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Pancreatic Cancer

Pancreatic Cancer and Survival: The Role of Chemotherapy 
  Submitted By: Desai Sameer P.

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PANCREATIC CANCER AND SURVIVAL: THE ROLE OF CHEMOTHERAPY
Authored by: Sameer P. Desai, M.D. and Mark M. Zalupski, M.D.

Division of Hematology/Oncology, Department of Internal Medicine
University of Michigan, Ann Arbor, MI


Introduction:

Pancreatic cancer can be challenging to diagnose and treat. Approximately 33,730 new cases are anticipated and 32,300 deaths expected in the United States in 2006. Although pancreatic cancer represents only 2% of new cancer cases, it is the fourth most common cause of cancer death. The cause of this cancer is largely unknown; however there is an association with advancing age, cigarette smoking and in some patients, a family history of this or other cancers. The symptoms of pancreatic cancer commonly include abdominal pain, weight loss and jaundice, although patients can be asymptomatic at initial diagnosis or have more vague symptoms including itching, loss of appetite, nausea and depression. These relatively nonspecific symptoms combined with the lack of an effective screening modality and the aggressive biology of this cancer results in most patients being diagnosed after the cancer has become surgically unresectable. The diagnosis is usually made after an ultrasound or computed tomography (CT) scan identifies an abnormality in the pancreas. Confirmation of the diagnosis requires some form of biopsy procedure. Once the tumor is diagnosed the degree of tumor spread (staging) can be useful information in treatment planning.

Staging- Usually divides the patients into three categories

1. Those with disease localized to the pancreas that can be surgically resected
2. Patients with disease localized to the pancreas, but involving major blood vessels that prevents surgical resection
3. Patients with disease spread beyond the pancreas to other organs which prevents surgical resection


Treatment is largely based on the stage of disease. Complete surgical removal is necessary for cure but surgery is feasible only in a small minority of cases and even when performed disease often recurs in a short time. Patients that are inoperable are offered palliative measures (non-curative treatment) to improve quality of life and in some cases lengthen remaining life. The current article will discuss the use of palliative chemotherapy in pancreatic cancer.

Chemotherapy for Pancreatic Cancer:

Chemotherapy involves the use of drugs that are either injected (given as a shot in a vein) or infused (slowly given to the patient via an IV) into blood vessels or ingested by mouth. These drugs then travel through the blood stream and reach cancer cells in the pancreas, lymph nodes and those that have spread to distant sites. Though these drugs may kill some cancer cells that are sensitive to its effect, chemotherapy is not able to entirely eliminate the cancer. In advanced pancreatic cancer, chemotherapy has been shown to relieve symptoms and improve survival when compared to the best supportive care or symptom management only. Therefore, chemotherapy has become the standard and most often used treatment for advanced pancreatic cancer. Prior to the middle 1990s, the most important chemotherapy agent used in pancreatic cancer was intravenous 5-fluorouracil (5FU). This drug has been used to treat many cancers for more than 40 years. In pancreatic cancer, 5FU was usually given either in a bolus injection or as a continuous infusion (> 24 hrs) using an implanted catheter. However as its activity as a single agent was relatively low, 5FU was commonly used in combination with other chemotherapy agents. The two most widely used combinations were 5FU and mitomycin C with either doxorubicin or streptozotocin.

In May of 1996 the Food and Drug Administration (FDA) approved the intravenous drug gemcitabine for use in patients with locally advanced or metastatic pancreatic cancer. This approval was based on two clinical studies which used a measure called clinical benefit response (CBR) to assess the effectiveness of the drug rather than the traditional use of tumor shrinkage rate. CBR was determined by assessing the change in the need for pain medications (analgesic consumption), pain intensity, weight and overall performance status of patients receiving the drug. In the first study, 63 patients given gemcitabine had a CBR of 23.8% as compared to 4.8% in 63 patients receiving 5FU. In the second study, 63 patients who had previously received 5FU based chemotherapy were treated with gemcitabine and had a CBR of 27%. The major side effects of gemcitabine: lowering of the blood counts, nausea, vomiting, rash and flu-like symptoms, were generally mild in intensity and manageable. There are now a large number of patients who have been treated with gemcitabine and the safety and tolerability of the drug remains excellent. Higher doses of gemcitabine have been evaluated in pancreatic cancer but do not seem to improve upon results. It does appear that there may be limited benefit to increasing the time (2-3 hrs) over which the gemcitabine is delivered. This modest benefit needs to be weighed against the extra time required and need for specialized infusion pumps. It has become apparent that gemcitabine by itself helps only a minority of patients and therefore clinical investigators continue to look for better options.

