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Saturday, October 13, 2007

INTRODUCTION — More than 37,000 Americans develop cancer of the pancreas each year; it is the fourth leading cause of cancer-related death in the United States [1]. Two types of cancer can affect the pancreas: The most common, cancer of the exocrine pancreas (hereafter referred to as pancreatic cancer), originates in the pancreatic ducts. The ducts are responsible for carrying pancreatic juice to the intestines, where it assists in the digestion of food. This type of pancreatic cancer is discussed in this topic review. Another type of cancer consists of a group of tumors that originate from the cells that make hormones such as insulin. Like pancreatic juice, these hormones are made by the pancreas, but instead of traveling through the pancreatic ducts, they are secreted directly into the blood. These tumors are collectively referred to as pancreatic endocrine tumors, and are not addressed here.

PANCREAS ANATOMY AND PHYSIOLOGY — A brief review of the anatomy and physiology of the pancreas and surrounding structures will help in the understanding of pancreatic cancer.

The pancreas is a large gland that is located in the abdomen near the stomach, liver, and a part of the small intestine called the duodenum (show figure 1). Glands are organs that manufacture and secrete fluids that the body needs in order to function. The pancreas makes insulin, a hormone needed for sugar metabolism, and pancreatic juices, which are secreted into the intestines and aid in the digestion of food, particularly fats.

Pancreatic juices are carried to the digestive tract through a series of tubes or "ducts," that join together to form the main pancreatic duct. The pancreatic duct then joins the common bile duct (show figure 1) before they empty together into the small intestine at a point called the papilla of Vater (not pictured in the figure). The common bile duct drains bile into the intestines after it is made in the liver and stored in the gallbladder. The ampulla of Vater is located inside the duodenum, the first part of the small intestine near the head of the pancreas.

The pancreas has three main parts: the head (which is the part closest to the duodenum and the common bile duct), the body (the middle portion), and the tail. Cancer can develop in any of these parts. Cancers that surround or are close to the ampulla of Vater may be referred to as "periampullary tumors", and sometimes it is difficult to know whether they arose from the pancreas, the ampulla of Vater, or the duodenum.

RISK FACTORS — A number of factors increase the risk of developing pancreatic cancer including smoking, chronic pancreatitis (chronic inflammation of the pancreas), and possibly diabetes mellitus. The majority of studies do not support a relationship between coffee intake and pancreatic cancer. Pancreatic cancer can cause diabetes mellitus in many patients, and this makes it difficult to interpret many of the studies that examine the relationship between diabetes mellitus and pancreatic cancer. (See "Patient information: Chronic pancreatitis").

Many patients with pancreatic cancer have a family history of chronic pancreatitis. A small number of these families have an inherited condition that predisposes them to pancreatic cancer, sometimes in conjunction with chronic pancreatitis (inflammation of the pancreas).

SIGNS AND SYMPTOMS — Most patients with pancreatic cancer experience pain, weight loss, and/or jaundice (yellowing of the skin). Pain is common, and is usually felt in the upper abdomen as a dull ache that radiates to the back. It may be intermittent (comes and goes), and it may be worsened by eating. Weight loss can be profound. Some people lose weight because of loss of appetite, the sensation of felling full after eating only a small amount of food, or diarrhea. If the pancreatic duct is blocked by the cancer and the pancreatic juice cannot enter the intestines, the stools may seem greasy and tend to float in the toilet bowl because they contain undigested fat. Jaundice is a sign of high levels of bilirubin (the main component of bile) in the blood. People with jaundice have yellow skin, whites of the eyes, and urine. A build-up of bilirubin in the blood can be caused by cancers in and around the pancreas, which block the ducts that drain bile from the liver into the intestines. As a result, bowel movements may not be a normal brown color, and instead have a grayish appearance, described as clay-colored stools.

Symptoms vary depending upon where the pancreatic cancer is located. Cancers that develop in the head of the pancreas tend to block the drainage of bile from the liver to the intestines, and typically cause jaundice. In contrast, tumors that arise in the body or tail are less likely to cause jaundice, and more often cause abdominal pain, weight loss, and diarrhea.

Other signs of pancreatic cancer include a recent and unusual onset of diabetes mellitus, a history of recent but unexplained blood clots in the legs (thrombophlebitis), or a previous unexplained attack of pancreatitis.

DIAGNOSIS — If a patient's signs and symptoms suggest the possibility of pancreatic cancer, a number of different tests can be done to help pinpoint the diagnosis. All tests are not needed in every patient. Three main questions that testing can help to answer are: Are the symptoms/signs caused by a problem with the pancreas? If so, is it pancreatic cancer? If it is pancreatic cancer, can it be surgically removed?

