There are two main types of pancreatic cancer. Those that arise from the ductal cells of the exocrine pancreas are termed pancreatic ductal adenocarcinoma. This is the most common and most lethal type. Those that arise from the endocrine cells in the pancreas are termed pancreatic neuroendocrine tumors or islet cell tumors. This form has a wide spectrum of biologic activity ranging from benign and indolent to more aggressive endocrine carcinomas.
|Syndrome or Condition||Mutated Gene||Relative Risk of Developing Pancreatic Cancer|
|Hereditary Non-Polyposis Colorectal Cancer (HNPCC)||MLH1, MSH2, MSH6||2x|
|Breast and Ovarian Cancer||BRCA1, BRCA2||10x|
|Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM)||p16||15-65x|
Although the risk of developing pancreatic cancer is much higher for individuals with a family history of the disease or for individuals harboring one of these genes, the absolute risk of developing pancreatic cancer is still quite low. The incidence of the disease among both men and women in the United States is only 12 per 100,000 people. Additionally, many people who do develop pancreatic cancer do not have any of the conditions listed above.
Pancreatic cancer often produces few symptoms in the early stages of the disease. Many symptoms of pancreatic cancer are vague and nonspecific in the beginning, so patients may ignore them. The best information available suggests that pancreatic cancer grows slowly for years before causing any symptoms at all, making it difficult for a patient or doctor to recognize a problem. There are several symptoms commonly associated with pancreatic cancer, but all of them are nonspecific and are more frequently caused by other conditions.
Obstructive jaundice develops when the bile duct is blocked and the bile backs up into the blood stream. Patients with jaundice have dark urine, often described as “cola” colored, light stools (clay colored), yellow eyes, and darkening of the skin. The bilirubin in the skin often causes pruritis (itching).
The most common cause, by far, of obstructive jaundice is a gallstone that has left the gallbladder and lodged in the common bile duct (the conduit from the liver and gallbladder to the small intestine). However, a cancer in the head of the pancreas can also obstruct the common bile duct, creating jaundice. While jaundice from a gallstone is usually associated with pain, pancreatic cancer is classically described as causing “painless jaundice.”
Although pancreatic cancer classically presents as “painless jaundice,” in fact, many patients with pancreatic cancer will experience abdominal or back pain.
Digestive difficulties including indigestion, nausea, weight loss, a poor appetite, and diarrhea are not uncommon in patients with pancreatic cancer and are likely due to direct involvement of a portion of the digestive tract by the tumor, or infiltration of the nerves to the digestive tract by the tumor. If the tumor blocks the digestive tract, the patient will suffer nausea, vomiting, and pain which may worsen after eating.
The pancreas makes enzymes that are necessary to breakdown the food that we eat so that it can be absorbed by the small intestine. Many patients with pancreatic cancer will not release enough pancreatic enzymes into the small intestine to properly digest their food, especially the fat that is eaten. This can be either due to poor function of the pancreas, or blockage of the pancreatic duct by the tumor, preventing the release of the enzymes into the intestine. Diarrhea results when the nutrients in food are not absorbed properly. When this occurs, stool may float due to the higher fat content, appear bulky, greasy, and unusually pale.
Just the presence of many tumors will cause weight loss, and pancreatic cancer is no exception. In addition to this, pancreatic cancer often causes indigestion, bloating and abdominal discomfort due to the local effects on the digestive system. Weight loss can be further exacerbated by a lack of pancreatic enzymes from obstruction or dysfunction of the pancreas.
Patients with pancreatic cancer can develop fluid in the abdomen which is called ascites. In patients with pancreatic cancer, the ascites has two potential causes. In patients with locally advanced disease, the cancer can obstruct the portal vein. In this situation, the blood draining from the intestine to the liver is blocked and the pressure that develops in the bowel causes fluid to leak into the abdomen. The second potential cause of ascites in patients with pancreatic cancer is from tumor that has spread into the peritoneal cavity (the sac that holds all of the abdominal organs). The fluid buildup can be massive and very uncomfortable and can even affect a patient’s breathing. Often the fluid can be controlled with medications (diuretics), but some patients will require drainage of the fluid (paracentesis). Although ascites can develop in patients with pancreatic cancer, there are many other causes such as cirrhosis.
