Understanding Your Condition

Pancreas

The pancreas is an organ that sits in the upper part of the abdomen, behind the stomach and the colon.  It has two main functions.  The first job of the pancreas is to make insulin which helps control the body’s sugars.  This is called the “endocrine” function.  The second job of the pancreas, called the “exocrine” function, is to make enzymes (substances) which help with digestion.

Overview of Pancreas Cancer

Cancer occurs in the pancreas when the cells that make up the organ grow out of control.  The cancer can then spread to surrounding lymph nodes (small defense organs we have around the body) and to other organs such as the liver, lung and lining of the abdominal cavity.

Pancreas cancer can be divided into two main categories.  Cancers of the exocrine pancreas make up over 90% of all types.  These are called adenocarcinomas. Cancers of the endocrine portion are called neuroendocrine tumors.  Adenocarcinoma and neuroendocrine cancers have very different characteristics and treatments, so it is very important to understand the exact diagnosis.

Worldwide, there will be nearly 500,000 people diagnosed with pancreas cancer this year, with approximately 430,000 deaths. In the United States, this translates to over 55,000 people diagnosed with pancreas cancer in 2019 and about 45,000 people will die of pancreas cancer over this same time.

Types of Pancreas Cancer

The pancreas is an organ that sits in the upper part of the abdomen, behind the stomach and the colon.  It has two main functions.  The first job of the pancreas is to make insulin which helps control the body’s sugars.  This is called the “endocrine” function.  The second job of the pancreas, called the “exocrine” function, is to make enzymes (substances) which help with digestion.

Cancer occurs in the pancreas when the cells that make up the organ grow out of control.  The cancer can then spread to surrounding lymph nodes (small defense organs we have around the body) and to other organs such as the liver, lung and lining of the abdominal cavity.

Pancreas cancer can be divided into two main categories.  Cancers of the exocrine pancreas are called adenocarcinomas. Cancers of the endocrine portion are called neuroendocrine tumors.  Adenocarcinoma and neuroendocrine cancers have very different characteristics and treatments, so it is very important to understand the exact diagnosis.

Worldwide, there will be nearly 500,000 people diagnosed with pancreas cancer this year, with approximately 430,000 deaths. In the United States, this translates to over 55,000 people diagnosed with pancreas cancer in 2019 and about 45,000 people will die of pancreas cancer over this same time.

Neuroendocrine Tumors of the pancreas are rare, accounting for only 1% of new pancreatic cancers per year and 10% of all patients living with pancreatic cancer at a given time. While most patients diagnosed with pancreatic neuroendocrine tumors are between 40 to 69 years of age, some can even be younger than 35 years. Men are 1.4 times more likely to get these tumors compared to women. Some pancreatic neuroendocrine tumors make hormones that produce hormonal symptoms (called functional tumors). However, the majority (40-91%) do not produce hormones and are called non-functional tumors. Rarely, pancreatic neuroendocrine tumors run in families and are linked to a genetic syndrome called Multiple Endocrine Neoplasia Type 1 syndrome.

Adenocarcinoma of the pancreas make up more than 90% of all pancreatic cancers and cause most pancreatic cancer-related deaths. The occurrence of pancreatic adenocarcinomas is slowly increasing. Unfortunately, these are more aggressive than the Neuroendocrine Tumors. They are equally common in males and females. African Americans have a higher chance of getting pancreatic adenocarcinomas.

Risks & Symptoms | Why do I get Pancreas Cancer?

Most of the time pancreatic adenocarcinoma occurs without any family history. However, approximately 5.5% of individuals with pancreatic cancer carry a genetic mutation in their germline DNA that is linked to pancreatic cancer. Some risk factors for getting pancreatic adenocarcinoma are as follows:

  • Obesity (Increased body mass index)
  • Chronic pancreatitis (Inflammation of the pancreas)
  • Diabetes or pre-diabetes
  • Familial pancreatic cancer syndrome (e.g. familial pancreatitis, Peutz-Jeghers syndrome, melanoma-pancreatic cancer syndrome, Lynch syndrome, familial BRCA1/2 mutation, familial Fanconi anemia pathway alterations, familial ATM mutations, Multiple endocrine neoplasia type 1)
  • Pre-cancerous lesions of the pancreas (e.g. mucinous cystic neoplasms or intraductal papillary mucinous neoplasms)

