What Is Known About the Causes

Once a man has been diagnosed with prostate cancer, he inevitably asks himself: What caused it? Personally, I very much wanted to know. Saying that I had a disease that strikes randomly, like a bolt of lightning, was not very satisfying. It would be better if I could understand its antecedents, even if my own behavior had somehow contributed to its cause.

Yet when I began searching the medical literature for answers, I was disappointed. A 2003 review of the subject stated that ''the etiology [cause] of prostate cancer remains virtually unknown.''1 Given that a federal ''war on cancer'' had been declared in 1971, this assessment was disquieting. Here we are, thirty-five years later, knowing little more than we knew then about the most common cancer to affect American men.

CLUES

In searching for causes of prostate cancer, scientists have major clues to work with. Seven of the most important are the following:

1. It increases with age.

Prostate cancer is the most age-dependent of all human cancers. It is very uncommon in young men; almost three quarters of cases

A Brief History of Prostate Cancer

The first case of prostate cancer in the medical literature was published in London in 1817. Prostate cancer was said to be ''a very rare disease'' in 1853, and a total of only fifty cases had been described worldwide as late as 1893. During the first half of the twentieth century, the incidence of prostate cancer increased markedly until it became the most common male cancer in Europe and North America. Part of the reason for the dramatic rise is that men are living longer, and prostate cancer increases with age. This accounts for only some of the increase, however; the other reasons are unknown. In recent decades, the incidence appears to have leveled off.

are diagnosed after age 65. However, when prostate tissue is randomly examined from younger men who died from other causes, early subclinical, cancer-like changes, often microscopic in size, are commonly found. In a study of autopsies in Detroit, 30 percent of men in their 30s and 50 percent of men in their 50s showed some early, cancer-like changes in their prostates.2 So apparently whatever initiates the cancer-causing process does so many years before the cancer manifests itself clinically. This suggestion was strengthened by a 2005 study reporting that a man's PSA level in his 30s predicts his chances of later developing prostate cancer.3

2. Its true incidence in the United States has apparently not changed over the past three decades.

In the early 1990s, there was great interest in what appeared to be a sharp increase in the incidence of prostate cancer. It is now evident that this apparent spike was due to the increasingly widespread use of the prostate specific antigen (PSA) blood test, introduced in 1986, which was detecting more early cases. Allowing for the increase expected with an aging population, the actual age-corrected incidence of prostate cancer in the United States does not appear to

Table 9. Ethnic Differences in Prostate Cancer in the United States, 2004 (age adjusted per 100,000 population)

Incidence rate

Death rate

African American

272

73

White

164

30

Hispanic

137

24

Asian American

100

14

Native American

54

22

source: Cancer Facts and Figures, 2004 (Atlanta: American Cancer Society, 2004).

source: Cancer Facts and Figures, 2004 (Atlanta: American Cancer Society, 2004).

have changed in recent decades. This fact suggests that whatever is causing the cancer has not changed either.

3. There are marked differences in incidence among ethnic groups in the United States.

Ethnic differences in the incidence of prostate cancer are among the greatest for any form of cancer. The incidence and death rates (mortality) for 1996-2000 are shown in Table 9. Thus, African Americans have an incidence of prostate cancer twice as high as Hispanics and five times as high as Native Americans, although all are minority groups. Minority group status per se does not seem to explain the differences in incidence. The incidence rate for African Americans is 66 percent higher than for whites. The comparable rate for 19731977 also shows a 66 percent difference, indicating that the disparity did not change between the 1970s and the 1990s.4

Possible reasons for the high incidence of prostate cancer among African American men have been widely debated; suggestions have included genes, diet, and testosterone level.5 Their high death rate is more understandable, since African American men are less likely to get PSA testing or rectal exams and have less access to specialized medical professionals.6 However, even when African Americans and white men have equal access to care, as in the Veterans Administration medical system or with prepaid medical plans, studies report that African Americans still go to their physicians with more advanced stages of prostate cancer.7 Whether this discrepancy is due to a real difference or to a greater reluctance among African Americans to seek appropriate care remains to be ascertained.

