Pancreatic Cancer Treatment and Management
Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor: last updated 12/2019
The treatment of pancreatic cancer is tailored to each individual and may consist of surgery, precision cancer medicines, chemotherapy, and radiation therapy. The specific treatment depends on the stage and genomic profile of the cancer. Optimal treatment will often require more than one therapeutic approach and is likely to involve several different types of physicians. These physicians may include a gastroenterologist, a surgeon, a medical oncologist, a radiation oncologist, or other specialists. Care must be carefully coordinated between the various treating physicians.(1)
The first precision cancer medicine became available for the treatment of pancreatic cancer in 2019. Lynparza (olaparib) delays cancer progression and improves survival when used to treat BRCA-mutated pancreatic cancer. Genomic biomarker testing of all pancreatic cancers is now essential in order to determine optimal treatment.
Surgery for Cancer of the Pancreas
Surgery for cancer of the pancreas is performed in order to remove the cancer and learn additional information for treatment planning. Surgery can be performed with curative intent for some patients with earlier stage cancers localized to the pancreas. Patients with more-advanced cancer may undergo surgery for reduction of symptoms and prevention of obstruction of the bile duct. Obstruction of the bile duct is a common complication of pancreatic cancer that may lead to jaundice (a yellow discoloration of the skin). Less frequently, surgery is performed to treat or prevent obstruction of the stomach outlet.
Radiation Therapy for Cancer of the Pancreas
Radiation therapy or radiotherapy uses high-energy rays to damage or kill cancer cells by preventing them from growing and dividing. Similar to surgery, radiation therapy is a local treatment and is not useful in eradicating cancer cells that have already spread to other parts of the body. Radiation therapy may be externally or internally delivered. External radiation delivers high-energy rays directly to the tumor site from a machine outside the body. Internal radiation, or brachytherapy, involves the implantation of a small amount of radioactive material in or near the cancer.
Radiation therapy is an important treatment modality for patients with advanced pancreatic cancer, but is rarely used alone. Optimal treatment of patients with pancreatic cancer often requires more than one therapeutic approach. Radiation therapy is usually given with chemotherapy, which can improve the average duration of survival for patients with localized and locally advanced disease.
Local Treatments for Pancreatic Cancer
There are several local treatments that can be used to try to reduce the size of the cancer or relieve the symptoms of pancreatic cancer. These treatments can be used alone or as part of an overall strategy in the management of pancreatic cancer.
NanoKnife® (Irreversible Electroporation)
How does NanoKnife work? NanoKnife uses short, repetitive, non-thermal high-energy pulses of electricity to destroy cancer cells. NanoKnife is a minimally invasive, probe-based technology that destroys tumors using pulsed, low-current, high-voltage electrical energy. This non-thermal electrical energy creates permanent “pores” in the cell membrane leading to irreversible swelling, apoptosis and cell death.
Under general anesthesia electrodes (needles) are inserted through the skin directly into and around the tumor. Anywhere from two to six probes are inserted around a cancer using ultrasound or a CT scan for guidance. The technology does require general anesthesia and can be done via a percutaneous or operative approach. NanoKnife’s unique advantage, which allows use in the pancreas, is the preservation of major vascular and ductal structures.
Sometimes open or keyhole surgery is used. Short pulses of electricity fire between the needles for several minutes. The electrodes may be repositioned and the process repeated until the whole tumor and a small area of surrounding tissue is treated.
These pulses of electricity destroy the tumor leaving the surrounding tissue, veins, nerves and ducts unaffected. Healthy cells and tissue can then grow back and regenerate within the area.
How long does NanoKnife take? The NanoKnife procedure typically lasts from two to four hours. Afterwards a patient is typically kept in the hospital overnight for observation and discharged the following day. Antibiotics are usually administered before and after the procedure to prevent infection.
A small clinical trial in 54 patients with unresectable pancreas cancer compared the use of NanoKnife to standard chemotherapy and radiation. (1). Most NanoKnife treated patients also received chemotherapy and radiation. Nineteen of the Nanoknife treated patients were subsequently able to undergo surgical resection of their cancer. Nanpkinfe treated patients survived longer compared to those treated with radiation and chemotherapy; 20 verses 13 months. (21)
CyberKnife® is a form of radiation treatment known as stereotactic radiotherapy and is also referred to as radio surgery. Unlike the name suggests, CyberKnife® is not actually a knife, but is the brand name for the machine which delivers the stereotactic radiotherapy by delivering beams of radiation to any part of the body from any direction, using robotic arms.
