Monograph Series on Aging-related Diseases: X. Prostate Cancer

Larry F Ellison, Julie Stokes, Laurie Gibbons, Joan Lindsay, Isra Levy and Howard Morrison

Abstract

Prostate cancer is the most commonly diagnosed cancer among Canadian men, excluding non-melanoma skin cancer. Prostate cancer incidence increases almost exponentially with age; most cases are diagnosed in men aged 65 years or older. With the possible exception of animal fat consumption, no known widespread modifiable risk factors have been identified. Although the prognosis is good if appropriate treatment occurs in the early stages of disease, the ability of existing early detection techniques to decrease mortality has not yet been demonstrated. The considerable economic and societal burden of prostate cancer and its treatment, coupled with the projected large increase in the number of new prostate cancer cases as the population ages, make this disease a very important public health issue.

Key words: Canada; diagnosis; morbidity; mortality; prostatic neoplasms; risk factors; screening; treatment

Introduction

This monograph on prostate cancer is the 10th in a series of aging-related disease monographs. From 1974 to 1993, over 80% of prostate cancer cases in Canada were diagnosed in men aged 65 and over; 90% of prostate cancer deaths from 1976 to 1995 also occurred in this age group.

The main focus of this paper is to review what is known of the etiology of prostate cancer. The paper also includes a description of the background and natural history of the disease; incidence, mortality and prevalence data for Canada; an examination of screening and diagnosis issues; and a brief section on prostate cancer treatment.

Background and Natural History

The prostate gland is a small, solid organ that lies at the neck of the bladder in males and surrounds the urethra.^1-3 At birth it weighs only a few grams; it increases in size until about age 20, when it reaches its adult weight of approximately 20 grams.^2,4,5 The gland starts to enlarge further at about the sixth decade of life.^1,2 This age-related increase is known as benign prostatic hypertrophy (BPH), which is a common cause of symptoms of urinary outflow obstruction, such as difficulty initiating urination, poor flow and increased frequency. The reader is referred to a previous monograph in this series¹ for more information regarding BPH.

Prostate cancer is often symptomless in its initial stages. When symptoms do develop because of significant localized disease, they are frequently indistinguishable from those caused by BPH. Metastatic disease is a cause of pain, especially bone pain.⁶

Two potential precursors of prostate cancer have been recognized: atypical adenomatous hyperplasia (AAH) and prostatic intraepithelial neoplasia (PIN).^7,8 PIN is an atypical proliferative disorder of the prostate gland⁹ that can be either high- or low-grade. There has been some question as to the premalignant potential of AAH;¹⁰ however, high-grade PIN, which may be detected on needle biopsy, has been identified by many as a main precursor.^9,11-15 While its natural history is not known,¹⁶ there have been suggestions that PIN precedes carcinoma by several years.^17-19

Even once carcinoma develops, not all histologic prostate cancers become clinically significant during the life of a patient. Prostate cancer is found incidentally in at least 10% of men undergoing prostatectomy for BPH and in more than 40% undergoing cystoprostatectomy for bladder cancer.²⁰ A summary of autopsy series shows that the prevalence of latent histological prostate cancer is approximately 30% in men over the age of 50 who had no clinical problems during life.²⁰

The intensity of diagnostic efforts in populations and individuals, therefore, is likely closely associated with detection rates, and this may partially explain why the clinical incidence of prostate cancer varies widely across international boundaries.²¹ In Canada the observed lifetime incidence rate of prostate cancer has been about one third of the autopsy prevalence.²⁰ This observation gives rise to the oft-quoted expression that "more men die with prostate cancer than of it" and to the clinical dilemma of separating newly diagnosed cancers destined to behave aggressively from those destined to have a totally latent or relatively benign course.

Survival of the patient with prostate cancer is related primarily to the size and extent of spread of the tumour at the time of diagnosis, which is indicated by the stage. There are two systems generally used to stage prostate cancer. The modified Jewett system²² describes the size and spread of the tumour from A through D. Substages of each of these further describe details of tumour progression. The American Joint Committee on Cancer uses the tumour, node, metastases (TNM) system^23-25 to stage prostate cancer. The Appendix describes both of these staging systems.

American statistics from the 1980s²⁶ show that 50-65% of prostate cancer cases were localized at diagnosis (clinical stages A and B), 9-17% had regional spread (stage C) and 20-25% were metastatic (stage D). The more recent use of new early detection techniques (see below) may have shifted these proportions toward earlier stages of disease. Similar data do not exist for Canada.

