Prevention of Pancreatic Cancer

Overview
No tests have yet been developed which are suitable for screening for pancreatic cancer in asymptomatic persons. However, counselling for smoking cessation is recommended since there is fair evidence that cessation does reduce the risk of the disease and good evidence that counselling is effective.

Burden of Suffering
Cancer of the pancreas is the fourth leading cause of cancer deaths in Canada in both men and women, accounting for 2,611 deaths in 1990 and an estimated 36,000 potential years of life lost. For 1993 it was estimated that there would be 2,750 new cases of pancreatic cancer and 2,900 deaths from the disease in Canada. In contrast with many other parts of the world, the age-specific mortality rates in Canada appear to have been dropping over the last 35 years.<1> This cancer is more common in men and older persons (the majority of cases being diagnosed between ages 60 and 80). Familial aggregations of pancreatic cancer are rare but have been described.

Since initial symptoms are usually nonspecific (e.g., abdominal pain and weight loss) and are frequently disregarded, some 80-90% of patients have regional and distant metastases by the time they are diagnosed. In Ontario only 8% of patients live more than five years after diagnosis. Pancreatic adenocarcinomas, which account for more than 90% of all pancreatic neoplasms, are only resectable in about 4-16% of cases at diagnosis and the five-year survival rate is less than 1%.

Cigarette smoking has been consistently associated with an increased risk of pancreatic cancer. The relative risk has ranged from 2 to 5 in numerous cohort and case-control studies of populations in the U.S., Canada, Europe, and Japan.<1-6> In the more recent studies, a dose-response relationship has been demonstrated.<2-4>

Several cohort studies and many population-based case-control studies have reported positive associations between pancreatic cancer and dietary factors such as meat, eggs, carbohydrates, refined sugar, cholesterol, fat and total calorie intake, as well as negative (protective) associations with intake of vegetables and fruits.<1,5,6> However, study results are inconsistent. Also, a decrease in any dietary factor and, possibly, a substitution with another foodstuff, could cause an increase in some other disease so further research is needed. (Nutritional counselling has also been evaluated in treatment of obesity (Chapters 30 and 48) and prevention of lung cancer (Chapter 64) with more general considerations being addressed in the chapter on nutritional counselling (Chapter 49)). Studies of the relationship between increased alcohol consumption and pancreatic cancer have yielded inconsistent results;<1,6-8> few have adequately assessed level and duration of intake, or evaluated the possibility of a link between alcohol, pancreatitis and pancreatic cancer. Current epidemiologic evidence does not support an association between pancreatic cancer and coffee consumption.<1>

Many population-based epidemiologic studies have reported an association between pancreatic carcinoma and diabetes mellitus, although the excess risk for the cancer is reduced, and in some studies nullified, when cases with recent onset are excluded.<1,9> It has not been adequately determined whether diabetes is a result of the cancer, or whether it might just increase the risk for pancreatic carcinoma.

Maneuver
Adenocarcinoma is the principal form of pancreatic neoplasm for which screening has been considered; in this chapter, "pancreatic cancer" refers to adenocarcinoma unless otherwise noted. There are no reliable screening tests for detecting pancreatic cancer in asymptomatic individuals. The deep anatomic location of the pancreas makes detection of small localized tumours unlikely during routine abdominal examination. Even in patients with confirmed pancreatic cancer, an abdominal mass is palpable in only 15-25% of cases. Magnetic resonance imaging and computerized tomography (CT) are too costly to use as routine screening tests, while more accurate tests such as endoscopic retrograde cholangio-pancreatography (ERCP) and endoscopic ultrasound are inappropriate for screening asymptomatic patients due to their invasiveness. Abdominal ultrasonography is a noninvasive screening test that has a reported sensitivity of 40-98% and a specificity as high as 90-94%. However, these data are based on examinations of symptomatic patients with suspected disease. They thus provide little information on the efficacy of abdominal ultrasound as a screening test in asymptomatic persons. Conventional ultrasonography is also limited by visualization difficulties due to obesity or the presence of bowel gas and by the range of resolution, 2-3 cm. Frequently tumours £2 cm in diameter have produced metastatic disease,<10> thus limiting the ability of ultrasound to detect early disease.

With most cases of pancreatic malignancy there are elevated levels of certain serologic markers such as CA19-9, peanut agglutinin, pancreatic oncofetal antigen, DU-PAN-2, carcinoembryonic antigen, alpha-fetoprotein, CA-50, SPan-1, and tissue polypeptide antigen. None of these markers is, however, tumour-specific or organ-specific; elevations of various serologic markers also occur in significant proportions of persons with benign gastrointestinal diseases or malignancies other than pancreatic cancer. Most of these markers have been studied exclusively in high-risk populations, such as symptomatic patients with suspected pancreatic cancer. CA19-9 has probably achieved the widest acceptance as a serodiagnostic test for pancreatic carcinoma in symptomatic patients, with an overall sensitivity of approximately 80% (68-93%) and specificity of 90% (73-100%); sensitivity was highest in patients with more advanced disease. Among healthy subjects, CA19-9 has specificity of 94% to 99%<11-13> but nevertheless generates a large proportion of false positive results due to the low prevalence of pancreatic cancer in the general population.<14> A study of mass screening of more than 10,000 asymptomatic persons for pancreatic cancer in Japan,<8> using either ultrasonography alone or CA19-9 plus elastase-1, found the likelihood of pancreatic cancer given a positive screening test to be 0.5%; only one of the four cancers discovered could be curably resected.

