Pancreatic Cancer

An adenocarcinoma of the pancreas is the most common type of pancreatic cancer.

What is the medical definition of the pancreas?

The pancreas is an organ in the upper abdomen located beneath and behind the stomach and adjacent to the first portion of the small intestine, called the duodenum. The pancreas is composed of glands that are responsible for a wide variety of tasks. The glandular functions of the pancreas can be divided into the following two categories:

• Exocrine: The exocrine glands secrete enzymes into ducts that eventually empty into the duodenum. These enzymes then help in the digestion of food as it moves through the intestines.
• Endocrine: The endocrine glands secrete hormones, including insulin, into the bloodstream. Insulin is carried by the blood throughout the rest of the body to assist in the process of using sugar as an energy source. Insulin also controls the levels of sugar in the blood.

The pancreas can be divided into the following four anatomical sections:

• Head -- The rightmost portion that lies adjacent to the duodenum
• Uncinate process -- An extension of the head of the pancreas
• Body -- The middle portion of the pancreas
• Tail -- The leftmost portion of the pancreas that lies adjacent to the spleen

What are the most common types of pancreatic cancer?

• The most common type of pancreatic cancer arises from the exocrine glands and is called adenocarcinoma of the pancreas.
• The endocrine glands of the pancreas can give rise to a completely different type of cancer, referred to as pancreatic neuroendocrine carcinoma or islet cell tumor.

What are issues related to the more common type of pancreatic adenocarcinoma?

• Pancreatic adenocarcinoma is among the most aggressive of all cancers. By the time that pancreatic cancer is diagnosed, many people already have disease that has spread to distant sites in the body (about 53%).
• Pancreatic cancer is also relatively resistant to medical treatment, and the only potentially curative treatment is surgery. For 2018, the American Cancer Society predicted that approximately 55,000 people in the United States will be diagnosed with pancreatic cancer, and approximately 44,000 people will die of this disease. These numbers reflect the challenge in treating pancreatic cancer and the relative lack of curative options.

The main recognized risk factors for pancreatic cancer include the following:

• Smoking (most common environmental risk factor)
• Obesity
• Advanced age
• Male sex -- The male-to-female ratio of pancreatic cancer is 1.3:1.
• Chronic pancreatitis -- Inflammation of the pancreas, usually from excessive alcohol intake or gallstones
• Diabetes mellitus
• Family history of pancreatic cancer and many other genetic factors such as mutation in KRAS2 gene and a history of familial adenomatous polyposis
• Consumption of red meat
• Black males in the U.S. have the highest rates of pancreatic cancer. The incidence of pancreatic cancer is 50% to 90% higher in African Americans than in any other racial group in the U.S.A.

The initial signs and symptoms of pancreatic cancer are often nonspecific and have a gradual or slow onset. The main symptoms of pancreatic cancer include the following:

• Pain in the abdomen, the back, or both; often the pain becomes constant
• Weight loss, often associated with the following:
  • Loss of appetite (anorexia)
  • Bloating
  • Diarrhea or fatty bowel movements that float in water (steatorrhea)
  • May present with new diabetes diagnosis (within the first year) in a person with weight loss and nausea
• Jaundice (yellowing of the skin)
• Pruritis
• Enlarged gallbladder
• Abdominal problems (ascites, abdominal mass)
• Depression
• Venous thrombosis
• Palpable lymph nodes (cervical, supraclavicular)

The symptoms of pancreatic cancer are generally vague and can easily be attributed to other less serious and more common conditions. This lack of specific symptoms explains the high number of people who have a more advanced stage of disease when pancreatic cancer is discovered.

The stage of cancer refers to how far it has spread throughout the body. Like with other types of cancer, pancreatic cancer has several stages, as outlined below.