Like conventional radiotherapy, CyberKnife® delivers high doses of radiation to the tumor. What is different is that many beams of lower doses are used at one time instead of just one large-dose beam. Each of the radiation beams delivers a small dose of radiation using sophisticated image guidance, and computer controlled robotics. The system is able to track the tumor’s position throughout and will respond to patients’ movements and breathing, ensuring only the tumor is targeted. This ensures that the tumor receives the high dose of radiation but surrounding normal tissue will receive significantly lower doses, making it safer for patients.
Conventional radiotherapy can take up to 6 weeks to be delivered, which usually involves daily visits to the radiotherapy unit. CyberKnife® only requires a few or even a single treatment.
Radiofrequency ablation is a minimally invasive technique that uses heat to destroy cancer cells. During radiofrequency-ablation, an electrode is placed directly into the cancer under the guidance of a CT scan, ultrasound, or laparoscopy. The electrode emits high frequency radio waves, creating intense heat that destroys the cancer cells
Systemic Therapy: Precision Cancer Medicine, Chemotherapy, and Immunotherapy
Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Some patients with early stage cancers already have small amounts of cancer that have spread away from the pancreas that cannot be treated with surgery or radiation. These patients require systemic treatment to decrease the chance of cancer recurrence. More advanced cancers that cannot be treated with surgery and radiation can only be treated with systemic therapy. Systemic therapies commonly used in the treatment of cancer include:
Precision Cancer Medicines
The purpose of precision cancer medicine is to define the genomic alterations in the cancers DNA that are driving that specific cancer. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
The "PARP inhibitor Lynparza is the first precision medicine to demonstrate improved survival for pancreatic cancer in patients with a specific genetic marker. ALL patients should ask their doctor about genomic biomarker testing to see if they are eligible to be treated with Lynparza or other precision medicines.(2)
Chemotherapy is any treatment involving the use of drugs to kill cancer cells. Cancer chemotherapy may consist of single drugs or combinations of drugs, and can be administered through a vein, injected into a body cavity, or delivered orally in the form of a pill. Chemotherapy is different from surgery or radiation therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread and can kill or eliminate cancers cells at sites great distances from the original cancer. The drugs are usually given in cycles so that a recovery period follows every treatment period.
Several chemotherapy medications administered alone or in combination can modestly prolong survival of patients with various stages of pancreatic cancer including the following;
- Gemzar® (gemcitabine)
- Onivyde™ (irinotecan liposome injection)
- Eloxatin® (oxaliplatin)
- Abraxane® (nab-paclitaxel)
- Tarceva® (erlotinib)
- Xeloda (capecitabine)
- 5-FU (fluorouracil)
- Taxol (paclitaxel)
- Sutent (sunitinib)
Individual chemotherapy medications are typically combined with others to create treatment "regimens" so that the cancer is being treated with multiple drugs simultaneously.(2-7)
New treatment strategies are sorely needed for the treatment of pancreatic cancer. ALL patients should inquire about participating in clinical trials and the role of newer precision cancer medicines.
Pancreatic Cancer Stages Are Treated Differently
In order to learn more about the most recent information available concerning the treatment of pancreatic cancer, click on the appropriate stage.
Stage I: Cancer is confined to the pancreas.
Stage II: Cancer may extend to the duodenum, bile ducts, or fat surrounding the pancreas, but does not invade any local lymph nodes.
Stage III: Cancer invades one or more of the local lymph nodes and has extended to major blood vessels.
Stage IV: Cancer has spread to the stomach, bowel, or distant locations in the body, which may include the liver, lungs, bones, or other sites.
Recurrent/Relapsed: The pancreatic cancer has been detected or returned (recurred/relapsed) following an initial treatment.
Surgery for Pancreatic Cancer
Choosing a Surgeon: Most clinical studies suggest that hospitals that treat a relatively large number of patients with cancer (high-volume hospitals) report lower surgical in-hospital death rates than hospitals that treat a small number of patients (low-volume hospitals). This is thought to be due to experience of the surgeon and to the presence of surgical teams with sub-specialty expertise.(1,8,9)
Surgery for pancreatic cancer is difficult in part because of the location of the pancreas. The pancreas is located in the middle of the abdomen between the liver and the spleen, just below and behind the stomach. The pancreas is a “retro-peritoneal” organ, meaning it is located behind and outside the abdominal cavity. The pancreas consists of a head and a tail. The head of the pancreas is connected to the last part of the stomach (the pylorus) and the first portion of the small intestine (the duodenum). The pancreas has a duct that carries digestive enzymes into the duodenum at the same location where the bile duct empties bile from the liver. Cancer in the head of the pancreas can block the bile duct and the outlet from the stomach. In all operations for pancreatic cancer, the bile duct has to be relocated to the middle section of the small intestine, called the jejunum, or less commonly, into the stomach. In some operations the bile duct is kept open with an artificial tube called a stent.
