Treatment Options for Pancreatic Neuroendocrine Tumors

The management of pancreatic neuroendocrine tumors (PanNETs) involves classification into non-functional or functional PanNET, and as localized or metastatic PanNET. In addition, while most PanNETs are sporadic, these endocrine neoplasms can also be manifestations of genetic syndromes. All these factors may assist in forming a risk stratification system permitting a tailored management approach. Most PanNETs are classified as non-functional because they are not associated with clinical sequelae of hormone excess. They are characterized by non-specific symptoms, such as abdominal pain or weight loss, resulting from mass effect related to the pancreatic tumor or secondary to distant metastases. Accurate staging of the disease is essential for determining the appropriate approach to therapy. As cure is only potentially possible with surgical resection of the tumor, it is recommended to remove all localized and limited metastatic disease. However, many patients present with metastatic and/or advanced local disease. In such instances, the goal of therapy is to control tumor growth and/or decrease tumor burden, lengthen survival, and palliate local symptoms and those of hormone excess. This typically requires a multimodal approach, including surgery, liver-directed treatment, and systemic medical therapy.

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Recurrence of Non-functional Pancreatic Neuroendocrine Tumors After Curative Resection: A Tumor Burden-Based Prediction Model

World Journal of Surgery ◽

10.1007/s00268-021-06020-8 ◽

2021 ◽

Author(s):

Ding-Hui Dong ◽

Xu-Feng Zhang ◽

Alexandra G. Lopez-Aguiar ◽

George Poultsides ◽

Flavio Rocha ◽

...

Keyword(s):

Prediction Model ◽

Neuroendocrine Tumors ◽

Curative Resection ◽

Tumor Burden ◽

Pancreatic Neuroendocrine Tumors

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Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Cancers ◽

10.3390/cancers13205117 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5117

Author(s):

Chandra K. Maharjan ◽

Po Hien Ear ◽

Catherine G. Tran ◽

James R. Howe ◽

Chandrikha Chandrasekharan ◽

...

Keyword(s):

Drug Resistance ◽

Neuroendocrine Tumors ◽

Molecular Mechanisms ◽

Treatment Options ◽

Somatostatin Receptor ◽

Therapeutic Targets ◽

Model Systems ◽

Pancreatic Neuroendocrine Tumors ◽

Acquired Drug Resistance ◽

Molecular Alterations

Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

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Update on the Surgical Treatment of Pancreatic Neuroendocrine Tumors

Scandinavian Journal of Surgery ◽

10.1177/1457496919900417 ◽

2020 ◽

Vol 109 (1) ◽

pp. 42-52 ◽

Cited By ~ 1

Author(s):

F. Jeune ◽

A. Taibi ◽

S. Gaujoux

Keyword(s):

Surgical Management ◽

Neuroendocrine Tumors ◽

English Language ◽

Hormone Secretion ◽

Genetic Alterations ◽

Tumor Board ◽

Pancreatic Neuroendocrine Tumors ◽

Genetic Syndromes ◽

Cross Sectional ◽

Management Alternative

Background and Aims: Pancreatic neuroendocrine tumors (PNET) arise from uncontrolled proliferation of neuroendocrine cell and further genetic alterations that may induce hormone secretion such as glucagon/insulin/gastrin/VIP. Their incidence is rapidelly growing, especially because of the frequent incidental diagnosis of small asymptomatic non-functionnal neuroendocrine tumors with the widespread use of cross-sectional imaging. The vast majority of pancreatic neuroendocrine tumors are sporadic but up to 5%–10% of them arise from genetic syndromes, the main one being Multiple Endocrine Neopalsm type 1 (MEN1). Appropriate management of patients with PNET is a complex challenge for surgeons, and require extensive medical collaboration. This review aims to summarize major and recent updates regarding the medico-surgical management of PNETs. Material and Methods: Review of pertinent English language literature. Results: This article provides a concise summary of the clinical presentation, diagnosis, surgical management, alternative treatments and follow up of PNETs. Conclusion: PNET are a rare, heterogeneous group of neoplasms with a generally favorable prognosis at least compared to pancreatic adenocarcinoma. Surgical resection is the cornerstone of their management, particularly for localized disease, and should always be discussed in multidisciplinary tumor board.