• Stage 0: There has been no spread, and the cancer is only limited to the top layers of cells in the pancreas ducts. 
• Stage I: There is only local growth, which means the pancreatic cancer is limited to the pancreas but has grown to
  • less than 2 cm across (stage IA) or
  • greater than 2 but no more than 4 cm (stage IB).
• Stage II: The cancer is over 4 cm and is either
  • limited to the pancreas or
  • there is local spread where the cancer has grown outside of the pancreas, or has spread to nearby lymph nodes, but not distant organs or sites.
• Stage III: The tumor may have spread to major blood vessels or nerves, but has not metastasized to distant sites.
• Stage IV: The cancer has spread to other organs.

Seeking immediate medical attention is important if any of the symptoms of pancreatic cancer occur. If pain, unexplained weight loss, or jaundice persists despite initial medical treatments, further evaluation should be pursued in a timely fashion.

A person who has been diagnosed with pancreatic adenocarcinoma should ask the doctor the following questions:

• Where is my cancer located?
• How far has the cancer spread?
• What treatment options do I have?
• What is the overall goal of treatment in my case?
• If the expectation of therapy is not to cure the cancer, then when should I consider hospice or palliative care and what do I need to know about advance directives?
• What are the risks and side effects of the proposed treatment?
• Am I eligible for a clinical trial? How do I find out?

On physical exam, the doctor may feel a mass in the center of the abdomen. However, pancreatic cancer is seldom diagnosed using a physical exam, and the absence of any abnormalities should not dissuade the doctor from obtaining an imaging test if the symptoms of pancreatic cancer are present and persistent. The main imaging tests used to help detect pancreatic cancer are as follows:

• Abdominal ultrasound: This may be the initial test if a person has abdominal pain and jaundice. This test is effective at looking for gallstones, a common condition that presents with similar symptoms as that of pancreatic cancer. If a pancreatic tumor is seen on ultrasound, a CT scan is still necessary to obtain more information.
• Abdominal computed tomography (CT): This is the test of choice to help diagnose pancreatic cancer. A CT scan can locate small tumors in the pancreas that might be missed by ultrasound. In addition, a CT scan can accurately show whether the mass has extended beyond the pancreas and what the relation is to nearby blood vessels and organs -- information vital to a surgeon planning an operation to remove the cancer. If a pancreatic tumor is suspected, then a specialized CT scan, called a pancreatic protocol scan, is preferred prior to surgery.
• Other tests include MRI, positron emission tomography (PET scan), and endoscopic techniques.

If a tumor is seen in the pancreas, the doctor may want to perform a biopsy so that a pathologist can confirm that the mass is cancer. A biopsy can be performed in the following ways:

• Percutaneous biopsy: This refers to a biopsy performed by inserting a needle through the skin into the body. A radiologist usually performs this procedure while using an ultrasound or CT scanner to guide the needle into the tumor. The procedure is generally painless.
• Endoscopic biopsy: A gastroenterologist performs this procedure by inserting a flexible tube with a camera at the tip (called an endoscope) through the mouth, into the stomach, and then into the duodenum. From here, a needle biopsy can be obtained with guidance from an ultrasound at the tip of the endoscope. A person is heavily sedated for this procedure, and it is generally painless.

If a tumor is seen in the pancreas and little doubt exists that the tumor is cancer, a surgeon may choose to attempt to remove the cancer completely without first obtaining a biopsy.

Once the diagnosis of pancreatic cancer is confirmed, routine blood studies are also performed to assess overall liver and kidney function.

In addition, a blood test called CA 19-9 is obtained. CA 19-9 is often produced by pancreatic cancers, and its level is elevated in about 80% of pancreatic cancer cases. The CA19-9 can not be used to establish a diagnosis of pancreatic cancer by itself. Checking the CA 19-9 levels can be a useful gauge of how the treatment is working.

After treatment, the doctor may check the CA 19-9 levels regularly in patients in whom the test was originally elevated, then fell, as one indicator of whether the cancer has returned after surgery or progressed on prior treatment. However, CA 19-9 is not an absolute test for pancreatic cancers, and other conditions may cause a rise in the CA 19-9 levels. Likewise, a normal or unchanged CA 19-9 level is not a guarantee that the cancer has not returned or progressed.