The predictive value of a positive test could be improved if a population at substantially higher risk could be identified. New-onset diabetes mellitus in adult patients might be useful as a marker for a population at high risk of having pancreatic cancer<1> but not all investigations of the relationship between these diseases have shown an increased risk. If a high risk is established, studies of screening efficacy might be warranted. Screening for diabetes mellitus in the non-pregnant adult is not recommended (Chapter 50).

Effectiveness of Prevention and Treatment
Primary prevention of pancreatic cancer may be possible through clinical efforts directed at the use of tobacco products. There is good evidence from randomized trials that smoking cessation strategies are effective;<15-17> more evidence on the effectiveness of cessation strategies is presented in Chapter 43 on preventing tobacco-related illness. Former smokers have been shown to have a decreased risk of the disease compared to current smokers.<2-4>

Evidence that early detection can lower morbidity or mortality from pancreatic cancer is, however, not conclusive. The reported five-year survival for localized disease, based on 1981-1987 U.S. data, is only 7%, not substantially higher than the five-year survival with regional (4%) and distant (1%) metastases. A recent comprehensive review of published reports on surgical resection of pancreatic cancer also estimated an overall 5-year survival rate of 8% for small tumours without evidence of local or distant spread. In part, this rate may reflect the fact that a proportion of patients with localized disease cannot be operated on because of concomitant medical problems, advanced age or other reasons.<10,18> Patients who have small localized tumours that are resected for attempted cure, which account for only 4-16% of the total, may have better 5-year survival rates (as high as 37-48% in the most experienced centers<10,18>) although the designs of most studies of surgical outcome suffer from lead-time, length, and selection biases. The morbidity associated with surgical resection is high (15-53%) but perioperative mortality is now less than 7% in the hands of experienced surgeons.<9>

Reports on the effectiveness of adjuvant external beam and/or intraoperative radiotherapy in improving survival among curatively resected patients, using historical controls, have yielded inconsistent results. In one small randomized controlled trial,<19> corroborated by a subsequent case series by the same authors, an adjuvant treatment program using combined radiation and chemotherapy following curative resection was associated with a significant median survival advantage of 9 months and a 5-year survival advantage of 14.5% in treated versus control cases; however, the study was closed early due to poor subject accrual and did not control for the substantially greater frequency of clinic visits by cases. Adverse effects of combined radiation and chemotherapy include leukopenia and gastrointestinal toxicity<19> and intraoperative radiotherapy frequently causes gastrointestinal bleeding, which may be life-threatening. Additional randomized controlled trials of adjuvant therapy are needed to confirm its effectiveness in improving survival in patients with early pancreatic carcinoma. New modalities being explored include immunotherapy and hormonal therapy.

Recommendations of Others
The U.S. Preventive Services Task Force recommends against routine screening for pancreatic cancer in asymptomatic persons.<20> No organizations have published recommendations to perform routine screening for pancreatic cancer in asymptomatic persons.

Conclusions and Recommendations
Even though smoking appears to only modestly increase the risk of pancreatic cancer, smoking cessation appears to be the only intervention for which there is evidence of a reduction in risk.<15-17> Therefore physicians should counsel their patients who smoke to give up the habit (B Recommendation to prevent pancreatic cancer specifically, although an A Recommendation for preventing other tobacco-related illness, see Chapter 43). No other risk factors for pancreatic cancer have been established so no other effective primary preventive measures are known.

In terms of secondary prevention, the screening tests employing CA19-9, or CA19-9 plus elastase-1 or ultrasound have not been shown to be effective in detecting early disease in asymptomatic individuals.<8,9,12-14> Other tests have not been sufficiently evaluated to allow recommendations to be formulated. Also, since the five-year survival for localized disease is so poor, the Task Force recommends that screening not be performed (D Recommendation).

Unanswered Questions (Research Agenda)

1. The occurrence of pancreatic cancer in patients with new-onset diabetes mellitus should be investigated to determine if these patients are a high risk group.
2. Nutritional studies should be carried out to explore possible risk factors for pancreatic cancer. Primary prevention might then be possible.

This review was initiated in October 1992 and the recommendations finalized in June 1993.

Full Citation
Morrison BJ. Prevention of pancreatic cancer. In: Canadian Task Force on the Periodic Health Examination. Canadian Guide to Clinical Preventive Health Care. Ottawa: Health Canada, 1994; 850-59.