An Update on Gastroenteropancreatic Neuroendocrine Tumors

Table: Incidence Rates of GEP-NETs in the United States: Cases per 100,000 Population per Year

Figure: Role of the Microenvironment in the Pathogenesis of Neuroendocrine Tumors (NETs)

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of neoplasms arising from the diffuse neuroendocrine system. The incidence of GEP-NETs has increased markedly over the past 3 decades, probably as a result of trends in imaging and improvements in diagnosis. Advances in molecular biology have translated into an expansion of treatment options for patients with GEP-NETs. Somatostatin analogs, initially developed for control of hormonal syndromes, have recently been proven to inhibit tumor growth. Newer drugs, targeting angiogenesis and mammalian target of rapamycin (mTOR) pathways, have been approved for progressive pancreatic NETs; however, their role in nonpancreatic NETs remains controversial. Alkylating cytotoxic agents, such as streptozocin and temozolomide, play an important role in the treatment of pancreatic NETs, although estimated response rates vary widely and phase III data are lacking. During the next few years, randomized clinical trials are expected to provide more clarity regarding the role of radiolabeled somatostatin analogs. Predictive biomarkers that would allow for individualized selection of treatments are needed.

Introduction

Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies arising in the diffuse neuroendocrine system. They are characterized by a relatively indolent rate of growth and a propensity to secrete a variety of peptide hormones and biogenic amines.[1] Although NETs may develop in almost any organ, they predominate within the pancreas and the gastrointestinal tract, where they are thought to originate from the islets of Langerhans and enterochromaffin cells of the gut, respectively. The term “carcinoid,” although somewhat archaic, is still widely used to describe NETs originating in the GI tract.

Gastroenteropancreatic NETs (GEP-NETs) present as hormonally functioning or nonfunctioning tumors and have distinct clinical features based on their site of origin. Since their seminal classification by Williams and Sandler in 1963,[2] gastrointestinal NETs are often subdivided into foregut (gastric, duodenal), midgut (jejunal, ileal, cecal), and hindgut (distal colic and rectal) tumors. While hindgut and foregut NETs are rarely associated with a hormonal syndrome, metastatic midgut carcinoids often secrete serotonin and other vasoactive substances, giving rise to the typical carcinoid syndrome, characterized primarily by flushing, diarrhea, and right-sided valvular heart disease. Malignant potential and growth rate also vary based on primary site. For example, NETs of the small intestine have a relatively high malignant potential but tend to progress rather indolently and are associated with a favorable life expectancy. Conversely, gastric and rectal NETs are often small superficial tumors of low malignant potential; however, in the metastatic setting they tend to progress relatively rapidly compared with midgut tumors.[3,4] Pancreatic NETs (pNETs) are usually hormonally silent but can secrete a variety of peptide hormones, including insulin, gastrin, glucagon, and vasoactive intestinal peptide (VIP).[5]

Impressive progress has been made in the field of biotherapy over the last decade. Recognition of somatostatin receptor (SSTR) downstream signaling as a key regulator of NET secretion and growth has led to an expansion in the role of somatostatin analogs (SSAs) for control of tumor progression. Identification of aberrant tumor angiogenesis and hyperactive mammalian target of rapamycin (mTOR) pathways as drivers of NET progression has provided a framework for the development and clinical testing of new drugs. As a consequence, treatment options for metastatic NETs have expanded and prognosis of patients with advanced disease has improved significantly.[4,6] In this review, we summarize biologic, pathologic, and clinical aspects of GEP-NETs, focusing on recent advances in their treatment.

Epidemiology

Although previously regarded as rare, GEP-NETs represent the second most common digestive cancer.[4,7] In the most updated series of 29,664 patients with GEP-NETs reported to the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute, an incidence of 3.65/100,000 individuals per year was reported.[8] The age-adjusted incidence of GEP-NETs has increased steadily over the last 4 decades, with a 3.6-fold increase occurring between 1973 and 2007.[7] The precise reasons for this steep rise in incidence are unclear, but the expanding use of endoscopic and imaging studies is believed to play a role. GEP-NETs are most common in the small intestine (30.8%), followed by the rectum (26.3%), colon (17.6%), pancreas (12.1%), and appendix (5.7%).[9] The Table summarizes the incidences of GEP-NET subtypes. Although no clear risk factors have been identified in non-syndromic patients, there appears to be a 3.6-fold increased risk of disease in individuals with a family history of carcinoid in a first-degree relative.[10]