New research findings released in 2016 may change aspects of pancreatic cancer. Researchers reported genomic analysis of 456 pancreatic ductal adenocarcinomas. Subsequent genetic expression analysis of these adenocarcinomas allowed them to be defined into four subtypes. These subtypes have not been previously discerned. The following is a list of these four new subtypes:

• Squamous: These types of tumors have enriched TP53 and KDMA mutations.
• Pancreatic progenitor: These types of tumors express genes involved in pancreatic development such as FOXA2/3, PDX1, and MNX1.
• Aberrantly differentiated endocrine exocrine (ADEX): These tumors show upregulation of genes (KRAS) and exocrine (NR5A2 and RBPJL) and endocrine (NEUROD1 and NKX2-2) differentiation.
• Immunogenic: These tumors contain pathways that are involved in acquired immune suppression.

These findings may allow future pancreatic cancer patients to be treated more specifically and, hopefully, more effectively. For example, the people with the immunogenic subtype could possibly respond to therapy where the immune system is re-engineered to attack this particular type of pancreatic cancer cell.

Pancreatic Cancer Treatment

The optimal treatment of pancreatic adenocarcinoma depends on the extent of the disease. The extent of cancer can be divided into the following three categories:

• Localized: The cancer is completely confined within the pancreas.
• Locally advanced: The cancer has extended from the pancreas to involve nearby blood vessels or organs by direct extension.
• Metastatic: The cancer has spread outside the pancreas to other parts of the body.

Surgery is the primary -- and likely the only curative -- treatment for pancreatic cancer. Most patients are unable to undergo a potentially curative operation. When such surgery is performed, but the pathology findings on the surgical specimens obtained do not appear favorable, then further treatment is often recommended in an attempt to reduce the likelihood of relapse and thereby increase the chance of a cure. This is called adjuvant therapy. Such treatment usually involves chemotherapy with or without radiation therapy.

Factors that increase the risk that the cancer may return after surgical removal are as follows:

• Tumor present at the edge of the surgical specimen (referred to as a positive margin)
• Tumor present within blood vessels or lymph channels
• Tumor tracking along nerves
• Surrounding lymph nodes containing cancer

Options for adjuvant therapy include the following:

• Chemotherapy and radiation therapy given simultaneously
• Chemotherapy alone

No standard recommendation is available for adjuvant therapy, and it remains an area of intense clinical research. Enrolling in a clinical trial should be considered.

For locally advanced pancreatic cancer that cannot be surgically removed safely, a combination of chemotherapy and radiation therapy or chemotherapy alone may be offered. This treatment remains controversial, and various centers have different recommendations based on a number of factors such as size of the disease and symptoms.

Chemotherapy is the cornerstone of treatment of pancreatic cancer that is locally advanced or metastatic. The chemotherapy agent most commonly used in this setting is gemcitabine (see Medications). However, in a 2013 study, a new oral agent termed S-1 (fluoropyrimidine S-1), when compared to gemcitabine showed remarkably better survival rates and may become the new drug that will offer higher survival rates to patients. There is a higher likelihood of benefit in cases of widespread or metastatic pancreatic cancer using combinations of chemotherapy drugs.

At specific intervals while a person is receiving treatment, imaging studies are repeated to help evaluate whether the tumor is getting smaller or bigger. If a time comes when the tumor grows despite chemotherapy, it may indicate that the cancer has become resistant to this particular therapy and an alternative plan needs to be considered.