Ultrasound of the abdomen — Patients with jaundice will typically have an ultrasound as a first step in the diagnostic process. An ultrasound uses sound waves that are transmitted through a wand-like instrument (a transducer) that applied to the abdomen. The purpose of this ultrasound is to determine whether the bile system is blocked, and to identify where the blockage appears to be located.

CT scan — CT scan, which uses x-rays and a computer to take detailed pictures of the body, may be the initial test ordered in patients who have abdominal pain or unexplained weight loss, particularly if the person is not jaundiced. CT may reveal a blockage of the bile and/or pancreatic ducts, a mass within the pancreas or in the periampullary area (where the bile duct, pancreas, and duodenum come together), and/or evidence of cancer spread beyond the pancreas (for example, to the liver). An injection of dye is usually given during the CT to allow the blood vessels surrounding the pancreas to be studied. The nature and extent of blood vessel involvement helps the surgeon to decide whether or not an operation should be performed.

Endoscopic retrograde cholangiopancreatography (ERCP) — ERCP is a dye study that may be used to outline the pancreatic duct system and bile duct system. It is performed by a gastroenterologist by inserting a small tube (called an endoscope) through the esophagus into the stomach, and then threading it through the duodenum to the papilla of Vater. Dye is then injected through the endoscope into the bile and pancreatic ducts. (See "Patient information: ERCP (endoscopic retrograde cholangiopancreatography)").

The ERCP may help to pinpoint the cause of jaundice, but is usually used only if less invasive tests do not provide enough information. An additional benefit of the ERCP is that if a blockage is identified in one of the bile ducts, it may be possible to place a flexible tube or catheter (also called a "stent") through the area that is blocked. This procedure can relieve the bile duct obstruction, allowing the bile to once again flow into the intestines, and lowering the amount of bilirubin within the blood. Whether or not this drainage procedure should be performed before a planned operation for pancreatic cancer in patients who present with jaundice is controversial.

Percutaneous transhepatic cholangiopancreatography (PTC) — PTC is an alternative way of visualizing the bile ducts to determine where a blockage is located. Instead of threading a tube into the bile system via the esophagus, a specially trained radiologist threads a tube into the bile ducts by inserting a needle into the liver from outside of the body, and then threading a catheter (over the needle) into the hepatic ducts (show figure 1). As with the ERCP, if a blockage is identified in one of the bile ducts, it may be possible to place a stent across the area that is blocked, thus relieving the bile duct obstruction.

Magnetic resonance cholangiopancreatography (MRCP) — MRCP is an MRI focusing on the bile ducts and pancreas. MRI uses magnetic fields and radio waves to produce detailed pictures of the body. It can create a very detailed three dimensional image of the pancreas, biliary ducts, liver, and surrounding blood vessels without the need for injection of dye. MRCP is sometimes done if an ERCP or PTC is not technically possible, or if the information provided by the ERCP and CT is incomplete and/or confusing.

Endoscopic ultrasound (EUS) — In this test, ultrasound is done from inside the body by placing the ultrasound transducer on the tip of an endoscope which is then passed into the duodenum by going down the esophagus. EUS is sometimes done if a small tumor is suspected, or to get more information about whether a pancreatic tumor can be removed by surgery.

Biopsy — A biopsy refers to the surgical removal of a small piece of tissue for examination under a microscope, looking for evidence of cancer. For patients suspected of having pancreatic cancer, a biopsy can be performed by inserting a biopsy needle into the area of abnormality. The needle can be inserted into a pancreatic tumor through the skin of the abdominal wall under guidance of a CT scan, or as part of an EUS procedure. Although a biopsy may be recommended if the diagnosis of pancreatic cancer is in doubt, or to confirm the diagnosis in patients who will not be having surgery, it may not be needed if the patient is thought to be a good candidate for surgery.

PANCREATIC CANCER STAGING — Treatment and prognosis for individual cancers depends upon the extent or "stage" of disease. The most commonly used pancreatic cancer staging system is the TNM ("Tumor, nodes, metastases") system (show table 1). It is based upon tumor size and how far the cancer has penetrated into the structures surrounding the pancreas, whether the cancer involves lymph nodes adjacent to the pancreas, and whether the cancer has spread to other organs. These factors are then combined to assign a "stage grouping" from I to IV, with stage I cancers being the earliest and least advanced stage disease and stage IV the most advanced. The final staging of a pancreatic cancer often depends upon the findings during surgery.

TREATMENT — Several approaches to treatment of pancreatic cancer are available. For patients whose cancer has not spread significantly and who are strong enough to withstand an operation, doctors will attempt to remove the cancer surgically. Surgery provides the only opportunity for cure. Surgery is not possible in many patients because the disease is often advanced at the time of diagnosis.