Bio-marker Testing: It is important that a portion of the cancer removed during surgery be made available for biomarker testing to determine whether any precision cancer medicines are available for treatment. Patients should discuss this with their surgeon prior to surgery to ensure it is performed.
Timing of Surgery: Surgical removal of the pancreas has historically been performed as initial treatment, with chemotherapy and/or radiation therapy administered after surgery. Pancreatic cancer, however, often involves the area around the entry of the pancreatic and bile ducts into the small intestine, and many patients who undergo initial exploratory surgery with the intent to perform curative surgery are found to have widespread cancer that cannot be removed. Most of these patients can only have a procedure to divert the bile duct and stomach to the jejunum to palliate symptoms and/or prevent obstructions without removing the cancer.
Some doctors have advocated the administration of chemotherapy and/or radiation therapy before surgery to shrink the cancer before surgery. This is referred to as “neoadjuvant therapy.” Patients with cancers that are “borderline” resectable may benefit from partial shrinkage of the cancer, which may allow a greater chance for complete removal of the cancer. Research suggests that neoadjuvant therapy may improve survival rates and delay cancer progression in individuals with resectable and "borderline" resectable cancer. There are several other potential advantages to administering neoadjuvant therapy before attempting surgical removal of the cancer. (19)
The side effects following surgery to remove pancreatic cancer are substantial and may delay the administering of post-operative (adjuvant) therapy. Approximately 25% to 33% of patients are unable to receive chemotherapy or radiation treatment following surgery. Additionally, some patients experience very rapid growth (recurrence) of pancreatic cancer following surgery. By administering neoadjuvant therapy, all patients are able to receive therapy for their cancer, while patients unlikely to benefit from treatment due to rapid growth of the cancer are spared the complications of surgery. Patients who experience cancer regression following neoadjuvant therapy are more likely to have their remaining cancer completely removed with surgery.
Pancreaticoduodenectomy (Whipple Resection): The usual operation for pancreatic cancer consists of removing the pancreas with the first part of the small intestine (duodenum) and the pylorus, or last part of the stomach. The stomach is then connected back to the middle of the small intestine (the jejunum) in a procedure called a gastrojejunostomy. The bile duct is rerouted into the jejunum. Recent clinical studies suggest that connections of the bile duct and pancreatic duct to the stomach (pancreaticogastrostomy) may be preferable to connection to the jejunum (pancreaticojejunostomy).
Partial Pancreatectomy: When cancer involves only the first part or head of the pancreas, the tail, which is uninvolved with cancer, can be preserved. This is called a partial pancreatectomy and requires that the pancreatic duct be rerouted to the stomach or jejunum. This is an important consideration as digestive juices from the remaining pancreas help in digestion, nutrition, and general well-being.
Pylorus-preserving procedure: In standard pancreatic surgery, the pylorus, or “valve” that controls emptying of the stomach, is removed. Rapid entry of food from the stomach to the small intestine can result in discomforting symptoms and leads to poor absorption of nutrients. This is referred to as the “dumping syndrome” and is caused by the removal of the pylorus. By preserving the pylorus, rapid emptying or dumping of food into the small intestine can probably be reduced; however, it is important that adequate removal of the cancer is not compromised by this procedure. Many surgeons, especially in Japan, are using pylorus-sparing surgery, although absolute documentation of benefit is currently lacking.
Complications of Surgery for Pancreatic Cancer: The most frequent early complications of surgery include infections in the abdomen, bleeding in the abdomen, leakage of bile and/or digestive juices from the rerouted bile and pancreatic ducts into the abdomen, inflammation of the bile ducts, and rapid emptying of the stomach (dumping syndrome). The most frequent late complications include: diabetes, diarrhea, and malnutrition.
If the cancer has spread and cannot be removed, the following surgeries may be done to relieve symptoms and improve quality of life
- Surgical biliary bypass: If cancer is blocking the small intestine and bile is building up in the gallbladder a surgeon can cut the gallbladder or bile duct and sew it to the small intestine to create a new pathway or “bypass” around the blocked area.
