eMedicine Specialties > Oncology > Carcinomas of Endocrine Organs

Neoplasms of the Endocrine Pancreas: Treatment & Medication

Author: Eric J Hanly, MD, Resident, Department of Surgery, The Johns Hopkins University School of Medicine; Fellow, Department of Surgery, The Johns Hopkins University School of Medicine
Coauthor(s): Ozanan R Meireles, MD, Research Fellow in Minimally Invasive Surgery, Department of Surgery, Johns Hopkins University School of Medicine; Michael R Marohn, DO, Associate Professor, Department of Surgery and Surgical Sciences, John Hopkins University School of Medicine; Charles J Yeo, MD, Samuel D Gross Professor and Chair of Surgery at Jefferson Medical College of Thomas Jefferson University and at Thomas Jefferson University Hospital; Keith D Lillemoe, MD, Professor and Chairman, Department of Surgery, Indiana University School of Medicine; Lisa H McGrail, MD, Associate Chief, Department of Hematology/Oncology, Malcolm Grow Medical Center
Contributor Information and Disclosures

Updated: Jun 29, 2006

Treatment

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 (Macdonald, 2000). Many pancreatic endocrine tumor syndromes are potentially life-threatening upon presentation; therefore, initial medical therapy is aimed at stabilization of the patient adequate enough for a complete preoperative evaluation (Metz, 1995).

With the exception of the administration of the somatostatin analogue octreotide, of which either the original short-acting form or the newer long-acting form can be helpful in the treatment of all functional pancreatic endocrine neoplasms except somatostatinoma, the specific therapy for each syndrome depends on the action of the particular hormone product secreted (Vinik, 1989). The use of specific pharmacologic agents (including chemotherapeutic agents) in the treatment of patients with endocrine neoplasms of the pancreas is discussed in Medication. Treatments for specific syndromes may include the following:

  • 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 (Boden, 1989; Fajans, 1989).
  • The 2 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 (Yeo, 2001).
  • 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 (O'Dorisio, 1989).
  • Patients with glucagonomas generally have nutritional depletion and often require blood transfusions, total parenteral nutrition, and preoperative control of hyperglycemia (Metz, 1995).
  • 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 (Moertel, 1994). Cryosurgery is reported to ameliorate symptoms in patients with hepatic metastases that are resistant to chemotherapy (Bilchik, 1997), and the treatment of these lesions with radiofrequency ablation has also been proposed (Brentjens, 2001).

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 (Yeo, 2001).

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 (Yeo, 2001). Surgical management of the primary tumor is similar for the different types of pancreatic endocrine neoplasms. Surgical treatments may include the following:

  • Small benign lesions remote from the main pancreatic duct can be enucleated (Menegaux, 1993; Yeo, 2001).
  • 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.
  • Tumors in the body or tail of the pancreas can be managed with distal pancreatectomy (Lillemoe, 1999).
  • Lesions in the head or uncinate process of the pancreas can be resected with pancreaticoduodenectomy (Phan, 1997; Udelsman, 1993).
  • 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.
  • 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 duodenal microgastrinomas (Sugg, 1993). Then, the localized microgastrinomas can be resected and the duodenal defect closed (Farley, 1994).
  • Rather than performing a blind regional pancreatectomy for an occult insulinoma or gastrinoma, selective provocative angiography (see Other Tests) should be performed so that the appropriate pancreatic segment can be resected, eg, distal pancreatectomy versus pancreaticoduodenectomy (Thompson, 1993).
  • Metastatic disease to the liver should be resected when possible. If facing unresectable disease, radiofrequency or cryosurgical ablation should be considered.
  • 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 (Gibril, 1995).

Consultations

  • Endocrinologist
  • Gastroenterologist
  • Pancreatic or oncologic surgeon
  • Medical oncologist

Diet

Patients with unresectable insulinoma may have some symptomatic relief by eating frequent small meals with a high starch and complex carbohydrate content (Fajans, 1989). In contrast to the symptoms of routine dyspepsia, diet modification rarely ameliorates the symptoms or complications of gastrinoma-associated hyperchlorhydria. Patients with VIPomas, glucagonomas, and somatostatinomas frequently have fluid, electrolyte, and nutritional deficits, and they often require parenteral supplementation (Metz, 1995).

Activity

Exercise often exacerbates the symptoms of insulinoma syndrome secondary to relative substrate deficiency such as hypoglycemia (Stefanini, 1974). Therefore, patients with insulinoma may need to avoid exercise until their tumor is successfully resected.

Medication

The goals of palliative medical therapy for pancreatic endocrine neoplasms are (1) the reduction of symptoms related to hormonal excess and (2) the control of tumor cell proliferation.

Recently, studies from a group in Sweden demonstrated that the combination of alpha-interferon and somatostatin analogs for the treatment of patients with advanced malignant endocrine pancreatic tumors resulted in radiological response in 3 (19%) of 16 patients (median duration, 23 mo) and biochemical response in 10 (62.5%) of 16 (median duration, 22 mo) (Fjallskog, 2002).