New onset diabetes, or difficulty in maintaining normal blood sugar in a previously well-controlled diabetic, are warning signs for pancreatic cancer. Patients with diabetes do not make enough insulin to properly control their blood sugar. While, for some patients the blood sugar can be reduced by adjusting the diet, many patients with diabetes will require medication, either in the form of pills (oral hypoglycemic agents) or insulin injections. While new onset or worsening diabetes is a warning sign of pancreatic cancer, the vast majority of diabetics do not have and will never develop pancreatic cancer.
Detecting and diagnosing pancreatic cancer can be difficult, especially because the symptoms are not always obvious, often develop gradually, and can be mistaken for other conditions. At times, pancreatic tumors are found incidentally when a patient is exploring another medical condition. If pancreatic cancer is suspected, there are a variety of tests your doctor may perform. After assessing your situation, your doctor may then perform blood tests, order imaging studies, and/or biopsy the mass. These tests will help your doctor arrive at the most accurate diagnosis and help to direct your treatment plan.
Your evaluation will begin with a thorough medical history and physical examination focusing on signs and symptoms associated with pancreatic cancer. Questions will focus on your symptoms, any unintentional weight loss, smoking history and family history. The physical examination will begin with your eyes and skin, looking for signs of jaundice and then focus on your abdomen. Your doctor will check for masses or fluid buildup in the areas near your pancreas, stomach, liver, and gallbladder. Your doctor will search for signs of lymph nodes at the belly button or above the left collar bone.
After a history and physical, your doctor will order tests to secure the diagnosis. Tests commonly used in the workup and management of patients with pancreatic cancer are outlined below.
There is no currently available blood test that can be used to definitively diagnose pancreatic cancer. Despite this, several blood tests are helpful in the workup and management of patients with the disease, including liver function tests and certain tumor markers.
The liver function panel includes a measurement of the protein level (albumin), the bilirubin, the transaminases (AST and ALT), and the alkaline phosphatase. This panel is obtained early in the workup of patients with pancreatic cancer. Obstruction of the bile duct? will cause an elevation in the bilirubin level and the alkaline phosphatase level, and may cause an elevation in the transaminases. Because many patients with pancreatic cancer have lost considerable weight, the protein level and albumin level are often low.
Tumor markers are molecules produced by a cancer that are released into the blood stream and can be measured. The two tumor markers that are commonly used in the management of patients with pancreatic cancer are CA 19-9 and CEA.
CA 19-9 is a carbohydrate commonly released into the blood by pancreatic cancer, and can be used as a barometer reflecting response to therapy. In patients with a known diagnosis of pancreatic cancer, an elevated CA 19-9 that falls with therapy provides a good indication that the therapy is working. However, some benign conditions, like pancreatitis and jaundice, will elevate the CA 19-9 level in the absence of cancer. For this reason, CA 19-9 cannot and should not be used as a screening tool for pancreatic cancer. Furthermore, not every person or tumor is capable of making CA 19-9, so it is only useful in a subset of patients with pancreatic cancer. The normal range of CA 19-9 in the blood of a healthy individual is 0-37 U/mL (units/milliliter).
CEA (carcinoembryonic antigen) is a protein that is released into the blood by several gastrointestinal cancers. Initially described in colon cancer, CEA is also released by many pancreatic cancers, making it a useful tool in the management of many patients with pancreatic cancer. However, the CEA can be elevated by several other factors in the absence of cancer (most notably smoking), so it is not a useful screening tool. Like CA19-9, CEA is most useful as a tool to measure the effectiveness of therapy. A falling CEA suggests that the therapy is working, while a rising CEA suggests that the treatment strategy may need to be revised. The normal range of CEA is less than 2.5 ng/mL (nanograms per milliliter).
The CEA is also useful in the workup and diagnosis of pancreatic cysts. There are several different types of pancreatic cysts. When fluid is aspirated from a cyst and sent for biochemical analysis, the CEA can be measured. Mucin producing cysts, most of which are benign at presentation, have malignant potential. An elevation of the cyst fluid CEA (typically above 192 ng/mL) helps in making the diagnosis of a mucin-producing cyst. The absolute level of CEA within the cyst fluid has not, however, been correlated with the presence or risk of developing a cancer in that cyst.
