Pancreatic neuroendocrine tumor (PNET) refers to several tumor types located in the pancreas. These tumors are classified as functional or nonfunctional depending on production and secretion of bioactive hormones. Functional PNETs cause clinical symptoms associated with their tumor classification. Some examples include gastrinomas, which are associated with gastrointestinal ulcers and diarrhea; glucagonomas, which are associated with diabetes, skin rash, and diarrhea; and vasoactive intestinal polypeptide tumors, which may produce extreme watery diarrhea, abdominal pain, and flushing. Because nonfunctional PNETs do not produce bioactive hormones and do not cause clinical symptoms, these tumor types (eg, pancreatic polypeptidoma) are diagnosed at a more advanced stage, often presenting with symptoms related to mass effect or metastasis (eg, abdominal pain, obstructive jaundice, or weight loss). PNET is relatively rare, with an incidence of <1 in 100,000. Most diagnoses occur in patients aged >40 years, with equal gender distribution. Causation of PNET is sporadic but associated less commonly with genetic syndromes (eg, multiple endocrine neoplasia type 1 or von Hippel-Lindau).

The malignant potential for PNET is determined by clinical symptoms and presence of metastatic disease rather than a specific immunohistochemistry profile. In addition, neuroendocrine tumors (NETs) are classified according to their degree of pathologic differentiation. Well-differentiated NETs typically include low and intermediate grades, whereas poorly differentiated NETs are considered biologically aggressive. Historically, staging of PNETs used the classification system of the World Health Organization, in which PNETs were considered (1) well-differentiated of benign or uncertain behavior, (2) welldifferentiated with low malignant potential, or (3) poorly differentiated with high-grade malignant potential based on the proliferation index of the Ki67 marker. The European Neuroendocrine Tumor Society (ENETS) developed a system of grading that uses both the Ki67 proliferation index and the number of mitoses per high-power field. More recently, ENETS and the American Joint Committee on Cancer each proposed a TNM staging system.

Treatment of PNET
Treatment of PNET is dependent on functional status as well as the absence or presence of metastatic disease. Optimal therapy for PNET includes medications (eg, somatostatin analogs, proton pump inhibitors) to control clinical symptoms followed by surgical resection, such as pancreaticoduodenectomy (also known as the Whipple procedure) or distal pancreatectomy, of the primary tumor. Surgical resection of hepatic metastases from PNET has a low morbidity and mortality rate and is recognized as the recommended treatment modality if >90% of a patient’s tumor burden is resectable.

Metastatic disease is not always amenable to surgical resection and requires alternative treatments, such as regional hepatic therapy (eg, radiofrequency ablation, arterial embolization, chemoembolization, and radioembolization) or peptide receptor radio - nucleotide therapy, which is currently only used outside the United States. These treatments are not curative but may be used for symptom palliation or disease control. Orthotopic liver transplantation has been attempted in a small subset of patients, but it has not received empirical support.

Effectiveness of Chemotherapy Limited
An additional treatment modality is the use of systemic chemotherapeutics. Traditionally effective chemotherapy combinations for well-differentiated PNET have included streptozocin combined with doxorubicin, fluorouracil, or both. Cisplatin and etoposide have been effective for short durations in poorly differentiated PNET. Recent clinical trials have indicated the potential use of temozolomide (Temodar), an alkylating agent that causes apoptosis through damage to the tumor’s DNA, alone or in combination with capecitabine (Xeloda) or thalidomide (Thalomid). Patients with high expression levels of the DNA repair enzyme O6-methylguanine DNA-methyltransferase demonstrate virtually no response to temozolomide.

Biotherapies Show Promise
Newer biologic agents are being used to treat PNET. Somatostatin analogs (eg, octreotide and lanreotide), which have long been used to mitigate the effects of functional PNETs, have recently been found to increase the effectiveness of octreotide acetate injection long-acting release (Sandostatin LAR) in patients with minimal hepatic tumor burden and delay disease progression. Preliminary data from the PROMID study revealed a median progressionfree survival (PFS) of 14 months in patients who received octreotide LAR compared with 6 months for patients in the placebo group. Final results from the phase 3 trial, which aims to determine the effect of lanreotide autogel on nonfunctional PNETs, have not been published [clinicaltrials.gov identifier: NCT0035496].

Molecular genetic investigation into PNET suggests that the deactivation of tumor suppressor genes such as TSC2 and PTEN activates the mammalian target of rapamycin (mTOR) pathway. This pathway promotes angiogenesis and cell growth and proliferation in PNETs. Two trials, RADIANT (RAD001 in Advanced Neuro en - docrine Tumors)-1 and RADIANT-3, demonstrated that 10 mg daily of the mTOR inhibitor everolimus (Afinitor) might be an effective treatment option for patients with advanced PNET. In the phase 2 RADIANT-1 trial, patients who received everolimus plus octreotide LAR demonstrated PFS of 16.7 months compared with 9.7 months for those given only everolimus. Clinical benefit, defined as stable disease and partial remission, was observed in both arms of the study. The phase 3 RADIANT-3 trial reported longer PFS with everolimus than with placebo (11 vs 4.6 months, respectively) and minimal treatment-related adverse effects.

Another promising therapy is sunitinib malate, a tyrosine kinase inhibitor that inhibits vascular endothelial growth factor (VEGF) and plateletderived growth factor. One phase 3 trial demonstrated a median PFS of 11.4 months in patients with well-differentiated PNET who received a 37.5-mg daily dose of sunitinib compared with a median PFS of 5.5 months for patients who took placebo. Additional trials investigating sunitinib in poorly differentiated NETs are planned.

Bevacizumab (Avastin), a monoclonal antibody targeting VEGF receptors, has also been used to treat neuroendocrine cancers in clinical trials. Patients on stable doses of octreotide LAR were given bevacizumab or pegylated interferon-α-2b separately for 18 weeks, with treatment discontinued earlier if disease progression was observed. After the initial trial phase, patients were started on a combination of bevacizumab and pegylated interferon- α-2b. At 18 weeks, the bevacizu mab monotherapy arm demonstrated a higher rate of PFS than the pegylated interferon-α-2b group (95% vs 68%, respectively). As a result of these findings, an ongoing phase 2 trial is actively recruiting patients with locally advanced or metastatic PNET to study the effects of using a combination of everolimus and octreotide with or without bevacizumab [clinicaltrials.gov identifier: NCT01229943]. Several other phase 2 clinical trials in progress are evaluating the effects of bevacizumab combined with many of the therapies previously discussed.

Conclusion
PNET is a rare tumor type for which surgical resection combined with cytotoxic chemotherapy has been the mainstay of treatment. Traditionally, the purpose of using medical therapies was to control clinical symptoms associated with functional PNETs. Chemotherapeutic agents such as streptozocin, cisplatin, and etoposide have been found to have minimal impact on disease survival, and recent clinical trials have investigated the efficacy and safety of biotherapies. Studies have shown that everolimus, sunitinib, and bevacizumab effectively prolong PFS, generating optimism that these and other new therapies might alter the disease trajectory for patients with PNET.

References

  1. O"berg K. Pancreatic endocrine tumors. Semin Oncol. 2010;37:594-561.
  2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors. V.2.2010.
  3. Kulke MH, Anthony LB, Bushnell DL, et al; for the North American Neuroendocrine Tumor Society. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39:735-752.
  4. Elaraj D, Sturgeon C. Neuroendocrine tumors of the pancreas. In: ACS Surgery: Principles and Practice. Philadelphia, PA: BC Decker, Inc; 2010.

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Dori L. Klemanski, MS, MS, RN, CNP