Medical Care
Treatment must be individualized in patients with a neoplasm of the endocrine pancreas, in order to balance management of the effects of hormone production with management of the symptoms related to the bulk of the tumor. [82] Many pancreatic endocrine tumor syndromes are potentially life-threatening upon presentation; therefore, initial medical therapy is aimed at stabilizing the patient sufficiently to permit a complete preoperative evaluation. [17]
The only effective medication for functional pancreatic endocrine neoplasms in general is a long-acting somatostatin analog (eg, octreotide). Somatostatin analog treatment can improve symptoms and quality of life in all the functional pancreatic endocrine neoplasms except somatostatinoma. [83]
Although octreotide-long-acting repeatable (LAR) is approved for use at doses of up to 30 mg every 4 weeks, a systematic review by Broder et al found multiple studies in which expert clinical opinion supported dose escalation to up to 60 mg monthly for symptom control in patients with neuroendocrine tumors and suggested that higher doses may be effective at preventing tumor progression. [84]
Al-Efraij et al reported that dose escalation of octreotide-LAR was associated with improved symptom control in neuroendocrine tumor patients whose symptoms were refractory to standard doses. However, they found that levels of the tumor markers chromogranin A (CGA) and 24-hour urinary 5-hydoxyindoacetate (5-HIAA) showed variable response to octreotide-LAR dose escalation, so measurement of those biomarkers may not provide an accurate assessment of therapeutic efficacy. [85]
Aside from somatostatin analog therapy, the specific treatment for each syndrome depends on the action of the particular hormone product secreted. [86] The use of specific pharmacologic agents (including chemotherapeutic agents) in the treatment of patients with endocrine neoplasms of the pancreas is discussed in Medication.
Lutetium Lu 177-dota-tate (Lu 177), the first peptide receptor radionuclide therapy (PRRT), was approved by the US Food and Drug Administration (FDA) in 2018. Approval was based on the NETTER-1 clinical trial, a single-institution, single-arm, open-label trial in more than 1,200 patients with somatostatin receptor–positive tumors. Results showed a 79% reduction in risk of disease progression or death in the Lu 177 arm compared with octreotide LAR 60 mg arm (95% CI: 0.13-0.32; p< 0.0001). Median progression-free survival (PFS) was not reached in the Lu 177 arm, compared with 8.5 months for octreotide LAR. An interim overall survival analysis determined that Lu 177 treatment led to a 48% reduction in the estimated risk of death (hazard ratio 0.52, 95% confidence interval [CI]: 0.32-0.84) compared with octreotide LAR. [87]
Chenk et al reported that therapy with long-acting somatostatin analogs decreases radioiosotope uptake in the thyroid, spleen, and liver on radiolabeled octreotide scintigraphy, but in most cases increases intensity of uptake within metastases. These authors suggest that pretreatment with somatostatin analogs before performing PRRT may enable delivery of higher doses to tumor while decreasing the dose to normal tissues. [88]
A study by Yao et al found that everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), significantly prolonged progression-free survival in parents with progressive advanced pancreatic neuroendocrine tumors when compared with placebo. It was associated with a low rate of severe adverse affects. [89]
A study by Raymond et al found that continuous daily administration of the multikinase inhibitor sunitinib (37.5 mg) improved PFS, overall survival, and objective response rate in patients with advanced pancreatic neuroendocrine tumors, compared with placebo. [90]
A retrospective chart review by Anthony et al looked at patients with pancreatic neuroendocrine tumors with and without carcinoid syndrome and their response to treatment with octreotide LAR. [91] Approximately 57% of patients demonstrated stable disease on octreotide LAR (dose range, 20-60 mg). Although this is a cancer not frequently seen in general endocrinology practice, its management with octreotide LAR is a helpful finding.