- Endoscopic stent: If the cancer is blocking the bile duct, surgery may be done to insert a stent (a thin tube) to drain bile that has built up in the area. The stent can either that drain the bile to the outside of the body or internally into the small intestine.
- Gastric bypass: If the cancer is blocking the flow of food from the stomach, the stomach may be sewn directly to the small intestine so the patient can continue to eat normally.
Precision Cancer Medicine for Pancreatic Cancer
Not all cancer cells are alike. Cancer cells may differ from one another based on what genes have mutations. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. This “genomic testing” is performed on a biopsy sample of the cancer and increasingly in the blood using a “liquid biopsy”
Once a genetic abnormality is identified, a specific precision cancer medicine or targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.
Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes.
Precision Cancer Medicines for Pancreatic Cancer
Lynparza (olaparib): The U.S. FDA advisory committee approved Lynparza for 1st-line maintenance treatment of germline BRCA-mutated metastatic pancreatic cancer in Dec. 2019. Approval was bases on the POLO clinical trial which demonstrated that Lynparza reduced the risk of disease progression or death by 47% and nearly doubled the time patients with gBRCAm metastatic pancreatic cancer lived without disease progression or death. (20)
**Pamrevlumab (**FG-3019) is a monoclonal antibody that inhibits connective tissue growth factor (CTGF), which is associated with pancreatic cancer and growth of abnormal stromal cells and tumor cells. Pamrevlumab has received Breakthrough Therapy Designation from the FDA and when used in combination with chemotherapy appears to improve responses in locally advanced pancreatic cancer compared to chemotherapy alone. (12)
Herceptin® (trastuzumab); is a currently available precision cancer medicine that binds to the HER2 receptor, (a protein on the surface of the cancer cells) in approximately 20% of patients with pancreatic cancer. This binding action promotes anticancer benefits through two distinct processes. First, the binding of Herceptin blocks growth factors from binding to HER2, thereby eliminating their stimulating effects on cancer cells. Second, the binding action of Herceptin appears to stimulate the immune system to attack and kill the cancer cells to which Herceptin is bound. Herceptin when combined with chemotherapy for treatment of patients that over express HER2 prolongs survival compared to treatment with chemotherapy alone. (13)
Larotrectinib (LOXO-101) has received Breakthrough Therapy Designation from the FDA for the treatment of advanced solid tumors with NTRK-fusion proteins. Larotrectinib targets a mutation where two genes join together in what’s known as tropomyosin receptor kinases (TRK) fusion, leading to the production of proteins that cause cancer growth. Growing research suggests that the TRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. (14)
Targeting RAS: More than 85% of pancreatic cancers have mutations in the ras gene; these malignant cells contain a unique enzyme (known as farnesyl transferase) whose activity appears to be required if the cells with the mutation are to divide. Specific drugs that inhibit farnesyl transferase have been developed and are being evaluated in clinical trials. Similarly, methods are being explored through which the normal (rather than mutated) gene can be directly injected into a tumor mass with the hope that a return to the usual pattern of cell division will lead to tumor regression. (15)
Erbitux® (cetuximab); is a precision cancer medicine that binds to epidermal growth factor receptors (EGFR), thereby suppressing cancer growth and spread. The addition of Erbitux to chemotherapy may modestly improve survival for patients with advanced pancreatic cancer. (16)
Radiation Therapy for Pancreatic Cancer
Radiation therapy or radiotherapy uses high-energy rays to damage or kill cancer cells by preventing them from growing and dividing. Similar to surgery, radiation therapy is a local treatment used to eliminate or eradicate visible tumor. Radiation therapy is not typically useful in eradicating cancer cells that have already spread to other parts of the body. Radiation therapy may be externally or internally delivered. External radiation delivers high-energy rays directly to the cancer site from a machine outside the body. Internal radiation, or brachytherapy, involves the implantation of a small amount of radioactive material in or near the cancer.
The role of radiation therapy alone for the treatment of pancreatic cancer is limited. Radiation therapy is usually given in combination with chemotherapy for treatment of stage I, II or III cancer, which can improve the average duration of survival for patients with localized and locally advanced disease. (17)
External Beam Radiation Therapy
Radiation therapy is delivered to the pancreas and surrounding lymph nodes from a machine outside the body, called a linear accelerator, or from a shielded repository of a powerful isotope, such as cobalt 60. External beam radiation therapy is most often administered in conjunction with chemotherapy. In some instances, patients with advanced disease are treated with radiation therapy alone for palliation. Conventional radiation therapy is administered over a course of 5-7 weeks. The Radiation Therapy Oncology Group (RTOG) is actively involved in improving radiotherapy techniques for pancreatic cancer. The RTOG has evaluated higher dose radiation delivered on a twice-a-day basis as well as low-dose liver irradiation in clinical trials. Definite improvement with these approaches awaits results of further study. Technical advances in treatment planning of radiation therapy are allowing more precise targeting of radiation to the cancer.