CT scanning is almost always used in the evaluation and management of patients with pancreatic cancer. The computer reconstructs images in three different planes allowing your physicians to determine the location of the tumor and its relationship to the surrounding structure. It is important that patients have both oral and intravenous contrast during the exam for accurate evaluation. The best quality images are obtained when the scan is timed properly to assess the arteries and veins around the pancreas and within the liver. During the exam, the patient lies on a table that moves through a ring shaped imager. CT scans do involve the use of ionizing radiation.
Alert: Some patients are sensitive to the intravenous contrast dye that is used for CT scans. CT scanning without the IV contrast has little utility for patients with pancreatic cancer. Many patients with a contrast sensitivity can safely receive the dye after being pre-medicated. Patients with a severe allergy to the dye will need to be evaluated using another imaging modality.
Also, the dye used for CT scans can affect kidney function. Many patients with mild renal insufficiency can safely undergo CT scanning with intravenous contrast, but some will require an alternative imaging modality.
MRI scans use radio waves and powerful magnets to produce images of the body and is often used in the evaluation of patients with pancreatic cancer. An MRI produces detailed cross-sectional images of the body in three different planes. In many respects, CT and MRI provide similar images, but the MRI gives the radiologist more options for altering the sequences to obtain images for specific purposes
An MRI exam can take up to an hour and a half and requires the patient to lie on a bed within a narrow tube. The machine often also makes a loud banging noise during the scan. Image quality is highly dependent upon the patient’s ability to lie still for the test and to hold their breath for short periods of time. Also, some patients feel claustrophobic within the machine and may require a mild sedative to tolerate the exam. Finally, many types of metal (including pacemakers) cannot be taken into the MRI machine. Certain medical devices that are made out of metal are specially designed to be MRI compatible (such as the metal stents used in bile ducts). Finally, an open MRI is generally not powerful enough to produce useful images of the abdomen. An MRI does not use ionizing radiation.
The most commonly used staging system for pancreatic cancer was developed by the American Joint Committee on Cancer (AJCC) and is outlined in the table below.
|Stage 0: Carcinoma in situ. This is not yet a cancer, but it is the final step in the transformation process from normal pancreas to cancer. The individual cells in carcinoma in situ look identical to cancer, but they have not yet become invasive and at this stage they do not yet have the ability to invade and spread to other organs.|
|Stage I: Invasive cancer stage that is confined to the pancreas only.|
|Stage IA:||The tumor is 2 centimeters or smaller and limited to the pancreas only|
|Stage IB:||The tumor is larger than 2 centimeters, but limited to the pancreas only|
|Stage II: Invasive cancer that has locally grown beyond the pancreas to involve adjacent organs but does not involve local blood vessels or distant parts of the body.|
|Stage IIA:||Cancer has not spread to local lymph nodes but has spread to nearby organs and tissue|
|Stage IIB:||Cancer has spread to local lymph nodes and may have spread to nearby organs and tissue|
|Stage III: Any invasive cancer that the surgeon cannot remove because of involvement of the local major blood vessels, but which has not yet spread to distant organs. Also called 'locally advanced', 'borderline', or 'inoperable.'|
|Stage IV: The cancer has spread outside of the pancreas to other parts of the body (most often the liver).|
While the staging system may appear confusing at first, it is heavily dependent upon whether or not a tumor can be removed by the surgeon, because the patients who do the best and live the longest are the ones in which the tumor can be removed surgically. Stage I is a tumor that is limited to the pancreas. Patients seldom present with stage I disease. Stage II is any tumor that the surgeon can remove. If there is no disease in the lymph nodes, then the stage is IIA. If there is disease in the lymph nodes, the stage is IIB. Stage III is a tumor that involves the local blood vessels preventing the surgeon from safely removing the tumor, but has not spread to a distant site. Sage IV is when the pancreatic cancer has spread to other organs (such as the liver or the lungs).
A patient's treatment plan will depend on the stage of the disease. Patients with Stage I or II disease will be offered surgical removal of the tumor. Patients with stage III will undergo chemotherapy and or radiation therapy in an effort to make the tumor operable. If the surgeon is ultimately able to remove the tumor, then the patient will have successfully been converted from stage III to stage II. The primary mode of therapy for patients with Stage IV disease is systemic chemotherapy.
