Treatment of pancreatic cancer
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Surgery

images-14.jpegThere are 2 general types of surgery used for pancreatic cancer:
Potentially curative surgery is used when imaging tests suggest that it is possible to remove all the cancer.
Palliative surgery may be done if imaging tests show that the tumor is too widespread to be completely removed. This is done to relieve symptoms or to prevent certain complications like a blocked bile duct or intestinal tract.
Several studies have shown that removing only part of the cancer does not help patients to live longer. Pancreatic cancer surgery is one of the most difficult operations a surgeon can do. It is also one of hardest for patients to undergo. There may be complications and it may take several weeks for patients to recover. Patients need to weigh the potential benefits and risks of such surgery carefully.

Potentially curative surgery

Most curative surgery is designed to treat cancers at the head of the pancreas. Because these cancers are near the bile duct, some of them cause jaundice and are found early enough to be removed. Surgeries for other parts of the pancreas are mentioned below, but these are only done when it’s possible to remove all of the cancer.
There are 3 procedures used to remove tumors of the pancreas:

Whipple procedure

Pancreaticoduodenectomy: This is the most common operation to remove a cancer of the exocrine pancreas. It involves removing the head of the pancreas and sometimes the body of the pancreas as well. Part of the stomach, small intestine, and lymph nodes near the pancreas are also removed. The gallbladder and part of the common bile duct are removed and the remaining bile duct is attached to the small intestine so that bile from the liver can continue to enter the small intestine.

This is a complex operation that requires much skill and experience. It carries a relatively high risk of complications that may even be fatal. When the operation is done in small hospitals or by doctors with less experience, more than 15% of patients may die as a result of surgical complications. In contrast, when this operation is performed in cancer centers by surgeons experienced in the procedure, less than 5% of patients die as a direct result of complications from surgery. Still, even in the best of hands, many patients suffer complications from the surgery. These can include:

  • Leaking from the various connections that the surgeon has to make
  • Infections
  • Bleeding
  • Trouble with the stomach emptying itself after eating

For patients to have the best outcomes, they should be treated by a surgeon who does many of these operations. In general, people having this type of surgery do better when it is performed at a hospital that does at least 20 Whipple procedures per year.
At the time of diagnosis, only about 10% of cancers of the pancreas appear to be contained entirely within the pancreas. Only about half of these turn out to be truly resectable once the surgery is started. Still, even if all the visible tumor is removed at the time of surgery, some cancer cells may have already spread to other parts of the body. These cells may eventually grow into new tumors and cause many problems -- even death. Among patients who have surgery with the intent of completely removing a cancer of the exocrine pancreas, the 5-year survival rate is about 20%.

Distal pancreatectomy

This operation removes only the tail of the pancreas or the tail and a portion of the body of the pancreas. The spleen is usually removed as well. This operation is used more often with islet cell tumors found in the tail and body of the pancreas. It is seldom used to treat cancers of the exocrine pancreas because these tumors have usually already spread by the time they are found.

Total pancreatectomy

This operation was once used for tumors in the body or head of the pancreas. It removes the entire pancreas and the spleen. It is now seldom used to treat exocrine cancers of the pancreas because there doesn't seem to be any advantage to removing the whole pancreas. It is possible to live without a pancreas. But when the entire pancreas is removed, people are left without any islet cells, the cells that make insulin. These people develop diabetes, which can be hard to manage because they become totally dependent on insulin.

Palliative surgery

If the cancer has spread too far to be completely removed, any surgery being considered would be palliative (intended to relieve or prevent symptoms). Because pancreatic cancer can progress quickly, most doctors do not advise surgery for palliation. However, sometimes surgery may begin with the hope it will cure the patient, but the surgeon discovers this is not possible. In this case, the surgeon may continue the operation as a palliative procedure to relieve or prevent symptoms.
Cancers growing in the head of the pancreas can block the common bile duct as it passes through this part of the pancreas. This may cause pain and digestive problems because the bile can't get into the intestine. The bile chemicals will build up in the body. There are 2 options for relieving bile duct blockage.
Surgery can be done to reroute the flow of bile from the common bile duct directly into the small intestine, bypassing the pancreas. This requires a large incision in the abdomen, and it may take weeks to completely recover. One advantage is that during this procedure, the surgeon may be able to cut the nerves leading to the pancreas or inject them with alcohol. This may reduce or get rid of any pain that may be caused by the cancer. Sometimes, the stomach connection to the duodenum (the first part of the small intestine) is rerouted at this time as well. Often, late in the course of pancreatic cancer, the duodenum becomes blocked by cancer, which can cause pain and vomiting that requires surgery. Bypassing the duodenum before this happens can help avoid a second operation.
A second approach to relieving a blocked bile duct does not involve surgery. Instead, a stent (small tube) is placed in the duct to keep it open. This is usually done through an endoscope (a long, flexible tube) while the patient is sedated. The doctor passes the endoscope down the patient's throat and all the way into the small intestine. The doctor can then insert the stent into the bile duct through the endoscope. The stent, which is usually made of metal, helps keep the bile duct open and resists compression from the surrounding cancer. After several months, the stent may become clogged and may need to be cleared. Larger stents are also available to keep the small intestine open if it is in danger of being blocked.
In general, the use of endoscopically-placed stents has replaced surgery to relieve bile duct obstruction. Stents can also be placed before surgery to relieve jaundice before the pancreas is removed.