Pathobiology

The pathogenesis of pNETs has become clearer in recent years. Chromosomal instability (CIN) has been implicated in tumor progression in pNETs, and losses of genetic material more often than chromosomal gains have been described.[11] Driver mutations of MEN1, DAXX or ATRX, and mTOR pathway genes have been identified as crucial factors in pNET tumorigenesis.[12] MEN1 is a tumor suppressor gene encoding menin, a protein that interacts with histone H3 methyltransferase to act as a scaffold for epigenetic coordination of transcription and cell proliferation. Likewise, DAXX/ATRX mutations appear to affect incorporations of histone H3.3 complexes into telomeres. Mutations in DAXX/ATRX are strongly associated with induction of the alternative lengthening of telomeres (ALT) pathway and CIN.[13] Mutations in mTOR pathway genes, including PTEN or PIK3CA, are identified in approximately 15% of pNETs.[12]

The genetic landscape of carcinoid tumors is much less well understood. Chromosome 18 deletions have been observed in up to 74% of small intestinal NETs, followed by arm-level gains of chromosomes 4, 5, 14, and 20,[14,15] but strikingly few recurrent somatic gene alterations have been described. Recently, the discovery of mutations and deletions in CDKN1B, the cyclin-dependent kinase inhibitor gene encoding p27, has raised the possibility that cell cycle dysregulation may play a role in the pathogenesis of small bowel NETs.[16] Although discrete mutations in mTOR pathway genes are rarely found in carcinoid tumors, overexpression of mTOR and/or its downstream targets is observed in a high frequency of cases and is associated with higher proliferative activity and adverse clinical outcomes.[17]

In recent years, the tumor microenvironment has emerged as a key factor in NET progression (Figure). GEP-NETs overexpress proangiogenic factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF).[18,19] As result, they are among the most extensively vascularized cancers. A paradoxical decrease in tumor vascularization has been noted recently with progressive de-differentiation in pNETs (the so-called “neuroendocrine paradox”),[20] but its biologic and clinical significance need further exploration. Infiltration of CD3+ T cells is a frequent event in NETs and is associated with better survival in patients with intermediate-grade disease.[21] In midgut NETs, an increase of systemic FOXP3+ T-regulatory cells (Tregs) seems to drive anergy by downregulation of the T-cell proliferative capacity.[22] Tumor-infiltrating mast cells have been reported to orchestrate a complex inflammatory and angiogenic response, and inhibition of their degranulation can cause vascular collapse and tumor regression.[23]

Pathology, Staging, and Prognosis

Histologic grade and differentiation correlate closely with clinical behavior of GEP-NETs. While grade refers to the proliferative activity of tumors, measured by Ki-67 index and/or mitotic rate, differentiation refers to the extent to which neoplastic cells resemble normal endocrine tissue. Poorly differentiated tumors are nearly always high-grade and behave in a biologically aggressive fashion.[24] The most recent classification proposed by the World Health Organization (WHO) distinguishes between well-differentiated (low- or intermediate-grade) and poorly differentiated (high-grade) tumors. Large series studies[6,25] have confirmed the prognostic relevance of the current grading system in both small bowel and pancreatic NETs. In one institutional study of midgut NETs, the 5-year survival rates for low- and intermediate-grade tumors were 79% and 74%, respectively, whereas patients with high-grade NETs had a 5-year survival rate of 40%.

Similarly, in pNETs the 5-year survival rates for low-, intermediate-, and high-grade tumors were 75%, 62%, and 7%, respectively.