Besides stage, the prognosis of prostate cancer patients is also affected by the patient's age, existing co-morbid conditions, the histological grade of the tumour and tumour volume.^27-30 The degree of tumour differentiation reported by the pathologist, usually expressed as a Gleason grade,^31,32 has been found to be correlated with likelihood of metastatic spread present at diagnosis as well as with patient survival.³¹ In general, the more poorly differentiated the tumour, the poorer the prognosis. Tumour volume correlates with local extent of disease, progression and patient survival, and penetration of the capsule appears to occur only in tumours larger than 1.4 cubic centimetres in volume.³⁰

Stage A1 tumours (lesions involving less than 5% of a resected prostate, usually low-grade) have crude survival rates that generally mirror those for the general population.³³ Some of these tumours do progress, though very slowly, such that up to 35% of men will develop clinical problems within 15 years, and up to 12% of untreated patients will die of prostate cancer within a 5-10-year period.^34-36

Reported crude five-year survival rates for untreated localized cancers range from approximately 80% for stage B1³⁷ to only 19% for stage B2 cancers.³³ This discrepancy is due, in part, to the fact that many putative stage B2 cancers are found at surgery to be understaged clinically and to have spread beyond the local capsule.³³

Stage C tumours have penetrated the prostate capsule, usually into the seminal vesicle and neck of the bladder. Lymph node metastases occur in approximately 50% of these cases, and survival of untreated patients is reported to be 42-54% at one year, 22% at three years and 10% at five years. Roughly 75% of untreated patients with Stage D prostate cancer are thought to die within 9-16 months of diagnosis.³³

Burden of Disease

Incidence

Though the number of small latent tumours seen in autopsy series seems to be rather consistent across countries and ethnic groups,^38,39 considerable international variation exists in the incidence of larger latent or clinically apparent prostate cancer tumours.⁴⁰ It is impossible to give accurate worldwide prostate cancer incidence estimates because, where they do exist, the quality of registration systems differs. Nevertheless, American estimates projected 334,500 new cases of prostate cancer in 1997.⁴¹ American men, and African-Americans in particular, are reported to have the highest incidence of prostate cancer in the world (Figure 1). European rates are lower than those in the US,⁴² and the lowest rates have been observed in Asia.^42,43 These variations may be partially due to differential use of diagnostic techniques⁴³ or currently unknown risk factors.

FIGURE 1
World-standardized prostate cancer incidence rates (per 100,000), 1983-1987, by country

*Vila Nova de Gaia
Source: Laboratory Centre for Disease Control, based on data from Reference 42

Incidence in Canada

Prostate cancer is the most commonly diagnosed cancer among Canadian men, excluding non-melanoma skin cancer.⁴⁴ In 1997 alone, almost 20,000 new cases were expected to be diagnosed,⁴⁴ and a recent report⁴⁵ estimated that the annual incidence of prostate cancer would reach 35,000 by the year 2016. It is estimated that about half of this projected increase will be due to the increasing incidence of the disease and the other half will be due to the increase in numbers of older men. The rising trend in incidence has been observed for many years; however, a dramatic increase has occurred since 1989 (Figure 2). These sharp increases in incidence have been mostly attributed to earlier detection.⁴⁶

FIGURE 2
Age-standardized prostate cancer incidence and mortality rates
for Canadian men, 1969-1997

* Estimated rates
Source: Reference 44

Table 1 shows the average annual incidence rates of prostate cancer over five-year intervals from 1974 to 1993. For all four periods, the incidence of prostate cancer increased with age, with at least a fivefold increase from ages 45-64 to 65-69 and more than a doubling of rates from ages 65-69 to 85 and over. While prostate cancer is very rare among Canadian males before age 45, incidence rises faster with age than for any other major cancer.⁴⁷ After age 45, incidence rates begin to grow in an almost exponential fashion. Whereas a Canadian male (at birth) has a 4.2% chance of developing prostate cancer by the age of 70, this increases to 9.5% by the age of 80.⁴⁴ Unlike lung or female breast cancer, prostate cancer does not reach a peak age of incidence in Canada before the age of 85.⁴⁷ The notable increase in new cases from one time period to the next is thought to be largely attributable to increases in the use of various techniques for detecting prostate cancer.^43,48,49

Table 2 presents provincial variations in average annual incidence rates for prostate cancer in Canada during the same four periods as Table 1. With occasional exceptions, the annual incidence increased over time in every province. During each of the first three periods there appeared to be an east-west trend, with incidence in the Atlantic provinces generally being relatively low. Some of the authors of this paper have shown previously⁴⁸ that this geographical gradient likely reflected differential detection rates related to variations in medical practice rather than differences in the prevalence of risk factors. After the advent of PSA testing (see Screening and Diagnosis section later in article) in approximately 1989, rates rose further throughout the country and those in the east began to approach those in the west.

Mortality

Prostate cancer mortality rates vary from country to country. High rates have been reported in the US, particularly among African-Americans; low rates, in China and Japan.^50,51 Mortality due to prostate cancer among African-American men has been found to be at least double that of Caucasian men,^41,49 and almost 10 times greater than that for men in Hong Kong and Japan.⁵²

Mortality in Canada

Prostate cancer is the second leading cause of cancer death in Canadian men aged 65 and over, after lung cancer. It has been estimated that 1 in 27 men will die of prostate cancer.⁴⁴ In 1997, 4100 prostate cancer deaths were expected in Canada,⁴⁴ and by the year 2016, this number is estimated to reach about 7800.⁴⁵ Figure 2 shows the slow increasing trend in prostate cancer mortality since 1969.

