Stage IV Pancreatic Cancer
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 typically consists of chemotherapy. The standard chemotherapy treatment of pancreatic cancer is Gemzar® (gemcitabine)-based chemotherapy.
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 is treatment using two or more techniques, and 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 Web site 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 (which provides a chance at long-term cure) is seldom an option. Therefore, the goal of treatment of patients with Stage IVA pancreatic cancer is to induce a remission, which is a cancer-free period that may last months or years, and to prevent and control symptoms.
Treatment for Stage IVA pancreatic cancer may include palliative surgery, chemotherapy, or chemoradiation, which is chemotherapy and radiation delivered together. Occasionally, a surgical bypass procedure may be performed to 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 include the liver and other areas of the abdominal cavity. To kill cancer cells that have spread throughout the body, a systemic treatment is necessary, and this is typically chemotherapy. Historically, patients with metastatic pancreatic cancer have been considered incurable and rarely survived more than one year. However, with newer treatments, some patients are surviving 1-2 years and can experience improved quality of life. In addition, the management of patients with Stage IV 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 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 or delivered orally in the form of a pill. Chemotherapy is considered a systemic therapy because the drugs circulate 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® (gemcitabine): Currently, 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.1 In a clinical trial comparing Gemzar to 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 with only 2% with 5-FU.
Combinations of chemotherapy drugs, called regimens, may produce more anticancer responses and improve the outcomes of patients with advanced pancreatic cancer than treatment with Gemzar alone. Many different chemotherapy drugs have been combined with Gemzar with the goal of improving patient outcomes.
Combining chemotherapy with radiation therapy, a technique called chemoradiation, may provide more benefit than chemotherapy alone for some patients with Stage IVA pancreatic cancer,2 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. Anticancer 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.3
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 Systemic Therapy: Chemotherapy and Targeted Therapy
Systemic therapy is treatment directed at destroying cancer cells throughout the body. Because patients with pancreatic cancer have small amounts of cancer that have spread away from the pancreas, an effective systemic treatment is needed to cleanse the body of micrometastases in order to improve a patient’s duration of survival and potential for cure.
Although it appears that more patients respond to combination treatment than single-agent treatment, only Tarceva has been demonstrated to improve survival when combined with Gemzar in a direct comparison. It has not been determined whether patients who receive other combinations live longer than those who receive single-agent Gemzar or Gemzar combined with Tarceva (see table 1). This is because the clinical trials evaluating the combinations in Table 1 have not been directly compared to single-agent Gemzar in a controlled clinical trial.
Table 1: Results from seven trials that evaluated different chemotherapy regimens in the treatment of advanced pancreatic cancer
|30* or 31%**
||26* or 47%**
*patients with locally-advanced disease (IVA)
**patients with metastatic disease (IVB)
***not measured in this trial
A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Cancer treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes. Conventional cancer treatments, such as chemotherapy and radiation therapy, cannot distinguish between cancer cells and healthy cells. Consequently, healthy cells are commonly damaged in the process of treating the cancer, which results in side effects. Chemotherapy damages rapidly dividing cells, a hallmark trait of cancer cells. In the process, healthy cells that are also rapidly dividing, such as blood cells and the cells lining the mouth and GI tract are also damaged. Advances in science and technology have led to the development of several different types of targeted therapies that are being evaluated in clinical trials.
Herceptin® (trastuzumab): Herceptin is a monoclonal antibody, which is a type of targeted therapy 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.
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 anticancer response. Approximately 24% of patients lived one year or more following treatment.11
Erbitux® (cetuximab): Another targeted monoclonal antibody therapy, 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 and is being evaluated in other cancers including pancreatic cancer.
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 over expression 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 patients who were treated with Gemzar alone (see table 2).12
Table 2: Gemzar with and without Erbitux
||Gemzar alone (historical data)
More recently, researchers in Italy evaluated the addition of Erbitux to Gemzar and Platinol among patients with advanced pancreatic cancer.13 Patients treated with all three drugs (Erbitux, Gemzar, and Platinol) did not have better outcomes than patients treated only with Gemzar and Platinol. Other studies, however, are continuing to evaluate the role of Erbitux in the treatment of pancreatic cancer.
Neoadjuvant therapy is treatment that is administered prior to surgery. The purpose of neoadjuvant therapy for patients with early-stage pancreatic cancer is to reduce the amount of cancer in the body and make the cancer more easily removed by surgery. Clinical trials are ongoing to evaluate neoadjuvant chemotherapy administered alone or in combination with adjuvant therapy, and the results of some small studies suggest that neoadjuvant therapy may improve survival.14
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.
Doctors evaluated the feasibility of using a specific mutant ras peptide vaccine as an adjuvant immunotherapy in pancreatic and colorectal cancer patients. Twelve patients with no evidence of disease after surgery, five with pancreatic cancer, and seven with colorectal cancer were vaccinated subcutaneously with 13-mer mutant ras peptide, corresponding to their tumor’s ras mutation. Vaccinations were given every four weeks, up to a total of six vaccines. No serious side effects were reported, and five out of eleven patients showed a positive immune response. The five pancreatic cancer patients had an average overall survival of more than 44 months, and the seven colorectal cancer patients had an average overall survival of over 41 months.15
Biological therapies are naturally occurring or synthesized substances that direct, facilitate, or enhance the body’s normal immune defenses. Biologic therapies include interferon, 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:
Vaccines: The purpose of a vaccine is to help the patient’s immune system destroy the cancer by activating the patient’s immune cells against the cancer. Vaccines are made from a variety of substances that often include the actual cancer cells removed from the patient. A difficulty in preparing vaccines is that the patient’s cancer cells must be processed immediately following surgery. Patients and their surgeon must therefore prepare in advance to ensure the removed cancer cells can be handled properly for vaccine preparation. Vaccines are currently being evaluated in clinical studies.