In a phase II study of 58 patients with well or moderately differentiated pancreatic neuroendocrine tumors, the response rate to combination treatment with the mTOR inhibitor temsirolimus and the vascular endothelial growth factor (VEGF)-A monoclonal antibody bevacizumab was 41%. At 6 months, the PFS rate was 79%. Median PFS was 13.2 months, and median overall survival was 34 months. The most common treatment-related adverse events were hypertension, fatigue, lymphopenia, and hyperglycemia. [92]
Combination treatment with bevacizumab and streptozocin plus 5-fluorouracil (5-FU) in an open-label study of 34 patients with progressive, metastatic, well-differentiated pancreatic neuroendocrine tumors resulted in median PFS of 23.7 months after a maximum of 24 months of follow-up. A partial response was seen in 19 (56%) patients, and 15 (44%) patients had stable disease. Overall survival at 24 months was 88%. The most common adverse events were hypertension, abdominal pain, and thromboembolism. [93]
Treatments for specific syndromes may include the following:
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Insulinoma - Upon initial presentation, patients with insulinoma may require immediate potassium replacement and dextrose administration. Hypoglycemia can often be managed in the preoperative period by administering diazoxide, which inhibits insulin release from both normal beta cells and insulinoma cells. [94, 31]
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Gastrinoma - The two main goals in the initial treatment of a patient with a gastrinoma are (1) to stabilize the general hemodynamic condition of the patient and control bleeding from gastrointestinal ulcers and (2) to establish a nonacidic gastric pH with the use of proton pump inhibitors (eg, omeprazole). [12]
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VIPoma - The primary initial concern in the treatment of a patient who presents first with VIPoma-associated diarrhea is the replacement of volume losses and the correction of acid-base and electrolyte abnormalities. [43]
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Glucagonoma - Patients with glucagonomas generally have nutritional depletion and often require blood transfusions, total parenteral nutrition, and preoperative control of hyperglycemia. [17]
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Somatostatinoma - Nutritional repletion and control of hyperglycemia are important aspects of good medical care in patients with somatostatinoma syndrome.
Extralymphatic metastatic spread of pancreatic endocrine neoplasms primarily involves the liver. Therefore, cytoreductive techniques that lower serum levels of the offending gastroenteropancreatic hormone by decreasing hepatic tumor bulk often improve the patient's quality of life. Similar to surgical resection of hepatic metastases (discussed below), hepatic arterial embolization with or without chemotherapy yields impressive results in terms of tumor, hormone, and symptom regression. [95] Cryosurgery is reported to ameliorate symptoms in patients with hepatic metastases that are resistant to chemotherapy, [96] and the successful treatment of these lesions with radiofrequency ablation has also been reported. [97]
Practice guidelines from the National Comprehensive Cancer Network recommend that patients being considered for surgery with possible splenectomy (eg, for treatment of glucagonoma) receive trivalent vaccine (ie, pneumococcus, Haemophilus influenzae type b, and meningococcus group C). [57]
Surgical Care
At the time of surgical exploration for pancreatic endocrine neoplasms, the pancreas and peripancreatic regions are completely evaluated. Dividing the gastrocolic ligament exposes the body and tail of the pancreas. This portion of the pancreas can be partially elevated out of the retroperitoneum by dividing the inferior retroperitoneal attachments to the gland. After the second portion of the duodenum is elevated out of the retroperitoneum by means of the Kocher maneuver, the pancreatic head and uncinate process are palpated bimanually. The liver is carefully assessed for evidence of metastatic disease. Potential extrapancreatic sites of tumoral involvement are evaluated in all cases, with particular attention to the duodenum; splenic hilum; small intestine and its mesentery; peripancreatic lymph nodes; and, in women, the reproductive tract. [12]
The goals of surgical therapy for pancreatic endocrine neoplasms include (1) controlling the symptoms of hormone excess, (2) safely resecting the maximal amount of tumor mass possible, and (3) preserving the maximal amount of pancreatic parenchyma possible. [12] Surgical management of the primary tumor is similar for the different types of pancreatic endocrine neoplasms. Surgical treatments may include the following:
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Tumors deep in the substance of the pancreatic gland, and therefore close to the main duct, have ill-defined capsules, and tumors larger than 2 cm in diameter should be treated with regional pancreatectomy.
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Tumors in the body or tail of the pancreas can be managed with distal pancreatectomy. [98]
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Tumors in the neck of the pancreas can now be managed with middle-segment pancreatectomy by oversewing the proximal pancreatic stump and draining the distal pancreatic duct via a pancreaticogastrostomy or pancreaticojejunostomy.