A large number of studies have been conducted to see if adding a second or third chemotherapy agent to gemcitabine can improve upon the results. Some of the initial studies added 5FU to gemcitabine in various doses and schedules. In general in these combination studies, though there have been more patients whose tumor shrinks in response to the combined treatment, the overall survival in these patients has not been found to be significantly better. There has been more enthusiasm for combining gemcitabine with other chemotherapy agents. One such drug is called cisplatin, and this has been compared in combination with gemcitabine to gemcitabine alone. In these studies, patients treated with the combination were noted to live on average 2 to 3 months longer, although statistically this difference was not considered significant. The combination of gemcitabine and cisplatin leads to a chance for increased side effects and this combination takes a longer time to deliver and requires hydration with intravenous (IV) fluids before and after. Another chemotherapy agent related to cisplatin and used in many other cancers of the gastrointestinal tract is oxaliplatin. Oxaliplatin has fewer side effects then cisplatin and no requirement for hydration. Gemcitabine combined with oxaliplatin has been studied and again seems to improve the likelihood of the tumor responding to the treatment but so far there has not been convincing evidence that the combination improves the overall survival of all patients. Gemcitabine has been combined with other chemotherapy agents in addition to those described above but until recently none have shown any significant improvements in overall survival. In a recent preliminary report, investigators in Europe combined gemcitabine with an oral form of 5FU called capecitabine. When compared with gemcitabine by itself, patients treated with the combination lived longer and this result was said to be statistically different than gemcitabine alone.

Future Directions:

Enthusiasm in oncology is mounting for the development of novel agents which act against specific targets which are felt to be driving the growth and survival of cancer cells. These novel agents often have fewer side effects, and are sometimes taken by mouth. One of the targets under study is the epidermal growth factor receptor (EGFR), a protein that is on the outside of many cancer cells including pancreatic cancer. EGFR appears to function as an “on switch” and helps the cancer survive and prosper within the body. Drugs have been developed which are directed against this EGFR protein, interfere with its function and “turn off the on switch” supporting growth and survival of the cancer. Erlotinib is an oral drug targeting EGFR which has been approved for use in lung cancer. This drug was combined with gemcitabine in patients with pancreatic cancer and also found to improve the overall survival of patients when compared to the gemcitabine alone, though the benefit was modest. Another therapeutic target in cancer is the vascular endothelial growth factor (VEGF) which appears to be important in the process of new blood vessel growth, called angiogenesis. As tumors grow, they require blood vessel formation to supply them with essential nutrients. Drugs which interfere with this process, termed anti-angiogenesis agents, have been promising in various cancers including colon, breast and lung cancer. These agents are being studied in pancreatic cancer in combination with gemcitabine, although results are not yet available.

Summary:

Pancreatic cancer continues to be a disease for which cure is available in only a small minority of patients afflicted with it. For those who cannot be cured, chemotherapy is considered a standard treatment option to improve quality of life. Researchers and clinical investigators are increasingly understanding the important pathways that drive cancer cells and permit their growth and spread. As these mechanisms are better understood, the development of newer agents directed against specific targets can be expected. This increased understanding and availability of more options is likely to lead to better and safer treatment with resulting improved quality of life for those suffering with this disease. However, all patients are unique in their treatment needs and any specific therapy should be done by an experienced Oncologist (cancer doctor). This article is not intended, and should not be used to guide care. It is only presented as a reference so that patients can gain a better understanding of the types of things their doctor may have to offer them in the treatment of their disease. 


 


Additional Authors:  

Works Cited:  
  Burris, H. A., 3rd, M. J. Moore, et al. (1997). "Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial." J Clin Oncol 15(6): 2403-13.
Cunningham, D., I. Chau, et al. (2005). "PS11 Best of ECCO 13 Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer." European Journal of Cancer Supplements 3(4): 12.
Heinemann, V., D. Quietzsch, et al. (2003). "A phase III trial comparing gemcitabine plus cisplatin vs. gemcitabine alone in advanced pancreatic carcinoma." Proceedings American Society of Clinical Oncology 22: 1003.
Jemal, A., R. Siegel, et al. (2006). "Cancer statistics, 2006." CA Cancer J Clin 56(2): 106-30.
Louvet, C., R. Labianca, et al. (2005). "Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial." J Clin Oncol 23(15): 3509-16.
Moore, M. J. (2005). "Brief communication: a new combination in the treatment of advanced pancreatic cancer." Semin Oncol 32(6 Suppl 8): 5-6.
 
 


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