In some cases, chemotherapy and/or radiation therapy will be recommended following surgery while in others it may be offered before surgery (termed neoadjuvant therapy). For patients who are not candidates for surgery, radiation and/or chemotherapy may be offered. In addition, other treatments are available to relieve the symptoms of pancreatic cancer (see "Treating signs and symptoms" below).

Laparoscopy — In some centers, laparoscopy is recommended before attempted surgical removal of a pancreatic cancer to get more information about the location and extent of cancer involvement. During a laparoscopy, the surgeon inserts a narrow tube into small incisions and uses a camera within the tube to view the inside of the abdominal cavity. If the surgeon finds evidence of cancer spread, the patient may be spared the complications and long recovery time of a major operation that would not likely cure the cancer. Postoperative recovery after a laparoscopy is faster than with a standard open surgical procedure because the incisions are smaller.

Surgery for tumors in the head of the pancreas — The standard operation for tumors located in the head of the pancreas is a Whipple procedure (a pancreaticoduodenectomy) [2]. In this procedure, the surgeon removes the pancreatic head, the duodenum (first part of the small intestine), part of the jejunum (the next part of the small intestine), the common bile duct, the gallbladder, and part of the stomach (show figure 2). A modification of the Whipple procedure (a pylorus-preserving Whipple procedure) has been developed that preserves the part of the stomach (the pylorus) that is important for stomach emptying [3].

In the past, complications and deaths following this operation were high, and cure rates were less than 10 percent. However, more recent results suggest better outcomes: In experienced hands, the death rate following surgery is less than 4 percent [4,5]. The long-term outlook for patients undergoing this surgery varies, depending in part on whether the cancer has affected the lymph nodes. Between 10 and 30 percent of patients undergoing a Whipple procedure for pancreatic cancer will be alive and cancer-free five years after the operation [4-9].

Better outcomes are achieved in hospitals that perform a large number of Whipple procedures and when the surgeon is experienced with the procedure [10] (see "Adjuvant therapy after surgery" below).

Surgery for tumors in the body or tail of the pancreas — Because tumors in the body or tail of the pancreas do not cause the same symptoms as those in the head of the pancreas, these cancers tend to be discovered at a later stage, when they are more advanced. If the patient has a tumor that can be removed surgically, a laparoscopic exploration is usually done first to make sure the cancer has not spread within the abdominal cavity. If surgery is still an option, part of the pancreas is removed, usually along with the spleen. However, long-term outcome for these patients is usually poor.

Adjuvant therapy after surgery — Adjuvant (additional) therapy refers to chemotherapy, radiation, or a combination of both that is recommended for patients who are thought to be at high risk of having cancer reappear (termed a recurrence or a relapse) after a tumor has been removed surgically. Even if the tumor has been completely removed, tiny cancer cells may remain in the body and grow, causing relapse after surgery. For such patients, adjuvant therapy can prevent relapse and prolong survival by eradicating the tiny cancer cells before they have had a chance to grow [6-9].

Many different studies have been done to evaluate the benefits and risks of these treatments, and more are underway. Despite the widespread opinion that adjuvant therapy is beneficial for patients who have undergone surgery for stage II or III pancreatic cancer (show table 1), research to date has not indicated the best way to give such therapy. Two different approaches may be recommended, including: Chemotherapy alone (typically with the drug gemcitabine) A combined approach of chemotherapy (either gemcitabine or 5-FU) given in conjunction with radiation therapy and also a period (usually four to six months) of chemotherapy alone (usually gemcitabine). This strategy is called chemoradiotherapy.

Whether either of these approaches is superior is unclear, and both are acceptable forms of adjuvant therapy. In the United States, a combined approach is recommended for most patients. However, outside of the United States, patients are frequently offered chemotherapy alone. Until more research is done, the best way to use these adjuvant therapies in particular cases will not be known. Many patients will be asked to participate in clinical trials that compare different approaches or that explore new strategies. (See "Clinical trials" below).

Treatment of locally advanced pancreatic cancer — Locally advanced pancreatic cancer has not yet spread to distant locations in the body, but has extended into surrounding organs or structures, making surgical removal impossible. The best therapy for locally advanced pancreatic cancer is unknown. Options include chemotherapy alone or a combination of radiation therapy with chemotherapy. This approach increases the average survival for patients with locally advanced cancer by about one year compared to no treatment, but rarely results in long-term survival.