Surgery to treat pancreatic neuroendocrine tumors and cancers

In addition to the procedures described above, some less extensive procedures may be used to remove pancreatic neuroendocrine tumors (NETs). Often laparoscopy is done first to better locate the tumor and see how far it has spread.
Sometimes with small tumors, just the tumor itself is removed. This is called enucleation. This operation may be done using a laparoscope, so that only a few small incisions are needed. This operation may be all that is needed to treat an insulinoma, since this type of tumor is often benign.
Small (tumors 2 inches or less) gastrinomas may also be treated with enucleation, but the duodenum (the first part of the small intestine) is removed as well. Larger gastrinomas may require a pancreaticduodenectomy or a distal pancreatectomy, depending on the location of the tumor.
The lymph nodes around the pancreas are removed in some cases as well. This is known as a peripancreatic lymph node dissection. The lymph nodes are removed so that they can be checked for signs of tumor spread.
Surgery may be used to remove metastases if a pancreatic NET has spread. This can be used with spread to the liver (the most common site of spread) and the lungs. Removing metastases can improve symptoms and prolong life in patients with pancreatic NETs. In rare cases, liver transplantation may be used to treat pancreatic NETs that have spread to the liver.

Ablative techniques

When a pancreatic neuroendocrine tumor has spread to other sites, the metastases can be removed by surgery and by other techniques as well. By treating metastases, symptoms can improve and the patient may live longer. These techniques are most often used to treat cancer spread in the liver. Sometimes these treatments are also used to treat areas of spread from pancreatic exocrine cancer when only a few are present.

  • Radiofrequency ablation: Radiofrequency ablation (RFA) uses radio waves to heat and destroy tissues, such as areas of cancer spread.
  • Microwave thermotherapy: In this procedure, microwaves are used to heat and destroy the abnormal tissue.
  • Cryosurgery: In cryosurgery, a probe is inserted into the tumor which freezes the tissue with liquid nitrogen or liquid carbon dioxide. The area being frozen is destroyed. This technique is also known as cryoablation.
  • Embolization: For an embolization procedure, a catheter is used to find the blood vessel feeding the tumor. Then a substance is injected into the blood vessel, cutting off the blood supply to the tumor. This causes the tumor to die. The substance injected can be just plain, tiny beads (microspheres), but the beads can be radioactive (and deliver radiation) as well. Sometimes the catheter is also used to inject chemotherapy drugs. This is called chemoembolization.

Radiation therapy

Radiation therapy uses high-energy x-rays (or particles) to kill cancer cells. It can be helpful in treating exocrine pancreatic cancer. Pancreatic neuroendocrine tumors (NETs) don’t respond well to radiation, and so it is rarely used to treat these tumors. Radiation is sometimes used to treat pancreatic NETs that have spread to the bone and are causing pain.

External beam radiation therapy is the type of radiation therapy most often used in treating cancers of the exocrine pancreas. This treatment focuses the radiation on the cancer from a machine outside the body. Having this type of radiation therapy is like having an x-ray, except that each treatment lasts longer, and the patient usually receives 5 treatments per week over a period of weeks or months.

Patients may receive preoperative (before surgery) or postoperative (after surgery) treatment. If surgery is planned, preoperative treatment is often preferred because postoperative treatment often has to be delayed for several weeks while the patient recovers from surgery (treatment right after surgery can interfere with wound healing).

Radiation therapy combined with chemotherapy (called chemoradiation or chemoradiotherapy) may be used in patients whose exocrine pancreatic tumors are too widespread to be removed by surgery. It is also sometimes used after surgery, to help keep the cancer from coming back.