The average annual mortality rates for prostate cancer from 1976 to 1995, age-adjusted to the 1991 census population, are displayed in Table 3. The mortality rate rose from 25.5 per 100,000 males in 1976-1980 to 27.2 in 1981-1985 and then to 30.7 in 1991-1995. As expected, mortality due to prostate cancer increased with age for all four time periods. While there was more than a sixfold increase in rates from ages 45-64 to 65-69, there was roughly a tenfold jump in rates from ages 65-69 to 85 and over.

Prevalence in Canada

It is difficult to obtain exact prevalence estimates of prostate cancer because of the uncertain natural history^53,54 and known high prevalence of latent disease.^53,55-57 One paper reported the prevalence of prostate cancer (diagnosed between 1975 and 1989, and patients still alive at the end of 1989) to be 45,500.⁵⁸ Another source estimated the number of prostate cancers diagnosed from 1986 to 1990 (five-year prevalence) in patients still living in 1990 to be 34,400 and the ten-year prevalence (diagnosed from 1981 to 1990, and still alive in 1990) to be 48,100.⁵⁹ However, these latter figures may be underestimates since they do not include prostate cancer cases diagnosed prior to 1981. The prevalence of this disease is expected to climb rapidly in the 1990s due to the previously described increase in incidence, assuming the absence of any major increase in mortality.

Risk Factors

We reviewed the literature to summarize current knowledge of potential risk factors for prostate cancer. References were identified through MEDLINE and a review of article bibliographies. Only English-language papers were considered.

Family History

Using genealogical records, Cannon et al.⁶⁰ found prostate cancer to have a stronger familial aggregation than either colon or breast cancer. First-degree relatives of prostate cancer cases have been shown to experience statistically significantly increased risks that approach 2.5.^61-64 The risk has been reported as higher in blacks (odds ratio [OR] = 3.2) than in whites (OR = 1.9), though the difference was not statistically significant.⁶³ The closer genetically a man is to an affected relative^61,62 and the more relatives he has with the disease,⁶¹ the greater his risk. Men with three affected relatives were at an 11-fold risk.⁶¹

At least two Canadian studies have found evidence for a familial role in prostate cancer development.^65,66 A population-based case-control study conducted in Quebec involving 140 Francophone hospital in-patients detected an OR of almost 9 for men with one to four first-degree relatives with prostate cancer.⁶⁵ McLellan and Norman⁶⁷ have speculated that this large OR may be due to the investigators' not limiting their calculations to cases with one or two affected relatives, as had been the practice in previous studies. In the other Canadian report, also a population-based case-control study, Fincham et al.⁶⁶ used the Alberta Cancer Registry to identify 382 prostate cancer cases. They reported that subjects with an affected first-degree relative were more than three times as likely to develop prostate cancer than those without one.

A segregation analysis by Carter et al.⁶⁸ revealed that a form of "hereditary" prostate cancer is the result of an autosomal-dominant inheritance of a rare high-risk gene that predisposes men to the early development of prostate cancer. Another segregation analysis conducted in Sweden confirmed the importance of an autosomal-dominant gene.⁶⁹ Subsequent research has identified chromosome 1q24-25 as containing a gene, HPC1, involved in the development of hereditary prostate cancer.^70,71 While hereditary prostate cancer may account for a significant proportion of early onset prostate cancer, the data of Carter et al.⁶⁸ suggest that, overall, only about 9% of this disease in the population is due to the effects of the hereditary prostate cancer gene. Although the large majority of prostate cancers, especially among the elderly, appear to result from environmental factors, genetic predisposition is likely to play a role in the etiology of many prostate cancer cases.

Hormones

Sex hormones, androgens in particular, may play a role in prostate cancer development. Androgens are required for the growth, maintenance and functional activity of the prostate gland.⁷² In addition, prostate cancer growth rates can be manipulated through hormonal therapy.⁷³ Research has suggested that the progression of prostate cancer from histological to clinically significant forms may be partially the result of an altered hormone metabolism.⁷⁴

The principal androgenic hormone in men is testosterone.⁷² It has been hypothesized that elevated levels of both testosterone and its active metabolite, dihydrotestosterone, may, over many decades, lead to prostate cancer.⁷⁵ Ross et al.⁷⁶ found that young African-American men had higher serum testosterone levels than white American men and suggested that the difference could explain the increased prostate cancer risk experienced by the former group. However, prostate cancer risk has not been found to be associated with prediagnostic levels of serum testosterone or serum dihydrotestosterone.^77-80

The results of Ross et al.⁸¹ raised the possibility that reduced activity of 5-alpha-reductase, the enzyme in the prostate that converts testosterone to dihydrotestosterone, is involved in the low prostate cancer incidence rates observed among Japanese men. Meikle et al.⁸² reported that men with prostate cancer had elevated clearance rates of testosterone and an increased conversion ratio of testosterone to 5-alpha-reduced metabolites.

Ethnic Group / Country of Residence

The highest incidence rates for prostate cancer are found among African-American men.⁸³ Their incidence rates are 1.5 to almost 2 times those for Caucasian-American men, though rates for the latter group are among the highest in the world. High incidence rates are also found in Canada and northern Europe, while very low rates originate from countries in eastern Asia such as Japan and China. Prostate cancer is much more common in developed than developing countries, and the global range of difference in incidence is at least 70-fold.