Antisecretory agents

Used to modulate the release of gastroenteropancreatic hormones from both normal and neoplastic APUD cells in the treatment of pancreatic endocrine tumor syndromes to reduce specific symptoms related to hormonal excess.


Octreotide (Sandostatin)

Somatostatin analogue that binds somatostatin receptors on pancreatic endocrine tumor cells and inhibits release of many gastroenteropancreatic hormones.
Useful adjunct in palliative treatment of patients with most functional metastatic pancreatic endocrine tumors. Evidence suggests that it may also have antiproliferative effects in rare cases. However, symptomatic and antiproliferative effects last only months and are probably of short duration secondary to down-regulation of cell-surface somatostatin receptors (Maton, 1989). Because octreotide is a somatostatin agonist, it is not useful in the treatment of patients with somatostatinoma syndrome (Pless, 1986). Doses of 300-600 mcg/d or higher seldom result in additional biochemical benefit.

Adult

50 mcg SC tid initially; may increase to 500 mcg tid

Pediatric

Not established

May reduce effects of cyclosporine

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Adverse effects are primarily related to altered GI tract motility and include nausea, abdominal pain, diarrhea, and increased incidence of gallstones and biliary sludge; hypoglycemia or hyperglycemia possible (due to alteration in counter-regulatory hormones [eg, insulin, glucagon, GH]); bradycardia, cardiac conduction abnormalities, and arrhythmias; hypothyroidism (due to inhibition of TSH secretion) caution in renal impairment; cholelithiasis; patients receiving insulin, oral hypoglycemics, beta-blockers, or calcium channel blockers may require dose adjustments

Immunotherapeutics

Used to modulate host immune responses to neoplastic cells. Control of tumor cell proliferation is the goal when these agents are used to treat patients with pancreatic endocrine tumor syndromes.


Interferon alfa-2a (Roferon-A) and alfa-2b (Intron A)

Protein product manufactured by using recombinant DNA technology.
Pancreatic endocrine tumor patients treated with human leukocyte interferon have objective response rates of 77%, with effects lasting > 1 year in some cases.
Responses represent primarily decreased hormone production rather than objective reduction in tumor bulk (Oberg, 1989). Mechanisms of hormone reduction and antitumor activity are not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response likely have important roles.

Adult

2 million U/m2 SC 3 times/wk for 30 d

Pediatric

Not established

Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in brain metastases, severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, and compromised CNS

Chemotherapeutics

Primarily reserved for patients with pancreatic endocrine neoplasms that are metastatic and/or unresectable.

While most experts agree that chemotherapy is indicated in patients who have symptoms from tumor bulk or uncontrolled syndromes of hormone excess that cannot be palliated with other means (eg, cytoreductive surgery, cryosurgery, radiofrequency ablation, hepatic artery embolization), no consensus exists on when therapy should be started in asymptomatic patients with metastatic or recurrent disease. One common practice is to reassess patients at 3- to 6-month intervals after diagnosis of metastatic or recurrent disease. Patients with clear tumoral progression are treated with chemotherapy, whereas those with stable lesions are monitored. No benefit from chemotherapy has been demonstrated in patients with metastases to only lymph nodes.

Studies of patients with advanced islet cell carcinomas in which streptozocin alone was compared with streptozocin plus 5-fluorouracil (5-FU) have overall response rates as high as 63%, and survival rates increased by as much as 1 year with combination therapy, although single-agent therapies have generally yielded lower response rates (Moertel, 1980). A study of streptozocin plus doxorubicin compared with streptozocin plus 5-FU revealed a better response rate of 69% and an increased survival rate for patients treated with streptozocin plus doxorubicin (Moertel, 1992). In a study of patients with all types of GI neuroendocrine tumors, streptozocin was found to be more effective in patients with islet cell tumors than in those with carcinoid tumors (Moertel, 1994). However, a small study of patients with islet cell carcinomas treated with the combination of streptozocin, doxorubicin, and 5-FU had a response rate of only 54% and no complete responses (Rivera, 1998).

A number of other chemotherapeutic drugs, such as the taxanes, platinum compounds, gemcitabine, camptothecin analogues, targeted receptor antagonists, and antiangiogenesis/antiendothelial agents, have demonstrated activity against pancreatic endocrine tumors, but none has been adequately evaluated in these neoplasms or has demonstrated results as good as those of various combinations of streptozocin, doxorubicin, and 5-FU (Macdonald, 2000).


Streptozocin (Zanosar)

Has diabetogenic action in some animals that is correlated with selective uptake of the drug by pancreatic beta cells (Schein, 1973). As a result, streptozocin is uniquely helpful in the treatment of insulinoma. Also inhibits cell proliferation and is cytolytic. Interferes with normal DNA function by means of alkylation and protein modification.