The remarkably low rate of prostate cancer among Native

Table 10. Prostate Cancer Death Rates per 100,000 Men (age adjusted, for the year 2000)

Trinidad and Tobago

32.3

Sweden

27.3

Norway

26.8

Denmark

23.1

Cuba

22.1

Ireland

21.6

New Zealand

21.2

Chile

19.9

France

19.2

United Kingdom

18.5

Germany

18.4

Australia

18.0

United States

17.9

Canada

17.1

Mexico

16.6

Croatia

15.3

Spain

15.0

Greece

10.7

Russia

6.8

Japan

5.5

Kazakhstan

5.2

Turkmenistan

1.8

China

1.0

source: Cancer Facts and Figures, 2003 (Atlanta: American Cancer Society, 2004).

source: Cancer Facts and Figures, 2003 (Atlanta: American Cancer Society, 2004).

Americans—one third the rate of whites and one fifth the rate of African Americans—has received relatively little attention from researchers. The low prostate cancer rate among Alaskan natives has been confirmed in several studies over the past half-century and is supported by reports of very low Arctic-area rates among Inuit men in Greenland and Sami (Lapp) men in northern Norway.8 Given the unusual diets of these groups, they would seem to be worth investigation by prostate cancer researchers.

4. There are marked differences in the incidence of prostate cancer in different countries.

Although access to health care differs among countries, the in cidence of prostate cancer varies markedly even among countries with similar access. The highest rates are for Scandinavian countries

''We must be doing something right!''

(Sweden, Norway, Denmark) and Caribbean countries (Trinidad and Tobago, Cuba). Confirmation of the high rate in the latter came from a study in Jamaica that reported an incidence of prostate cancer among the highest in the world.9 The high rate of prostate cancer among African Americans and African Caribbeans raises the question of the rate in African nations. A limited number of studies have been done, but those suggest intermediate rates compared to other countries.10

At the lower end of the incidence spectrum are countries such as Japan and China, whose rates have been verified in several studies. There is some evidence, however, that the incidence of prostate cancer is increasing in Asia; in both Japan and Singapore, the rate doubled between 1978 and 1997.11

In summary, national differences in prostate cancer death rates vary more than thirtyfold. Such massive differences are found in few other diseases except those that are known to be caused by infectious agents.

5. When men move from a low-incidence country to a high-incidence country, their risk of getting prostate cancer increases.

Studies of migrants continue to intrigue researchers. Japanese immigrants to the United States have an incidence of prostate cancer four times higher than Japanese men in Japan. Whether the Japanese

Prostate Cancer Epidemiology

men emigrate to the United States early in life or later in life does not seem to make a difference. Japanese American and Chinese American men who were born in the United States have twice as high an incidence of prostate cancer as Japanese and Chinese men who are immigrants. Similarly, Chinese immigrants to Australia have prostates twice as large, as measured by ultrasound, as those of Chinese men in China.12

6. Dogs are the only mammals besides humans that frequently develop spontaneous prostate cancer.

Prostate cancer in dogs is similar to that in humans in many ways. It is age dependent and becomes clinically manifest as cancer at a time corresponding to human cancer.13 Dog prostate glands show similar cancer-like changes in younger dogs. Finally, prostate cancer in dogs has a tendency to spread to lymph nodes and bones, just as it does in humans. One of my colleagues, on reading a draft of this book, asked whether anything is known about the relative incidence of canine prostate cancer in different countries. Alas, the answer is apparently no.

7. The incidence of prostate cancer among men with schizophrenia is low.

Five studies of cancer incidence among individuals with schizophrenia in Denmark, Finland, and Israel have reported an unusually low rate of prostate cancer; in the Scandinavian studies, the rate was approximately half the rate expected. A follow-up study suggested that antipsychotic medication may exert a protective effect.14 Genes, diet, and decreased exposure to other possible causative agents should also be considered.

Given the known facts, what might be causing prostate cancer? In recent years, five major theories have received the most research attention. Let us now consider each of them.

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