Pancreatic cancer at early stages can be without symptoms and warning signs. However, symptoms can include weight loss, jaundice, floating stools, pain, dyspepsia, nausea, vomiting, and occasionally pancreatitis. Sudden onset of diabetes in individuals older than 50 years has been linked to pancreatic cancer. In addition, if individuals with pre-existing diabetes develop ongoing unintentional weight loss, jaundice or abdominal pain, they should be further evaluated to rule out pancreatic cancer. Functional pancreatic neuroendocrine tumors in addition, can lead to hormonal symptoms. These symptoms depend on the type of hormone being over-produced by these tumors and are listed as follows:

  • Insulin (Low blood sugar, sweating, passing out, palpitations)
  • Glucagon (Flushing, diarrhea, high blood sugar, skin rash, blood clots)
  • Gastrin (Stomach ulcers, Intestinal ulcers, diarrhea)
  • Vasoactive Intestinal Polypeptide (Watery diarrhea, Low potassium)
  • Somatostatin (High blood sugar, diarrhea, floating stools)
Diagnosis

Diagnosis | Overview

Symptoms linked to pancreatic cancer are often not unique to pancreatic cancer. These symptoms can be found in other disease processes as well. Therefore, a high index of suspicion is needed, especially in individuals who are older or have a family history of pancreatic cancer. Commonly, persistent abdominal pain, jaundice or unexplained weight loss are reasons to obtain a CT (computed tomography) or an MRI (magnetic resonance imaging) scan of the abdomen. A finding of a mass in the pancreas is worrisome for pancreatic cancer and it cannot be ignored.

Currently, the United States Preventive Services Task Force does not recommend routine screening for pancreatic cancer in individuals without symptoms.

Diagnosis | Labs

Initial evaluation of an individual suspected of pancreatic cancer includes a complete blood count, electrolyte levels, kidney function tests and liver function tests. The abnormalities on these tests are not unique to pancreatic cancer in anyway and can be present in other disease. Individuals with jaundice have high bilirubin levels. Those with cholangitis (infection of bile ducts) may have elevated white blood cells. Sometimes, electrolyte imbalances are noted in individuals with diarrhea or poor nutrition. Doctors will order “tumor markers” in blood if the diagnosis of pancreatic cancer is suspected. These tumor markers are substances (antigens or hormones) produced by the pancreatic cancer.

For pancreatic adenocarcinoma, these include cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), tissue polypeptide antigen, pancreatic anti-oncofetal antigen. The most commonly used tumor marker is CA19-9. It is important to know that this “tumor marker” can also be elevated in certain benign conditions of the liver, pancreas and bile ducts. By itself, elevation in CA19-9 is not good enough to make a diagnosis of pancreatic cancer.  However, the degree of CA19-9 elevation is factored into decisions regarding treatment planning (e.g. benefit of upfront surgery, sequencing of various treatments, response to chemotherapy or radiation, and monitoring recurrence after surgery).

Patients with pancreatic neuroendocrine tumors may have elevation of chromogranin A in their blood and 5-hydroxy indoleacetic acid (5-HIAA) in their urine among other markers. These tumor markers can aid in the diagnosis, treatment planning and monitoring of individuals with pancreatic neuroendocrine tumors. For patients with functionally active pancreatic neuroendocrine tumors, hormone levels can be measured in the blood. The type of hormone that is elevated will depend on the type of tumor (See Risks and Symptoms)

Diagnosis | Endoscopy – ERCP/EUS

Your Doctor may recommend one or more endoscopy-guided procedure. Endoscopy is a procedure where a camera at the end of a tube is passed down the mouth into the stomach and intestine. Under guidance using endoscopy two procedures can be performed: 1) Endoscopic Retrograde Cholangiopancreatography (ERCP); or 2) Endoscopic Ultrasound (EUS). ERCP is a technique that in addition to endoscopy uses X-ray guidance to evaluate the bile duct or the pancreatic duct. In addition, it can allow the doctor to perform a biopsy of the bile duct or pancreatic duct. If the bile duct is blocked, it can allow the doctor to place a stent to relieve the blockage. EUS is a technique that allows the doctor to perform endoscopy-guided internal ultrasound to evaluate the pancreas in more detail. Through this approach a biopsy of the pancreatic mass or nearby lymph glands can be performed. In addition, doctors can learn more about the relationship of the pancreatic cancer to essential blood vessels. Both ERCP and EUS can be performed at the same time. A biopsy is not always necessary prior to surgery. However, it is necessary prior to any other treatment for pancreatic cancer.

