Most well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETS) are well vascularized with a high expression of proangiogenic molecules such as vascular endothelial growth factor, along with overexpression of tyrosine kinase inhibitors (epidermal growth factor receptor, insulin growth factor receptor, and downstream signaling pathways IPI3K-AKT-mTOR).
Mammalian Target of Rapamycin
Mammalian target of rapamycin (mTOR) is an intracellular serine/threonine kinase that is a central regulator of multiple signaling pathways (i.e., IGF-1, EGF, VEGF). It regulates apoptosis, cell proliferation, and cell growth by modulating cell cycle progression. Activation of mTOR is linked to increased rates of proliferation and cancer progression; such patients have been found to have shorter progression-free survival and overall survival.16 Recent whole-exome genomic analysis of PNETs demonstrates that approximately 15% of tumors are associated with somatic mutations in genes associated with the mTOR pathway such as PTEN, PI3K, and TSC2.17 Everolimus is an oral mTOR inhibitor. The RADIANT 3 trial, published in the New England Journal of Medicine in 2011, was a multicenter, double-blinded, phase III trial of everolimus versus placebo. Those receiving everolimus experienced a prolongation in median progression-free survival of 6.4 months compared to placebo and had a 65% reduction in relative risk of disease progression (p < 0.001). Since crossover was allowed in this trial, no difference in overall survival was detected.18
Vascular Endothelial Growth Factor
Vascular endothelial growth factor (VEGF) is known to be a key driver of angiogenesis in PNET. PNETs show widespread expression of VEGF receptors along with platelet-derived growth factor receptors (PDGFRs) and c-kit. Sunitinib is a multitarget tyrosine kinase inhibitor that targets VEGFR 1–3, PDGFR alpha and beta, c-kit, flt-3, and the RET proto-oncogene. A recent randomized, double-blinded, placebo-controlled phase III trial of advanced well-differentiated PNET compared sunitinib to placebo. In this study, patients who received sunitinib experienced a median progression-free survival of 11.4 months as opposed to 5.5 months (p < 0.001) for those receiving placebo. The objective response rate was 9.3% versus 0% (p = 0.0066). Median overall survival was never reached; however, hazard ratios favored those treated with sunitinib. The authors concluded that sunitinib improved progression-free survival, overall survival, and overall response rates in patients with PNETs.19
Building on the synergistic effects of mTOR and VEGFR inhibition, a phase II trial of temsirolimus (mTOR inhibitor) combined with bevacizumab demonstrated that 80% of patients (44 of 50) were free of disease progression at 6 months and the objective response rate was 37%.20 Everolimus has also recently been combined with depot octreotide in a phase II Italian trial of gastroenteropancreatic and lung NETs with 92% of treated patients demonstrated to have clinical benefit and 72% found to maintain stable disease for >6 months.20
Transarterial Embolization and Chemoembolization
Neuroendocrine tumors are hypervascular tumors and, when metastatic to the liver, derive greater blood supply from the hepatic artery than the portal vein. Transarterial embolization (TAE, or bland embolization) and transarterial chemoembolization (TACE) are therefore logical treatment options for control of unresectable PNET hepatic metastases. Objective response rates and midterm results are encouraging;21 however, when compared to robust data sets of patients who underwent surgical resection (70.5% 5-year overall survival), long-term outcomes after TAE/TACE are often not available and can vary widely (14% to 75%).22 Liver-directed therapies are consistently useful adjuncts for symptom control in patients with hormone-secreting NETs, complementing other strategies such as SSAs.23-25 Despite a large clinical experience spanning three decades, optimal treatment protocols vary across institutions. The timing of liver-directed therapy and the exact chemoembolic regimen remain areas of debate. Controversy persists as to whether TACE provides a clear advantage over bland embolization,21 although the former is generally preferred for treatment of PNETs. However, the addition of a chemotherapeutic agent does not usually impart additional procedural morbidity or mortality.26 Postembolization syndrome consisting of fever, nausea, and abdominal pain occurs commonly, but is typically transient and self-limited. Hepatic toxicity is avoided in those patients with extensive hepatic disease by treating a small portion of the liver at each session.27 In one study, the presence of a biliary-enteric anastomosis lowered the median overall survival from 31.6 to 10.8 months for PNETs, likely due to the risk for hepatic abscess with colonized bile (due to biliary stent or a biliary-enteric anastomosis). In addition, a large hepatic tumor burden (>20% of the hepatic volume) and distant organ metastasis were unfavorable prognostic factors.28
