Efficacy and safety of capecitabine-temozolomide (CAPTEM) regimen in patients with neuroendocrine neoplasms - experience from NETwerk, a Belgian ENETS Center of Excellence.

Neuroendocrine neoplasms (NEN) are rare tumors originating from neuroendocrine cells, commonly found in the gastrointestinal tract and the pulmonary tract. Metastatic well-differentiated neuroendocrine tumors (NET) grade 3 present unique challenges, as they are positioned between the more indolent NET grade 1-2 and the aggressive neuroendocrine carcinomas (NEC). Due to the scarcity of data regarding the optimal systemic treatment for metastatic NET grade 3 and aggressive NET grade 2 subtypes, guidelines remain inconclusive. This retrospective study analyzed data from the NETwerk database, encompassing patients treated with the capecitabine-temozolomide (CAPTEM) regimen between June 2016 and January 2024. The cohort included patients with NET grades 1-3 and NEC. The study focused on assessing the efficacy and safety of CAPTEM. In total, data from 36 patients was analyzed. The median progression-free survival (mPFS) was 13 months, and median overall survival (mOS) was 17 months. Overall response rate (ORR) was 25.8%, and the disease control rate (DCR) was 67.7%. NET grade 2 patients had the highest mPFS, while NET grade 3 exhibited the most favorable mOS. Subgroup analysis showed that panNEN had superior mPFS and mOS compared to other primary tumor sites, with significant differences in mOS based on NEN type. Safety analysis in 20 patients indicated good tolerance and safety. CAPTEM is an efficient and safe regimen for metastatic NEN, with promising outcomes in NET grade 2-3 patients. The promising findings pave the way for further exploration into various aspects of CAPTEM, to better define its position in the therapeutic landscape of NEN.

PurposePatients with metastatic high-grade neuroendocrine neoplasms (NEN) have an unfavorable prognosis. Treatment patterns and therapy outcome are scarcely evidenced, especially considering the WHO classification updates since 2017, and were thus investigated in this study.MethodsThis retrospective single-center analysis evaluated patients with neuroendocrine tumors grade 3 (NET G3) or neuroendocrine carcinomas (NEC) treated at the Medical University of Vienna since 2010. The primary endpoints were progression-free survival (PFS) and overall survival (OS) following first-line treatment.ResultsA total of 80 patients were included, 53 (66%) had NEC and 27 (34%) NET G3. Thirty patients had pancreatic NEN (38%), 29 gastrointestinal NEN (36%), 20 an unknown primary (25%), and one gall bladder NEC. All patients had metastatic disease, and all but four received systemic therapy. Platinum/etoposide was the most frequent palliative first-line treatment in NEC (41/47, 87%) and capecitabine/temozolomide (CAPTEM) in NET G3 (14/27, 52%). Overall, the median PFS and OS from first line start were 16.1 and 43.9 months for NET G3 and 6.1 and 12.7 months for NEC, respectively. Median PFS for platin/etoposide in NEC was 6.1 months (overall response rate [ORR] 56%) and for CAPTEM in NET G3 16.9 months (ORR 46%). Irrespective of the limited sample size (n = 4–11), second-line median PFS was short in NEC (FOLFIRI 2.8, FOLFOX 2.6, CAPTEM 5.4, other 2.6 months) and longer in NET G3 (8.2–11.1 months).ConclusionsThe present data from a large European NET center show that multiple treatment strategies are used in NEN and highlight the varying outcomes between NET G3 and NEC.

LGR5 is expressed in various tumors and has been identified as a putative intestinal stem cell marker. Here we investigated LGR5 expression in colorectal neuroendocrine neoplasms and analyzed the correlation with pathological characteristics. We evaluated the clinicopathological features of 8 neuroendocrine tumor (NET) grade 1 (NET G1), 4 NET Grade 2 (NET G2), and 8 NET Grade 3 (NET G3; also termed neuroendocrine carcinoma, or NEC) cases. We examined LGR5 expression using an RNAscope, a newly developed RNA in situ hybridization technique, with a tissue microarray of the neuroendocrine neoplasm samples. LGR5 staining in individual tumor cells was semi-quantitatively scored using an H-score scale. We also performed a combination of LGR5 RNA in situ hybridization and synaptophysin immunohistochemistry. All cases contained tumor cells with some LGR5-positive dots. For all cases, H-scores showed a positive correlation with nuclear beta-catenin expression. In the NEC group, there was a strong positive correlation between H-score and beta-catenin expression. Our findings suggest that LGR5 may serve as a stem cell marker in NEC, as is the case in colon adenocarcinoma. The positive correlation between H-score and beta-catenin expression suggests that LGR5 expression might be affected by beta-catenin expression in neuroendocrine neoplasms and especially in NEC.

