Intravenous versus oral etoposide : efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3)

High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs, G3) are aggressive cancers of the digestive system with poor prognosis and survival. Platinum-based chemotherapy (cisplatin/carboplatin + etoposide) is considered the first-line palliative treatment. Etoposide is frequently administered intravenously; however, oral etoposide may be used as an alternative. Concerns for oral etoposide include decreased bioavailability, inter-and intra-patient variability and patient compliance. We aimed to evaluate possible differences in progression-free survival (PFS) and overall survival (OS) in patients treated with oral etoposide compared to etoposide given as infusion. Patients (n = 236) from the Nordic NEC study were divided into three groups receiving etoposide as a long infusion (24 h, n = 170), short infusion (= 5 h, n = 33) or oral etoposide (n = 33) according to hospital tradition. PFS and OS were analyzed with Kaplan-Meier (log-rank), cox proportional hazard ratios and confidence intervals. No statistical differences were observed in PFS or OS when comparing patients receiving long infusion (median PFS 3.8 months, median OS 14.5 months), short infusion (PFS 5.6 months, OS 11.0 months) or oral etoposide (PFS 5.4 months, OS 11.3 months). We observed equal efficacy for the three administration routes suggesting oral etoposide may be safe and efficient in treating high-grade GEP-NEN, G3 patients scheduled for cisplatin/carboplatin + etoposide therapy.Peer reviewe

Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms.

BACKGROUND The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients. METHODS Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed. RESULTS For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment. CONCLUSION Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (NTC02248012)

Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma

Background Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC. Materials and methods Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS). Results All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses. Conclusion In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients.Peer reviewe

Germline pathogenic variants in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms.

High-grade gastroenteropancreatic (HG-GEP) NEN are highly aggressive cancers. The molecular etiology of these tumors remains unclear and the prevalence of pathogenic germline variants in patients with HG-GEP-NEN is unknown. We assessed sequencing data of 360 cancer genes in normal tissue, from 240 patients with HG GEP-NEN; 198 patients with NEC and 42 with NET G3. Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in 3 patients and a recurrent MUTYH variant in 2 patients, indicating that these genes may be important underlying risk factors for HG-GEP-NEN, when mutated. Further, germline variants were found in canonical tumor suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in-silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0-17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP-NEC. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG GEP-NEN with germline pathogenic variants is relatively high, but still <10%, meaning that that germline mutations cannot be the major underlying cause of HG GEP-NEN

Surgical Treatment as a Principle for Patients with High-Grade Pancreatic Neuroendocrine Carcinoma : A Nordic Multicenter Comparative Study

This study aimed to evaluate the role of surgery for patients with high-grade pancreatic neuroendocrine carcinoma (hgPNEC) in a large Nordic multicenter cohort study. Prior studies evaluating the role of surgery for patients with hgPNEC are limited, and the benefit of the surgery is uncertain. Data from patients with a diagnosis of hgPNEC determined between 1998 and 2012 were retrospectively registered at 10 Nordic university hospitals. Kaplan-Meier curves were used to compare the overall survival of different treatment groups, and Cox-regression analysis was used to evaluate factors potentially influencing survival. The study registered 119 patients. The median survival period from the time of metastasis was 23 months for patients undergoing initial resection of localized nonmetastatic disease and chemotherapy at the time of recurrence (n = 14), 29 months for patients undergoing resection of the primary tumor and resection/radiofrequency ablation of synchronous metastatic liver disease (n = 12), and 13 months for patients with synchronous metastatic disease given systemic chemotherapy alone (n = 78). The 3-year survival rate after surgery of the primary tumor and metastatic disease was 69 %. Resection of the primary tumor was an independent factor for improved survival after occurrence of metastatic disease. Patients with resected localized nonmetastatic hgPNEC and later metastatic disease seemed to benefit from initial resection of the primary tumor. Patients selected for resection of the primary tumor and synchronous liver metastases had a high 3-year survival rate. Selected patients with both localized hgPNEC and metastatic hgPNEC should be considered for radical surgical treatment.Peer reviewe

Trastuzumab with triple chemotherapy (DOC) in patients with advanced gastroesophageal cancer:A phase I dose-finding trial

108 Background: Trastuzumab (T) improves efficacy of doublet chemotherapy (TOGA trial) in HER2 positive patients with advanced gastro-esophageal (GE) cancer but safety and efficacy with triple chemotherapy is presently unknown. We initiated a dose-finding trial to establish a safe 4 drug combination of docetaxel (D), short-time infusion of oxaliplatin (O), continuously capecitabine (C) and trastuzumab (T). Methods: This phase I, dose-finding trial was approved by the local etic committee. All pts had histologically confirmed GE adenocarcinoma. Therapy was given day 1 with escalating doses of D (42mg/m2 to 51 mg/m2 as a 60 minutes infusion), O (100 mg/m2 as a 30 minutes infusion) and C (1,250 mg/m2/day continuously). DOC was repeated every 3 weeks for a maximum of 6 courses. T was given as a loading dose (8 mg/kg) followed by 6 mg/kg every 3 weeks until PD or unacceptable toxicity. Toxicity was evaluated according to NCIC-CTC 3.0. DLT was evaluated after the first course and defined as non-haematological toxicity grade ≥ 3, neutropenia grade 4 more than 7 days or febrile neutropenia. Response was evaluated by the investigator according to RECIST 1.0 every 9th weeks. Data was updated September 1, 2013. Results: From May 2010 to October 2012 we included 11 pts. Median age was 62years (range 32-73), 5/11 pts had PS 0, all pts had metastatic disease. Neutropenia grade 3-4 was observed in two pts, one had febrile neutropenia grade 3 after four courses. Two pts had grade 3 vomiting, fatigue, or nausea, respectively and one patient had diarrhoea grade 3. Only one pt developed a DLT (grade 3 vomiting, nausea and fatigue). Dose-intensity, after six courses, in all 11 pts was: D = 89%, O= 88% C = 81% and T = 100%. Median number of DOC was 6; all pts continued T to a median of 12 courses and one pt is presently receiving T. Partial response was obtained in 9 pts (81%). Progression free survival was 8.8 months and overall survival was 16.5 months. Five pts are presently alive. Conclusions: DOC-T in HER2 positive GE pts is safe and easily administered in an out-patient setting. The recommended doses for further evaluation are: D 51 mg/m2, O 100 mg/m2, C 1,250 mg/m2. Efficacy is very promising and deserves evaluation in larger trials. Clinical trial information: NCT01295086. </jats:p