Researchers from the Johns Hopkins Kimmel Cancer Center conducted a Phase II trial to evaluate the GVAX vaccine designed to stimulate the immune system to fight pancreatic cancer.15 The vaccine is comprised of radiated pancreatic cancer cells that are not able to replicate or grow. The cells have been modified to secrete a substance referred to as granulocyte macrophage colony stimulating factor (GM-CSF), which stimulates the immune system to recognize pancreatic cancer cells and attack them.
The trial included 56 patients who underwent the surgical removal of their cancer, followed by the first vaccine at eight weeks post surgery. One month later, standard chemotherapy and radiation were administered, followed by three more vaccines given every month. The final vaccine booster is given at six months following chemotherapy/radiation.
At a median follow-up of 32 months:
- Survival at one year was 88%.
- Survival at two years was 76%.
The researchers concluded that the addition of the cancer vaccine to standard chemotherapy and radiation therapy appears promising when comparing one- and two-year survival rates to historical rates of survival in patients with operable pancreatic cancer.
Virulizin®: Virulizin is a biological therapy that activates the body’s own immune system to recognize and eliminate cancer cells. The exact mechanism by which 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. In the Phase III trial the addition of Virulizin to Gemzar resulted in a median overall survival of 6.8 months and a one-year survival rate of 27.2% compared with six months and 16.8% for Gemzar alone.17 Virulizin is not currently FDA approved for the treatment of pancreatic cancer in the United States.
New Radiation Therapy Techniques
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.
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 handheld 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 chlorine 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.18
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, 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 to Managing Side Effects.
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2 Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas: Comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst 1988;80:751-755.
3 Li C-P, Chao Y, Chi K-H, et al. Concurrent Chemoradiotherapy Treatment of Locally Advanced Pancreatic Cancer: Gemcitabine versus 5-Fluorouracil, A Randomized Controlled Study. International Journal of Radiation Oncology Biology Physics 2003;57:98-104.
4 Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: A prospective, randomized phase III study of the Gruppo Oncologia, dell’Italia Meridionale. Cancer 2002;94:902-910.
5 Rocha Lima CM, Savarese D, Bruckner H, Dudek A, et al. Irinotecan plus gemcitabine induces both radiographic and CA 19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer.Journal of Clinical Oncology 2002;20:1182-91.
6 Kindler HL, Dugan W, Hochster H, et al. Clinical outcome in patients (pts) with advanced pancreatic cancer treated with pemetrexed/gemcitabine. Proceedings of the 38th Annual Meeting of the American Society of Clinical Oncology 2002;21, Abstract #499.
7 Louvet C, Andre T, Lledo G, et al. Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: final results of the GERCOR multicenter phase II study. Journal of Clinical Oncology 2002;20:1512-1518.
8 Reni M, Passoni P, Panucci MG, Nicoletti R, et al. Definitive Results of a Phase II Trial of Cisplatin, Epirubicin, Continuous-Infusion Fluorouracil, and Gemcitabine in Stage IV Pancreatic Adenocarcinoma Journal of Clinical Oncology 2001;19:2679-2686.
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10 Fine RL, Fogelman DR, Sherman W, et al.: The GTX regimen: A biochemically synergistic combination for advanced pancreatic cancer (PC). Proceedings from the 39th Annual Meeting of the American Society of Clinical Oncologists 2003, Abstract #1129.
11 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.
12 Abbruzzese JL, Rosenberg A, Xiong Q, LoBuglio A, et al. Phase II study of anti-epidermal growth factor receptor (EGFR) antibody cetuximab (IMC-C225) in combination with gemcitabine in patients with advanced pancreatic cancer. Proceedings from the 37th Annual Meeting of the American Society of Clinical Oncologists 2001, San Francisco CA, Abstract #518.
13 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 randomised, multicentre, Phase II trial. Lancet Oncology. 2008;9:39-44.
14 Takai S, Satoi S, Yanagimoto H et al. Neoadjuvant chemoradiation in patients with potentially resectable pancreatic cancer. Pancreas. 2008 Jan;36(1):e26-32.
15 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 Epub ahead of print,
16 Laheru D, et al. A Safety and Efficacy Trial of Lethally Irradiated Allogeneic Pancreatic Tumor Cells Transfected with the GM-CSF Gene in Combination with Adjuvant Chemotherapy for the Treatment of Adenocarcinoma of the Pancreas. Proceedings from the International Conference of AACR-NCI-EORTC. November, 2005. Philadelphia, PA. Abstract #C28
17 Lorus Therapeutics Inc. Press Release. Lorus announces results of Virulizin Phase III Clinical Trial. October 18, 2005. Available at: http://www.lorusthera.com/investor/engpr/2005_Virulizin_clinical_trial.pdf (Accessed April 7, 2008).
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