Over the past two decades, pancreatic surgery has undergone dramatic improvement, which has made the operations much safer and better tolerated. Advances in surgical technique have also allowed surgeons to offer surgery to an ever increasing subset of patients with pancreatic cancer. Despite this, these procedures remain complex and have several associated complications. Because of this, your best outcomes will be achieved under the care of an experienced pancreatic surgeon.
The Whipple procedure is typically performed on patients with tumors in the head of the pancreas. In this operation, the surgeon removes the tumor with the head of the pancreas and the first portion of the small intestine, called the duodenum. The gallbladder is also removed during the surgery. In a classical Whipple, the lower third of the stomach is also removed. A more recent modification of the Whipple procedure (the pylorus preserving Whipple) preserves the entire stomach. Once the tumor is removed with the surrounding structures, the remnant of the pancreas (the neck, body, and tail of the gland), the bile duct and the stomach are sewn into the remaining small intestine.
A Whipple procedure typically requires between 4 and 6 hours to complete. When patients wake up from the surgery, they will have two temporary tubes coming out of the abdomen. One is a surgical drain that is placed next to all of the new connections. About 5% of patients will leak from one of the new connections. If this occurs, it almost never requires returning to the operating room. However, all of the leaking fluid does need to be aspirated. Patients get sick with infection if the fluid is allowed to pool in the abdomen. The leaking fluid is typically captured by the drain which can be removed in the office about a month after the surgery once the leak has sealed.
The second tube coming out of the abdomen comes directly out of the stomach and is called a gastrostomy tube. The stomach tends to be lazy after a Whipple procedure; it often does not empty well in the early postoperative period. Most patients are eating solid food by about a week after surgery. However, up to 15% of patients will have delayed return of their stomach function. The stomach needs to be well drained until it is functioning. The gastrostomy tube is the most comfortable and safest way to achieve this. Most patients return home with the gastrostomy tube taped to their sides. After two weeks, the surgeon can safely remove the tube in the office with minor, if any, discomfort.
This operation also carries a 2% risk of bleeding that would require a return to the operating room and about a 5% risk of infection (wound infection, urinary tract infection, abdominal abscess). These infectious complications are aggressively managed until they resolve. There is also a risk of blood clots developing in the leg veins. Both cancer and surgery increase this risk. For this reason patients are kept on low dose blood thinners for their entire hospital stay.
The pancreas has two functions. One is to make insulin to control the blood sugar. The Whipple procedure removes part of the pancreas and, thus, some of the insulin producing cells (beta islet cells). Patients with normal preoperative blood sugar who undergo this operation have about a 10% chance of developing diabetes, which would require insulin injections to manage. Patients who have diet-controlled diabetes before the surgery have a higher chance of needing insulin after the operation, and almost all patients who are taking an oral hypoglycemic agent preoperatively will require insulin to control their blood sugar after the operation.
Patients can expect to stay in the hospital for 7 to 10 days after the surgery. What keeps patients in the hospital the longest is waiting for their stomach function to return. Once home, the full recovery is expected to take about two months.
The body and tail of the pancreas are removed during a distal pancreatectomy. The end of the pancreas is then over-sewn or stapled closed and the pancreatic fluid drains normally into the duodenum. Depending on the location of the tumor, its relationship to the major vascular structures, the type of tumor and the body habitus of the patient, this can be achieved using three different approaches. The traditional approach is performed through an abdominal incision, usually under the ribs on the left side. This approach is usually needed for large malignant tumors or those that involve the local blood vessels. Smaller, less aggressive and more distal tumors in the tail of the pancreas are often amenable to a minimally invasive approach (either laparoscopic or robot-assisted). In this approach, the procedure is performed through 4 smaller port sites, one of which needs to be extended for extraction of the specimen. The minimally invasive approach offers patients less pain, a smaller scar, and a quicker recovery. This approach is employed when it is safe and feasible without compromising the oncologic outcome for the patient. About 10% of the time a minimally invasive procedure needs to be converted to a traditional open approach for the safety of the patient.
The blood supply to the spleen runs through the back of the tail of the pancreas. If the tumor is involving these vessels, then the vessels with the spleen will also need to be removed during the distal pancreatectomy. If the blood supply to the spleen is not compromised by the tumor, then the spleen can often be preserved.