Until recent years, the ability to stratify patients with NETs into prognostic groups has been limited by the absence of a commonly accepted staging classification. In 2006, Rindi et al[26,27] proposed a four-stage TNM classification for GEP-NETs. Both the European Neuroendocrine Tumour Society (ENETS) and the American Joint Committee on Cancer (AJCC) adopted the staging system for midgut and hindgut NETs, whereas slightly different classifications were embraced for pNETs. In aggregate, the ENETS/AJCC classification was highly prognostic for overall survival (OS) in midgut carcinoids.[28] The 5-year OS rates were 100% for stage I and II tumors vs 91% for stage III (locoregionally advanced) and 73% for stage IV tumors. Although the ENETS TNM staging system was described as superior to the AJCC classification for stratification of patients with pNETs,[29] the prognostic validity of both systems is widely recognized.[25,29] The 5-year OS rates for stages I, II, III, and IV are 100%, 88%, 85%, and 57%, respectively, using ENETS classification and 92%, 84%, 81%, and 57%, respectively, using the AJCC system.

Treatment of Localized and Locally Advanced GEP-NETs

Patients who are diagnosed with localized GEP-NETs are usually treated surgically. The approach to surgery depends largely on the primary tumor size and localization and can vary from conservative procedures to extended surgical resection. A conservative or “watchful waiting” approach is currently advocated for small, incidentally discovered pNETs. In particular, based on evidence that patients with incidentally diagnosed pNETs smaller than 2 cm have a 5-year survival of 100%,[30] ENETS guidelines currently recommend a “wait and see” policy in selected patients with asymptomatic sporadic pNETs.[31] However, this management approach should be considered only in the presence of low-grade tumors, a setting in which fine-needle aspiration or biopsy is mandatory.

Pancreaticoduodenectomy and distal pancreatectomy remain the mainstay for pNETs larger than 2 cm and for symptomatic disease involving the head or body/tail of the pancreas, respectively. Surgical resection of midgut NETs is recommended even for small, asymptomatic tumors detected incidentally. Right hemicolectomy is usually performed for tumors arising in or near the ileocecal valve, whereas partial small bowel resection is an option for more proximal lesions. Regional lymphadenectomy is recommended. Moreover, since small intestine NETs are multifocal in one-quarter of cases, the entire bowel must be carefully examined during the surgical procedure. There is some controversy regarding the necessity of resecting primary small-bowel NETs in patients with distant metastases. However, in patients who are experiencing symptoms (pain, bleeding, intermittent bowel obstruction) or are likely to survive for a long enough period of time to experience such symptoms in the future, resection may be an option.[32,33] Rectal lesions less than 1–2 cm can be managed with endoscopic or transanal excision, whereas patients with larger tumors should undergo low anterior resection or abdominoperineal resection.[33] Very few data are available to guide the treatment of small-duodenal NETs. Surgical options range from endoscopic resection for superficial, asymptomatic tumors, to duodenectomy or pancreaticoduodenectomy for more invasive neoplasms.[32]

Systemic Treatment of Metastatic GEP-NETs

Therapeutic options for patients with metastatic GEP-NETs have improved in recent years. The role of SSAs has expanded from treatment of the carcinoid syndrome to inhibition of tumor growth, and radiolabeled SSAs have demonstrated efficacy in patients harboring SSTR-overexpressing tumors. Biologic agents targeting the mTOR and VEGF pathways have been approved for pNETs, but their role in gastrointestinal NETs remains controversial. Cytotoxic drugs continue to be the standard therapy for poorly differentiated GEP-NETS, and are active in pNETs.

Somatostatin Analogs and Peptide Receptor Radiotherapy (PRRT)

The development of SSAs has had a profound impact on management of metastatic GEP-NETs. Initially developed to palliate hormonal symptoms in patients with carcinoid syndrome, SSAs have recently been shown to have antiproliferative activity. The SSAs currently available in clinical practice are octreotide and lanreotide.

Both compounds bind avidly to SSTR2 and moderately to SSTR5 and have similar efficacy of symptom control in patients with carcinoid syndrome.[34] Small trials and clinical series[35,36] have demonstrated that both octreotide and lanreotide are also effective at palliating the hormonal syndromes associated with pNETs, with the exception of insulinomas, in which their activity is more modest. Loss of response to SSAs in patients with carcinoid syndrome has been explained by tachyphylaxis, resulting from SSTR desensitization and/or SSTR gene mutations.[37] Both octreotide and lanreotide are exceptionally well-tolerated agents. Side effects are generally mild, and include nausea, steatorrhea, and bloating. In patients complaining of gas or steatorrhea, supplemental use of pancreatic digestive enzymes can be considered. Long-term administration of SSAs can result in an increased rate of biliary stone and sludge formation due to the inhibitory effects of SSAs on gallbladder contractility. Above-label doses of SSAs are commonly administered to patients who experience suboptimal control of their hormonally related symptoms.[38] Doses higher than 60 mg monthly may be associated with only minimal marginal benefit.[39] Patients experiencing exacerbation of symptoms towards the final week of each treatment cycle may benefit from an increased frequency of administration. Supplemental dosing of short-acting octreotide also serves to control breakthrough symptoms.

