Therapies for Progressive Pancreatic Neuroendocrine Tumors

Introduction:

Neuroendocrine tumors can develop in different organs. The one which arises in the pancreas is called a pancreatic neuroendocrine tumor. Surgical tumor removal is the treatment option for these cancers. In addition, medical therapy is advised in patients with advanced or progressive pancreatic neuroendocrine tumors. This additional medical therapy is used to control tumor growth and reduce symptoms.

What Are Pancreatic Neuroendocrine Tumors?

Cancers in the islet cells or hormone-producing cells of the pancreas are called pancreatic neuroendocrine tumors. They are also called islet cell cancers. The tumor cells secrete excess amounts of hormones resulting in too many hormones accumulating in the body, and are called functional tumors. However, some pancreatic neuroendocrine tumor cells do not secrete excess hormones and are called non-functional hormones.

What Are the Indicators of Pancreatic Neuroendocrine Tumors?

The symptoms of pancreatic neuroendocrine tumors include:

• Ulceration in the stomach.

• Heartburn.

• Less blood sugar level.

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• Tiredness.

• Muscle cramps.

• Diarrhea or constipation because of indigestion.

• Abdominal pain.

• Jaundice (yellow discoloration of skin and sclera of the eye).

What Are the Causes of Pancreatic Neuroendocrine Tumors?

The main cause of pancreatic neuroendocrine tumors is not clear.

• When the islet or hormone-producing cell in the pancreas develops changes or mutations in DNA (deoxyribonucleic acid), abnormal growth and cell division results in pancreatic neuroendocrine tumors. In some cases, the tumor can metastasize (spread) to other organs and parts of the body.

• Certain inherited diseases can increase the risk of getting pancreatic neuroendocrine tumors. For example, Von Hippel-Lindau disease (a genetic condition with the presence of tumors in different body parts including the pancreas), Von Recklinghausen’s disease (also called neurofibromatosis 1) developing tumors in the nerves), tuberous sclerosis (non-cancerous tumors incurring in different parts of the body), or type 1 multiple endocrine neoplasias (tumors of endocrine glands).

How Are Pancreatic Endocrine Tumors Diagnosed?

The initial diagnosis is assessing the signs and symptoms if present. Next, the patient’s past medical and family history is considered. Then, clinical evaluation by various tests, including CT (computed tomography uses a combination of x-rays and computer technology to produce cross-sectional slices of the pancreas), MRI (magnetic resonance imaging) produces a detailed view of the pancreas by using a strong magnetic field), PET (positron emission tomography) uses radioactive drugs to differentiate any abnormal activities), and blood tests and biochemical tests are performed. Sometimes a biopsy is also taken into consideration.

What Are the Treatment Options for Pancreatic Endocrine Tumors?

The treatment strategies include:

1. Surgical Treatment:

Surgery is the option to cure pancreatic neuroendocrine tumors completely.

• Most pancreatic tumors are surgically removed. In a few cases, surgical resection is ruled out due to high surgical risk or if the tumor has metastasized to various body parts.

• Removing the primary tumor along with the lymph nodes is primary resection.

• Enucleation is the scooping of the tumor with a thin margin, usually done in small pancreatic neuroendocrine tumors. Distal pancreatectomy involves the removal of the pancreatic body and tail. Pancreaticoduodenectomy is the surgical removal of the pancreatic head, a portion of the stomach that is the duodenum. Total pancreatectomy removes the complete pancreas, the gallbladder, and the common bile duct.

• In the case of advanced diseases, the resection type depends upon the tumor’s extent. When a tumor is metastasized to other organs, resection of the other organs is also considered. For example, partial hepatectomy is considered along with pancreatectomy in the case of liver metastasis.

2. Medical Therapy:

Medical treatment is required to control excess hormone production, reduce symptoms, and decrease cancer growth in patients who do not undergo surgical resection due to cancer metastasis or advanced or recurrent pancreatic neuroendocrine tumors.