Diagnosis | CT/MRI

A good quality CT scan or MRI is critical to assess the extent of pancreatic cancer. A CT or MRI scan are two different modalities and the decision to perform one or the other is largely dependent on the preference of your doctor. Both scans are able to provide cross-sectional images (similar to slices of a bread loaf). They not only give the first indication of a mass/ cancer in the pancreas, but also allow doctors to stage the cancer. Stage is the extent to which the cancer has spread. This information is essential before any treatment recommendations can be formulated. The CT or MRI scan is performed with a dye injected in your vein. This dye opacifies blood vessels and allows doctors to capture precise information on the relationship of the pancreatic cancer to the blood vessels. This information is needed for your pancreatic surgeon to determine if you are a surgical candidate.

Diagnosis | Need for Biliary Stent

Some individuals have jaundice (yellow color of eyes and skin) as their first symptom. This happens because the mass in the pancreas blocks the bile duct in a location where it courses through the pancreas on its way from the liver to the intestine. This causes a component of bile – bilirubin – to back up into the liver and ultimately into the blood stream. This blockage can be relieved by placing a plastic or metallic stent (tube) into the bile duct under endoscopy guidance as described above (See Endoscopy – ERCP/EUS). However, stent placement is not always necessary if the treatment plan is to surgically remove the tumor within a week (as surgery will address the blockage of the bile duct). Doctors will recommend stent placement when the patient has infection of the bile duct (cholangitis – fevers in addition to jaundice), surgery is delayed for any reason (e.g. chemotherapy is needed before surgery, patient not strong enough for surgery), or if the patient has severe symptoms from jaundice (mainly severe itching). Occasionally, a stent cannot be placed using endoscopy guidance. In that situation, your doctor may recommend placement of a stent through the liver using radiology guidance.

Treatment | Adenocarcinoma

Cancer of the pancreas or pancreas adenocarcinoma refers to cancer originating within the exocrine portion of the pancreas. Since the pancreas is near major blood vessels of other organs in the abdomen such as the liver, intestines and the aorta, advanced pancreas cancer may present with some degree of involvement of these blood vessels. A marker used to assess treatment response with pancreas cancer is tumor marker CA 19-9. Since this tumor marker also depends on a certain blood type that is naturally absent in some patients, it is not uncommon to find patients with proven cancer, but CA 19-9 within the normal range. When patients present with pancreas cancer that does not involve any major blood vessels, with mild to moderately elevated CA 19-9 level, they are classified as resectable pancreatic cancer. When pancreatic cancer involves either the portal or mesenteric vein, less than half the circumference of the artery, or has very high CA 19-9, it is classified as borderline resectable cancer. If major arteries are circumferentially involved by tumor, it is classified as locally advanced tumor. Bear in mind, this classification is primarily based on the appearance of the tumor on staging imaging performed and is different from the stage of cancer, which is defined, based on size, lymph node spread, and involvement of distant organs. Based on the degree of involvement, the treatment team may choose to either operate on the cancer first followed by chemotherapy, and/or chemoradiation therapy. With advanced tumors, the treatment approach includes administration of chemotherapy first to assess for response. This can be either tumor shrinkage (bear in mind absence of tumor shrinkage after chemotherapy does not necessarily indicate lack of response), or decreasing level of CA 19-9, followed by chemoradiation followed by surgery and additional chemotherapy after. Stage IV pancreatic cancer is cancer that has spread to other organs such as the liver or lungs.  It also includes cancer that has spread to bones within the abdomen or lymph nodes in the area that would not be removed during pancreatic surgery.

Distal Pancreatectomy Splenectomy Surgery

Pancreatic cancer (ductal adenocarcinoma) in the tail of the pancreas is often recognized at a more advanced stage as these tumors cause vague symptoms such as weight loss, lack of appetite, and back pain, rather than bile duct or pancreas duct obstruction which more commonly occurs with pancreas tumors in the head of the gland.  Despite this, they are less likely to be involving major vascular structures that need to be preserved or will limit resectability.  Distal pancreatectomy for adenocarcinoma is usually performed with a splenectomy for several reasons.  First, the total number of lymph nodes harvested is generally higher; second, pancreas cancer may spread to the spleen in some cases; and third, the blood supply to the spleen is sometimes compromised by the tumor or the planned surgery. Depending upon the extent and location of the tumor, adenocarcinomas of the body or tail of pancreas may be removed with open surgery or minimally-invasive techniques including laparoscopic or robotic surgery.  These procedures are generally shorter hospital stays than a Whipple procedure, because generally no bowel needs to be removed or reconnected.  The risks of this surgery are like any major abdominal surgery, including bleeding, infection, and injury to local structures.  Specific to distal pancreatectomy with or without splenectomy are the risks of pancreatic fluid leaking from the place where the organ was divided; fluid leaking from the lymph channels that run near and around the pancreas and worsening or new onset of diabetes or pancreatic insufficiency.  Your surgeon will be able to help advise you further on your specific risk profile.  If the spleen is removed, it is generally of no long-term consequence, but as the spleen is involved in how the immune system deals with certain bacteria (Pneumococcus, Meningococcus, and Haemophilus, also called “encapsulated bacteria”) you will need to obtain several vaccines as well as boosters to make up for the loss of the spleen.