Side effects of radiation therapy may include mild skin changes resembling sunburn or suntan, nausea, vomiting, diarrhea, and fatigue. Patients usually lose their appetite and have trouble keeping up their weight. Usually these effects go away a few weeks after the treatment is complete. Radiation therapy may make the side effects of chemotherapy worse.

Chemotherapy

Chemotherapy (chemo) uses anti-cancer drugs injected into a vein or given by mouth. These drugs enter the bloodstream and reach all areas of the body, making this treatment potentially useful for cancers that have metastasized (spread) beyond the organ they started in.

Treating exocrine pancreatic cancer


Chemotherapy

Chemo may be used at any stage of pancreatic cancer. It is commonly used in people with advanced cancer. Chemo may be used after the cancer has been removed with surgery to try to kill any cancer cells that may have been left behind (but can't be seen). This type of treatment is called adjuvant treatment. It is used to help stop the cancer from coming back later. In people who are expected to have surgery, chemo and radiotherapy may be given to shrink the tumor beforehand. When treatment is done before surgery it is called neoadjuvant treatment.

Gemcitabine (Gemzar®) is the chemotherapy drug used most often to treat pancreatic cancer. Another commonly used drug is 5-fluorouracil (5-FU). Sometimes, other drugs may be used along with gemcitabine or 5-FU, such as cisplatin, irinotecan (Camptosar®, CPT-11), paclitaxel (Taxol®), docetaxel (Taxotere®), capecitabine (Xeloda®), or oxaliplatin (Eloxitan®).

Chemotherapy drugs kill cancer cells but also damage some normal cells. This can lead to side effects, which depend on the type of drugs, the amount taken, and the length of treatment. Common short-term side effects include:
  • Nausea and vomiting
  • Loss of appetite
  • Hair loss
  • Mouth sores
  • Diarrhea

Because chemotherapy can damage the bone marrow, where new blood cells are made, blood cell counts might become low. This can result in:
  • Increased chance of infection (due to a shortage of white blood cells)
  • Bleeding or bruising after minor cuts or injuries (due to a shortage of platelets)
  • Fatigue and shortness of breath (due to low red blood cell counts)
  • Many of the chemotherapy drugs used for pancreatic cancer can cause diarrhea.

Other side effects can occur depending on what chemo drugs are used. For example, cisplatin can cause kidney damage (called nephropathy). Doctors try to prevent this problem by giving the patient lots of fluid before and after the drug is given. Both cisplatin and oxaliplatin can cause nerve damage (called neuropathy). This can lead to symptoms of numbness, tingling, or even pain in the hands and feet. For a day or so after treatment, oxaliplatin can cause nerve pain that gets worse with exposure to cold. This often causes pain with swallowing that is worse when trying to swallow cold foods or liquids. Most side effects disappear once treatment is stopped.

Targeted therapy

As researchers have learned more about the gene changes in cells that cause cancer, they have been able to develop newer drugs that specifically target these changes. These drugs are often referred to as targeted therapy. They work differently from standard chemotherapy drugs and often have different (and less severe) side effects. (See Related Research for more information.)
A drug called erlotinib (Tarceva®) has helped some patients with advanced pancreatic cancer. This drug is taken as a pill. Erlotinib targets a protein on the surface of cancer cells called EGFR, which normally prompts cancer cells to grow. When combined with gemcitabine, it has been shown to be slightly better than gemcitabine alone. Some people may get more benefit from this combination regimen than others. Common side effects of erlotinib include an acne-like rash, diarrhea, loss of appetite, and feeling tired.

Treating pancreatic neuroendocrine tumors


Chemotherapy

Chemotherapy (chemo) is not very helpful in treating these tumors, so it isn't often used. When chemo is used the preferred drugs are doxorubicin (Adriamycin® and streptozocin. Recently, a special form of doxorubicin known as liposomal doxorubicin (Doxil®) has been used instead of the regular drug. In the newer form, the drug is dissolved in fat droplets, which allows it to be given with less serious side effects. Other chemo drugs that have been helpful in treating these tumors include fluorouracil (5-FU), dacarbazine (DTIC), and temozolomide (Temodar®). Some recent studies have found that combining temozolomide with thalidomide or with capecitabine (Xeloda) can be helpful.

