Pancreatic cancer is considered stage IV if it has spread to distant locations in the body, such as the liver, lungs, or adjacent organs including the stomach, spleen, and/or the bowel. Sometimes it can only be determined that a pancreatic cancer is in stage IV once surgery is completed.

Patients diagnosed with stage IV pancreatic cancer can be broadly divided into two groups:

• Stage IVA pancreatic cancer is locally confined, but involves adjacent organs or blood vessels, thereby hindering surgical removal. Stage IVA pancreatic cancer is also referred to as localized or locally advanced.
• Stage IVB pancreatic cancer has spread to distant organs, most commonly the liver. Stage IVB pancreatic cancer is also called metastatic.

The goal of treatment for patients with localized IVA disease is to induce a remission, or a disease-free period that may last months or years. Management of patients with stage IVB disease is often aimed at controlling symptoms and pain from the cancer.

Stage IV pancreatic cancer is generally not removable by surgery and is therefore rarely curable and often difficult to control. A surgical procedure may be possible to reduce symptoms and improve quality of life in some patients, but the recommended treatment for advanced pancreatic cancer is typically  chemotherapy . The standard chemotherapy drug for the treatment of pancreatic cancer is  Gemzar®  (gemcitabine).

The following is a general overview of treatment for stage IV pancreatic cancer. Treatment may consist of surgery, radiation, chemotherapy, biological therapy, or a combination of these treatment techniques. Multi-modality treatment, which is treatment using two or more techniques, is increasingly recognized as an important approach for improving a patient's chance of cure or prolonging survival. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient's situation may influence how these general treatment principles are applied and whether the patient decides to receive treatment. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

Treatment of Localized Stage IVA Pancreatic Cancer

Pancreatic cancer is often not diagnosed until it is in stage IVA, meaning the cancer has invaded adjacent organs or major blood vessels. When this occurs, surgical removal of the cancer and a chance at long-term cure is seldom an option. Therefore, the goal of treatment of patients with stage IVA pancreatic cancer is to cause a remission, which is a cancer-free period that may last months or years, and to prevent and control symptoms.

Treatments for stage IVA pancreatic cancer may include palliative surgery,  chemotherapy , or  chemoradiation , which is chemotherapy and radiation delivered together. Chemotherapy is the use of anti-cancer drugs to destroy cancer cells throughout the body. Radiation therapy uses high energy x-rays to kill cancer cells at the location in the body where the x-rays are focused. Occasionally, a surgical bypass procedure may alleviate complications of the cancer, such as jaundice, intestinal obstruction, or pain, thereby improving quality of life.

Treatment of Non-Localized Stage IVB (Metastatic) Pancreatic Cancer

The majority of patients with stage IV cancer have metastatic disease (stage IVB), which means that cancer has spread to distant locations in the body that often includes the liver and other areas of the abdominal cavity. To kill cancer cells that have spread in the body, a systemic treatment is necessary, which is typically  chemotherapy . Historically, patients with metastatic pancreatic cancer have been considered incurable and rarely survived more than one year. However, patients are offered treatment with chemotherapy for the purpose of prolonging their life and alleviating symptoms from progressive cancer. Sometimes, management of patients with stage IVB pancreatic cancer is focused on reducing pain and maintaining nutrition. Pain relief can be achieved by destroying the nerves that provide sensation in the area around the pancreas. This is usually performed by injection of alcohol or other chemicals either through the skin or during an open abdominal operation.

Chemotherapy

Chemotherapy involves the use of anti-cancer drugs to destroy cancer cells throughout the body. Chemotherapy is considered a systemic therapy because the drug circulates throughout the body and can kill cancer cells that have spread to locations distant from where the cancer started. Chemotherapy is commonly used to treat both locally advanced (stage IVA) and metastatic (stage IVB) pancreatic cancer.

Gemzar®: The standard chemotherapy drug for the treatment of advanced pancreatic cancer is Gemzar®, which has been shown to improve response to treatment, time to cancer progression, and survival duration when compared with the older chemotherapy drug 5-fluorouracil. In a clinical trial comparing Gemzar® and 5-FU, Gemzar® produced significant improvement in disease-related symptoms, as well as prolonging survival. The number of patients surviving one year after treatment with Gemzar® was 18%, compared to only 2% with 5-FU.

