Browse Month: August 2008

Etiologic factors

ETIOLOGIC FACTORS

Recent investigations have identified a number of factors that may contribute to the pathogenesis of pancreatic cancer. These factors can be organized into general areas of risk that include environmental factors, associated medical or surgical factors, heritable genetic factors (familial pancreatic cancer), and occupational exposures.

ENVIRONMENTAL FACTORS

A number of important environmental risk factors have been investigated for their role in the etiology of pancreatic cancer.

Cigarette Smoking.

Cigarette smoking is the most firmly established risk factor associated with pancreatic cancer. Pancreatic malignancies can be induced in animals through long-term administration of tobacco-specific N-nitrosamines or by parenteral administration of other N-nitroso compounds. These carcinogens are metabolized to electrophiles that readily react with DNA, leading to miscoding and activation of specific oncogenes such as K- ras. Induction of pancreatic cancer in these systems can be modulated by additional factors, including changes in bile acid composition, cholecystokinin (CCK) levels, and diet.

At the clinical level, numerous case-control and cohort studies have reported an increased risk of pancreatic cancer for smokers in both the United States and Europe, and current estimates suggest that approximately 30% of pancreatic cancer cases are due to cigarette smoking. Recent studies that have explored the dose-response relationship have shown that the risk of pancreatic cancer increases as the amount and duration of smoking increase and that long-term smoking cessation (more than 10 years) reduces risk by approximately 30% relative to the risk of current smokers. Application of molecular epidemiologic techniques that are being developed for lung cancer may provide greater specificity in linking tobacco exposure with the development of pancreatic cancer and may facilitate the study of chemopreventive strategies.

Dietary Factors

Over the past 10 years, numerous dietary factors have been implicated in pancreatic cancer development. Generally, high intakes of fat or meat increase risk, and diets high in fruits and vegetables reduce risk. When the available studies are analyzed in greater detail, the associations between dietary intake and pancreatic cancer become more complex. For example, high fat intake, usually in the form of high meat intake, increases risk. However, a recent study has suggested that the effect may vary by source of fat and by patient population. Investigators found that large amounts of fat from any source increase the risk of pancreatic cancer in men but that only fat from nonmeat or nondairy sources increases the risk in women. Other studies have reported an increased risk of pancreatic cancer with high total energy intake, high total cholesterol intake, or high ingestion of carbohydrates. These clinical observations are supported by laboratory studies in animal models in which high-fat and high-cholesterol diets have been shown to promote pancreatic carcinogenesis.

Decreased rates for pancreatic cancer have been associated with high consumption of vegetables, citrus fruits, fiber, and vitamin C. The association of diets high in citrus with a reduced risk of pancreatic cancer is particularly interesting given the recent observation that limonene, a natural product found in citrus fruits, is a potent inhibitor of the K- ras oncoprotein.

Data regarding the effect of coffee consumption and excessive alcohol consumption appear conflicting. For each of these factors, a few studies have suggested an increased risk of pancreatic cancer (coffee, alcohol), but most studies conducted over the past 10 years have failed to consistently demonstrate such a risk (coffee, alcohol). In some cases, significant methodologic problems may have confounded interpretation of the data, leading to erroneous conclusions.

New Treatments for Pancreatic Cancer

Pancreatic cancer accounts for approximately 27,000 deaths per year in the United States and 50,000 deaths per year in Europe (excluding the former USSR). Only 1% to 4% of patients with adenocarcinoma of the pancreas will be alive 5 years after diagnosis. Thus, incidence rates are virtually identical to mortality rates. In the United States in 1995, pancreatic cancer was be the fifth leading cause of adult deaths from cancer (after lung, colorectal, breast, and prostate cancers) and was responsible for close to 5% of all cancer-related deaths.

EPIDEMIOLOGY

The incidence of pancreatic cancer declined slightly from 1973 to 1991, with 26,300 new cases (2% of all cancer diagnoses) estimated in 2006. Studies evaluating this trend suggest that the decreased incidence is due to a steady decline in the rate for white men, which peaked during the period 1970 to 1974. By contrast, rates for white women, black men, and black women have not fallen. In Japan, the incidence of cancer of the pancreas has increased sharply from 1.8/100,000 in 1960 to 5.3 in 100,000 in 1985. Overall, incidence in mortality statistics are very similar for the United States and Western Europe. Between 1989 and 1991, mortality rates for pancreatic cancer in the United States were 10 in 100,000 for men, and 7.2 in 100,000 for women. Although overall mortality rates in industrialized societies appear similar, geographically and ethnically dissimilar populations show considerable differences in mortality rates from pancreatic cancer.
The risk of developing pancreatic cancer is low in the first three to four decades of life but increases sharply after age 50, with most patients between ages 65 and 80 at diagnosis. The male to female ratio has ranged from 1.7:1.0 in older series to 1.3:1.0 in a more contemporary series. Historically, the male to female ratio was reported to decrease with age; however, this trend was not observed in a recent series from Memorial Sloan-Kettering Cancer Center. Interestingly, in several animal models of pancreatic cancer, tumors are more reproducibly induced in male animals.
Racial differences in mortality rates for pancreatic cancer have also been observed. Pancreatic cancer mortality rates for American blacks are higher than for any other ethnic group in the United States and are considerably higher than the rates observed for African blacks, suggesting an environmental contribution to this increased risk.

These broad epidemiologic categories do little to identify persons at high risk for pancreatic cancer. To define high-risk groups, we must consider the contribution of specific etiologic factors.