The spleen is a large lymph node that is important in education of a child’s immune system. In adulthood, the spleen only protects us from three specific bacteria (Pneumococcus, Neisseria meningitidis, and Haemophilus influenzae) all of which can be prevented with vaccines. Patients that have their spleens removed will need to be vaccinated against these organisms every 5 years.
A distal pancreatectomy takes about 3 hours to complete. There is a risk of bleeding after the surgery, requiring a return to the operating room. Minor infections can also occur. The most common complication following the procedure is leaking of pancreatic juice out of the back of the gland. This is usually not a dangerous complication, because the pancreatic enzymes are not activated. But the fluid does tend to collect behind the stomach causing local inflammation and making it difficult to eat. Many times these fluid collections will resolve on their own, but in some cases, a temporary drain will need to be placed either by a radiologist or a biliary endoscopist to clear the collection and improve symptoms.
When a benign or low grade tumor is located within the neck of the pancreas, it may be amenable to a central pancreatectomy. In this procedure, the middle portion of the gland is removed. The part of the pancreas towards the duodenum is over-sewn and will drain normally into the small intestine. The disconnected tail of the gland is then sewn into either the back of the stomach or the small bowel so that the digestive enzymes that are produced by that portion of pancreas can enter the lumen of the GI tract and be used for digestion. This procedure is done in an effort to spare as much of the normal pancreas as possible and reduce the risk of postoperative diabetes and pancreatic insufficiency (needing to take supplemental enzymes to properly digest food).
A central pancreatectomy requires between 2 and 4 hours to complete. Potential complications include bleeding and infection, as with the distal pancreatectomy. Patients can also leak from the new connection between the tail of the pancreas and the GI tract, making the overall complication rate a little higher than a distal pancreatectomy. However, the reduction in the rate of postoperative diabetes usually justifies the slightly higher surgical complication rate for this procedure.
This operation, which takes from 4 to 6 hours, is a combination of the Whipple procedure and a distal pancreatectomy such that entire pancreas is removed with the first portion of the small intestine called the duodenum, and the gallbladder. Often the spleen is removed as well. Once the tumor and the organs are removed, the bile duct and the stomach are reconnected to the small intestine.
Patients who have their entire pancreas removed will have a lifelong dependence on insulin to control their blood sugar, and oral pancreatic enzymes to properly digest their food.
The length of hospitalization depends on the specific procedure performed and the approach that was undertaken (traditional versus minimally invasive), but most patients will be in the hospital for anywhere from 3 days (minimally invasive distal pancreatectomy) to 10 days (Whipple). Once home, the full recovery is expected to take 6 to 8 weeks. Your body has to work hard to recover from the operation, and many patients will feel fatigued. During this period of time, patients struggle the most with eating. After pancreatic surgery, patients can expect to have a reduced appetite, and fill up quickly when eating. Many patients are not hungry and experience symptoms of nausea and bloating. Although the early postoperative period can be challenging, most patients will experience marked improvement in these symptoms by 2 months after the operation.
When recovering from a pancreatic operation, patients do best when they set the goal to eat small, frequent meals/snacks every three hours. In general, fat should be avoided and protein-containing foods are the best. In the early postoperative period, the most important thing is to stay well-hydrated. Many patients benefit from working with our clinical nutritionist throughout the course of their disease, especially when recovering from surgery.
When patients wake up from the surgery there will be a (temporary) drain in the stomach that comes out of the abdomen through the abdominal wall. This is called a gastrostomy or G-tube. It will be hooked up to a bag to continuously drain the stomach. For the first one to two days following the surgery, the tube will be left open to drain into the bag. During this initial period, patients are encouraged to drink anything that light can be seen through (clear liquid diet). During this initial phase, the stomach is being rested by the drainage. On or around postoperative day 2, the surgical team will ask the patient not to eat or drink anything and the nurse will clamp the gastrostomy tube for intervals of 6 hours. After 6 hours, the clamp will be removed and the nurse will measure the amount of residual fluid in the stomach. The stomach itself secretes about one to two liters (one to two quarts) of fluid a day. So, if the stomach is emptying, then the residuals should be low (less than 300 cc) after a 6 hour clamp. Once a low residual is seen, the tube will be clamped for a full 24 hours. If the residual remains low after the 24 hours of clamping, then the tube is kept clamped and the patient’s diet is advanced, first with liquids and then with solid food as tolerated.