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Tumor Burden Score Predicting Tumor Recurrence of Non-functional Pancreatic Neuroendocrine Tumors after Curative Resection

HPB ◽

10.1016/j.hpb.2019.10.1707 ◽

2019 ◽

Vol 21 ◽

pp. S257

Author(s):

Dinghui Dong ◽

Xufeng Zhang ◽

Timothy M. Pawlik

Keyword(s):

Neuroendocrine Tumors ◽

Tumor Recurrence ◽

Curative Resection ◽

Tumor Burden ◽

Pancreatic Neuroendocrine Tumors

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Updates and management algorithm for neuroendocrine tumors of the uterine cervix

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2019-000504 ◽

2019 ◽

Vol 29 (6) ◽

pp. 986-995 ◽

Cited By ~ 9

Author(s):

Gloria Salvo ◽

Antonio Gonzalez Martin ◽

Naomi R Gonzales ◽

Michael Frumovitz

Keyword(s):

Neuroendocrine Tumors ◽

Treatment Options ◽

Distant Metastases ◽

Large Cell ◽

Initial Therapy ◽

Small Cell ◽

Oncologic Outcomes ◽

Low Grade ◽

High Tendency ◽

Neuroendocrine Carcinomas

Neuroendocrine carcinomas of the cervix account for less than 2% of all invasive cervical cancers and are classified as low-grade (carcinoid, atypical carcinoid tumor) or high-grade (known as small- and large-cell) neuroendocrine carcinomas. There are increasing data showing that cervical neuroendocrine carcinomas may be associated with the human papillomavirus (HPV), especially HPV18, and most will stain positive for p16. Immunohistochemistry markers such as synaptophysin and CD56 are the most sensitive markers. Although there are no commonly associated mutations,PIK3CA,KRAS, andTP53are the most frequently found mutations in neuroendocrine tumors. Neuroendocrine cervical carcinomas are exceedingly aggressive tumors with a high tendency for nodal involvement and distant metastases. Age, lymph node metastases, smoking, pure small-cell histology, and tumor size are independent prognostic factors. Overall, the 5-year survival rate is 36% and the median overall survival ranges between 22 and 25 months. Treatment options are often extrapolated from small-cell lung cancer and limited retrospective studies. The preferred treatment is a multimodal approach of surgery, chemoradiation, and systemic chemotherapy. The most common chemotherapy regimen used as initial therapy is a combination of cisplatin and etoposide. In the setting of recurrent disease, a combination of topotecan, paclitaxel, and bevacizumab has demonstrated favorable outcomes. Multicenter tumor registries, such as the Neuroendocrine Cervical Tumor Registry (NeCTuR), are an opportunity to evaluate patterns of disease treatment and oncologic outcomes.

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Tumor burden in serotonin secreting pancreatic neuroendocrine tumors after initiating telotristat ethyl.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.367 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 367-367

Author(s):

Susan Giacalone ◽

Valentina Di Gialleonardo ◽

Kris Murali ◽

Vijay N. Joish

Keyword(s):

Neuroendocrine Tumors ◽

Clinical Laboratory ◽

Data Extraction ◽

Tumor Burden ◽

Low Grade ◽

Pancreatic Neuroendocrine Tumors ◽

Radiological Data ◽

Before And After ◽

Well Differentiated ◽

Practice Methods

367 Background: Pancreatic neuroendocrine tumors (pNETs) characterized by high serotonin levels and carcinoid syndrome (CS) are rare. We evaluated tumor burden in a subgroup of patients with pNETS from the real-world TELEACE study before and after initiating telotristat ethyl (TE) in US clinical practice. Methods: Detailed methods of the TELEACE study have been reported previously. This was a retrospective, single arm, pre-post physician panel-based chart review of patients who received TE for at least 6 months. Descriptive statistics analyzed demographic, clinical, laboratory and radiological data extracted from medical charts of TELEACE patients with pNETS. Results: Fifty-two patients with pNETS initiating TE were eligible for this analysis. The average age at the time of TE initiation was 60+10.4 years; 64% were males. The majority of patients had well-differentiated (60%) tumors and low-grade (54%) tumor status. Patients received TE for an average of 11.5+7.84 months, and 21% were still receiving TE at the time of data extraction. Diarrhea and flushing were the most common CS symptoms recorded at the time of TE initiation. Urinary 5-HIAA levels were reported for 9 patients before and for 2 patients after TE initiation. Mean (median) 5-HIAA levels before and after TE initiation were 693 (211) and 22 (22) µmol/24h, respectively. Significant mean reduction in tumor size of 0.67 cm after TE initiation (P = 0.017) was observed. Conclusions: This subgroup analysis of the TELEACE study population showed that the addition of TE to somatostatin analog treatment may positively impact tumor burden for patients with functional pNETs.

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Overall survival with everolimus, sunitinib, and placebo for advanced pancreatic neuroendocrine tumors: A matching-adjusted indirect comparison of randomized trials.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14621 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14621-e14621

Author(s):

James E. Signorovitch ◽

Elyse Swallow ◽

Evan Kantor ◽

Xufang Wang ◽

Tomas Hass ◽

...