Until recently, evidence of the anti-proliferative effects of SSAs derived only from single-arm phase II trials documenting disease stabilization in roughly 50% of patients with progressive GEP-NETs treated with octreotide or lanreotide.[40,41] To confirm the hypothesis that SSAs can inhibit tumor growth, the phase III PROMID study[42] compared octreotide LAR (long-acting release) vs placebo in 85 patients with advanced midgut NETs. The study reported a statistically and clinically significant improvement in median time to progression (TTP) from 6 months on the placebo arm to 14.3 months on the experimental arm (hazard ratio: 0.34; P = .000072). The small number of deaths in each treatment arm and the high rate of crossover precluded any analysis of differences in OS. More recently, the CLARINET trial[43] randomized 204 patients with hormonally nonfunctioning GEP-NETs to receive either depot lanreotide, at a dose of 120 mg every 4 weeks for 96 weeks, or placebo. A highly significant improvement in progression-free survival (PFS) was described in the lanreotide arm (with median study-drug exposure of 24 months, median PFS was unreached on lanreotide vs 18 months in the placebo group; P < .001). Pasireotide is a novel multireceptor-targeted SSA with avid binding affinity to four of the five SSTR subtypes. However, its role in GEP-NETs remains to be defined. In a phase III study of patients with refractory carcinoid syndrome, pasireotide did not demonstrate improvement in control of flushing or diarrhea.[44] The antiproliferative effects of pasireotide are being tested in several clinical studies.[45,46] However, enthusiasm for pasireotide is diminished by the high rate of hyperglycemia associated with its use.

Radiolabeled SSA therapy (also known as peptide receptor radiotherapy or PRRT) has been shown to be an effective treatment for GEP-NETs, as it allows targeted delivery of radionuclides to SSTR-expressing tumor cells. Selection criteria for PRRT include evidence of strong radiotracer uptake on somatostatin-receptor scintigraphy (SRS)- ideally higher than occurs in normal liver tissue. Early clinical trials of PRRT used high doses of ¹¹¹In-pentetreotide, the isotope used in SRS. Although symptom relief was often observed, objective tumor responses were rare, probably as a consequence of the short tissue penetration of Auger electrons emitted by the ¹¹¹In isotope.[47,48] The agents ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE represent the latest generation of radiolabeled SSAs and yield more impressive therapeutic effects. ⁹⁰Y is a high-energy β-particle emitter and was initially reported to yield objective radiographic responses in more than 25% of patients.[49] However, a subsequent large multicenter trial of 90 patients with metastatic carcinoid tumors reported a response rate of only 4%, despite a 70% rate of disease stabilization.[50] Since ¹⁷⁷Lu emits both β and γ rays, labeled peptides can be used for treatment as well as for dosimetry and monitoring of tumor response. A large nonrandomized trial recently reported a 30% radiographic response rate in 310 patients with GEP-NETs receiving ¹⁷⁷Lu-octreotate. Responses were particularly high in patients with pNETs.[51] The first phase III registration trial of ¹⁷⁷Lu-octreotate vs high-dose octreotide in patients progressing on standard-dose octreotide is now open. PRRT toxicities include myelosuppression and renal insufficiency, with the latter generally ameliorated by concurrent amino acid infusion.