Chemoradiation therapy

Combining chemotherapy with radiation therapy, a technique called chemoradiation, may provide more benefit than chemotherapy alone for some patients with stage IVA pancreatic cancer, but is not typically a treatment for patients with stage IVB disease. Researchers from Taiwan have reported that patients with stage IVA pancreatic cancer who were treated with radiation therapy plus Gemzar® chemotherapy fared better than those treated with radiation therapy plus 5-FU chemotherapy. Anti-cancer responses occurred in 50% of patients treated with Gemzar®, compared with only 17% for those treated with 5-FU. The average time to cancer progression was 14.5 months for patients treated with Gemzar®, compared with only 7.1 months for those treated with 5-FU. Patients treated with Gemzar® reported better pain control than those treated with 5-FU.

Strategies to Improve Treatment of Stage IV Pancreatic Cancer

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. Future progress in the treatment of stage IV pancreatic cancer will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active exploration to improve the treatment of stage IV pancreatic cancer include the following:

Advances in Chemotherapy

Researchers continue to evaluate chemotherapy, particularly potential combinations of drugs and new approaches to dose and schedule. Combinations of chemotherapy drugs, called regimens, may produce more anti-cancer response than treatment with just one drug. Also, investigators continue to evaluate the best way to administer Gemzar®.

Combination chemotherapy (regimens): While it appears that more patients respond to combination treatment than single-agent treatment, it has not been determined whether patients who receive combinations live longer than those who receive single-agent Gemzar® (see table 1). This is because the clinical trials evaluating these combinations did not directly compare two groups of patients: those that received the combination and those that received single-agent Gemzar®.

Table 1 Results from seven trials that evaluated different chemotherapy regimens in the treatment of advanced pancreatic cancer

*patients with locally-advanced disease (IVA)

**patients with metastatic disease (IVB)

***not measured in this trial

Neoadjuvant Therapy

In an effort to increase the chance that a cancer may be surgically removed, some cancer centers may use radiation therapy and chemotherapy before surgery to shrink the cancer. The use of treatment before surgery is referred to as "neoadjuvant therapy." In addition to potentially shrinking cancer so that it can be removed, neoadjuvant therapy allows patients to avoid the difficulty of undergoing treatments after surgery, which is a time when they may be experiencing side effects. Surgery to remove pancreatic cancer is associated with substantial side effects that may delay further treatment or may even render a patient incapable to tolerating adjuvant treatment. Approximately 25% to 33% of patients are unable to receive chemotherapy or radiation treatment following surgery. Furthermore, a treatment plan that includes neoadjuvant therapy guarantees that systemic therapy is delivered immediately, which can increase the chance of eradicating small amounts of cancer that may have already spread to distant locations in the body. Neoadjuvant therapy is currently being administered at some cancer centers and being evaluated in clinical trials.

New Radiation Therapy Technique

Three-dimensional conformal radiation therapy (3D-CRT): 3D-CRT 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 with advanced pancreatic cancer may 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 these cancer cells.

Biological therapy

Biological therapies are naturally occurring or synthesized substances that direct, facilitate, or enhance the body's normal immune defenses. Biologic therapies include interferons, interleukins, monoclonal antibodies, vaccines, and other compounds. Monoclonal antibodies are proteins that can be made in the laboratory and are designed to recognize and bind to very specific sites on a cell. This binding action promotes anti-cancer benefits by eliminating the stimulating effects of growth factors and by stimulating the immune system to attack and kill the cancer cells to which the monoclonal antibody is bound. In an attempt to improve survival rates, the following biological therapies are being tested alone or in combination with chemotherapy in clinical trials:

Erbitux™: Another monoclonal antibody, Erbitux®, binds to epidermal growth factor receptors (EGFR), thereby suppressing cancer growth and spread. Erbitux™ was FDA-approved for the treatment of colon cancer in February 2004.

Researchers from the M.D. Anderson Cancer Center have reported that the addition of Erbitux™ to Gemzar® may improve survival for patients with advanced pancreatic cancer. This trial involved 40 patients with advanced pancreatic cancer who had tested positive for overexpression of EGFR. Results indicate that more of the patients who received Gemzar® plus Erbitux™ lived one year or more and were cancer-free for longer than the patients who were treated with Gemzar® alone

Table 2 Gemzar with and without Erbitux™

Virulizin®: Virulizin® is a biological therapy that activates the body's own immune system to recognize and eliminate cancer cells. The exact mechanism that Virulizin® works has not been identified with certainty. However, researchers think that it induces apoptosis (cell death) of cancer cells by stimulating the release of tumor necrosis factor and stimulating macrophages, the clean-up cells of the immune system.