Whipple Surgery

Also known as a “pancreaticoduodenectomy”. This operation is to remove tumors or masses that are in the head of the pancreas. The blood supply of the head of the pancreas overlaps the blood supply to the lower part of the bile duct, the first portion of the intestine and the end of the stomach.  Therefore, a portion of all of these need to be removed together. To perform the Whipple operation, the gallbladder must be removed, the first portion of the intestine, a portion of the pancreas and the lower portion of the bile duct. The remainder of the intestine is then brought up and reconstruction is performed.  The first connection is the pancreas to the small intestine, followed by the bile duct to the small intestine and lastly the stomach to the intestine. The average length of stay in the hospital is 7 days.  The most common complications related to this specific operation are pancreas leak and delayed gastric emptying. The pancreas is a very soft gland and when sutured to the intestine can leak.  Often drains are placed around this connection during the initial surgery and can be removed in the hospital prior to discharge or in the office after a few weeks. Delayed gastric emptying is when the stomach does not empty properly after this operation. This is managed with medications, sometimes nutrition through the IV and occasionally with placement of a nasogastric tube to decompress the stomach temporarily.  Rarely, patients need a percutaneous gastrostomy tube to decompress the stomach.

Medical Therapy

Medical management with chemotherapy plays an important role in the treatment of pancreatic adenocarcinoma.  The type and timing of medical therapy is typically discussed between the medical oncologist and surgeon treating a patient.  There are three ways in which chemotherapy can be administered. At the time of diagnosis, some patients may not be helped by surgery.  These patients have cancer that has either spread to organs beyond the pancreas or has grown into critical arteries around the pancreas and cannot be removed.  Attempting to remove the tumor from these patients would place them at risk for serious complications, without providing significant benefit.  These patients may receive palliative chemotherapy.

Palliative chemotherapy has been shown to prolong life expectancy for patients with unresectable pancreatic cancer, though it usually does not offer a cure. Other patients may benefit from surgery, but surgery may initially be expected to be difficult.  Usually this means that the tumor has grown into important veins or is starting to touch critical arteries.  These patients are often treated with chemotherapy BEFORE surgery to shrink or stabilize the tumor.  This is referred to as neoadjuvant chemotherapy and is done to increase the success of the eventual operation and improve the chances of cure.  Some patients may have a tumor which appears to be safe for surgical removal when it is first diagnosed (resectable).  These patients may or may not receive chemotherapy before surgery, depending on the preference of their surgeon.  These patients will most likely receive chemotherapy AFTER surgery. This is referred to as adjuvant chemotherapy, which may decrease the chances that the cancer will come back in the future. There are a number of chemotherapy regimens that have are used in treatment of pancreatic cancer.  Oral agents can be taken as pills, while intravenous (IV) agents may be delivered through a port (a small plastic device that is surgically placed on the chest wall just under the collarbone and connected to a vein in the neck).  IV chemotherapy agents are delivered at an infusion center, usually over the course of several hours or may be delivered through a pump that patients take home with them.  A discussion between the surgeon and the medical oncologist will determine which medications would be best for each individual patient.  Gemcitabine is an IV medication that is typically given 3 times a month (on days 1, 8, and 15).  Common side effects include flu-like symptoms, fatigue, nausea/vomiting, poor appetite, skin rash, and low blood counts.  Capecitabine is an oral medication, usually taken twice a day with meals.  Common side effects include skin rash, itching, pain and/or peeling of the skin on the palms of hands and soles of feet, diarrhea, fatigue, and nausea/vomiting.  Abraxane is an IV medication that is also usually given 3 times a month (on days 1, 8, and 15).  Common side effects include hair loss, peripheral neuropathy (numbness and tingling of hands and feet), nausea/vomiting, weakness and fatigue, diarrhea, and muscle/joint pain.  FOLFIRINOX is a combination IV medication given every 2 weeks.  Common complications include easy bruising, fatigue, nausea/vomiting, hair loss, diarrhea and decreased cell counts.  If side effects from any of these medications become too severe, a medical oncologist will either decrease the dose, or transition to a different medication.