Adult

1-1.5 g/m2 IV qwk for 6 wk, followed by 4-wk observation period

Pediatric

Administer as in adults

Aminoglycosides, loop diuretics, and doxorubicin may increase nephrotoxicity; phenytoin may decrease effects

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Severe nausea and vomiting common; liver dysfunction and myelosuppression can occur; renal toxicity is dose-related and cumulative; closely monitor renal, hepatic, and hematologic function


Doxorubicin (Adriamycin, Rubex)

Inhibits topoisomerase II and produces free radicals that may destroy DNA. Combination of these events can inhibit growth of neoplastic cells.

Adult

60-75 mg/m2 IV as a single dose; repeat q21d
Alternatively, 20-30 mg/m2/d IV for 2-3 d; repeat in 4 wk

Pediatric

35-75 mg/m2 IV as a single dose; repeat q21d
Alternatively, 20-30 mg/m2 qwk

May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity

Documented hypersensitivity; severe heart failure, cardiomyopathy, and impaired cardiac function; preexisting myelosuppression

Pregnancy

D - Unsafe in pregnancy

Precautions

Irreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose in impaired hepatic function


Fluorouracil (Adrucil)

Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase and interferes with RNA synthesis and function. Has some effect on DNA.

Adult

15 mg/kg/d IV continuous infusion (24 h) for 5 consecutive d

Pediatric

Not established

Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, and thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents

Documented hypersensitivity; bone marrow suppression; serious infection

Pregnancy

D - Unsafe in pregnancy

Precautions

Nausea, oral and GI tract ulcers, immune system depression, and bone marrow suppression may occur; adjust dose in renal impairment

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Multimedia: Neoplasms of the Endocrine Pancreas
References
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Further Reading

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Keywords

pancreatic cancer, pancreas cancer, pancreatic neoplasm, pancreas neoplasm, pancreatic islet cell tumor, pancreatic islet cell adenoma, pancreatic endocrine tumor, pancreatic neuroendocrine tumor, insulinoma syndrome, insulinoma, Zollinger-Ellison syndrome, ZES, gastrinoma syndrome, gastrinoma, Verner-Morrison syndrome, WDHA syndrome, watery diarrhea, hypokalemia, achlorhydria, pancreatic cholera, vasoactive intestinal peptide-releasing tumor, VIPoma, glucagonoma syndrome, somatostatinoma syndrome, calcitoninoma, parathyrinoma, growth hormone releasing facto-secreting tumor, GRFoma, adrenocorticotropin hormone-secreting tumor, ACTHoma, neurotensinoma, pancreatic endocrine neoplasm, pancreatic polypeptidomas, PPomas, islet cell tumor, pancreatic cholera, MEN 1 syndrome, MEN-I syndrome, MEN-1 syndrome, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type I, MEN syndrome, APUDomas

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Contributor Information and Disclosures

Author

Eric J Hanly, MD, Resident, Department of Surgery, The Johns Hopkins University School of Medicine; Fellow, Department of Surgery, The Johns Hopkins University School of Medicine
Eric J Hanly, MD is a member of the following medical societies: American Medical Association, Association of Military Surgeons of the US, MedChi, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Coauthor(s)

Ozanan R Meireles, MD, Research Fellow in Minimally Invasive Surgery, Department of Surgery, Johns Hopkins University School of Medicine
Ozanan R Meireles, MD is a member of the following medical societies: American College of Surgeons and Society of American Gastrointestinal and Endoscopic Surgeons
Disclosure: Nothing to disclose.

Michael R Marohn, DO, Associate Professor, Department of Surgery and Surgical Sciences, John Hopkins University School of Medicine
Disclosure: Nothing to disclose.

Charles J Yeo, MD, Samuel D Gross Professor and Chair of Surgery at Jefferson Medical College of Thomas Jefferson University and at Thomas Jefferson University Hospital
Charles J Yeo, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Endocrine Surgeons, American College of Surgeons, American Gastroenterological Association, American Hepato-Pancreato-Biliary Association, American Surgical Association, Association for Academic Surgery, Johns Hopkins Medical and Surgical Association, Pancreas Club, Phi Beta Kappa, Sigma Xi, Society for Surgery of the Alimentary Tract, and Society of University Surgeons
Disclosure: Nothing to disclose.

Keith D Lillemoe, MD, Professor and Chairman, Department of Surgery, Indiana University School of Medicine
Disclosure: Nothing to disclose.

Lisa H McGrail, MD, Associate Chief, Department of Hematology/Oncology, Malcolm Grow Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Michael C Perry, MD, Professor, Department of Internal Medicine, Nellie B Smith Chair of Oncology, Director, Division of Hematology and Oncology, University of Missouri at Columbia/Ellis Fischel Cancer Center
Michael C Perry, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Missouri State Medical Association, Southern Association for Oncology, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center
Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, American Society for Therapeutic Radiology and Oncology, and American Society of Clinical Oncology
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

John S Macdonald, MD, Professor of Medicine, New York Medical College; Chief, Division of Medical Oncology, St Vincent's Hospital and Medical Center; Medical Director, Saint Vincent's Comprehensive Cancer Center
Disclosure: Nothing to disclose.

 
 
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