Several migrant studies have found that prostate cancer rates shift toward those of the host country. Early studies by Haenszel and Kurihara⁸⁴ and Locke and King⁸⁵ found the rates among Japanese-Americans to be intermediate between the very low rates of Japanese men in Japan and the high rates among white males in the US. More recent studies concur with these results; Yu et al.⁸⁶ and Stellman and Wang⁷¹ found white males in the US to have considerably higher prostate cancer rates than Chinese men in China, with Chinese-Americans having intermediate rates. These outcomes suggest that the underlying cause of disease is related, at least in part, to environmental factors.

Socio-economic Status

Whether or not low socio-economic status is a risk factor for prostate cancer has been difficult to test because ethnic minorities are overrepresented in low socio-economic groups in many studies. While both positive and negative results have been found, in general, the data support the concept that socio-economic status is not an important risk factor in the development of prostate cancer.⁷⁴

Occupation

Many industries, occupations, and work-related exposures have been studied in relation to prostate cancer. However, the focus has primarily been on cadmium exposure, work in the rubber industry and farming. Farming was associated with increased risk of prostate cancer in 17 of 24 studies examined in a 1991 review.⁸⁷ In 10 of these studies the results were statistically significant. In a retrospective cohort study, Morrison et al.⁸⁸ found an association between number of acres sprayed with herbicides and risk of prostate cancer mortality after 17 years of follow-up. The National Academy of Science's committee to review the health effects of exposure to herbicides in Vietnam veterans concluded that there was limited suggestive evidence linking herbicide exposure to prostate cancer.⁸⁹

Analyses based on the rubber industry as a whole have found both positive and negative associations with prostate cancer. The International Agency for Research on Cancer decided that, while there was "limited" evidence for an excess occurrence of prostate cancer in rubber workers, the data were inadequate to establish a causal association.⁹⁰

A review of studies conducted to determine whether exposure to cadmium places a man at greater risk for prostate cancer concluded that cadmium exposure may weakly increase risk.⁷⁴ Some research suggests that cadmium interferes with the zinc-hormone relationships in the prostate.⁹¹ Zinc is required by several enzymes involved in the replication and repair of DNA and RNA, and the prostate contains the highest concentration of zinc of any organ in the body.⁹² As occupational exposures to zinc and cadmium usually occur together, it is difficult to evaluate their separate or interactive effects.⁹³ Elghany et al.⁹³ failed to find an increased risk of prostate cancer among welders or electroplaters, even though people working in such jobs experience high levels of cadmium exposure.

Physical Activity

It has been proposed that physical activity may lower both body fat and testosterone levels and, hence, possibly reduce prostate cancer risk for men who are very active.^94,95 The results to date, however, have been conflicting. Studies have reported that highly physically active men experience decreased,^94-97 increased^2,98-100 or similar^101,102 risks of prostate cancer compared with inactive men.

Research into the relation between occupational exercise and prostate cancer tends toward finding a protective effect for more physically active jobs. Recently conducted studies in China⁹⁵ and Turkey¹⁰³ indicated that individuals who worked in sedentary jobs were at an increased risk for prostate cancer. The results were independent of whether physical activity was measured by total energy expenditure or percentage of occupational time spent sitting. Two other studies have also reported an inverse association with occupational physical activity.^104,105 However, a study of the lifetime occupational physical activity levels among Hawaiian men concluded that physical activity may be positively associated with the risk of prostate cancer.¹⁰⁶

Anthropometry

The evidence for an association between high body mass index (BMI) and prostate cancer risk is very limited. In a case-control study of 48-79-year-olds conducted in northern Italy, Talamini et al.¹⁰⁷ observed that the risk of being diagnosed with prostate cancer rose with increasing BMI. The OR for men in the highest group (BMI >= 28) was nearly 4.5 times that of the reference group (BMI < 23). Studies of Japanese (relative risk [RR] = 1.33), Dutch (OR = 1.5) and Seventh-Day Adventist men (RR = 1.17) have all reported elevated, though non-significant, risk estimates.^108-110 On the other hand, a cohort study of over 20,000 men of various ethnicities in Hawaii¹¹¹ found high BMI to be slightly protective (RR = 0.7; 95% confidence interval [CI] = 0.5-1.2), while several other studies found no difference in mean BMI between cases and controls.^106,112-115

It has been suggested that previous findings of positive associations between BMI and prostate cancer might be accounted for more by muscle mass than by fat tissue.^108,116 Severson et al.¹⁰⁸ found the muscle, not the fat area, of the upper arm to be significantly related to prostate cancer risk. Increased muscle mass may be a marker for higher levels of androgens.⁷²

Diet

A dietary etiology for prostate cancer is consistent with the descriptive epidemiology, including observations on migrants, geographic variations and temporal trends, making it a promising area of research.¹¹⁷ A high positive correlation has been reported between prostate cancer incidence rates and the corresponding rates of several other cancers thought to be related to diet (e.g. breast and colon cancers).¹¹⁸ However, epidemiologic studies have not provided consistent evidence concerning the relation between specific dietary factors and prostate cancer risk.¹¹⁹