The following chemotherapy drugs may be included as part of the treatment regimen depending on the stage of pancreatic cancer:

• S-1, a new chemotherapy oral agent, may replace gemcitabine (see below) as the most effective chemotherapeutic drug to treat pancreatic cancer.
• Gemcitabine (Gemzar): Gemcitabine is given intravenously once a week for 7 weeks (or until toxicity limits treatment), and then no treatment is given for 1 week. Then, cycles are resumed of gemcitabine once each week for 3 weeks in a row followed by 1 week off. This drug has direct effects on the cancer cells and is usually given alone for the treatment of metastatic pancreatic cancer. Side effects include fatigue, nausea, increased risk of infection because of its effects on the immune system, and anemia.
• Fluorouracil (5-FU): Fluorouracil is usually given intravenously as a continuous infusion using a medication pump. This drug has direct effects on the cancer cells and is usually used in combination with radiation therapy because it makes cancer cells more sensitive to the effects of radiation. The side effects include fatigue, diarrhea, mouth sores, and hand-and-foot syndrome (redness, peeling, and pain on the palms of the hands and the soles of the feet).
• Capecitabine (Xeloda): Capecitabine is given orally and is converted by the body to a compound similar to 5-FU. Capecitabine has similar effects on the cancer cells as 5-FU and is also generally used in combination with radiation therapy. Side effects are similar to intravenous continuous infusion of 5-FU.
• Oxaliplatin: This has been used in combination with 5-FU. It can cause some unusual effects on the nervous system, including cold sensitivity.
• Irinotecan: This has been used together with 5-FU and oxaliplatin in the FOLFIRINOX combination. It can cause diarrhea in some cases.
• Nab-paclitaxel (Abraxane): This has also shown some benefit in combination chemotherapy for this disease. This agent may also lower blood counts, as can virtually all of the chemotherapy agents discussed.

Currently, many other drugs are being investigated for the treatment of pancreatic cancer. These drugs include bevacizumab, vatalanib, cetuximab, and erlotinib. Whether any of these drugs will improve the results obtained with gemcitabine alone is not yet known. Other drugs like S-1 may be found to increase survival times. Enrollment in clinical trials is encouraged.

Medications are available to alleviate the side effects of the treatments. If side effects occur, an oncologist should be notified so that they can be addressed promptly. An oncologist also monitors blood and urine for signs of toxicity.

Pancrelipase (pancreatic enzyme replacement) may be given if the function of the pancreas is impaired, usually after the surgical removal of a portion of the pancreas. This oral medication is taken with meals to aid in the digestion of food and in the prevention of a problem with absorption of nutrients called steatorrhea.

Pain may be associated with pancreatic cancer, and a variety of pain medications exist to help control any discomfort. Good communication with the oncologist and nurses allows for optimal management of pain.

The treatment of pancreatic cancer depends on whether complete surgical removal of the cancer is possible. Complete surgical removal of the cancer is the only known cure for pancreatic cancer. Only 15% to 20% of people with pancreatic cancer have disease that can be surgically removed at the time of diagnosis.

Pancreatic cancer that is localized and may be completely removed is considered resectable. If all the cancer could not be removed with surgery or if a surgery would not be safe to perform, then the cancer is considered unresectable.

The features of unresectable pancreatic cancer include the following:

• The cancer has spread (metastasized) outside of the pancreas to other organs (for example, liver or lungs).
• The cancer is wrapped around one of the major blood vessels near the pancreas.

If the cancer is resectable and if no other health issues exist that make the surgery unsafe, then a surgeon attempts to remove the cancer.

• Whipple procedure: This is done when the pancreatic cancer is in the head or uncinate process. This procedure removes the head and uncinate process of the pancreas, the duodenum, and the gallbladder. A portion of the stomach is often removed as well.
• Distal subtotal pancreatectomy: This is performed when the pancreatic cancer is in the body or tail of the pancreas. This procedure removes the body and tail of the pancreas as well as the spleen.

These are major surgeries with the risk of both intra-operative and postoperative complications. Mortality rates are lower if the surgery is performed in a center where a lot of pancreatic surgeries are performed. Centers that have a low volume of pancreatic surgeries can produce as high as a 10% to 15% mortality rate. Those centers with a high volume of pancreatic surgeries may produce as low as a 2% mortality rate.

Radiation therapy

Radiation therapy is treatment that uses high-energy X-rays aimed at the cancer to kill cancer cells or to keep them from growing. For pancreatic cancer cases, radiation therapy is usually given in conjunction with chemotherapy.

