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The current goal of treatment of advanced unresectable NET is improvement of symptoms and survival. Tumor burden reduction is desirable insofar as it is subsumed in these goals. The current standard of care for hormone-related symptom control remains a somatostatin analogue. Other therapies, including surgical resection of hepatic metastases, hepatic artery embolization/chemoembolization, and peptide receptor radionuclide therapy, are useful adjuncts. For PNETs, additional systemic treatment options are also available.
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Somatostatin Analogues
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Somatostatin analogues such as octreotide and lanreotide are the primary medications for control of symptoms from hormonally active NETs. Octreotide is an intermediate-acting somatostatin analogue that can be administered subcutaneously every 6 to 12 hours. It provides complete or partial relief of flushing or diarrhea in about 85% of patients with carcinoid syndrome and produces a biochemical response rate of up to 72% (33). The dose of octreotide varies from 50 to 500 μg.
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Long-acting somatostatin analogues have obviated the need for multiple daily injections in most patients. Depot octreotide (10, 20, or 30 mg) is given intramuscularly once a month (34). An intermediate-acting somatostatin analogue should be used to supplement long-acting agents until steady state is reached. Rarely, somatostatin analogue can cause sinus bradycardia or cardiac conduction abnormalities. Caution is advised in patients with preexisting cardiac disease. Cholelithiasis may develop with long-term use of somatostatin analogues. Hypoglycemia or, more commonly, hyperglycemia may occur, especially among patients with brittle diabetes. Steatorrhea may occur but can be managed with pancreatic enzymes. Lanreotide is an alternative somatostatin analogue and, in extended release form, is administered subcutaneously monthly in doses of 60, 90, or 120 mg.
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Somatostatin analogues also have anticancer activity. Interim analysis of the phase III randomized trial of depot octreotide 30 mg monthly in untreated metastatic midgut NET (PROMID) demonstrated a significantly longer time to progression with octreotide compared with placebo (14.3 vs 6 months, P < .001) (35). An international, double-blind, placebo-controlled, phase III trial of lanreotide (120 mg every 28 days) in patients with a nonfunctioning NET (CLARINET) also demonstrated significantly improved progression-free survival with lanreotide compared with placebo (median, not reached vs 18 months, P < .001) (36).
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Surgical Resection of Hepatic Metastases
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Liver metastases are generally resectable if: (1) all tumors in the liver can be completely resected and (2) an adequate volume of liver (20% of the standardized total liver volume) with adequate biliary drainage, arterial inflow, and venous outflow can be preserved. If the locoregional and hepatic tumor burden is completely resectable, then this is the preferred management of metastatic NETs, whether functional or nonfunctional. Hepatic resection is most effective for low-grade NETs (37). Debulking at least 90% of the hepatic tumor burden in patients with functional metastases improves endocrine symptoms and may prolong survival (38).
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Radiofrequency Ablation
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Local ablative therapies such as radiofrequency ablation (RFA) are being used increasingly for treatment of liver tumors. Radiofrequency ablation involves placing a probe in the liver tumor percutaneously or intraoperatively using image-guidance techniques. The radiofrequency waves increase the intratumoral temperature, resulting in tumor destruction.
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Radiofrequency ablation has been used for the treatment of hormone-related symptoms in selected patients with NET liver metastases, alleviating symptoms in up to 80% of cases (39). Furthermore, RFA may achieve local control of liver metastases in up to 74% of patients. The use of RFA is generally limited to patients with five or fewer lesions in the liver, with each tumor measuring less than 3 cm in size. The largest reported series using RFA in NET patients with liver metastases included 34 patients with 234 tumors treated in 42 sessions with laparoscopic RFA. “Complete” or “significant” symptom relief was achieved in 80% of the symptomatic patients and lasted an average of 10 months (range, 6-24 months) (39).
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Hepatic Arterial Embolization and Chemoembolization
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Liver metastases from NETs are hypervascular, receiving over 80% of their blood supply via the hepatic artery, whereas liver parenchyma receives 60% to 70% of its perfusion from the portal vein. Thus, embolizing the hepatic artery targets tumor metastases while leaving parenchyma relatively unharmed. The addition of a chemotherapeutic agent to the embolic material, also known as transcatheter arterial chemoembolization (TACE), allows delivery of relatively larger doses of chemotherapy to the tumor, combining local cytotoxicity and ischemia. The most frequently used chemotherapeutic agents for NET TACE include doxorubicin, cisplatin, mitomycin C, and streptozocin (40,41).
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Potential benefits include symptom relief, slowing progression, and reducing tumor burden before resection or ablation. Many retrospective reports in markedly heterogeneous populations have shown that either technique can reduce tumor burden, hormone levels, and symptoms in NET patients. No study has clearly demonstrated one technique to be superior. The primary risk is postembolization syndrome, which is typically self-limited and characterized by gastrointestinal distress, fever, leukocytosis, and transaminitis. Major complications such as liver and/or renal failure, gallbladder perforation, cholangitis, peptic ulcer hemorrhage, and abscess formation are rare (42). Embolization can occasionally precipitate carcinoid crisis as well.