Pancreatic neuroendocrine tumors (PNET) are relatively rare. Here, we present clinical and pathological characteristics of PNETs to show a relationship between computed tomography (CT) imaging and the 2010 World Health Organization (WHO) classification. We retrospectively reviewed the records of 41 PNET patients who were treated between 2002 and 2012. All tumors were classified as neuroendocrine tumor (NET) grade 1 (G1), NET grade 2 (G2), or neuroendocrine carcinoma (NEC) grade 3 (G3) on the basis of the 2010 WHO classification system. Twenty-five tumors were classified as G1, 11 as G2, and five as G3. Mean sizes of the G1, G2 and G3 tumors were 1.84 ± 0.54, 4.90 ± 0.84, and 5.62 ± 1.18 cm, respectively, (P < 0.01). A PNET is typically hypervascular and exhibits contrast enhancement on enhanced CT. Higher percentage of G1 tumors demonstrated typical imaging and showed a significantly greater distinct mass compared with G2 and G3 tumors. Although PNET has many imaging features that appear on CT, G2 and G3 tumors often show atypical imaging features, particularly with large sizes and/or ill-defined features, when compared with G1 tumors. If a PNET has atypical imaging features, possibility of malignancy should be considered.

Recent updates on grading and classification of neuroendocrine tumors.

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e15694 Background:Grade 3 (G3) NETs have a poor prognosis and limited treatment options (usually chemotherapy). PRRT is a potential treatment option if all sites of disease demonstrate high uptake on somatostatin-receptor imaging (SSRI). We retrospectively evaluated the efficacy of PRRT in G3 NETs. Methods: We reviewed records of patients with metastatic G3 NETs (Ki-67 &gt; 20%) who received PRRT at our institution. Patients were treated with up to 5 cycles of PRRT, predominantly 177Lu-DOTA-octreotate. Further maintenance PRRT was administered upon progression if deemed suitable on SSRI. Radio-sensitizing chemotherapy was administered unless contra-indicated. Kaplan-Meier estimate was used to determine median overall survival (OS) and median time to new treatment/death (TNTD) defined from start of PRRT. Subgroup-analysis was performed for patients with Ki67 &lt; 55% and ≥55%. Results: 26 patients with metastatic G3 NET received PRRT; 22 combined with chemotherapy (capecitabine/temozolomide (n = 12), 5-fluorouracil or capecitabine (n = 8), other (n = 2)). 58% were male. The median age was 62 (range 16-78 years). 61% had pancreatic NET, 19% small bowel, 8% lung, 8% unknown primary, 4% rectal. 77% had received at least one line of prior chemotherapy. 54% received prior platinum-based chemotherapy. Median follow-up was 33 months (range 8-83 months). Patients received a median of 4 cycles of PRRT (range 1-15). The estimated median OS from start of PRRT was 18 months: for Ki-67 &lt; 55% (n = 21), 20 months; and Ki-67≥ 55% (n = 5), 9 months. The estimated median TNTD was 12 months: for Ki-67 &lt; 55%, 16 months; and Ki-67≥55%, 4 months. 31% of patients were alive without a change in treatment modality following PRRT. Conclusions: In thispoor prognosis G3 NET cohort of whom 77% had received prior chemotherapy, a median OS of 18 months from start of PRRT is encouraging and warrants further study. PRRT is a promising treatment option for patients with G3 NET with high somatostatin-receptor expression selected by SSRI.

The classification of neuroendocrine neoplasms has evolved significantly. In the current World Health Organization (WHO) classification, well-differentiated grade 3 neuroendocrine tumors (G3-NETs) are distinguished from poorly-differentiated neuroendocrine carcinomas (NECs) based on morphology despite using the same proliferation indices, which poses diagnostic challenges. This review aims to assist pathologists in making an accurate diagnosis, which is crucial for patient management as G3-NETs and NECs have different prognoses and chemotherapy responses. A literature review and meta-analyses were conducted to summarize current knowledge of G3-NETs and NECs, focusing on histopathologic and genetic characteristics. Grade 3 neuroendocrine tumors and NECs are distinct entities with differences in histopathology, genetics, and clinical presentations. Grade 3 neuroendocrine tumors have a lower Ki-67 proliferation index and tumor mutational burden compared to NECs. Distinct gene mutations and pathways have been identified in G3-NETs and NECs, offering potential for developing a diagnostic gene panel. The 2022 WHO classification recognizes the use of immunohistochemistry for somatostatin receptors 2/5, TP53, Rb, Menin, P27, ATRX, and DAXX to distinguish G3-NETs and NECs. In particular, TP53 and ATRX immunohistochemistry may be useful in routine diagnostics. Specific immunohistochemistry and genetic tests should be developed and incorporated into the classification to reliably distinguish G3-NETs from NECs.