Energy intake

A significant positive association between energy intake and risk of prostate cancer has been reported in at least three case-control studies.^119-121 In one study,¹²¹ the association was stronger for advanced prostate cancer (fourth quartile versus first quartile RR = 1.70; 95% CI = 1.10-2.61) while in another,¹²⁰ the effect was restricted to older men (68-74 years old), particularly those with aggressive tumours. In three other case-control studies,^101,122,123 including one with information on tumour aggression,¹⁰¹ energy intake was unrelated to prostate cancer risk. This was also the finding in a cohort study conducted by Severson et al., though the result was based on only a 24-hour food recall assessment.¹⁰²

While several possible mechanisms have been proposed,^119,121 including an alteration of the activity of the sympathetic nervous system,¹²¹ the interpretation of a positive association between energy intake and prostate cancer risk is unclear as differences in energy intake between individuals are largely determined by differences in physical activity, body size and metabolic efficiency.¹²⁴

Fat intake

Ecological correlation studies from the 1970s showed strong positive associations between prostate cancer incidence or mortality and fat consumption among a number of countries and across the US.^125-127 Based on a correlation coefficient of 0.74 between national consumption levels of fat and national mortality rates of prostate cancer, Armstrong and Doll¹²⁵ hypothesized that dietary fat may be a major cause of prostate cancer.

Many case-control studies have examined the association between fat and prostate cancer,^{101,107,113-5,119,120,122,123,128-32} though only five^{101,119,120,122,131} adjusted for energy intake. The 14 studies differed in terms of study design (hospital or population controls) and method of dietary assessment (direct or indirect). In some cases, fat intake was inferred from the frequency of consumption of meat, dairy products and other foods known to have a high fat content.^{107,128-30,132} Other studies assessed fat intake in a more comprehensive manner using food composition data to approximate actual fat intake.^{101,113-5,119,120,122,123,131} Despite these methodological differences, only four studies^{119,122,123,130} failed to show a positive association with total fat intake.

The association between fat intake and prostate cancer risk has also been explored in at least eight cohort studies,^{102,110,111,133-7} the most methodologically sound of which was conducted by Giovannucci and colleagues.¹³³ Measuring fat intake as a nutrient and adjusting for energy intake, the only cohort study researchers to do so, they observed a significant positive association between increased fat intake and risk of advanced prostate cancer. A positive association between consumption of foods high in fat and subsequent risk of prostate cancer has been reported in three studies.^110,111,134 While two other studies did not detect an association,^135,136 both had limited food frequency data. Severson et al.¹⁰² detected a weak association with eggs and with margarine, butter and cheese as a group but not with fat as a nutrient, though this was only measured as part of a 24-hour food recall survey.

With respect to specific components of fat, Giovannucci et al.¹³³ and Gann et al.,¹³⁷ who measured plasma fatty acids, reported similar results. Both found a strong positive association between µ-linolenic acid, an essential polyunsaturated fatty acid, and prostate cancer risk; no clear linear relation across quartiles of exposure, suggesting a threshold effect; that low levels of linoleic acid, another polyunsaturated fatty acid, may further exaggerate the effect; and an independent association with red meat but no association with dairy foods. The findings with regard to polyunsaturated fat are supported by two case-controls studies.^120,122

Dietary fat intake has been more consistently linked to prostate cancer than any other modifiable risk factor. Evidence of an association appears to be strongest for µ-linolenic acid and among advanced stage cases. However, a causal mechanism has yet to be established.

Vitamin A

Vitamin A is a generic term for all substances that possess the biologic properties of retinol.¹³⁸ It may be ingested either as a preformed vitamin or as a provitamin.¹³⁹ The relation between intake of preformed vitamin A, naturally found only in food from animal sources,¹³⁹ and prostate cancer has been specifically examined in at least seven studies. In five of these studies^{129,135,140-2}  a positive association was reported, although in two of these studies^135,140 the effect was restricted to a certain age range. Slightly decreased risks with increased consumption were found in two related studies;^119,122 however, study response rates were low.

The results of published reports examining the relation between serum vitamin A or serum retinol and prostate cancer have been mixed.^143-147 An increased risk of prostate cancer was associated with lower serum retinol levels in a hospital-based case-control study conducted in the Netherlands.¹⁴³ However, a treatment effect or an effect from the disease process itself could not be easily dismissed; low serum retinol levels may be a metabolic consequence of cancer rather than a precursor.¹⁴⁸ The findings from three nested case-control studies differed with regard to serum retinol and prostate cancer incidence. One study suggested an inverse relation,¹⁴⁴ a study of Japanese-Americans in Hawaii reported no association,¹⁴⁹ while a weak positive association was observed in the third,¹⁴⁵ which was based on only 32 prostate cancer cases.