Radiation

The most common type of radiation treatment used for pancreatic cancer is called external-beam radiation therapy, which is radiation given from a machine outside the body. Radiation therapy refers to using high-energy x-rays or other particles to destroy cancer cells. A radiation oncologist is a doctor who specializes in giving radiation to treat cancer. If radiation is considered as part of your treatment plan, a radiation oncologist should be part of the treatment team. He or she would determine the type of radiation used and the schedule/regimen of radiation treatments to be delivered. Traditionally, radiation treatment is given in small doses and spread out over 5-6 weeks. Currently the alternate methods of radiation delivery have not proven better and are frequently given as part of clinical trials Radiation can be provided in different ways:

  • Conventional/standard radiation given over 5-6 weeks in small doses
  • Stereotactic body radiation therapy (SBRT) can provide more localized treatment in fewer doses but has not yet proven to be the same or better than conventional radiation.
  • Proton beam therapy uses protons instead of X-rays to destroy cancer cells. This method can decrease the amount of normal tissue that receives radiation. However, it remains available in very few centers and is also not proven to be better than conventional radiation

Like chemotherapy, radiation is ideally provided in addition to surgery in selected cases. Usually radiation and chemotherapy are provided together (chemoradiation). Chemo will be given at the same time as radiation therapy because it can enhance the effects of the radiation therapy, which is called radiosensitization. Combining chemotherapy and radiation therapy may help shrink the tumor enough so it can be removed by surgery. However, chemotherapy given at the same time as radiation therapy must be given at lower doses than when given alone. It can be given before surgery (neoadjuvant) or after surgery (adjuvant) at the discretion of the multidisciplinary team. The details of how these treatments are brought together is based on your tumor and how your team believes you can tolerate the treatments that are available. Current guidelines suggest that the main reasons for using radiation therapy as part of pancreatic cancer treatment are:

  • Before surgery (Neoadjuvant)- to downstage/ shrink a tumor and sterilize the planned surgical margin for large or difficult to remove tumors.
  • After surgery (Adjuvant)- if there is a high risk of local recurrence (positive margins or lymph node positive)
  • Instead of surgery if the tumor is locally advanced and cannot be removed (unresectable)
  • Symptomatic treatment (bleeding, pain or obstruction) at the site of the pancreas or other metastatic sites

Side effects from radiation therapy may include fatigue, mild skin reactions, nausea, upset stomach, and loose bowel movements. Most side effects go away soon after treatment is finished. Talk with your health care team about what you can expect and how side effects will be managed.

Clinical Trials

Immunotherapy is a treatment type that helps your own immune system attack cancer cells. The goal is to stimulate the natural body reaction that fights germs and other illness, including cancer. Drugs can be given in various forms including injection, IV, or oral depending on the drug used. Immunotherapy has been developed for several other cancers, but at this time is being studied for pancreatic cancer. Various clinical trials have been done or are ongoing that use cancer vaccines to try to treat a variety of types of cancer, including pancreatic cancer. Such vaccines may be made from various sources, including pancreatic cancer cells, bacteria, or a person’s specific tumor cells. Depending on the circumstances, vaccines may be given either after, during, or instead of chemotherapy. The immune checkpoint inhibitor pembrolizumab (Anti-PD-1 inhibitor) may be an option for pancreatic cancers that have certain genetic mutations (High MSI), but this represents only a small percentage of patients. Immune checkpoint inhibitors are already approved for other types of cancer, like melanoma and lung cancer, but not for pancreatic cancer. These drugs generally need to be combined with some type of chemotherapy since immunotherapies alone have not shown significant results. Ongoing studies in pancreatic cancer are testing the combination of immune checkpoint inhibitors with chemotherapy, radiation therapy, or with other new immunotherapies. Targeted therapy refers to treatment with drugs that have been developed to “target” these differences within the cell. Unlike chemotherapy, targeted therapy drugs alter the inner workings of the cell focusing on the part of the cancer cell that makes it different from the healthy cell.   Because they leave the healthy cells alone the side effects of targeted therapies are different from standard chemotherapy treatments. Unfortunately, not all tumors have the same targets.