Biliary neuroendocrine neoplasms (NENs) represent <1% of all NENs. The aim of this retrospective study is to present the clinical characteristics, management and prognosis profiles of 28 biliary NEN patients from a large tertiary center, and identify factors related to prognosis. Nine tumors originated from the gallbladder, two from the extrahepatic bile duct and 17 from the ampulla of Vater. One patient was classified as neuroendocrine tumor (NET) Grade 1, three patients were classified as NET Grade 2, 18 were graded neuroendocrine carcinoma (NEC) Grade 3 and six were classified as mixed adenoneuroendocrine carcinoma (MANEC). The overall survival rate and disease-free survival rate did not have statistically significant differences between tumors of different locations or different grading. Recurrence of disease correlated with poor prognosis (p < 0.001). Lymphovascular invasion and invasion beyond the submucosa were related to higher risk of local lymph node metastases. Multivariate analysis identified patient age (p = 0.021) and R0 resection margin (p = 0.027) as independent prognostic factors associated with overall survival. Our study included relatively large numbers of biliary tract NENs with intact follow-up information. Patients with biliary neuroendocrine tumors showed different clinical outcomes according to tumor locations and tumor grades. Achieving R0 resection is important for better prognosis.

Peptide receptor radionuclide therapy (PRRT) represents a cornerstone of treatment regimens for patients with low proliferative neuroendocrine tumors (NETs). However, in patients experiencing somatostatin receptor-positive NET with higher proliferation rates, a value and potential therapeutic benefit of PRRT as part of multimodal treatment approaches and potentially with addition of radiosensitizing agents has not yet been established. In this study, 20 patients with histologically confirmed gastroenteropancreatic (GEP) NET with proliferation rates (Ki67) between 15% and 55% were treated either with PRRT only (n = 10) or with a combination therapy (n = 10) comprising PRRT and capecitabine/temozolomide (CAP/TEM) for at least 2 consecutive cycles. Disease control rate in patients treated with PRRT alone was 60% (40% stable disease and 20% partial response). Strikingly, in patients treated with PRRT in combination with radiosensitization (CAP/TEM), the disease control rate was 90% (20% stable disease and 70% partial response). The median progression-free survival in the PRRT only group was 12 months, whereas the median progression-free survival in the PRRT + CAP/TEM group was 26 months and has not been yet reached for all patients in the group during the observation period. The median disease-specific survival for patients with PRRT alone was 51 months, whereas this end point was not yet reached in the PRRT + CAP/TEM group. Moreover, the PRRT + CAP/TEM group showed a significantly higher reduction of SSTR-PET-based metabolic tumor volume and chromogranin A levels compared with the PRRT only group. Importantly, adverse events of all grades did not differ between both groups. PRRT + CAP/TEM represents a highly promising and well-tolerated therapeutic regimen for patients experiencing somatostatin receptor-positive NET with higher (Ki67 ≥ 15%) proliferation rate. Prospective randomized clinical trials are warranted.

Introduction: Neuroendocrine neoplasms are derived predominately from enterochromaffin or Kulchitsky's cells. The estimated prevalence of neuroendocrine tumors (NET) is 1 to 2 cases per 100,000 people, of which gastrointestinal tract (GIT) is the most common site. And being a rare tumor, it is less studied Aim of the Study: To study the clinicopathological profile of Neuroendocrine tumors of GIT. Materials and Methods: All specimens of neuroendocrine tumors received from the Department of Surgery and Department of digestive health diseases during the period from September 2008 to September 2012 were included. Clinical details were collected from the medical records in all cases. The tumors were classified based on WHO classification 2010 using morphological findings on H&E slides. Immunohistochemistry was done in 40 cases using Synaptophysin, Chromogranin and Neuron specific enolase. Results: There were 886 neoplasms diagnosed in GIT of which 53 (5.98%) were NET. The mean age of presentation was 50 years. The male: Female ratio observed is 2:1. The most common presenting symptoms were abdominal pain followed by loss of appetite and weight. Carcinoid syndrome was seen in 2/53 (3.8%) patients .The most common site involved was Stomach followed by duodenum and ileum. NET Grade 1 was seen in 22 cases, NET Grade 2 was seen in 9cases, NET Grade3 was seen 4 cases and mixed adenocarcinoma and neuroendocrine carcinoma (MANEC) was seen in 18 cases. Metastasis to liver was seen in 3 cases Most of the NET tumors expressed the IHC markers, 95% were positive for NSE, 87.5% were positive for Synaptophysin and 82.5% cases were positive for Chromogranin. Conclusion: Neuroendocrine tumors (NETs) are uncommon malignancies of GIT. Stomach was the most common anatomical site. NET grade 1 was the most common histological subtype. IHC markers NSE, Synaptophysin and chromogranin can be used in diagnosis of NETs. Keywords: Neuroendocrine tumors, Gastrointestinal tract, Histomorphology,