Symptoms Directed Therapy -

• If the functional pancreatic neuroendocrine tumor is unresectable, then hormone control should be done because the increase in the production of hormones can cause various illnesses and result in death. Somatostatin is a hormone that will help in reducing the secretion of various other hormones like growth hormones. Various somatostatin analogs are used to reduce symptoms of pancreatic neuroendocrine functional tumors.

• The pancreatic neuroendocrine tumor associated with gastrin secretion resulting in severe peptic ulcers is called gastrinoma. Gastrinoma associated with hypersecretion of gastric acids is treated with high proton pump inhibitors. Omeprazole (60 milligrams), Rabeprazole (60 milligrams), Esomeprazole (120 milligrams), Pantoprazole (120 milligrams), or Lansoprazole (45 milligrams) daily. Hydrogen receptor blockers can also be used.

• A pancreatic neuroendocrine tumor associated with extra insulin production is called insulinoma. It can cause low blood sugar levels leading to sweating, confusion, and weakness. It can be controlled by nutritional supplements, frequent small meals, and decreasing insulin secretion with the help of Diazoxide.

• A pancreatic neuroendocrine tumor associated with excess production of the hormone glucagon is called glucagonoma. Parenteral or intravenous supplements of nutrients and vitamins are considered. There is an increased chance of thromboembolism, so anticoagulants are administered.

• Vasoactive intestinal peptide (VIP) tumors produce more vasoactive intestinal peptide hormone. It causes increased secretion from the intestine and relaxation of some muscles in the gastrointestinal system. Somatostatin analogs are used to control glucose and hydration.

• In somatostatinoma, there may be excess secretion of somatostatin. This is a rare pancreatic neuroendocrine tumor. Parenteral supplementation of nutrients, hydration, and medications to reduce diabetes. Pancreatic enzyme supplements are used to reduce diarrhea.

Controlling Growth of the Tumor - There are three medical therapy groups for tumor growth control. They are:

• Somatostatin Analogues - A peptide that reduces the secretion of several hormones. Octreotide and Lanreotide are examples of somatostatin analogs.

• Molecular Targeted Therapy - Everolimus and Sunitinib will improve the survival rates in people with advanced pancreatic neuroendocrine tumors. Everolimus is a Rapamycin inhibitor used commonly as a second-line treatment in progressive pancreatic neuroendocrine cancer. Hyperglycemia is an adverse effect associated with Everolimus which can be added as an advantage in patients with refractory hypoglycemia and insulinoma. Sunitinib is a tyrosine kinase inhibitor used to treat progressive pancreatic neuroendocrine tumors. Increased blood pressure, renal toxicity, hepatotoxicity, and hand-foot skin reaction are common adverse effects of Sunitinib. Multi-targeted kinase inhibitors like Axitinib, Sorafenib, Pazopanib, and a combination of Temsirolimus and Bevacizumab are also used to treat progressive pancreatic neuroendocrine tumors.

• Cytotoxic Chemotherapy - Streptozocin-based chemotherapy like Dacarbazine, a combination of Streptozocin and Doxorubicin, and Bevacizumab with Streptozocin, Temozolomide-based chemotherapy like the combination with Bevacizumab and Capecitabine and platinum-based chemotherapy like the combination with Cisplatin and Etoposide, is used in the treatment of progressive pancreatic neuroendocrine tumors.

3. Radiation Therapy -

• External Beam Radiotherapy (EBRT) - Use of an external source of radiation to kill the cancerous cells.

• Peptide Receptor Radionuclide Therapy (PRRT) - Use targeted radiation to somatostatin receptors that cause tumor shrinkage.

Conclusion:

Pancreatic neuroendocrine tumors are rarer than exocrine tumors. It can be seen more in males than in females. It is most commonly associated with an inherited gene or syndrome. Non-functional pancreatic tumors are more common than functional pancreatic tumors. In progressive pancreatic neuroendocrine tumors, the first line of treatment in medical therapy is by somatostatin analogs. Everolimus and Sunitinib are considered the second line of treatment.