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In patients with extensive liver tumor burden, multiple embolization sessions may be required, starting with the hepatic lobe with greatest tumor burden. Embolization of the whole liver in one session runs the risk of prolonged postembolization syndrome or liver failure. The timing of subsequent embolizations is determined primarily by symptoms, tumor behavior, and patient tolerance.
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The timing of embolizations in the disease course remains controversial. Although some investigators advocate early embolization to reduce tumor burden before initiating systemic therapy, late embolization can also be effective. In a randomized study, NET patients treated with initial liver embolization followed by interferon therapy had a higher objective response rate after 1 year (86%) than patients who received interferon only (42%), without altering survival (43). In contrast, when embolization or chemoembolization was performed at a median of 37 months after diagnosis, the median survival after embolization was 80 months, indicating that later embolization is still effective (44).
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Selective Internal Radiation Therapy
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Intra-arterial radioembolization with yttrium-90 (90Y) microspheres is an emerging technique being used increasingly in patients with unresectable liver lesions. Yttrium-90 is a pure β emitter with a mean soft tissue penetration of 2.5 mm and a maximal depth of 1.1 cm. Radioembolization with 90Y has a significantly lower incidence of postembolization syndrome than embolization or chemoembolization, allowing it to be performed as an outpatient procedure. However, great care must be taken with 90Y radioembolization to avoid nontarget delivery of radioactive microspheres to organs, making an angiogram with selective embolization of all extrahepatic arteries essential before treatment.
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There is limited literature on the use of radioembolization for treatment of neuroendocrine liver metastases. In a retrospective review of 148 patients with NET liver metastases treated with 185 separate 90Y radioembolization procedures, complete response was observed in 3% of patients, and a partial response was observed in 66.7%. The median survival duration was 70 months (45). Further investigation, long-term follow-up, and prospective clinical trials are warranted to determine the exact role of this treatment method in the management of NET.
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Peptide Receptor Radionuclide Therapy
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Radiolabeled somatostatin analogues have also been developed. A prospective study of 90Y-DOTA-Tyr3-octreotide in 90 patients with metastatic, symptomatic carcinoid tumors refractory to octreotide treated showed subjective improvement in over 50% of patients and objective radiologic responses in 4% of patients (46). In another report of 310 patients treated with 177Lu-DOTA-Tyr3-octreotate, the reported radiologic response rate was 30%, but without intent-to-treat analysis incorporating the additional 194 patients accrued to the protocol, meaningful interpretation is challenging (47). The ongoing phase III NETTER-1 study, comparing 177Lu-DOTA-Tyr3-octreotate to high-dose octreotide long-acting release (60 mg intramuscularly every 28 days) in patients with advanced small bowel NETs should allow clearer conclusions to be drawn.
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High-grade NETs are responsive to platinum-based chemotherapy (13). Well-differentiated extrapancreatic NETs respond poorly to cytotoxic chemotherapy. Pancreatic NETs respond better. The authors’ group noted radiographic response rates of 39% in a series of 84 PNET patients using a regimen of 5-fluorouracil, doxorubicin, and streptozocin (FAS) (41). This regimen is derived from prior streptozocin-based chemotherapy regimens observed in randomized studies to achieve biochemical responses (48,49).
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The NET field has made significant progress over the past 5 years, principally in the area of targeted therapy. Building on the observation that increased VEGF portends poor survival in NET patients, the VEGF receptor (VEGFR) inhibitor sunitinib was tested in a phase III study (50). An interim analysis demonstrated a hazard ratio for progression or death of 0.42 favoring sunitinib over placebo (P < .001) in 154 PNET patients with advanced and progressive disease. This resulted in the regulatory approval of sunitinib for the indication. Simultaneously, the mTOR inhibitor everolimus was studied in RADIANT-3. This randomized phase III trial investigated everolimus versus placebo in 410 patients with advanced, progressive PNET. The hazard ratio for progression or death was 0.35 (P < .001) favoring everolimus over placebo (51).
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The phase II study of sunitinib showed limited evidence of benefit in extrapancreatic NET patients (52). The RADIANT-2 study of everolimus in extrapancreatic NET patients, although limited by randomization imbalance and informative censoring in central radiology review, also failed to demonstrate statistically significant benefit (53). It is hoped that RADIANT-4, a randomized study of everolimus in nonfunctional extrapancreatic NET patients buttressed against informative censoring, will convincingly answer the question of whether mTOR inhibition has a role in a broader range of NETs.
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Additional Symptom Control Methods
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Carcinoid symptoms can be exacerbated by epinephrine, exercise, emotions, eating tryptophan-rich foods, and ethanol and may be controlled through modulating these factors or supplementing dietary nicotinamide. Medical management of carcinoid symptoms can include a bronchodilator for bronchospasm, loperamide or diphenoxylate for diarrhea, and diuretics for fluid overload secondary to valvular dysfunction. A proton pump inhibitor can manage gastric hypersecretion in gastrinoma patients. Since our initial report, multiple groups have confirmed the efficacy of everolimus for the management of malignant hypoglycemia due to insulinoma (54).