Interferon-α

Interferons (IFNs) can inhibit tumor growth through a variety of mechanisms, including stimulation of T cells, inhibition of angiogenesis, and induction of cell cycle arrest.[52] Early trials of IFN-α reported objective response rates (ORRs) in the 5% to 10% range, with higher rates of disease stabilization or palliation of hormonal syndrome.[53] When added to octreotide in the treatment of patients with refractory carcinoid syndrome, IFN-α was shown to improve symptoms in 49% of patients.[54] Based on preclinical evidence showing that IFN induces the expression of SSTRs in NET cells, several randomized studies investigating SSA/IFN combinations have been carried out. In one multicenter study of 68 patients with metastatic midgut NETs, patients were randomized to octreotide plus IFN-α vs octreotide alone. A strong trend towards improvement in the 5-year survival rate (57% with the combination vs 37% with octreotide alone; P = .13) was noted.[55] Similar data were reported in a study comparing octreotide alone or in combination with IFN-α in 105 patients with progressive metastatic GEP-NETs. Again, median OS was longer in the combination arm (54 months vs 32 months), but the difference was not statistically significant (P = .38).[56] A three-arm trial of 80 therapy-naive patients with advanced GEP-NETs compared lanreotide vs IFN-α as single-agent therapy vs lanreotide plus IFN-α in combination. The ORR was low (≤ 7%) in all three arms and time to tumor progression was nearly identical.[57] It is difficult to draw any definitive conclusions regarding the effects of IFN in patients with GEP-NETs. In fact, studies carried out until now were not adequately powered to evaluate the impact of IFN on OS, and no optimal dosing regimen has been established. However, midgut NETs appear to be most sensitive to the antisecretory and antiproliferative effects of IFN-α. Chronic toxicities such as flulike symptoms, myelosuppression, myalgias, and depression are recognized side effects of IFN but are relatively manageable in patients treated with low doses of IFN-α.

mTOR Inhibitors

The mTOR inhibitor everolimus has been extensively studied in GEP-NETs. The phase II RADIANT 1 trial compared everolimus alone vs everolimus plus octreotide in 160 patients with advanced, progressive pNETs. Response rate and median PFS were 9% and 9.7 months in the monotherapy arm vs 4% and 16.7 months in the combined therapy arm.[58] RADIANT 2 randomized 429 patients with hormonally active carcinoid tumors to treatment with everolimus plus octreotide vs placebo plus octreotide. On central radiographic review, median PFS increased from 11.3 months in the control arm to 16.4 months in the experimental arm (P = .026). While clinically significant, the primary endpoint fell short of its prespecified statistical significance threshold (P < .024).

One major reason for this failure was loss of progression events because of discrepancies in central vs local radiographic review.[59] The results of the RADIANT 2 trial have generated some controversy regarding the role of everolimus in nonpancreatic NETs. The RADIANT 3 trial randomly assigned 410 patients with low- and intermediate-grade pNETs to treatment with everolimus vs placebo. Everolimus was associated with an ORR of only 5%, but the study demonstrated a clinically and statistically significant improvement in PFS, which increased from 4.6 months on the placebo arm to 11 months on the everolimus arm (P < .001). Based on these results, everolimus was approved for treatment of patients with advanced pNETs.[60] Side effects of everolimus include hyperglycemia, cytopenias, aphthous oral ulcers, rash, diarrhea, and atypical infections. Pneumonitis is a relatively rare but potentially serious adverse event. A phase III study of everolimus in nonfunctional NETs (RADIANT 4) is ongoing and may lead to a better definition of the role of mTOR inhibition in patients with carcinoid tumors.

Angiogenesis Inhibitors

Angiogenesis inhibitors can suppress the VEGF receptor (VEGFR) or neutralize circulating VEGF. The tyrosine kinase inhibitor (TKI) sunitinib targets VEGFR-1, -2, and -3; platelet-derived growth factor receptor (PDGFR); and c-KIT. A phase II study demonstrated that sunitinib was associated with ORRs of 2.4% and 16.7% in patients with carcinoid tumors and pNETs, respectively.[61] On this basis, a phase III trial evaluated sunitinib at 37.5 mg daily vs placebo in 171 patients with low- and intermediate-grade pNETs. A statistically significant improvement in PFS was demonstrated in the TKI arm (11.1 months vs 5.5 months; P < .001), and the ORR associated with the drug was 9.3%.[62] Sunitinib is currently approved for treatment of pNETs. Its toxicities include diarrhea, nausea, fatigue, hypertension, palmar-plantar erythrodysesthesia, and cytopenias. Pazopanib is a TKI with a target profile similar to that of sunitinib and was recently evaluated in a nonrandomized phase II study of 37 patients with GEP-NETs. The ORR was 24% on independent review, and a median PFS of 9.1 months was reported.[63] Based on these results, a randomized phase III trial of pazopanib vs placebo for advanced carcinoid tumors is ongoing.