A major unanswered question is: which patients benefit from the use of radiation therapy? Researchers have tried a new strategy, which uses radiotherapy in a selected group. With this strategy, chemotherapy alone (usually gemcitabine) is given to all patients for three months. Chemoradiotherapy is then added if the cancer has not progressed during that time. Although this approach reserves radiation therapy for the subgroup of patients who seem most likely to benefit, the survival benefit of adding radiation therapy to chemotherapy remains uncertain.

Chemotherapy — Patients with metastatic pancreatic cancer (stage IV) have a poor prognosis, with survival averaging only three to six months. Chemotherapy may be offered as a means of slowing the spread of the disease or to relieve disease-related symptoms.

Many different chemotherapeutic drugs and drug combinations have been studied. To date, none has consistently been proven to be more effective than single agent gemcitabine. The combination of gemcitabine with a second drug (a tablet called erlotinib [Tarceva®]) was compared to gemcitabine alone in one trial. The preliminary results showed that gemcitabine plus erlotinib was associated with longer survival [11], but the length of added survival was short (approximately two weeks). In addition, the cost of erlotinib ($3,000 per month) may be prohibitive in some cases.

As a result, gemcitabine alone is considered the standard first-line treatment for advanced pancreatic cancer by most oncologists. Gemcitabine is typically administered once per week for three of every four weeks. On average, about 25 percent of patients benefit, in that they feel better and possibly gain weight. Importantly, single agent gemcitabine is reasonably well tolerated, with little nausea, vomiting, hair loss, or bone marrow suppression (lowering of the blood counts, which may increase the risk of an infection). Still, the average survival for patients treated with gemcitabine is approximately 6 months, and only 10 to 20 percent will live for one year or longer.

Patients with advanced disease should talk with their health care providers about the benefits and side effects of chemotherapy. Many patients will be asked to participate in clinical trials that compare different chemotherapy drugs or combinations or that explore new strategies. (See "Clinical trials" below).

TREATING SIGNS AND SYMPTOMS — Treatment for pancreatic cancer may include a number of other therapies to improve disease-related symptoms. The symptoms that are most often treated include jaundice, bowel obstruction, pain, and weight loss.

Jaundice — Jaundice is caused by an obstruction to the flow of bile through the common bile duct into the intestine (show figure 1). The most common treatment is the placement of a stent, which is a small tubular device that is inserted into a duct to keep it open. The stent can usually be placed through an endoscope during an ERCP procedure (see "Endoscopic retrograde cholangiopancreatography (ERCP)" above). Initially, a plastic stent is placed, particularly if surgical removal of the cancer is possible. However, plastic stents often get clogged by debris and may become infected and require replacement. Once a decision is made that surgery is not possible, the plastic stent is replaced with a metal one.

If stenting is not possible due to technical reasons, bypass surgery can be done to create a detour around the blockage and restore the drainage of bile. However, this is rarely necessary.

Bowel (duodenal) obstruction — About 15 to 20 percent of patients with pancreatic cancer will develop an obstruction in the duodenum caused by growth of tumor into this part of the small intestine, or from compression from a growing tumor which is outside of the duodenum in the head of the pancreas (show figure 1). A preventive bypass surgery may be performed to create a detour between the stomach and a lower part of the intestine.

An alternative to bypass surgery for some patients is placement of a stent in the duodenum through an endoscope. Stents are effective, less expensive than surgery, and are a reasonable option, provided that they are place by an experienced endoscopist familiar with the technique. Bypass may be required if a stent cannot be placed or if stenting fails to relieve the obstruction.

Pain — Many patients with pancreatic cancer have abdominal pain because the pancreas lies in front of the celiac plexus, the nerve center for many of the abdominal organs. Cancers affecting the pancreas can grow locally and invade this structure, causing severe pain that can be difficult to control. In some patients, medication alone is enough to control the discomfort. Radiation therapy may also help alleviate pain in some cases by shrinking the tumor.

An additional treatment that is being used with increasing frequency is celiac plexus neurolysis (CPN). In this procedure, nerves that transmit pain signals from the area of the tumor are injected with alcohol so that they are unable to transmit signals normally. This procedure can be performed in one of three ways: in the operating room at the time of the initial surgical exploration, by a radiologist using a needle that is inserted into the area of the celiac plexus from outside of the body under CT guidance, or through an endoscope by a specially trained gastroenterologist, using endoscopic ultrasound.

Weight loss — Weight loss is common in patients with pancreatic cancer. There can be many causes. One cause is related to a decrease in the absorption of food due to a lack of the pancreatic enzymes that are found in pancreatic juice. Some patients benefit from taking pancreatic enzyme replacement. Other causes of weight loss, such as vomiting or depression, can also be addressed and treated.

CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute

1-800-4-CANCER (www.cancer.gov)People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology (www.plwc.org/portal/site/PLWC)National Comprehensive Cancer Network