A multifaceted model for managing NETs

"[In] the treatment of neuroendocrine tumors, it's best that you try to do local options for local disease, regional options for regional disease, and systemic options only when you have failure of the first 2, or the development of systemic disease."—Dr Eugene Woltering

Until the recent advent of multidisciplinary resource centers, many patients were managed by individual clinicians with wide-ranging backgrounds, resulting in care that often depended on the training of the clinician, rather than the requirements of the patient.1

But, NETs are complex cancers with the potential to involve multiple comorbidities. Management of a NET may depend on factors such as tumor size, grade, stage, location, secretory status, and potential associated symptoms, if any.1,2 Gathering input from a multidisciplinary team gives physicians an opportunity to improve outcomes.1

Among the management options that may be considered on a patient-by-patient basis are:

  • Surgery with curative intent for localized NETs. Surgery can also play a palliative role in certain metastatic patients3
  • Chemotherapy and other systemic agents
  • Targeted radionuclide therapy1
  • Radiofrequency ablation and chemoembolization to address
  • Hepatic metastases
  • Clinical trial participation4,5

Surgery

"I think the first question that we ask when we see a NET is, could the tumor or the tumors be removed surgically?"—Dr Philippe Ruszniewski

The aim of any management strategy should be curative where possible.2 Surgery is the only curative option currently available for NETs.1 First-line intervention usually involves surgical resection of the primary neoplasm and associated nodal disease, if appropriate.3 For patients who are diagnosed early enough to be candidates for surgery, the aim is to keep the patient disease- and symptom-free for as long as possible.2

Before surgical resection of functional pancreatic NETs, symptoms of hormonal excess must be controlled.6,7 Recommended management of the symptoms of hormonal hypersecretion depends on the hormone secreted.8 For example, glucose levels in patients with insulinomas should be stabilized with diet and/or diazoxide. Gastrin hypersecretion in patients with gastrinomas may be managed with proton pump inhibitors (PPIs).6

Patients who already have advanced-stage NETs present unique surgical challenges.9 Operative therapy is rarely curative in the setting of metastatic disease, but it can have an important role in achieving palliation in selected patients.3

Surgical debulking may be an option in appropriate patients for relief of symptoms; indeed, it may be the only option for patients with life-threatening symptoms due to hormonal excess for which other approaches have proven ineffective.10 Patients with advanced-stage NETs may also benefit from a multidisciplinary combination of surgery and other interventions.9

Surgery for hepatic metastases

Chemotherapy and other systemic agents2

The role of cytotoxic chemotherapy is changing with the increasing realization that slow-growing GI NETs generally respond poorly to this modality. 8,11 However, the technique is considered a viable option for inoperable or poorly differentiated tumors, particularly where metastases and angioinvasion are present. 2,11

Targeted radionuclide therapy

131I-MIBG is currently the only licensed therapy that serves as a palliative option for certain patients with inoperable or metastatic neoplasms. The use of this modality has been limited by the fact that the uptake of isotope by some neoplasms is insufficient to achieve palliation.1 Other forms of targeted radionuclide therapy are currently under development.

Radiotherapy

  • Radiofrequency ablation (RFA)–Randomized clinical trials are needed to further our understanding of the use of RFA in managing NETs. But the technique is recommended to stabilize or reduce the size of nonresectable neoplasms, including hepatic metastases in which embolization has not been effective.2,6 It may also have a role in reducing hormone secretion functional metastatic neoplasms.2 However, because neuroendocrine metastases often are small and numerous, management may require multiple sessions over several years2
  • External beam radiation–Although evidence suggests that NETs may be resistant to radiation therapy, the technique may alleviate bone pain due to metastases2,6

Key points to consider when developing a management plan for NET patients12

  • Location of the primary tumor
  • Histologic grade and differentiation of the tumor
  • Stage of tumor
  • Presence or absence of hormonal symptoms

"As a whole, I think we need to do a lot more clinical trials to understand the disease and to develop better treatment options for patients."—Dr James Yao

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2. Ramage JK, Davies AHG, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut. 2005;54(suppl 4):iv1-iv16.
3. Chambers AJ, Pasieka JL, Dixon E, Rorstad O. The palliative benefit of aggressive surgical intervention for both hepatic and mesenteric metastases from neuroendocrine tumors. Surgery. 2008;144(4):645-653.
4. Zuetenhorst JM, Taal BG. Metastatic carcinoid tumors: a clinical review. Oncologist. 2005;10(2):123-131.
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6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine Tumors. V.1.2011.
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8. Kulke MH, Anthony LB, Bushnell DL, et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39(6):735-752.
9. Boudreaux JP, Putty B, Frey DJ, et al. Surgical treatment of advanced-stage carcinoid tumors. Ann Surg. 2005;241(6):839-846.
10. Ong SL, Garcea G, Pollard CA, et al. A fuller understanding of pancreatic neuroendocrine tumours combined with aggressive management improves outcome. Pancreatology. 2009;9(5):583-600.
11. Öberg K, Astrup L, Eriksson B, et al; Nordic NE Tumour Group. Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part I–general overview. Acta Oncol. 2004;43(7):617-625.
12. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128(6):1717-1751.