Erlotinib is approved by the FDA for patients with advanced pancreatic cancer in combination with gemcitabine. Erlotinib blocks the effect of the epidermal growth factor receptor (EGFR), a protein that can become abnormal and help cancer grow and spread. The side effects include a skin rash similar to acne, diarrhea, and fatigue.

Larotrectinib is a treatment that is not specific to a certain type of cancer but focuses on a specific genetic change called an NTRK fusion. This type of genetic change is found in a range of cancers, including pancreatic cancer. It is approved (Nov 2018) as a treatment for pancreatic cancer that is metastatic or cannot be removed with surgery and has worsened with other treatments. Side effects include anemia, fatigue, and gastrointestinal symptoms.

Central Pancreatectomy Surgery Resections of the pancreas most often consist of either (1) removal of the right end of the pancreas, known as the head of the pancreas, together with the segment of intestine attached to it known as the duodenum and a portion of the bile duct by means of an operation known as a pancreaticoduodenectomy or Whipple procedure or (2) removal of the left end of the pancreas, known as the tail of the pancreas, usually together with the adjacent spleen by means of an operation known as a distal or left-sided pancreatectomy. In selected patients, a central pancreatectomy that removes the mid-portion of the pancreas while sparing the head and the tail of the pancreas may be considered.  This operation is not recommended for treatment of the most common malignant tumors of the pancreas known as adenocarcinomas (and usually denoted by the term “pancreatic cancer”), as removal of tissue around the pancreas including lymph nodes to which cancer can spread is very limited.   Instead, it is usually reserved for abnormalities in the central portion of the pancreas that (1) are not believed yet to be malignant but have the potential to become malignant (2) have uncertain malignant potential or (3) are benign but symptomatic. A central pancreatectomy consists of (1) resection of the mid portion of the pancreas (2) closure of the right-sided cut end of the pancreas adjacent to the pancreatic head as is done with a distal pancreatectomy and (3) attachment of the left-sided pancreatic remnant to either a segment of small intestine or the stomach, as is done with a Whipple-type procedure.  The procedure frequently can be performed as a laparoscopic or robotic procedure.  Because a central pancreatectomy results in two cut ends of the pancreas, there is an increased risk of postoperative drainage from the pancreas compared to either a Whipple procedure or distal pancreatectomy.   Instead of a central pancreatectomy, abnormalities in the mid-pancreas can be resected by means of either a right sided resection (Whipple type procedure) that is extended further towards the left or a distal pancreatectomy that is extended further towards the right to include the mid-pancreas.  However, a central pancreatectomy preserves more pancreas and therefore more pancreatic endocrine and exocrine function, and therein lies the benefit of a central pancreatectomy in carefully selected patients.

Treatment | Neuroendocrine

Neuroendocrine tumors of the pancreas (PNETs) are rare lesions that have a range of behaviors and presentations.  While some are associated with genetic mutations and syndromes (Multiple Endocrine Neoplasia being most common) others arise in the setting of no abnormalities.  The treatment for these tumors depend on several things: how large the original (or primary) tumor is; if the tumor is “functional” or secreting endocrine hormones like insulin or gastrin that can cause other symptoms; and if the tumor has gained the ability to spread into the lymphatics, nerves, or blood stream and seed metastases to the lymph nodes, liver, or other parts of the body.  Because these tumors are relatively rare and our understanding of their behavior is changing rapidly, consulting with a specialist medical or surgical oncologist who treats PNETs is recommended.  It is also important to note that the behavior of a PNET is different than a neuroendocrine tumor arising from the stomach or lungs, and that PNET have different treatments and prognoses. Medical management of pancreatic NETs can slow the progression of metastases if present in the lymph nodes or liver; it can also alleviate symptoms from PNET hormone secretion in “functional” tumors.  There are a variety of medications available (including somatostatin analogues like octreotide and mTOR inhibitors like evirolimus) Small PNETs without evidence of metastasis to the lymph nodes or liver can be observed in some cases and removed if they are enlarging over time.  Unlike other tumors that spread to the liver, PNETs can be “de-bulked”, meaning that the majority (but not every single) tumor in the liver can be removed and can slow the progression of the disease and improve prognosis and symptoms.  Tumors that would be unsafe to remove can be treated in a variety of ways as well, with ablation or embolization.  Which treatments patients receive depends in large part upon the distribution and number of tumors as well as their ability to tolerate the medications or surgeries proposed. In some cases of large or advanced tumors, chemotherapy such as temazolamide and capecitabine or carboplatin/etoposide are employed to slow disease, improve symptoms, or bring tumors to a resectable state. No one treatment is a cure-all for PNETs and in many cases, multimodal therapy over a long period is required to keep the disease in check and prevent it from causing symptoms, obstruction, or pain.

