor angiogenesis, hypoxia resistance, and DNA damage repair. Despite progress, we address the significant challenges still faced by patients and researchers engaged in efforts to improve outcomes in these rare cancers.

Quantitative SSTR-PET/CT for predicting response and survival outcomes in patients with pancreatic neuroendocrine tumors receiving CAPTEM.

BACKGROUND: This study aimed to evaluate the predictive and monitoring role of somatostatin receptor (SSTR) positron emission tomography-computed tomography (PET/CT) and clinical parameters in patients with neuroendocrine liver metastases (NELM) from pancreatic neuroendocrine tumors (pNET) receiving capecitabine and temozolomide (CAPTEM). PATIENTS AND METHODS: This retrospective study included twenty-two patients with pNET and NELM receiving CAPTEM who underwent pre- and post-therapeutic 68Ga-DOTATATE/-TOC PET/CT. Imaging (including standardized uptake value [SUV] of target lesions [NELM and pNET], normal spleen and liver) and clinical (Chromogranin A [CgA], Ki-67) parameters were assessed. Treatment outcome was evaluated as response according to RECIST 1.1, progression free survival (PFS) and overall survival (OS). RESULTS: The median PFS (mPFS) was 7 months. Responders had a significantly longer mPFS compared to non-responders (10 vs. 4 months p = 0.022). Median OS (mOS) was 33 months (mOS: responders = 80 months, non-responders = 24 months p = 0.182). Baseline imaging showed higher SUV in responders, including absolute SUV, tumor-to-spleen (T/S), and tumor-to-liver (T/L) ratios (p < 0.02). All SUV parameters changed only in the responders during follow-up. Univariable Cox regression analysis identified baseline Tmax/Smean ratio and percentage change in size of pNETs as significant factors associated with PFS. A baseline Tmax/Smean ratio < 1.5 was associated with a shorter mPFS (10 vs. 4 months, (p < 0.05)). Prognostic factors for OS included age, percentage change in CgA and in T/S ratios in univariable Cox regression. CONCLUSIONS: SSTR-PET/CT can be useful for predicting response and survival outcomes in pNET patients receiving CAPTEM: Higher baseline SUV values, particularly Tmax/Smean ratios of liver metastases were associated with better response and prolonged PFS.

Dilemmas in Diagnosis and Management of Gastroenteropancreatic Mixed Neuroendocrine Non-neuroendocrine Neoplasms: First Single-Centre Report from India.

PURPOSE: Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) is a rare neoplasm comprising of exocrine and neuroendocrine elements, each representing ≥ 30% lesion. It is commonly misdiagnosed as adenocarcinoma or grade-3 neuroendocrine neoplasm (NEN). Management is not well-defined. METHODS: Retrospective analysis of prospectively entered data at our centre from January 2011 to January 2018 revealed 16 MiNENs off 130 neuroendocrine neoplasms (NENs). These were analysed for demographics, clinicopathological characteristics, management strategies and prognosis. RESULTS: Four out of 16 patients, metastatic at presentation, were started on chemotherapy. Eleven of remaining 12 patients had pre-operative biopsy. Only two were diagnosed MiNEN. Four patients (33.34%) received 5-fluorouracil (5-FU)-based neoadjuvant chemotherapy and underwent curative surgery with adjuvant cisplatin+etoposide (Cis-Eto). Out of these, two patients (16.6%) developed metastasis and were shifted to capecitabine+temozolomide (Cap-Tem). Six patients (50%) with neuroendocrine-dominant MiNEN received adjuvant Cis-Eto after surgery. Two (16.6%) developed metastases for which Cap-Tem was started. One of them developed locoregional and liver metastasis. Three patients (25%) have succumbed to progressive disease, three (25%) are on treatment, and six (50%) are disease-free at 4-30 months. CONCLUSION: Preoperative diagnosis of MiNEN is challenging, and it needs quality histopathological examination and immunohistochemistry. The 30% criteria is therapeutically insignificant, and treatment based on most aggressive component is prognostically more relevant. Neoadjuvant 5-FU-based regimens may downstage adenocarcinoma-dominant tumours. There are no guidelines on adjuvant Cis-Eto. Cap-Tem can be considered second-line chemotherapy. Poor survival is reported irrespective of site of origin and adjuvant therapy.

Randomised phase II trial of CAPTEM or FOLFIRI as SEcond-line therapy in NEuroendocrine CArcinomas and exploratory analysis of predictive role of PET/CT imaging and biological markers (SENECA trial): a study protocol.

INTRODUCTION: Patients with metastatic or locally advanced, non-resectable, grade 3 poorly differentiated gastroenteropancreatic (GEP) and lung neuroendocrine carcinomas (NECs) are usually treated with in first-line platinum compounds. There is no standard second-line treatment on progression. Accurate biomarkers are needed to facilitate diagnosis and prognostic assessment of patients with NEC. METHODS AND ANALYSIS: The SEcond-line therapy in NEuroendocrine CArcinomas (SENECA) study is a randomised, non-comparative, multicentre phase II trial designed to evaluate the efficacy and safety of folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) or capecitabine plus temozolomide (CAPTEM) regimens after failure of first-line chemotherapy in patients with lung NEC and GEP-NEC. Secondary aims are to correlate the serum miRNA profile and primary mutational status of MEN1, DAXX, ATRX and RB-1 with prognosis and outcome and to investigate the prognostic and predictive role of the Ki-67 score and 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) or 68Ga-PET/CT. The main eligibility criteria are age ≥18 years; metastatic or locally advanced, non-resectable, grade 3 lung or GEP-NECs; progression to first-line platinum-based chemotherapy. A Bryant and Day design taking into account treatment activity and toxicity was used to estimate the sample size. All analyses will be performed separately for each treatment group in the intention-to-treat population. A total of 112 patients (56/arm) will be randomly assigned (1:1) to receive FOLFIRI every 14 days or CAPTEM every 28 days until disease progression or unacceptable toxicity or for a maximum of 6 months. Patients undergo testing for specific biomarkers in primary tumour tissue and for miRNA in blood samples. MiRNA profiling will be performed in the first 20 patients who agree to participate in the biological substudy. ETHICS AND DISSEMINATION: The SENECA trial, supported by Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), was authorised by the locals Ethics Committee and the Italian Medicines Agency (AIFA). Results will be widely disseminated via peer-reviewed manuscripts, conference presentations and reports to relevant authorities.The study is currently open in Italy. TRAIL REGISTRATION NUMBER: NCT03387592; Pre-results. EudraCT-2016-000767-17. PROTOCOL VERSION: Clinical Study Protocol Version 1, 7 November 2016.