Using data from the National Health and Nutrition Examination Survey, Reichman et al.¹⁴⁶ reported an increased risk of developing prostate cancer for men with a serum vitamin A level in the lowest quartile compared to those with a level in the highest quartile (RR = 2.2; 95% CI = 1.1-4.3). However, in the Nutrition Canada Survey cohort,¹⁴⁷ men with a serum vitamin A level in the highest quartile were found to be at increased risk (RR = 2.0; 95% CI = 1.1-3.5). Reasons for the discrepant results are not readily apparent. The two cohort studies were similar in many respects, including the time period of the study, the length of follow-up, the overrepresentation of elderly and low-income individuals, and the adjustment for the confounding effects of age.

Provitamin A originates from a small percentage of the various carotenoids found in plant sources.^139,150 Because associations related to carotenoids do not necessarily imply a mechanism involving conversion to vitamin A,¹¹⁷ studies that have only used an index of vitamin A that combines the dietary intake of preformed and provitamin A^114,131,151 are difficult to interpret. Since most carotenoids, including those with provitamin A activity, can also act as singlet oxygen quenchers and as antioxidants under certain conditions,¹⁵⁰ studies relating carotenoids to prostate cancer are reviewed in the next subsection.

Antioxidants

The relation between dietary intake of carotenoids (primarily ß-carotene) and risk of prostate cancer has been extensively investigated in both case-control^{107,113,119,120,122,123,129,130,132,140,152} and cohort^{102,110,134,135,141,142,153,154} studies. Though several of the above-mentioned studies looked at the consumption of fruits and vegetables, both individually and as food groups, the majority were nutrient-based. Nutrient-based studies are preferred because they protect against the potential confounding effects of other nutrients contained in the same food item;¹³¹ such studies have reported positive,¹²⁹ negative^113,123,130 and null^{119,141,142,153} associations. In two reports the direction of the association was found to differ by the age group studied.^120,135 Serum ß-carotene has been shown to be positively associated with prostate cancer risk¹⁴⁵ in one study, but to have no association in two others.^143,144

Lycopene, a non-provitamin A, is the most efficient scavenger of singlet oxygen among the common carotenoids¹⁵⁵ and is the predominant carotenoid in prostate gland tissue.¹⁵⁶ Tomato-based products or lycopene (the major dietary source of which is tomatoes)¹⁵⁷ have been reported to reduce prostate cancer risk in several studies.^{110,132,141,144}

In a recent prospective study of nearly 50,000 health professionals, Giovannucci et al.¹⁴¹ observed a protective effect for frequent consumption (i.e. more than 10 servings a week versus less than 1.5 servings) of tomatoes, tomato sauce, tomato juice, and/or pizza (RR = 0.65; 95% CI = 0.44-0.95) and an inverse relation between lycopene intake and prostate cancer risk (RR = 0.79; 95% CI = 0.64-0.99). An inverse association (OR = 0.50), particularly among men younger than age 70 (OR = 0.35), was also noted in a nested case-control study that examined prediagnostic plasma lycopene levels.¹⁴⁴ Intake of tomatoes was significantly related to lower risk of prostate cancer in a cohort study of Seventh-Day Adventists¹¹⁰ and non-significantly related in a case-control study.¹³²

Only a sparse body of literature exists concerning relations between prostate cancer and other antioxidants such as selenium and vitamin C. In a recent randomized controlled trial whose original end-points were incidences of basal and squamous cell carcinomas,¹⁵⁸ selenium (a surrogate for the selenium-containing antioxidant enzyme called glutathione peroxidase)¹⁵⁹ supplementation was found to be associated with a significant reduction in prostate cancer incidence (RR = 0.37; 95% CI = 0.18-0.71). Previously conducted studies using prediagnostic serum selenium levels had not reported a significant association,^160,161 though one study included only 11 prostate cancer cases.¹⁶¹

The majority of studies that reported on vitamin C and prostate cancer risk found no effect.^{66,115,121,123,131,153,162-4} An exception was the study by Graham et al.¹¹⁴ that noted a positive association (OR = 2.32, trend p < 0.01) that was enhanced among men over age 70 (OR = 3.41, trend p < 0.05). Two other studies^115,120 reported elevated, though non-significant, risk estimates of approximately 40-50% among subjects in the highest quartile of vitamin C intake as compared to those in the lowest quartile.

In summary, with the possible exception of lycopene, there is little evidence that prostate cancer risk varies with consumption of dietary antioxidants.

Vitamin D

It has been recently hypothesized^165,166 that vitamin D deficiency may be a risk factor for prostate cancer. Using a nested case-control design, Corder et al.¹⁶⁵ found that lower prediagnostic serum levels of 1,25-dihydroxyvitamin D (1,25-D), a vitamin D metabolite, were significantly associated with an increased risk of clinically detected prostate cancer, particularly in men with low levels of 25-dihydroxyvitamin D (OR = 0.41). In an extension of this study, the observed protective effect was attributed to seasonally lower summer levels of 1,25-D in case subjects.¹⁶⁷ A subsequent nested case-control study,¹⁶⁸ however, failed to support these findings. Higher levels of either 1,25-D or 25-dihydroxyvitamin D were not associated with a reduction in prostate cancer risk, though a non-significant inverse association (OR = 0.67) was observed among men simultaneously in the highest quartiles of both metabolites relative to those simultaneously in the lowest. A smaller study of prediagnostic serum vitamin D metabolite levels,¹⁶⁹ also failed to support the findings of Corder et al.¹⁶⁵