Bevacizumab is a monoclonal antibody against VEGF-A. A phase II trial randomized 44 patients to receive bevacizumab or pegylated IFN-α for 18 weeks, followed by both agents in combination. At the end of the single-agent administration period, the rate of PFS was 95% in the bevacizumab arm vs 68% in the IFN-α arm.[64] However, a follow-up phase III study comparing bevacizumab vs interferon did not meet its primary endpoint of improvement in PFS.

Cytotoxic Chemotherapy

Responses to chemotherapeutics are extremely heterogeneous in GEP-NETs and are influenced by tumor differentiation/grade and primary site location. Poorly differentiated GEP-NETs are typically responsive to platinum-based regimens, which are associated with response rates exceeding 50%.[65] Recent data emphasize the predictive role of the proliferative rate, since tumors with Ki-67 fractions above 55% are significantly more likely to respond to platinum/etoposide compared with high-grade tumors with lower rates of proliferative activity.[66]

Unfortunately, there are no effective salvage regimens that have demonstrable activity in patients with platinum-resistant cancers. On the other hand, pNETs appear to be sensitive to alkylating agents, including streptozocin, dacarbazine, and temozolomide, as well as fluoropyrimidines. The nitrosurea streptozocin was evaluated in two randomized trials in the 1970s and 1980s. The first of these studies reported response rates of 63% in the streptozocin plus fluorouracil (5-FU) arm vs 36% in the streptozocin monotherapy arm.[67] The second trial compared streptozocin plus doxorubicin vs streptozocin plus 5-FU, and reported response rates and time to progression of 69% and 20 months vs 45% and 6.9 months, respectively.[68] However, a lack of rigorous radiographic assessment in these older studies has hampered the ability to make definitive conclusions about the efficacy of streptozocin. More recently, a retrospective study investigated the combination of streptozocin, 5-FU, and doxorubicin in 84 patients with pNETs; the response rate was 39%, with a median response duration of 9.3 months.[69] However, clinical use of streptozocin is limited by concerns about toxicity, including effects such as myelosuppression, nausea, and renal insufficiency.

The oral alkylator temozolomide has recently emerged as an active agent in the treatment of pNETs. A phase II study investigating the combination of temozolomide and thalidomide demonstrated an ORR of 45% in the subset of 11 patients with pNETs.[70] In a retrospective study of temozolomide and capecitabine in 30 chemonaive patients with pNETs, the radiographic response rate was 70% and the median PFS was 18 months.[71] When combined with bevacizumab, temozolomide was associated with a response rate of 33% and a median PFS of 14.3 months in a heavily pretreated subset of patients with pNETs.[72] An Eastern Cooperative Oncology Group (ECOG)-sponsored prospective randomized trial of temozolomide alone or in combination with capecitabine is underway in the United States and will provide much-needed prospective data in a large cohort of patients with pNETs. Temozolomide is fairly well tolerated. Side effects include thrombocytopenia and nausea.

There are no studies comparing cytotoxic drugs vs targeted agents, and there are no validated strategies to guide treatment selection. As a general principle, chemotherapy may be more appropriate in patients with rapidly progressive, bulky, and/or symptomatic tumors. The cost of intravenous drugs, such as streptozocin and 5-FU, is substantially lower than the price of newer targeted agents. Temozolomide and capecitabine have recently come off patent, therefore their cost is expected to decrease significantly.

Midgut NETs are particularly chemoresistant, possibly due to their low proliferative activity as well as their high expression of methyl-guanine-methyl-transferase (MGMT), a DNA repair enzyme.[73] Future studies of cytotoxics in GEP-NETs should stratify patients based on primary site and tumor grade. Also, predictive factors of response to chemotherapeutics are warranted.

