Neuroendocrine tumors arise in tissues of the endocrine system and pancreatic neuroendocrine tumors (PNETs) are among the most common neuroendocrine tumors.1
While treatment is not required in all cases of PNET, surgery is frequently the first-line treatment when there is an indication for intervention. However, when patients with PNETs present with metastatic or locally advanced disease, additional treatment options may include systemic medical therapy, liver-directed treatment, and radiation.2
In the management of PNETs, it is important to differentiate between functional and nonfunctional PNETs. Most PNETs are nonfunctional as they are not associated with clinical manifestations of hormone excess, but rather nonspecific symptoms related to the pancreatic mass effect or secondary to distant metastases.1,3
In cases of resectable disease, surgical resection of the tumor and regional lymph nodes is the only treatment approach that can lead to a cure in patients with PNET. The extent of the surgery is dependent on the individual patient and tumor and may include enucleation, distal pancreatectomy, or pancreaticoduodenectomy.4
There is significant controversy regarding whether surgery should be recommended in all PNET cases as several studies have shown that active surveillance may be safe for small (≤2 cm) asymptomatic nonfunctioning PNETs.3 The National Comprehensive Cancer Network guidelines recommend surgical intervention for nonfunctional PNETs that are >2 cm, invasive, or node-positive tumors.
When surgical intervention is not expected to accomplish removal of the entire tumor, tumor debulking can be considered. Debulking is not curative; the main goal of this approach is symptom control in functional tumors and possibly prolonged survival in functional and nonfunctional PNETs.1,6
Medical treatment may be required in cases of advanced or metastatic disease, with 2 main goals: symptom control and control of tumor growth.
Various treatment options are available for alleviating symptoms related to functional PNETs in accordance with the specific hormone excess. For instance, in patients with gastrinoma, high doses of proton pump inhibitors are recommended for acid hypersecretion and somatostatin analogs may alleviate the associated diarrhea.6 Frequent small meals and diazoxide are commonly used in patients with insulin excess secondary to insulinoma.3 Parenteral nutrition with vitamin supplements is recommended in patients with glucagon excess secondary to a glucagon-secreting PNET.7
Telotristat ethyl was approved by the United States Food and Drug Administration for carcinoid syndrome with persistent diarrhea, as it was shown to decrease the frequency of bowel movements in patients with serotonin-producing neuroendocrine tumors that were not well controlled on somatostatin analogs.8
Pancreatic enzyme supplements are particularly important following extensive pancreatectomy and may reduce stool frequency and improve abdominal pain, flatulence, and stool consistency.9
Control of Tumor Growth
Several treatment options are available for controlling tumor growth.
1. Somatostatin Analogs
Octreotide and lanreotide are somatostatin analogs that bind mainly to somatostatin receptor type 2 and inhibit hormone secretion from tumor cells.10 These may be important for controlling symptoms of functional PNETs and have also been found to prolong progression-free survival.5,10 Various guidelines suggest initiation of somatostatin analog treatment in asymptomatic patients with well-differentiated, unresectable PNETs.5,6
Common side effects of somatostatin analog therapy may include nausea, bloating, flatulence, diarrhea, steatorrhea, cholelithiasis, mild glucose intolerance, and bradycardia.5,10
2. Molecularly Targeted Therapies
Everolimus (Afinitor®), an oral mammalian target of rapamycin (mTOR) inhibitor, is a common second-line treatment for patients with progressive metastatic PNETs.5 In clinical trials, it was found to prolong median progression-free survival.5 Possible side effects include pneumonitis, hyperglycemia, stomatitis, dyslipidemia, peripheral edema, increased blood pressure, headache, insomnia, constipation/diarrhea, and neuromuscular pain.11
Sunitinb (Sutent®), an oral multitargeted tyrosine kinase inhibitor, may improve overall and progression-free survival and was approved for the treatment of progressive well-differentiated PNETs in patients with unresectable, locally advanced, or metastatic disease.5,12 Possible side effects include elevated blood pressure, renal toxicity, myelosuppression, hand-foot skin reaction, thyroid dysfunction, arterial thromboembolism, heart failure, and hepatotoxicity.12
3. Cytotoxic Chemotherapy
There is no consensus on the best chemotherapeutic regimen and there are various possible agents for treatment of patients with symptomatic and/or progressive PNETs. The combination of capecitabine and temozolomide (CAPTEM) may improve overall and progression-free survival.13 In patients with pancreatic neuroendocrine carcinoma that is poorly differentiated and has a rapidly progressive clinical course, platinum-based chemotherapy is recommended.6
While the role of external beam radiotherapy for PNETs is limited, peptide receptor radionuclide therapy may have an important role in the management of these tumors.14
Peptide receptor radionuclide therapy is based on 177Lu-DOTATATE and involves delivery of targeted radiotherapy to tumor cells that express somatostatin receptors. This treatment modality can lead to tumor shrinkage and was found to improve overall and progression-free survival in patients with well-differentiated midgut neuroendocrine tumors, with additional reports supporting this modality for PNETs.14
In patients with hepatic-dominant metastatic disease, liver-directed treatment options may be considered.5 There are several treatment options, including surgical resection of liver metastases, ablation (radiofrequency ablation, cryoablation, or microwave ablation), hepatic arterial embolization, chemoembolization, or radioembolization.5 In a small minority of highly-selective patients with refractory disease, liver transplantation may be considered.