The goals of radiation therapy are as follows:

• Kill cancer cells that cannot be surgically removed to reduce the risk of the cancer returning or spreading.
• Treat tumors that cannot be surgically removed and that are causing symptoms, such as pain or jaundice.

Typically, radiation treatments are given 5 days a week, for up to 6 weeks. Each treatment lasts only a few minutes and is completely painless; it is similar to having an X-ray film taken. However, some patients may experience nauseam diarrhea, heartburn, and related problems during the last few weeks of therapy or for several months following completion of treatment. Today, medications control those symptoms far better than they used to do.

The main side effects of radiation therapy include mild skin irritation, loss of appetite, nausea, diarrhea, or fatigue. These side effects usually resolve soon after treatment is complete (within 1 to 2 months).

Other therapy

Pancreatic cancer may cause symptoms that cannot always be relieved by surgery, chemotherapy, or radiation therapy. These symptoms include the following:

• Pain
• Jaundice from obstruction of the bile duct

Therapies aimed at relieving the symptoms of pancreatic cancer, but not at treating the cancer itself, include the following:

• Celiac plexus neurolysis (CPN): Sometimes referred to as a celiac block, celiac plexus neurolysis involves an injection of a chemical (usually alcohol) into the collection of nerves in the back of the abdomen, but in the front of the spine called the celiac plexus that receives pain signals from the pancreas. This chemical injection damages or numbs these nerves and reduces the sensation of pain caused by a pancreatic tumor.
  • The injection is performed either using an endoscope with ultrasound guidance or through the skin using a CT scanner for guidance.
  • Side effects include temporary diarrhea and lowering of blood pressure; abdominal pain occurs during and immediately after the procedure.
• Biliary stenting: This involves placing a hollow tube, called a stent, into the bile duct to keep it open despite the external pressure from a growing pancreatic tumor. This prevents jaundice by allowing the bile to flow freely and unimpeded from the liver, past the pancreas, and into the intestine. This procedure is usually performed with an endoscope by a gastroenterologist, but it can also be performed percutaneously (through the skin) under CT guidance by an interventional radiologist.

Because pancreatic cancer has a risk of returning after surgical or adjuvant medical therapy, continuous vigilant follow-up with the doctor is important. On a routine schedule recommended by the doctor, the following are performed:

• Physical exams
• Blood studies, including CA 19-9
• Periodic imaging studies, usually CT scans at 6-month intervals or earlier if needed to assess new symptoms

No known preventative measure exists for pancreatic cancer; however, minimizing certain risk factors is important. Risk factors that can be controlled include limiting smoking and excessive alcohol intake.

Pancreatic Cancer Prognosis

Despite recent advances in the surgical and medical treatment of pancreatic cancer, the prognosis associated with this disease is still relatively poor.

For people who have pancreatic cancers completely removed by surgery, the probability of being alive in 5 years is 20% to 30%. If lymph nodes were found to contain cancer at the time of surgery, then the probability of being alive in 5 years decreases to 10%.

The addition of chemotherapy after surgical removal of the pancreatic cancer is likely to increase this probability of being alive in 5 years, but only by about 10%.

For people who have unresectable locally advanced pancreatic cancer, surviving beyond 3 years is rare. For those with metastatic pancreatic cancer who have symptoms of weight loss or pain, the chance of surviving 1 year is less than 20% for those undergoing chemotherapy and less than 5% for those who choose not to receive chemotherapy.

These statistics underscore the importance of clinical trials attempting to discover more effective therapies for this disease. People with pancreatic cancers are encouraged to ask their doctor about the possibility of participating in a clinical trial that is well-suited for them.

Being diagnosed with cancer is a physically and emotionally trying experience. Many avenues for support exist within the local community and beyond, both for the patient and for the patient's family and friends. The American Cancer Society has information on many local support groups. In addition, social workers, counselors, psychiatrists, and clergy can also be helpful in providing information and companionship through difficult times caused by the cancer.