Three-dimensional conformal radiation therapy can precisely target radiation to the areas of where cancer cells may be located, and therefore minimize side effects from radiation to normal structures such as the liver, stomach and kidneys. Because many patients develop areas of cancer cells in the liver, low-dose radiation therapy aimed at the entire liver has been used in an attempt to destroy cancer cells.
Intraoperative Radiation Therapy (IORT): Intraoperative radiation therapy (IORT) is a single dose of radiation therapy that is delivered directly to the area of surgery during the operation. IORT is performed in specially-equipped operating rooms. During IORT, the radiation doctor can see the area being treated and move sensitive normal structures, such as the small bowel, away from the radiation beam. Results from some studies evaluating IORT indicate that cancer may recur less often in the area of the surgery.
Three-dimensional Conformal Radiation Therapy: Three-dimensional conformal radiation therapy can precisely target radiation to the areas where cancer cells may be located and therefore, minimize side effects from radiation to normal structures such as the liver, stomach and kidneys. Because many patients develop areas of cancer cells in the liver, low-dose radiation therapy aimed at the entire liver has been used in an attempt to destroy cancer cells.
Side Effects of Radiation Therapy
Although patients do not feel anything while they are receiving radiation treatment, the effects of radiation gradually build up over time. Many patients experience fatigue as treatment continues. Loose stools or diarrhea is also common.
Strategies to Improve Treatment
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Areas of active investigation aimed at improving the treatment of pancreatic cancer include the following:
Portal Vein Chemotherapy Infusion: Because many patients develop cancer recurrence in the liver, chemotherapy delivered directly into the blood supply of the liver has been used in an attempt to eradicate cancer cells. By infusing chemotherapy over several days or weeks through the portal vein, the chemotherapy is delivered directly to the cancer. Cancer cells appear to be killed more effectively. Portal vein infusion is being evaluated in clinical trials at many cancer centers.
Extended Pancreaticoduodenectomy: More-extensive operations for pancreatic cancer have been advocated by some surgeons to obtain wider surgical margins with the goal of removing all cancer cells in the area and preventing cancer recurrences in the area of the surgery. Regional or extended pancreaticoduodenectomy involves removal of surrounding veins and wider dissection of lymph nodes around the pancreas. This procedure has been popularized by some cancer centers in the United States and Japan.
Endoscopic Surgery: In order to avoid complications associated with surgical entry into the abdomen and retroperitoneal space, doctors have attempted to use endoscopic surgery. An endoscope is a flexible tube through which the surgeon can visualize, sample, and operate inside various body cavities. Laparoscopy is the term for using an endoscope in the abdomen.
Surgeons in Spain have evaluated the feasibility of performing a bypass of the stomach and bile duct through a laparoscope in patients with obstruction of the bile duct and stomach. (11) These doctors treated 12 patients successfully with simultaneous biliary and gastric bypass. The average age of these patients was 72 years (ranging from 50-82 years). All had obstruction of the stomach and bile duct with jaundice. The average time of the procedure was an hour and a half. Complications included infections in two and pneumonia in one. One patient died two days after laparoscopic surgery. The average stay in the hospital was one week. None of the patients had recurrence of jaundice and all were able to maintain oral nutrition. The average survival was three months. These doctors concluded that gastric and biliary bypass by laparoscopic surgery was a safe procedure and effective treatment of stomach obstruction in patients with unresectable pancreatic cancer.
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- Safran H, Ramanathan R, Schwartz J, King T, et al. Herceptin and Gemcitabine for Metastatic Pancreatic Cancers That Overexpress her-2/neu. Proceedings from the 37th Annual Meeting of the American Society of Clinical Oncology 2001, San Francisco CA, Abstract #517.
- Cascinu S, Berardi R, Labianca R, et al. Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomized, multicentre, Phase II trial. Lancet Oncology. 2008;9:39-44.
- Toubaji A, Achtar M, Provenzano M et al. Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers.Cancer Immunol Immunother. 2008 Feb 23.
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