Targeted therapy

The drug sunitinib (Sutent®) attacks both blood vessel growth and other targets that stimulate cancer cell growth. When used to treat patients with pancreatic neuroendocrine tumors (NETs) with spread outside of the pancreas, it has been shown to slow tumor growth and help patients live longer. The most common side effects are nausea, diarrhea, changes in skin or hair color, mouth sores, weakness, and low blood cell counts. Other possible effects include tiredness, high blood pressure, heart problems, bleeding, hand-foot syndrome (redness, pain, and skin peeling of the palms of the hands and the soles of the feet), and low thyroid hormone levels. This drug was recently approved by the FDA to treat pancreatic NETs that cannot be removed with surgery or have spread outside the pancreas. This drug comes in pill form that is taken once a day to treat pancreatic NETs.
Everolimus (Afinitor®) works by blocking a cell protein known as mTOR, which normally promotes cell growth and division. When used to treat patients with pancreatic neuroendocrine tumors (NETs) with spread outside of the pancreas, it has been shown to slow tumor growth, although it's not yet clear if it helps patients live longer. Everolimus is a pill that is taken once a day to treat pancreatic NETs. Common side effects of this drug include mouth sores, increased risk of infections, nausea, loss of appetite, diarrhea, skin rash, feeling tired or weak, fluid buildup (usually in the legs), and increases in blood sugar and cholesterol levels. A less common but serious side effect is damage to the lungs, which can cause shortness of breath or other problems. This drug was recently approved by the FDA to treat pancreatic NETs that cannot be removed with surgery or have spread outside the pancreas.

Other drugs

for treating pancreatic neuroendocrine tumors

Octreotideis an agent chemically related to a natural hormone, somatostatin. It is very helpful for some patients with pancreatic endocrine tumors. It can stop the tumor from releasing its hormone into the blood stream. This reduces symptoms and helps patients feel better. This drug can be expected to help anyone with a tumor that can be seen on somatostatin receptor scintigraphy. Octreotide can help reduce diarrhea in patients with VIPomas, glucagonomas, and somatostatinomas. It also helps the rash of glucagonomas. This drug may even cause tumors to stop growing. The main side effects are pain at the site of the injection, and rarely, stomach cramps, nausea, vomiting, headaches, dizziness, and fatigue. Octreotide causes sludging of bile in the gallbladder which can lead to gallstones (cholelithiasis). It can also result in insulin resistance that can make pre-existing diabetes more difficult to control.

The standard version of octreotide is short-acting and is used 2 to 4 times a day. This drug is available as a long-acting injection that only needs to be given once a month, which may help patients more than the short-acting version. A similar drug, lanreotide, is also available. It is also given as an injection once a month. A newer drug called pasireotide is currently being studied.

Diazoxideis a drug that can block insulin release from the pancreas. It can be used to prevent low blood sugars (hypoglycemia) in patients with insulinomas. This drug is often used to normalize blood glucose levels before surgery, to make the operation safer for the patient.
Proton pump inhibitors block acid secretion from the stomach. These drugs often need to be taken in higher than usual doses, but are very helpful in preventing ulcers in patients with gastrinomas. Examples of these drugs include omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), and others.

Treating pancreatic cancer by stage


It is hard to stage pancreatic cancer accurately by imaging tests. Doctors must do their best to decide before surgery whether there is a good chance the cancer can be completely removed. Surgeons usually consider an exocrine pancreatic cancer resectable (completely removable by surgery) if it is staged as T1, T2, or T3. That means it doesn't extend far beyond the pancreas, especially into nearby large blood vessels (T4). There is no accurate way to assess the lymph node spread of the tumor before surgery.

Exocrine pancreatic cancer


Resectable: If imaging tests show a reasonable chance of completely removing the cancer, surgery should be done if possible, as it offers the only chance to cure this disease. Based on where the cancer started, either a pancreaticoduodenectomy (Whipple procedure) or a distal pancreatectomy is usually used.
In most but not all cases, either chemotherapy alone or chemotherapy plus radiation therapy (chemoradiation) is used as well. This treatment may be given before or after surgery. Some centers favor giving it before surgery because the recovery after surgery is often long, which can delay or even prevent its use. But it is not yet clear whether this approach is better than giving it after surgery. Many surgeons are concerned about preoperative therapy. They feel that patients may become weakened and are therefore less able to withstand the surgery.
Unfortunately, even when surgery has removed all of the tumor that can be seen, the cancer often comes back. Studies have shown that giving chemotherapy after surgery can delay the cancer's return by about 6 months. It may also help some patients live longer. Either gemcitabine (Gemzar) or 5-FU can be used for this. It is not yet clear whether adding radiation to chemotherapy would result in more of a benefit.