It has been suggested that the potential protective effects of 1,25-D may be restricted to the biologically active free 1,25-D.¹⁷⁰ Free 1,25-D can be estimated by dividing total 1,25-D concentration by vitamin D-binding protein concentration.¹⁷¹ A case-control study conducted by Schwartz et al.¹⁷² reported that men with prostate cancer had significantly lower serum levels of free 1,25-D. In contrast, Corder et al.¹⁶⁷ did not find a lower free 1,25-D serum concentration in men with prostate cancer, while Gann et al.¹⁶⁸ reported free 1,25-D to be reduced (though not significantly) among prostate cancer cases older than 61 years (OR = 0.65). Further research into a relation between vitamin D metabolites and prostate cancer is necessary.

Alcohol

A biologically plausible protective role for alcohol in prostate carcinogenesis originated from research reporting that alcohol may increase metabolic clearance of testosterone.¹⁷³ However, virtually all studies conducted have demonstrated an absence of any overall relation.^{98,110,111,113,128,135,174-81}    One exception was a recent case-control study¹⁸² wherein significantly elevated risks were seen for those who had 22-56 drinks per week (OR = 1.4; 95% CI = 1.0-1.8) and 57 or more drinks per week (OR = 1.9; 95% CI, 1.3-2.7) in comparison to never-users.

Smoking

There have been many case-control studies concerning cigarette smoking and prostate cancer,^{66,112,113,128,152,174,176,177,180,183-94} only five of which reported a statistically significant association^{180,183,185,192}  or "marked" disparity in the proportion of smokers between cases and controls.¹⁸⁴ The lack of an association in many of these studies may be partly due to the use of hospital patients as controls; the controls used in all five positive studies cited above were population-based. Despite reporting increased risks for current (OR = 1.5; 95% CI = 1.0-2.4) and former (OR = 1.4; 95% CI = 1.0-1.5) smokers of 40 or more cigarettes per day, the lack of consistent findings in population subgroups and the lack of a clear trend in effect led Hayes et al.¹⁹² to doubt the existence of a causal association.

Early cohort studies of cigarette smoking and prostate cancer mortality^{98,135,136,195-7} were relatively small and, with one exception,¹³⁵ did not observe an association among former or current cigarette smokers in comparison to never-smokers. Though they reported an 80% increase in risk, Hsing et al.¹³⁵ found no evidence of a trend in effect. Three of the studies^98,195,197 also considered the number of cigarettes smoked by current smokers, but still found no association.

Since 1991, results have been published from four large cohort studies that each observed in excess of 500 prostate cancer deaths. An overall statistically significant increase in risk in the range of 20-35% was reported in three of these studies.^198-200 In one case,¹⁹⁹ a trend in effect was noted, the highest risk being experienced by those who smoked 40 or more cigarettes per day (RR = 1.5; 95% CI = 1.2-1.9). A lesser effect was found for former smokers (RR = 1.13; 95% CI = 1.03-1.24). The fourth study,²⁰¹ a 40-year follow-up of nearly 35,000 British male doctors, found prostate cancer mortality rates to be virtually identical between current and never-smokers.

Cohort studies of cigarette smoking and prostate cancer incidence have produced mixed results. While three studies,^102,110,202 including a very large Norwegian one,²⁰² reported no association, two others detected a statistically significant positive relation.^175,181 In the Iowa 65+ Rural Health Study,¹⁸¹ those who smoked 20 or more cigarettes per day experienced a nearly threefold increase in risk relative to non-smokers. The positive association reported by Hiatt et al.¹⁷⁵ was limited to those who smoked more than one package of cigarettes per day.

In early 1996, participants of an international consensus conference on smoking and prostate cancer unanimously agreed that there was inadequate evidence that smoking is associated with prostate cancer incidence.²⁰³ The inconsistent results of the incidence studies combined with the findings of the large cohort analyses of mortality have led Rodriguez et al.²⁰⁰ to suggest that smoking may adversely affect survival in prostate cancer patients.

Sexual Activity

Although extensively studied, the role of sexual activity in the development of prostate cancer is still unclear. Both hormonal factors and infectious agents have been proposed as increasing prostate cancer risk. Key²⁰⁴ summarized a number of studies and found the relative risks for early first intercourse, large number of sexual partners and a history of any sexually transmitted disease to be elevated. However, it has also been reported that celibate men develop prostate cancer as frequently as the general population.²⁰⁵

Vasectomy

Studies examining the relationship between vasectomy and prostate cancer have yet to demonstrate a pattern. Giovannucci and colleagues found significantly elevated relative risks of approximately 1.6 in both a retrospective²⁰⁶ and a prospective cohort.²⁰⁷ However, Sidney²⁰⁸ found no association, a result that was confirmed in a second report based on additional years of follow-up.²⁰⁹ In a very large multi-ethnic case-control study conducted in the US and Canada, a history of vasectomy was not significantly associated with prostate cancer risk.²¹⁰ A similar conclusion had been reached in three previous reports.^211-213