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When a preoperatively occult gastrinoma is not found during surgical exploration, despite the use of intraoperative ultrasonography and endoscopic transduodenal illumination, longitudinal duodenotomy can be performed at the level of the second portion of the duodenum to allow eversion of the duodenum to assess for duodenal microgastrinomas. [101] Then, the localized microgastrinomas can be resected and the duodenal defect closed. [102]
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Rather than performing a blind regional pancreatectomy for an occult insulinoma or gastrinoma, selective provocative angiography (see Workup/Imaging Studies) should be performed so that the appropriate pancreatic segment can be resected, eg, distal pancreatectomy versus pancreaticoduodenectomy. [28]
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In the past, most patients with metastatic neoplasms of the endocrine pancreas died of the hormone-excess states, but with the development of increasingly effective medical therapies to control this pathophysiologic condition (ie, proton pump inhibitors for gastrinomas; octreotide for other endocrine tumors), the major determinant of long-term patient survival is becoming the malignant nature of the tumors. For this reason, hepatic metastases are debulked with cytoreductive surgical resection. However, most surgeons believe that this aggressive approach should be reserved for patients in whom near 100% tumor removal can be achieved with reasonable safety. [105]
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In a study of survival data of 882 patients with metastatic nonfunctioning pancreatic neuroendocrine tumors (NFpNET), resection of the site of the primary NFpNET was associated with greater survival of 65 (95% confidence interval 60-86) versus 10 (8-12) months for those without resection (P < 0.0001). [106]
Consultations
See the list below:
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Endocrinologist
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Gastroenterologist
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Pancreatic or oncologic surgeon
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Medical oncologist
Diet and Exercise
Dietary considerations in patients with functional endocrine pancreas neoplasms include the following:
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Patients with unresectable insulinoma may gain some symptomatic relief by eating frequent small meals with a high starch and complex carbohydrate content. [31]
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In contrast to the symptoms of routine dyspepsia, diet modification rarely ameliorates the symptoms or complications of gastrinoma-associated hyperchlorhydria.
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Patients with VIPomas, glucagonomas, and somatostatinomas frequently have fluid, electrolyte, and nutritional deficits, and they often require parenteral supplementation. [17]
Exercise often exacerbates the symptoms of insulinoma syndrome secondary to relative substrate deficiency such as hypoglycemia. [107] Therefore, patients with insulinoma may need to avoid exercise until their tumor is successfully resected.
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Neoplasms of the endocrine pancreas. CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (Yeo, 1993).
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Celiac axis angiography illustrating neoplasms of the endocrine pancreas. Contrast is seen opacifying the common hepatic artery (CHA) and splenic artery (SA). The superior pancreatic artery (arrow) is seen as an early U-shaped branch of the splenic artery.
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Highly selective distal angiography illustrating neoplasms of the endocrine pancreas. With the arterial catheter now advanced into the superior pancreatic artery, the contrast blush of this vascular tumor is easily seen (arrows).
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Neoplasms of the endocrine pancreas. Intravenous and oral contrast-enhanced CT scan image in a patient with chronic diarrhea and elevated levels of serum vasoactive intestinal peptide. In the venous phase of this scan, the splenic vein (SV) is clearly seen draining the 5-cm tumor (T) located anteromedial to the spleen (S) in the tail of the pancreas.
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Neoplasms of the endocrine pancreas. Schematic diagram of provocative angiography. Access to the central venous and arterial systems is obtained through cannulation of a femoral vein and a femoral artery. In the selective arterial secretin stimulation test, secretin is injected selectively into the splenic, gastroduodenal (a branch of the common hepatic), and inferior pancreaticoduodenal (a branch of the superior mesenteric) arteries with concomitant and subsequent hepatic venous sampling for gastrin. Based on the level of gastrin in each hepatic venous sample, the location of the gastrinoma is arterially mapped. An analogous method can be used in the selective arterial calcium stimulation test to determine the location of occult insulinomas that respond to calcium stimulation by secreting insulin.
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Neoplasms of the endocrine pancreas. Graphic depiction of the results of a selective arterial secretin stimulation test in a patient with an occult gastrinoma. The gastrin gradient (the rise in hepatic vein gastrin concentration divided by the basal value) is plotted over time. An increase in gastrin gradient from 0 to 2 thus represents a 200% rise compared to the basal level. A significant rise in hepatic vein gastrin concentration is observed both after the injection of secretin into the superior mesenteric artery (SMA) and after secretin injection into the gastroduodenal artery (GDA), but no such increase occurs following secretin injection into the splenic artery (SPL). This patient's neoplasm is thus localized to the head of the pancreas or the duodenum
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Neoplasms of the endocrine pancreas. Octreotide scan (anterior view) in a patient with a pancreatic endocrine tumor. The large pancreatic-tail neoplasm is seen retaining tracer in the patient's left upper quadrant. Several tracer-enhancing hepatic metastases are seen in the patient's right upper quadrant and epigastrium. Tracer is also seen in the bladder following renal excretion (round density in the hypogastrium) (Yeo, 2001).
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Neoplasms of the endocrine pancreas. CT scan with oral and intravenous contrast in a patient with a glucagon-secreting neoplasm. This 10-cm contrast-enhancing tumor (T) is seen obliterating the normal appearance of the tail of the pancreas (Yeo, 2001).
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Neoplasms of the endocrine pancreas. Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV) (Rosch, 1992).