An early phase clinical trial evaluating Virulizin® in the treatment of pancreatic cancer demonstrated that 58% of patients lived six months or longer. On average, patients lived 6.8 months. Treatment with Virulizin® was well-tolerated.

Virulizin® was granted “fast track” status by the FDA. Fast-track status expedites the review and approval process of an agent that is intended for life-threatening diseases. The phase III clinical trial, which is the last trial prior to FDA approval, involves patients with advanced pancreatic cancer who will receive treatment with either Gemzar ® alone or Gemzar® plus Virulizin®.

Herceptin®: Herceptin® is a monoclonal antibody that binds to HER2 receptor, which is a protein on the surface of some cancer cells. This binding action promotes anti-cancer benefits through two distinct processes. First, the binding of Herceptin® blocks growth factors by 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.

Researchers from Brown University have found that treatment of patients with advanced pancreatic cancers that overexpress HER2 with Gemzar® plus Herceptin® appears to produce longer survival than treatment with Gemzar® alone. Approximately 72% of patients treated with the combination demonstrated an anti-cancer response. Approximately 24% of patients lived one year or more following treatment.

Photodynamic Therapy

Photodynamic therapy is an emerging type of treatment that is still being evaluated and refined in clinical trials and laboratories. Photodynamic therapy works through the use of a photosensitizing agent and light. The photosensitizing agent is injected into a patient's vein a couple of hours prior to surgery. During this time, the agent selectively collects in rapidly growing cells such as cancer cells. During surgery, the physician applies a certain wavelength of light through a hand held wand directly to the site of the cancer and surrounding tissues. The energy from the light activates the photosensitizing agent, causing the production of a toxin that accumulates in the cancer cells and ultimately destroys them.

Researchers from England have reported that photodynamic therapy may be a safe and effective treatment option for some patients with inoperable pancreatic cancer. In this trial, 16 patients were first given the photosensitizing agent meso-tetrahydroxyphenyl chlorin through a vein. Three days later, light was delivered to the cancer through the guidance of computerized tomography (CT) scans. Fourteen patients were able to leave the hospital within 10 days. The average survival time was 9.5 months and 44% of the patients were alive at one year following therapy. Treatment was very well tolerated in the majority of patients; however, two patients developed bleeding that was controlled by surgery and three patients developed an obstruction in their large intestine.

Gene Therapy

Gene therapy is defined as the transfer of new genetic material into a cell for therapeutic benefit. This can be accomplished by replacing or inactivating a dysfunctional gene or replacing or adding a functional gene into a cell to make it function normally. A few gene therapy studies are being carried out in patients with advanced pancreatic cancer. If successful, these therapies could be applied to patients with earlier stage disease.

ONYX-015: ONYX-015 is one type of gene therapy that has been investigated in pancreatic cancer. ONYX-015 is a genetically engineered, or altered, adenovirus—a virus that causes a common cold. This virus has been altered in such a way that it will infect and kill cancer cells with a mutated p53 gene, but will not kill normal healthy cells. Many different types of cancers develop due to a mutation (alteration) in a certain gene called the p53 gene, which is the gene responsible for regulating normal cell death. ONYX-015 was developed to specifically target and infect cells with a destroyed or mutated p53 gene.

Researchers from UCLA recently conducted a clinical trial evaluating the effectiveness and tolerability of injections of ONYX-015 plus the chemotherapy agent Gemzar® in the treatment of 21 patients with inoperable pancreatic cancer that had spread either locally or to distant sites in the body. The injections were guided by ultrasound and delivered directly into the areas of cancer in the pancreas. Anti-cancer responses or stabilization of cancer was achieved in nearly 50% (10) of patients, while 11 patients had cancer progression or could not tolerate therapy.

Phase I Clinical Trials

New chemotherapy drugs continue to be developed and evaluated in patients with advanced cancers in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the safety and tolerability of a drug and the best way of administering the drug to patients.

Managing Side Effects

Managing the side effects of cancer and/or cancer treatment is an important part of receiving optimal care. Side effects cause inconvenience, discomfort, and may occasionally be fatal. Additionally and perhaps more importantly, side effects may prevent doctors from delivering the prescribed dose of therapy at the specific time and schedule of the treatment plan. Because the expected outcome from therapy is based on delivering treatment at the dose and schedule prescribed in the treatment plan, a change from the treatment plan may reduce your chance of achieving an optimal outcome. This is extremely important to understand. In other words, side effects not only cause discomfort and unpleasantness, but may also compromise your chance of cure by preventing the delivery of therapy at its optimal dose and time. For more information, go the Managing Side Effects section.