Drug-eluding bead transarterial chemoembolization (DEB-TACE) has gained recent attention given its favorable pharmacokinetic profile. Initial trials indicated high response rates and a safety profile similar to conventional TACE;29 however, subsequent studies have raised concern for increased biliary toxicity.30 A recent phase II trial was suspended prematurely because 54% of patients developed bilomas after treatment with doxorubicin-loaded beads, although early radiographic response was as high as 78%.31
Arterial embolization of the beta-emitting radioactive isotope yttrium-90 (90Y) embedded in either resin microspheres (SIR-Spheres) or glass microspheres (TheraSphere) enables delivery of radiation directly to liver tumors. In a multicenter retrospective study of 148 patients with a variety of neuroendocrine tumors treated by SIR-Spheres, the objective response rate was 63% and short term toxicities were lower than with TACE. However, concerns remain regarding radiation hepatitis in patients with large volume disease.32 Additional studies suggest that 90Y radioembolization is a viable treatment option for patients refractory to systemic therapy or other liver-directed therapies.33,34
Surgical resection is considered the first-line treatment for patients with PNETs and is the only known curative modality. In a retrospective analysis of 728 patients with PNETs obtained from the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2000, median survival was 43 months. Surgical resection of the tumor was associated with significantly improved survival compared with patients who were recommended for, but did not undergo, resection (114 months vs. 35 months; p < 0.0001). This survival benefit was demonstrated for patients across all disease stages (localized, regional, and metastatic). The authors concluded that reasonable operative candidates should be considered for resection of their primary tumors.35 In cases such as those with PNET of the pancreatic head, resection of the primary is advocated to avoid local complications of biliary and gastric outlet obstruction. Surgical debulking can also reduce symptoms related to tumor burden and hormone production, although debulking remains controversial and is rarely performed by the authors.
In the setting of PNET located in the pancreatic head with synchronous liver metastases, treatment remains controversial. Liver-directed therapy may include resection, ablation, radiation, or chemo-/radioembolization. As previously discussed, treatment of the liver (with hepatic artery–directed therapy) in the setting of a biliary-enteric anastomosis carries an attendant risk of hepatic abscess. It has been shown that patient morbidity is directly related to the timing of the liver-directed therapy in that staged (liver-directed therapy after surgical resection of the primary tumor resulting in a biliary-enteric anastomosis) as opposed to simultaneous (bile is sterile at the time of combined pancreas surgery and liver-directed therapy) primary liver–directed therapy is more likely to result in liver abscess (22.2% vs. 7%; p < 0.05). Overall morbidity in a dual center series of 126 patients was quoted at 41% for staged procedures as opposed to 26% for simultaneous (p = 0.02). Recommendations from this report were to either do the liver-directed therapy first or do a combined pancreas-liver surgery.36
Medical College of Wisconsin (MCW) Algorithm
As disease presentation is so varied, our approach is usually personalized, based on the extent of disease, biopsy results assessing for Ki-67 and MGMT, and the age and medical comorbidities of the patient (anticipated tolerance of the patient to multiple therapies in combination and/or in series). Ideally, a CgA suppression test is performed as well.9
For patients with localized disease in whom surgery can be done without major (life altering) morbidity, complete resection of the pancreatic tumor is usually the first therapeutic option. This would also be true for a combined pancreas-liver resection if the pancreatic surgery (distal pancreatectomy or pancreaticoduodenectomy) and the liver resection (wedge, bisegmentectomy) were both straightforward. However, if surgical removal was assessed to be complex/difficult (multiorgan resection, large tumor, etc.), very high-risk for perioperative morbidity or mortality, or would result in significant long-term morbidity (e.g., nutritional depletion due to the need for intestinal resection and/or deinnervation of the midgut due to the extent of autonomic deinnervation), we would consider a neoadjuvant approach. If the tumor was low grade (especially if octreoscan positive, therefore expressing somatostatin receptors), we would utilize a combination of SSAs and systemic therapy in the hope of downstaging the tumor to allow for a safer and perhaps less complicated operation. If MGMT expression was low, capecitabine and temozolomide would be an obvious choice. If the patient was found to have a high Ki-67 or has shown rapid disease progression then cytotoxic chemotherapy is an obvious first choice.37 In the setting of significant symptoms secondary to a large tumor burden in the liver, which are not controllable on SSAs, we may consider chemo- or radioembolization early in the treatment algorithm. Acceleration to mTOR and VEGF inhibitors in the setting of more aggressive clinical scenarios is not uncommon.
