Pancreatic Cancer – Cause, Diagnosis, Treatment and the Future

By Robert J. Mayer, M.D.

The frequency of pancreatic cancer in the United States has increased in parallel with the increase in life expectancy of the general population. Approximately 29,000 Americans are expected to develop pancreatic cancer during 2001 of whom more than 98 percent will eventually die of the disease. Pancreatic cancer is presently the fifth most common cause of cancer-related mortality, appears to occur somewhat more often in males than females and in blacks than in whites, and rarely develops before the age of 50.

Cause, Symptoms, Diagnosis

Little is known about the causes of pancreatic cancer. Cigarette smoking is the most consistently reported risk factor for the development of the tumor, with the disease being two to three times more common in heavy smokers than in non-smokers. There is no convincing evidence linking pancreatic cancer to alcohol abuse, the presence of gallstones, or coffee consumption.

Approximately 95 percent of malignant pancreatic tumors arise in the glandular ducts of the organ which normally convey enzymes needed for digestion to the small bowel; such glandular cancers are known as adenocarcinomas and represent what is generally known as “pancreatic cancer”. The remaining five percent of pancreatic malignancies arise in islet cells – those components of the pancreas which synthesize hormones such as insulin. Islet cell tumors behave in a far less aggressive manner than do ductal adenocarcinomas. With the exception of jaundice, the initial symptoms that are experienced by patients with pancreatic carcinomas are often insidious and are usually present for longer than two months before the tumor is diagnosed. Pain and weight lose occur in more than 75 percent of patients; the pain typically has a gnawing quality that occasionally spreads from the area of the stomach to the back and often suggests spread of disease to nerves in the abdomen indicative of unresectability. The weight loss that is observed in most patients with pancreatic cancer results primarily from loss of appetite, although malabsorption of fats due to an inadequate supply of pancreatic enzymes may also be a factor in the initial stage of the disease. Jaundice, which is caused by blockage of the bile duct, occurs in more than 80 percent of patients who have tumors in the part of the gland adjacent to the small bowel and bile duct (pancreatic “head”) and its accompanied by darkening of the urine and a clay-like appearance of the stool. The early diagnosis of a potentially respectable pancreatic carcinoma is extremely difficult despite the availability of such imaging techniques as CT-scans; the non-specific initial symptoms and the inaccuracy often associated with such scans have made the development of effective screening programs extremely difficult. Patients with vague, persistent abdominal complaints in whom gall bladder and ulcer disease have been excluded, should be considered for CT-scanning to provide an explanation for the symptoms. Occasionally, the placement of a fiberoptic tube (i.e. endoscope) through the esophagus, stomach, and small bowel to the opening of the pancreatic and biliary ducts(i.e. endoscopic retrograde cholangiopancrdatography [ERCP[) may clarify ambiguous CT finding and may provide the opportunity to biopsy a suspicious area. Although a variety of blood tests including so called “tumor markers” have been examined for use in the dagnosis or follow-up of pancreatic cancer, none has proven to be satisfactory. The most widely studied of these blood rests is CA19-9, the levels of which, when elevated, may help diffentiate a benign disorder from a carcinoma.

Treatment

Complete resection is the only effective treatment of pancreatic ductal carcinoma. Regrettably, such curative operations are possible in less than 15 percent of patients and are limited, for all practical purposes, to those individuals with tumors in the pancreatic head that have caused jaundice leading to an earlier diagnosis. Tumor spread to other sites in the abdomen such as the lining of the abdominal cavity (“peritoneum”), liver, or to the lungs is a contraindication to major surgery. Removing a pancreatic cancer requires an experienced surgeon since the procedure is technically difficult and has been associated with significant complications when performed by “non-experts.”

For those individuals whose cancers are unresectable, symptomatic control should be the primary goal of management. Radiation therapy (often accompanied by chemotherapy) to reduce pain, surgical or endoscopic correction of a blocked bile duct, and sufficient amounts of opioid analgesics may all be indicated. The results of standard chemotherapy in the management of patients with unresectable pancreatic cancer have been disappointing, although occasional patients benefit significantly from the use of gemcitabine or 5-flourouracil.

The Future

Because of the inadequacy of present methods of treatment, pancreatic cancer represents an ideal setting in which to explore the efficacy of many of the newly developed forms of biological anti-tumor treatment which have recently received considerable attention from the media. For example, more than 85 percent 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 inhibitors of farnesyl transferase have been developed by at least three pharmaceutical companies and have entered 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. Lastly, some pancreatic cancer cells appear to contain an excess amount of the protein product of a gene called her-2-neu; this molecular abnormality was initially observed in breast cancer cells and has been the focus of monoclonal antibody therapy directed against the protein. Whether this monoclonal antibody, known as herceptin, will be as effective a form of treatment in pancreatic cancer as it appears to be in breast cancer, will soon be the focus of several studies.

It is clear that pancreatic cancer represents one of the most serious forms of human malignancy. At long last, however, the disease is beginning to receive appropriate attention in terms of research support. Laboratory investigators are attempting to develop models of the tumor in mice which simulate the human experience so as to better understand the biology of the disease and to serve as a mechanism to test new forms of treatment. Along with these efforts, research must continue to try to better understand what it is in our environment that causes tumors to arise in the pancreas and to identify effective yet simple means of detecting the disorder at an early, more curable stage. An increasing number of excellent research questions are being posed by investigators through out the United States; our challenge and responsibility will be to provide fiscal support to allow these questions to be addressed so that progress against this dreaded disease may finally be made.

Robert J. Mayer, M.D., is the Director of the Center for Gastointestinal Oncology at the Dana-Farber Cancer Institute, a Professor of Medicine at Harvard Medical School and Director of the National Pancreas Foundation.