Keyword(s):

Overall Survival ◽

Neuroendocrine Tumors ◽

Performance Status ◽

Indirect Comparison ◽

Progression Free Survival ◽

Distant Metastases ◽

Number Needed To Treat ◽

Pancreatic Neuroendocrine Tumors ◽

Early Stopping ◽

Prior Use

e14621 Background: No randomized trial has compared everolimus (EVE) and sunitinib (SUN) for treatment of advanced pancreatic neuroendocrine tumors (pNET). This study indirectly compared overall survival (OS) with EVE vs. placebo (PBO), and OS and progression-free survival (PFS) with EVE vs. SUN. Methods: Individual patient data were used from the RADIANT-3 trial of EVE 10 mg/day vs. PBO (cutoff: April 2010); published summary data were used from the A6181111 trial of SUN 37.5 mg/day vs. PBO (cutoff: June 2010). To adjust for cross-trial differences, RADIANT-3 patients were subjected to A6181111 exclusion criteria and weighted to match A6181111 baseline demographics, performance status, time since diagnosis, disease sites, distant metastases and prior therapy. After matching, OS was compared between balanced trial populations for EVE vs. the PBO arm from A6181111 (which had access to SUN after progression or early stopping) and vs. the SUN arm. PFS was also compared. Analyses did not adjust for early stopping of A6181111, which may bias towards longer PFS and OS with SUN vs. PBO. Results: 394 patients from RADIANT-3 (after excluding 15 with worse performance status than allowed in A6181111 and 1 missing baseline data) and all 171 patients in A6181111 were included. RADIANT-3 patients differed from A6181111 patients in baseline performance status, prior use of somatostatin analogues, and prior use of systemic chemotherapy before matching. After matching, all baseline characteristics were well-balanced between trials. EVE was associated with significantly prolonged OS vs. PBO in A6181111 (hazard ratio [HR] for death = 0.61, 95% CI = 0.38-0.98, p=0.04), corresponding to a 1-year number needed to treat of 8.3 patients to prevent 1 death. OS and PFS were longer, but not statistically different, with EVE vs. SUN (HR for death = 0.81, 95%CI=0.49-1.31, HR for progression = 0.84, 95% CI=0.46-1.53). Conclusions: After adjusting for cross-trial differences, treatment of advanced pNET with everolimus was associated with significantly prolonged OS compared to placebo. OS and PFS were longer, but not statistically different, with everolimus compared to sunitinib.

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Overall survival with everolimus, sunitinib, and placebo for advanced pancreatic neuroendocrine tumors: A matching-adjusted indirect comparison of randomized trials.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.237 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 237-237 ◽

Cited By ~ 2

Author(s):

James Signorovitch ◽

Elyse Swallow ◽

Evan Kantor ◽

Xufang Wang ◽

Peter Metrakos

Keyword(s):

Overall Survival ◽

Neuroendocrine Tumors ◽

Performance Status ◽

Indirect Comparison ◽

Progression Free Survival ◽

Distant Metastases ◽

Pancreatic Neuroendocrine Tumors ◽

Early Stopping ◽

Significant Difference ◽

Prior Use

237 Background: Everolimus and sunitinib are approved in the US and EU for treating advanced pancreatic neuroendocrine tumors (pNET). No randomized trial has directly compared these treatments for pNET. This study indirectly compared overall survival (OS) with everolimus vs. 1) placebo and 2) sunitinib. Methods: Individual patient data were used from the RADIANT-3 trial of everolimus 10 mg/day vs. placebo (cutoff: April 4, 2010); published summary data were used from the A6181111 trial of sunitinib 37.5 mg/day vs. placebo (cutoff: June 1, 2010). To adjust for cross-trial differences, RADIANT-3 patients were subjected to exclusion criteria used in A6181111 and then re-weighted to match A6181111 in terms of baseline demographics, performance status, time since diagnosis, disease sites, distant metastases and prior therapy. After matching, OS was compared between balanced trial populations for everolimus in RADIANT-3 vs. 1) the placebo arm in A6181111, which had access to sunitinib after early stopping, and 2) the sunitinib arm in A6181111. Progression-free survival (PFS) was also assessed, but was confounded by early stopping of A6181111. Results: Analyses included 394 patients from RADIANT-3 (after excluding 15 with worse performance status than allowed in A6181111 and 1 with missing baseline data) and all 171 patients in A6181111. Before matching, patients in RADIANT-3 had better performance status, more prior use of somatostatin analogues and less prior use of systemic chemotherapy. After matching, these and all other baseline characteristics were well-balanced between trials. Everolimus was associated with prolonged OS vs. placebo in A6181111 (hazard ratio [HR] for death = 0.61, 95% CI = 0.38-0.98, p=0.04). No statistically significant difference was observed with everolimus vs. sunitinib in OS (HR for death = 0.81, 95%CI=0.49-1.31) or in PFS (HR for progression = 0.84, 95% CI=0.46-1.53). Conclusions: After adjusting for cross-trial differences, treatment of advanced pNET with everolimus was associated with prolonged OS compared to treatment with placebo.

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