Liver-Directed Therapies

The liver is the predominant site of metastases in patients with GEP-NETs. Liver-directed therapies include surgical resection or ablation, transarterial embolization (TAE) or chemoembolization (TACE), and liver transplantation. As rule of thumb, surgery may represent an option when more than 90% of liver tumors can be successfully resected or ablated. Different ablation techniques can be used, including cryoablation, alcohol ablation, and radiofrequency ablation. Usually, ablation methods are reserved for unresectable oligometastases smaller than 5–7 cm in diameter. Although palliation of symptoms and prolonged survival durations are commonly reported in retrospective studies or institutional series,[74,75] no randomized trials have compared surgical vs nonsurgical approaches in the management of GEP-NETs metastatic to the liver.

Angiographic liver-directed techniques such as TAE and TACE are employed mainly for diffuse or widely scattered liver metastases. The biologic rationale supporting the use of embolization strategies is that liver metastases are predomdinantly vascularized by the hepatic arterial circulation, whereas the normal parenchyma derives its blood supply primarily from the portal vein. Regarding TAE, various particulate and occlusive materials have been used, including polyvinyl alcohol (PVA) and trisacryl gelatin microspheres. In the presence of bilobar metastases, staged lobar embolizations may be necessary. No completed randomized trials have ever compared bland embolization to TACE, and the superiority of one technique to another has never been demonstrated. Symptomatic and radiographic responses to embolization techniques have been recorded in 53% to 100% and 35% to 74% of patients, respectively. The median PFS has been estimated at 18 months.[76] Short-term, predictable toxicities are associated with embolization and include nausea, pain, fever, and fatigue.

A novel approach to liver metastases from GEP-NETs involves embolization of ⁹⁰Y embedded either in a resin microsphere (SIR-Sphere) or a glass microsphere (TheraSphere). The goal of this technique, also called selective internal radiotherapy (SIRT), is to produce tumor necrosis through direct delivery of radiation. Response rates associated with radioembolization in metastatic GEP-NETs have been somewhat encouraging. In one retrospective multicenter study of 148 patients treated with SIR-Spheres, the ORR was 63%.[77] However, SIRT has never been compared prospectively to other embolic treatments, and long-term toxicities such as radiation fibrosis represent potential risks. Moreover, the cost of SIRT substantially exceeds the cost of more traditional embolotherapies. Widespread adoption of SIRT should await prospective randomized trials.

The role of liver transplantation for patients with metastatic GEP-NETs is still debated. Promising results have been reported, with 5-year survival of up to 90% in patients with well-differentiated GEP-NETs, but long-term cures are quite rare. Better outcomes have been reported for gastrointestinal tumors than for pNETs.[78] According to ENETS guidelines,[79] strict criteria should be used for selection of candidates for liver transplantation, including low proliferative rate (Ki-67 < 10%), age < 55 years, absence of extrahepatic disease, pretransplant primary tumor resection, limited (< 50%) liver involvement, and stable disease for at least 6 months before transplantation. In the largest reported multicenter retrospective study in this area, of 213 patients who underwent liver transplantation for NET metastases, the 5-year OS was 52% and the disease-free survival rate was 30%. In addition to the transplant procedure, predictors of poor outcome included hepatomegaly, tumor dedifferentiation, and major surgical resection. The authors reported that at a mean follow-up of 56 months, 17% of the patients had died from early or late complications of the liver transplantation.[80]

Conclusions

SSAs remain the cornerstone of therapy for well-differentiated GEP-NETs, both for control of hormonal syndromes and inhibition of tumor growth. While everolimus and sunitinib are active in pNETs, the role of mTOR and angiogenesis inhibitors in carcinoid tumors remains undefined. Temozolomide- or streptozocin-based cytotoxic regimens play an important role in patients with pancreatic NETs, particularly for those with progressive, bulky, or symptomatic tumors. There is a clear need for predictive markers that would allow for individualized selection of treatments. Advances in radiopharmaceuticals and liver-directed therapies further broaden the therapeutic landscape for patients with GEP-NETs, but they also raise questions about optimal treatment sequence. It is important to note that overtreatment of asymptomatic patients with stable or mildly progressive disease may adversely impact patient quality of life and survival. Moreover, availability of novel agents can lead to the misconception that newer therapies are inherently superior to established treatments. Future clinical trials should address the selection and sequencing of treatments, to balance efficacy with toxicity and cost.

Financial Disclosure: Dr. Strosberg has served as a consultant for Genentech, Ipsen, Novartis, and Pfizer, within institutional conflict-of-interest payment guidelines. Dr. Cives has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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