617 Background: Currently, there is no published data on the efficacy of SSAs for well-differentiated G3 NETs. Randomized trials have demonstrated a progression-free survival (PFS) benefit and limited tumor response for lower grade 1-2 NETs, but the optimal systemic therapy for metastatic/unresectable G3 NETs is unknown. We sought to evaluate the efficacy of SSAs in G3 NETs. Methods: We performed a retrospective analysis of Mayo Clinic patients treated with SSAs for metastatic/unresectable G3 NETs, querying data from 1992 - present. Inclusion criteria were: centrally reviewed pathology confirming well-differentiated morphology, G3 based on WHO classification, SSA monotherapy, and radiological data available to assess response. Patients who had prior lines of treatment were included as long they subsequently were treated with single-agent SSA. Poorly-differentiated tumors were excluded. The primary endpoint was PFS. Best overall response was determined by radiographic regression, stabilization, or progression of tumor size. Results: Ninety patient records were reviewed, with 14 meeting inclusion criteria (diagnosed 2014 – 2018). Median Ki-67 proliferative index was 25%. Two patients (14%) had a partial response to SSA therapy, five (36%) had stable disease, and seven (50%) had progressive disease. The estimated median PFS was 4.4 months (95% CI 2.9 – 24). Of the 7 patients with stable disease or partial response, the median time to progression was 8.7 months. Three patients had stable disease for greater than 9 months (24, 29 and 42 months, respectively). Overall survival was not estimable. There was no association of Ki-67 index with PFS based on a proportional hazards model. Conclusions: This is the first report on the efficacy of SSAs for G3 NETs. Although half of the patients in our series had at least stable disease, the PFS was modest at only 4.4 months. Given their favorable side-effect profile compared to cytotoxic chemotherapy, SSAs may present an attractive option to be further explored in a prospective fashion. We are presently updating this data by reassessing response using RECIST criteria.

Circulating tumor cells (CTC) play important roles in various cancers; however, few studies have assessed their clinical utility in neuroendocrine tumors. This study aimed to prospectively evaluate the prognostic value of CTC counts in Asian patients with neuroendocrine tumors before and during anti-cancer therapy. Patients who were diagnosed with unresectable histological neuroendocrine tumors between September 2011 and September 2017 were enrolled. CTC testing was performed before and during anti-cancer therapy using a negative selection protocol. Chromogranin A levels were also assessed. Univariate and multivariate Cox’s proportional hazard model with forward LR model was performed to investigate the impact of independent factors on overall survival and progression-free survival. Kaplan–Meier method with log-rank tests were used to determine the difference among different clinicopathological signatures and CTC cutoff. The baseline CTC detection rate was 94.3% (33/35). CTC counts were associated with cancer stages (I-III vs. IV, P = 0.015), liver metastasis (P = 0.026), and neuroendocrine tumor grading (P = 0.03). The median progression-free survival and overall survivals were 12.3 and 30.4 months, respectively. In multivariate Cox regression model, neuroendocrine tumors grading and baseline CTC counts were both independent prognostic factors for progression-free survival (PFS, P = 0.005 and 0.015, respectively) and overall survival (OS, P = 0.018 and 0.023, respectively). In Kaplan-Meier analysis, lower baseline chromogranin A levels were associated with longer PFS (P = 0.024). Baseline CTC counts are associated with the clinicopathologic features of neuroendocrine tumors and are an independent prognostic factor for this malignancy.

Laryngeal neuroendocrine neoplasms (NENs) are rare tumors that account for a small proportion of all laryngeal malignancies. They exhibit a wide range of differentiation and proliferative activity, and are often graded accordingly, using markers such as mitotic count and Ki-67 labeling index. We present the case of a 76-year-old man with progressive dysphagia and a supraglottic mass. Initial biopsy findings were inconclusive, raising suspicion of poorly differentiated carcinoma or metastatic disease. A re-biopsy of the larynx under general anesthesia and neck dissection revealed features consistent with neuroendocrine tumor (NET) Grade 2 (Ki-67 index 17%). Due to the limited efficacy of nonsurgical treatments and absence of somatostatin receptor expression, total laryngectomy was performed. Histopathological analysis of the resected specimen demonstrated increased mitotic activity and a Ki-67 index of 28%, leading to a revised diagnosis of NET Grade 3. This case highlights the diagnostic limitations of small biopsy specimens in the head and neck region and underscores the importance of stepwise evaluation, including surgical pathology, in establishing an accurate diagnosis and guiding curative treatment decisions in rare laryngeal NETs.

Clinical features of 20 patients with curatively resected biliary neuroendocrine tumours