The only available treatment modality that can lead to the cure of PNETs is surgical intervention. However, many patients with advanced or metastatic disease require additional treatments, which may be directed by symptom control and/or control of tumor growth. When the disease is mostly limited to the liver, liver-directed therapies may be considered. In unresectable PNETs with extra-hepatic involvement, somatostatin analogs are frequently used as first-line treatment and molecularly targeted therapies may be used subsequently. Other treatment modalities may include peptide receptor radionuclide therapy or chemotherapy.
1. Ro C, Chai W, Yu VE, Yu R. Pancreatic neuroendocrine tumors: biology, diagnosis, and treatment. Chin J Cancer. 2013;32(6):312-324.
2. Garcia-Carbonero R, Sorbye H, Baudin E, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology. 2016;103(2):186-194.
3. Falconi M, Eriksson B, Kaltsas G, et al. Consensus guidelines update for the management of functional p-NETs (F-p-NETs) and non-functional p-NETs (NF-p-NETs). Neuroendocrinology. 2016;103(2):153-171.
4. Öberg K, Knigge U, Kwekkeboom D, Perren A; on behalf of the ESMO Guidelines Working Group. Neuroendocrine gastro-entero-pancreatic tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(Suppl 7):vii124-vii130.
5. Shah M, Goldner W, Halfdanarson T, et al. NCCN clinical practice guidelines in oncology: neuroendocrine and adrenal tumors. J Natl Compr Canc Netw. 2018;16(6):693-702.
6. Kunz P, Reidy-Lagunes D, Anthony L, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42(4):557-577.
7. Sandhu S, Jialal I. Glucagonoma Syndrome. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2019. Accessed January 6, 2020. https://www.ncbi.nlm.nih.gov/books/NBK519500/
8. Kulke MH, O’Dorisio T, Phan A, et al. Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. Endocr Relat Cancer. 2014;21(5):705-714.
9. Chaudhary A, Domínguez-Muñoz JE, Layer P, Lerch MM. Pancreatic exocrine insufficiency as a complication of gastrointestinal surgery and the impact of pancreatic enzyme replacement therapy. Dig Dis. 2020;38:53-68.
10. Stueven AK, Kayser A, Wetz C, et al. Somatostatin analogues in the treatment of neuroendocrine tumors: past, present and future. Int J Mol Sci. 2019;20(12):3049.
11. Afinitor. Highlights of prescribing information. Novartis. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022334s6lbl.pdf
12. Sutent. Highlights of prescribing information. Pfizer. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021938s033lbl.pdf
13. Chauhan A, Farooqui Z, Murray LA, et al. Capecitabine and temozolomide in neuroendocrine tumor of unknown primary. J Oncol. 2018;2018:3519247.
14. Chan DL, Thompson R, Lam M, et al. External beam radiotherapy in the treatment of gastroenteropancreatic neuroendocrine tumours: a systematic review. Clin Oncol (R Coll Radiol). 2018;30(7):400-408.