With regard to surgery, PNETs can be enucleated if they are small and don’t communicate with the pancreatic duct. Enucleation can often be done utilizing minimally invasively techniques either through the laparoscope or utilizing the robot. If the tumor cannot be enucleated due to size or location, then principles of major pancreatic resections that we’ve previously published for pancreatic adenocarcinoma are employed.38,39 However, more commonly, PNETs tend to grow much larger and can sometimes “push” rather than invade the portal vein/superior mesenteric vein, thus the need for vascular resection/reconstruction is less common. In contrast to the management of exocrine pancreatic cancer, liver resection for synchronous or metachronous metastatic disease is often recommended for PNETs, assuming no underlying cirrhosis or extensive pretreatment. As briefly mentioned, if appropriate, a synchronous liver-pancreas operation is considered, thereby combining a less complex pancreas procedure with hepatic surgery. The assumption here being that the patient is otherwise young, healthy, and of good performance status; we would not combine a complex resection of the primary pancreatic tumor with a complex liver resection—a two-staged procedure would be utilized in such a situation.
A 52-year-old woman presented with complaints of cervical pain. Past medical history included elevated lipids and prediabetes. She was a nonsmoker and nondrinker. Family history revealed only colon cancer in her mother. MRI revealed a tumor at T2 and nuclear medicine bone scan showed uptake in T2 and her manubrium. Positron emission tomography (PET) scan was positive for 18-fluoro-deoxyglucose (FDG) activity in the liver, pancreas, sternum, T2 vertebra, and thyroid. Pre-referral biopsies were nondiagnostic in the liver and there was no evidence of malignancy in the thyroid. Subsequent sternal biopsy showed metastatic PNET. She was enrolled in RADIANT 1 trial and received everolimus and octreotide. Sixteen months later, there was a mixed response of the various liver and pancreatic lesions and she became jaundiced requiring a biliary stent. She was given capecitabine and temodar for 9 months with shrinkage of the dominant liver lesion. Laboratories at the time of referral showed a CgA of 6 (scale 0 to 5), VIP of 50.2 (range: 20 to 42), pancreastatin 404 (<135), substance P 284 (range: 0 to 240). Carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen, calcitonin, gastrin, and human pancreatic polypeptides were all within normal limits. Computed tomography scan revealed a 1-cm lesion in the pancreatic head with gland atrophy and upstream pancreatic duct dilatation, but no vascular involvement and no enlarged lymph nodes (Fig. 146-1). The dominant liver lesion emanated from the caudate lobe and encompassed the biliary and portal bifurcation (Fig. 146-2). Satellite liver lesions were noted in segments 7 and 4 (Fig. 146-3). The sternum and spine showed sclerosis and importantly, no active lesions. She underwent pylorus preserving pancreaticoduodenectomy followed by a combined, same anesthetic central hepatectomy of parts of segments 4, 1, and 8 along with wedge resections of two lesions in segment two. The gallbladder was removed, an extended lymphadenectomy completed, and a complex biliary reconstruction performed after pancreaticogastrostomy to include four biliary-enteric anastomoses (Fig. 146-4). Final pathology revealed American Joint Committee on Cancer ypT2N1(3/23)M1 PNET with perineural invasion, no vascular invasion, and all resection margins negative for tumor involvement. Her perioperative course was uneventful and repeat imaging showed a well perfused, regenerating liver and no fluid collections (Fig. 146-5A, B).
Axial CT imaging of the pancreatic head revealing an indistinct pancreatic head lesion (red arrow) and endobiliary stent (white circle). In this patient, the SMV is fully patent and the SMA has an uninvolved fat plane encircling it. CT, computed tomography; SMA, superior mesenteric artery; SMV, superior mesenteric vein.
A. Axial CT imaging of the dominant liver lesion situated anterior to the biliary and portal bifurcation as depicted by red arrows. B. Axial CT imaging of the dominant liver lesion showing its extension into the caudate lobe of the liver again depicted by the red arrows.
Axial CT imaging in the portal venous phase showing a satellite lesion in segment 7 (A) and segment 4 (B) of the liver as pointed out by red arrows.
Intraoperative photograph of the resection bed within the liver demonstrating skeletonization of the portal and hepatic arterial system. This patient required complex biliary reconstruction with four biliary-enteric anastomoses. HA, hepatic artery; LHA, left hepatic artery; LPV, left portal vein; RHA, right hepatic artery; RPV, right portal vein; SMA, superior mesenteric artery.
A. Postoperative axial CT image illustrating excellent hepatic perfusion and hepatic venous patency to the level of the IVC. The usual postoperative fluid is seen in the segment 7 and the central tumor resection bed. B. Postoperative axial CT image illustrating normal hepatic perfusion and the Roux-en-Y biliary-enteric limb sutured to segmental bile ducts. CT, computed tomography; IVC, inferior vena cava.