Whipple Surgery

Neuroendocrine tumors can be located anywhere within the pancreas. Based on the size, symptoms, or Ki 67 index (activity of neuroendocrine cells), the surgeon may recommend removal of this tumor. The pancreas is a flat and long organ, located in the upper portion of the abdomen, behind the stomach. The portion of the pancreas to the right of the spine is called the head of the pancreas. This portion is closely associated with the duodenum or the beginning of your small intestine and surrounds the bile duct. Therefore, in order to remove this portion of the pancreas, a pancreatoduodenectomy or the “Whipple” procedure is necessary. The Whipple operation is performed in two steps. The first step includes removal of the head of the pancreas, the duodenum in its entirety, the gallbladder and the bile duct up to the liver. A portion of the stomach is also removed, which can be performed in different ways. The classic approach is where half the stomach is removed, pylorus preserving (valve that regulates the flow of food from the stomach to the duodenum) or dividing the stomach just before the pylorus. The second portion of the operation is putting everything back together to maintain the flow of digestive juices and food. The first connection typically performed is between the pancreas and the small intestine, and the second connection is between the bile duct and the intestine downstream from the pancreatic connection. The last connection is between the stomach and the small intestine. The surgeon may or may not leave a drain in place by the pancreatic connection to detect leakage from the pancreas. One risk specific to the operation is diabetes, since a portion of the pancreas is removed during the operation. Other risks include DGE or gastroparesis, where the stomach may not be able to stretch to accommodate food, or not empty out the food eaten.

Central Pancreatectomy Surgery

When a tumor is in the body of the pancreas, a central pancreatectomy can be performed. It is important that the lesion in the body of the pancreas being removed is not cancerous, i.e., does not have the ability to spread to the lymph nodes, as this operation will not remove lymph nodes surrounding the pancreas. This operation is preferred when removing a small tumor, which is not cancerous, can spare a significant portion of the pancreas. The spared pancreas continues to produce insulin, and digestive juices. Therefore, it is necessary to connect the distal or the tail portion of the pancreas to intestine. This is usually performed in a Roux en Y fashion, i.e., a portion of the intestine is fashioned like a “Y” and the limb of the intestine that does not have food passing through it is connected to the pancreas. The advantage of this operation is that it preserves most of the pancreas and reduces the likelihood of diabetes post-surgery.

Enucleation Surgery Enucleation is a surgery that allows for maximal preservation of pancreas tissue.  It is a safe procedure with good long term survival results in select cases.  The procedure is indicated for mostly functional tumors (a tumor that produces an excess of a hormone causing patient symptoms) less than 2 cm in size and not near the bile or pancreas duct.  It is most commonly performed on insulinomas, a pancreas neuroendocrine tumor which is commonly a benign lesion.  In rare cases it can be performed on pancreas mucinous cystic neoplasm and small (< 1cm) low risk nonfunctional pancreas neuroendocrine tumors.  The procedure is not indicated for most functional tumors which have a higher risk of being malignant; tumors greater than 3cm in size; the presence of lymph node or metastatic disease; tumors close to the pancreas or bile duct; or duodenal wall tumors.  Enucleation has been associated with a high pancreas leak rate but decreased blood loss, time in the operating room, and length of stay in the hospital compared with larger pancreas resections. The procedure can be performed by an open or laparoscopic approach.  Whether the procedure is performed laparoscopic or open, the first step in the procedure is to locate the lesion with intraoperative ultrasound and determine the lesions proximity to the pancreas duct.  An incision is made over the lesion and the pancreas tissue is divided using a variety of techniques to dissect the pancreas tissue from around the tumor.  Dissection of the tumor near the pancreas duct is normally performed without using cautery.  Once the tumor is enucleated, the surgeon will ensure bleeding is controlled.  At the end of the procedure a drain is placed in the region of the enucleation in case of a leak.  At times, a stent will be placed in the pancreatic duct prior to the surgical procedure.