Locally advanced: Locally advanced cancers of the pancreas are those that have grown too far to be completely removed by surgery, but have not yet reached distant parts of the body. Several studies have shown that only removing part of the cancer does not help patients to live longer. Therefore, surgery has a limited role in these cancers. It is used mainly to relieve bile duct blockage or to bypass a blocked intestine caused by the cancer pressing on other organs.
The standard treatment options for locally advanced cancers are chemotherapy either alone or along with radiation therapy. In some cases, this treatment will cause the cancer to shrink enough to allow it to be removed completely with surgery. This treatment may help some patients live longer even if the cancer doesn't shrink enough to be able to be removed. When radiation is given, the chemo drug can be either gemcitabine or 5-FU.Giving chemo and radiation together may work better to shrink the cancer, this combination has more side effects and can be harder to take than either treatment alone.

Metastatic (widespread): Because these cancers have spread through the lymphatic system or bloodstream, they cannot be removed by surgery. These cancers have also spread too far to be treated by radiation therapy alone. Even when imaging tests show that the spread is only to one area of the body, it has to be assumed that small groups of cancer cells (too small to be seen on imaging tests) are already present in other organs of the body.
One standard treatment for advanced pancreatic cancer is chemotherapy with gemcitabine. It can cause the cancer to shrink and help patients live longer. People who get this treatment also seem to have fewer symptoms related to their cancer. Adding other drugs to gemcitabine may improve the chance the tumors will shrink and may help people live longer. So far, only erlotinib and capecitabine have been shown to help some patients live longer when given along with gemcitabine. Overall, the benefit of giving erlotinib along with gemcitibine was very small (patients lived about 2 weeks longer). Erlotinib doesn't seem to help all patients, so experts are trying to find a way to figure out who should get the drug and who try something else. Capecitabine also only seemed to help some of the people who received it with gemcitabine. Most doctors give chemo with gemcitabine for pancreatic cancer, and consider adding another drug on a case-by-case basis.
Another option that may help patients live longer is a combination of chemo drugs called FOLFIRINOX. This consists of 4 drugs: 5-FU, leucovorin, irinotecan, and oxaliplatin. In a recent study, this treatment helped patients live longer than gemcitabine, but had more severe side effects.
Because the treatments now available don't work well for most patients, people may want to think about taking part in a clinical trial involving chemotherapy combinations (with or without radiation therapy) and new targeted therapies.
Doctors don't agree on what is the best therapy to give someone when gemcitabine stops working. If a patient wants more treatment and is strong enough, different chemo drugs may be used. Some patients are given one of the targeted agents. Enrolling in a clinical trial may be the best choice at this point.

Recurrent cancer: Cancer is called recurrent when it come backs after treatment. Recurrence can be local (in or near the same place it started) or distant (spread to organs such as the liver, lungs, or bone). When pancreatic exocrine cancer recurs, it is essentially treated the same way as metastatic cancer, and is likely to include chemotherapy if the patient can tolerate it.

Cancer of the ampulla of Vater

The ampulla of Vater is the area where the pancreatic duct and the common bile duct empty their secretions into the duodenum (the first part of the small intestine). Cancer of this site can arise from the pancreatic duct, the duodenum, or the common bile duct. Surgery with pancreaticoduodenectomy (Whipple procedure) is often successful as cancer treatment with a 5-year survival rate of 30% to 50%. More advanced ampullary cancers are treated like pancreatic cancer. In many patients, ampullary cancer cannot be distinguished from pancreatic cancer until surgery has been done. Post-operative chemoradiotherapy is often recommended in patients who have had successful resection of their ampullary carcinoma.

Pancreatic neuroendocrine tumors

If the tumor is resectable, it will be removed by surgery. What procedure is used depends on the type of tumor, its size, and its location in the pancreas. Surgery can range from as little as enucleation to as much as a pancreatoduodenectomy (Whipple procedure). Lymph nodes are often removed to check for tumor spread. Laparascopy may be done before resection to better locate and stage the tumor. Prior to any surgery, medications are often given to control the symptoms caused by the tumor. For gastrinomas, drugs to block stomach acid are used (like proton pump inhibitors). Often, people with insulinomas are treated with diazoxide to keep the blood sugar from getting too low. If the tumor was visible on somatostatin receptor scintiography, octreotide may be used to control any symptoms. After surgery, the patient will be watched closely for signs that the cancer may have come back or spread.
Pancreatic NETs are generally slow growing so lab tests and imaging are used to monitor the patient and the tumor growth. Many patients with cancers that have spread outside of the pancreas benefit from treating symptoms like diarrhea or hormone problems. Often, chemo or targeted therapy is delayed until the patient is having symptoms that can’t be controlled with other drugs or has signs of tumor growth on scans. When treatment is started, either sunitinib (Sutent) or everolimus (Afinitor) may be used. Surgery or ablative techniques may also be used to treat metastases in the liver.



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