Most patients are able to tolerate solid food by about a week after the surgery. Waiting for the stomach to function is typically what keeps most patients in the hospital the longest. Once home, patients do the best by eating small frequent meals throughout the day.
Chemotherapy is the use of medications to kill cancer cells. Some chemotherapeutic agents are taken as oral medications, while most are given as an intravenous infusion. The drugs enter the bloodstream and are systemically delivered to most of the organs and tissues in the body. Chemotherapy generally attacks rapidly dividing cells, which are found in cancer. However, the drugs will also destroy some normal cells in the body that are also rapidly dividing, which accounts for many of the unpleasant side effects of these medications. Normal rapidly dividing cells in the body include hair follicles and the lining of the gastrointestinal tract, which accounts for the hair loss and gastrointestinal distress often encountered when being treated with chemotherapy drugs.
There are multiple chemotherapy regimens that have proven efficacy in treating patients with pancreatic cancer. Most of the regimens are based on a drug called gemcitabine (trade name Gemzar). Most centers add additional drugs to the gemcitabine-based therapy to increase the response to therapy. A second common regimen is called FOLFIRINOX, which is often reserved for younger patients because of the considerable toxicity associated with the treatment. Increasingly, new agents are being tested and are becoming available for patients with pancreatic cancer. One recently approved drug -- erlotinib (trade name Tarceva) -- has been added to the regimen of appropriate patients.
Ongoing clinical trials are available to test new regimens and new drugs. Enrolling in a clinical trial is not guaranteed to help an individual patient, but it will certainly help physicians make treatment for pancreatic cancer safer and more effective for patients in the future. For more information about available clinical trials at Winthrop click here.
Chemotherapy given after an operation is called adjuvant. Chemotherapy delivered prior to an anticipated operation to remove the tumor is termed neoadjuvant. And chemotherapy given to patients with metastatic disease is called palliative.
Some patients with pancreatic cancer will be treated with radiation therapy, which is often combined with a low dose of chemotherapy designed to enhance the susceptibility of the cancer to the x-ray treatment. Like surgery, radiation is a form of local therapy, and the treatment is only delivered to a specified area of the body that is predetermined and mapped out by the radiation oncologist. Like chemotherapy, this can be used in an adjuvant or neoadjuvant setting. It can also be used for palliation to stop slow bleeding from a tumor into the gastrointestinal tract.
Traditional abdominal radiotherapy is administered in multiple small fractions over a period of 5 weeks. New approaches and better technology have been developed and are being used to decrease the number of sessions required and to decrease the amount of radiation that is delivered to the normal organs and tissues in the body.
The side effects of radiation therapy are typically isolated to the treatment area. Some common side effects associated with radiation therapy to the abdomen include nausea, vomiting, and diarrhea. These side effects may occur a few days or weeks after radiation treatments have started, and may continue for several weeks after completing the treatments. The side effects typically subside over time after the treatments are completed.
Malignant tumors in the head of the pancreas often obstruct the bile duct and produce jaundice, which is a yellowing of the skin and eyes that often causes itching. Even if the tumor cannot be surgically removed, the obstruction of the bile duct can be relieved by a variety of methods to resolve the jaundice. The mainstay of bile duct decompression is endoscopic placement of a stent. Plastic stents typically will stay open for about 6 to 8 weeks before needing to be changed. These are often used when the patient is expected to go to surgery to remove the tumor within a couple of weeks of the endoscopy. Patients that require a longer period of stenting typically will have a metal stent placed, which will stay open for a year or more.
If endoscopic attempts at relieving biliary obstruction fail, the patient may have an external drain placed through the abdominal wall into the bile duct directly through the liver (percutaneous transhepatic cholangiocatheter or PTC). This is less desirable because the patient’s bile will collect in a bag that is external.
Finally, the bile duct can be bypassed surgically by sewing the small intestine into the bile duct above the level of the obstruction. This is needed less frequently, as non-operative approaches have become more feasible and durable.
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