Distal Pancreatectomy and Splenectomy Surgery

When the tumor involves the portion of the pancreas away from the head, i.e., the neck, body or tail, a distal pancreatectomy with or without splenectomy is preferred. If the tumor has potential to spread to the lymph nodes, a concomitant splenectomy is performed. This is necessary, as the blood vessels to the pancreas and spleen are intimately associated with each other, and it is not possible to remove lymph nodes surrounding the body and tail of the pancreas while preserving the spleen. If it is determined that splenectomy is necessary, the patient will need vaccinations against certain bacterial organisms. The vaccinations can be performed at least two weeks before or after surgery. Depending on pre-surgery medical conditions, i.e., prediabetes, and/or BMI, the patient may become diabetic after a distal pancreatectomy. It is not common to have pancreatic insufficiency after this surgery, but that would be a risk as well. Pancreatic insufficiency occurs when the pancreas does not secrete enough juices to help in digestion of the food you eat, specifically foods rich is fats or proteins. Symptoms include bloating, abdominal cramps, and loose stools that can be foul smelling or float on water. Once confirmed, pancreas insufficiency can be easily treated with synthetic enzyme supplementation.

Medical Therapy

The best treatment for most pancreatic neuroendocrine tumors is surgical removal, even if the tumor has spread outside of the pancreas to other parts of the body.  When surgery is not possible, medications can be given.  The medications have two purposes: to slow the growth of the tumors and to reduce symptoms if the tumors make hormones.  Medical treatments do not cure neuroendocrine tumors. The most common medications used are called somatostatin analogues.  Somatostatin is normally produced by our digestive system to decrease the function of neuroendocrine cells.  When given as an injectable medication, synthetic somatostatins (e.g. octreotide and lanreotide) decrease the release of hormones and growth of neuroendocrine tumors.  Early in treatment, patients may have mild digestive symptoms such as bloating, diarrhea and nausea.  These symptoms usually go away with time. Chemotherapy is generally ineffective for neuroendocrine tumors and is rarely used because the benefit is limited compared to the side effects.  New classes of medications are showing some benefit for these tumors.  These include immunotherapy which boosts the body’s immune system against the tumor, and biologics which interfere with the blood supply to these tumors. These newer agents tend to have less side effects and are likely to be more effective than chemotherapy.  Based on your symptoms and whether the tumor has spread, your doctor may suggest combining these medications with somatostatin-like drugs.

Radiation In general, radiation therapy does not play a role in the care of patients with neuroendocrine tumors confined to the pancreas.  Surgery remains the best therapy.  There are circumstances where radiation is used to treat neuroendocrine tumors which have spread to other sites within the body that cause symptoms such as pain.  Examples include tumors that have spread to the bone or brain.  Radiation is targeted to a specific site within the body and is given in small amounts over a number of days.  Like an X-ray, radiation is delivered through the body and side effects vary and depend on the location being treated.  Common side effects include tiredness, bruising and inflammation of the skin, dehydration and fevers. Radiolabeled somatostatin is new therapy that combines a medication that binds to some neuroendocrine tumors in a fashion similar to a lock and key.  Attached to the medication is a radioactive particle, such that the radiation is delivered specifically to the tumor to cause less systemic side effects.

Clinical Trials Targeted Therapy

Most pancreatic neuroendocrine tumor (PNETs) cells have receptors on their surface for the hormone “somatostatin”, though a small percentage do not.  Other normal cells of liver tissue do not express these receptors.  Because of this we are able to label somatostatin with chemicals that emit energetic particles which can be detected by a scanner and localize the tumors (DOTATATE scans).  The same principle is involved in the emerging treatment of PNETs with Peptide Receptor Radionucleotide Therapy (or “PRRT”), that take a molecule that fits into the somatostatin receptor and attach a radiation emitting molecule to it.  This then concentrates the radiation to the site of the tumors and has been shown to be very effective in shrinking tumors and metastases.  In many cases, PRRT is used in conjunction with other modes of treatment including medication and surgery.  Until recently, PRRT was only approved in Europe, but now several centers in the United States have PRRT programs.  The radiation is very focused and localized to the tumor cells and causes little to no collateral damage to nearby cells.

Immunotherapy

Immunotherapy for PNETs is still a treatment that is being studied but is promising for the estimated 1/3 of PNETs that express the protein PD-L1.  When PD-1 binds with the receptor PD-L1, the net effect is immune-suppression.  Expression of this receptor on cancer cells is a way in which they can evade the immune system, which plays a large role in destroying cancer cells in the body. Immunotherapy uses a protein (an antibody) which blocks the interaction of PD-L1 and PD-1 and prevents the immunosuppression, allowing the immune system to stay active near the tumor and fight tumor cells that it recognizes as “non-self”.