Though their study included only five prostate cancer cases who reported a history of vasectomy, Ross et al.²¹⁴ found vasectomy to be associated with lower risk. On the other hand, a study conducted in China²¹⁵ reported a strong positive association using neighbourhood controls, while Rosenberg et al.,²¹⁶ as part of a hypothesis-generating exercise, found large risk estimates regardless of whether cases were compared to cancer or non-cancer controls. Other case-control studies have reported increased risks ranging from 40% to 70%.^185,217,218

A major concern in the study of vasectomy and prostate cancer has been detection bias.²¹⁰ Vasectomized men may be more likely to subsequently visit a urologist, resulting in an increased chance of being diagnosed with prostate cancer.²¹⁹ In addition, while most studies have used self-reported history of vasectomy, no study to date has validated this against medical records.²¹⁰ Many studies have also used self-reported disease status, though it has been suggested that a history of prostate cancer is not always accurately reported.²²⁰ In a review of possible mechanisms, Howards²²¹ concluded that it seems highly unlikely that there is a biological mechanism supporting a relationship between vasectomy and prostate cancer.

Screening and Diagnosis

As highlighted in the previous section, modifiable risk factors have not been clearly established, so effective measures to prevent the occurrence of prostate cancer do not exist at this time. As a consequence, much attention has focused on the use of early detection measures to control this disease. Diagnosis of the cancer is usually made by histologic examination of tissue derived from a needle biopsy of the gland. Tests used to aid in the diagnosis include the digital rectal examination (DRE), transrectal ultrasound (TRUS) and serum prostate-specific antigen (PSA). Controversy exists about the appropriateness of using these tests as screening modalities in asymptomatic men, mainly because it is not known if early detection can actually influence the natural history and outcome of the disease.

The DRE is the most commonly used test, though it has not undergone systematic evaluation of its efficacy and it is not known whether routine annual screening by DRE reduces prostate cancer mortality.^222,223 A DRE may not be able to detect small tumours formed in certain sections of the prostate gland, and the quality of the test depends on the skill and experience of the examiner.²⁶ TRUS is generally thought not to be an appropriate screening test, primarily because of its low sensitivity and specificity, its invasiveness and its cost. It is generally used as a confirmatory diagnostic test and aid to biopsy when DRE or PSA tests indicate the possibility of a tumour.²⁶

PSA is a protein found in prostate epithelial cells and secreted into seminal fluid. It can be detected in serum using immunoassays; serum levels are increased in the presence of both BPH and prostate cancer.²²⁴ PSA levels are routinely monitored in patients after treatment to assess risk of relapse and treatment success,²²⁵ but, because of the test's simplicity, low cost and independence of examiner's skill, it is currently receiving much attention as a promising test for the early detection of prostate cancer.^226,227 There is evidence that use of PSA increases the detection of early stage prostate cancers.^226,228-231 Catalona et al.²²⁸ found that PSA-detected tumours were organ-confined in 51% of cases versus 34% detected by DRE, focal penetration of the capsule occurred in 15% of PSA-detected cancers versus 23% detected by DRE, extensive capsular penetration occurred in 24% versus 43%, positive seminal vesicles occurred in 6% versus 14% and positive lymph nodes occurred in 4% versus 7%.

The sensitivity of PSA in detecting prostate cancer is thought to be between 70% and 80%,^226,232,233 which means that approximately one man in four with prostate cancer will miss having a diagnosis made when PSA is used to screen an asymptomatic population. The positive predictive value of the PSA test in detecting prostate cancer has been reported to range from 28% to 35%.^226,228,232 This reflects a low specificity due, in part, to the presence of elevated PSA levels among men with other prostatic conditions such as BPH. As a consequence, approximately three out of four men with an elevated PSA will not have prostate cancer confirmed upon further diagnostic workup.²²⁶ While detecting many cancers early, this widespread use of PSA results in large numbers of unnecessary biopsies and in several missed cancers. Further, there is currently no evidence that screening for prostate cancer with PSA will reduce mortality from the disease. Randomized controlled trials are needed to avoid biases inherent in observational studies (e.g. selection, length and lead-time biases). There are ongoing studies in the US and Europe,^234,235 but these will not yield definitive results until well into the next decade.

At present, there is disagreement as to the appropriateness of the PSA test for routine screening of the general population. Table 5 outlines the screening guidelines for prostate cancer issued by North American organizations. Evidence-based groups such as the Canadian Task Force on the Periodic Health Examination and the US Preventive Services Task Force do not recommend routine use of PSA as a screening tool for prostate cancer. Neither of these groups feel that current evidence warrants its use in the general population to detect prostate cancer, primarily because of its relatively low specificity and the possibility of detecting indolent tumours that would not progress.^236,237

Treatment

A variety of treatment modalities are used to try to control prostate cancer. Radical prostatectomy (preferably a nerve-sparing procedure, which is thought to have lower rates of associated side effects) or radiation therapy has curative intent in men with localized cancers. Hormonal cytoreductive therapy, using anti-androgen products, is sometimes used as an adjunct in these men too. Local radiotherapy (for regional disease) and partial or total androgen blockade (achieved through chemical or surgical castration) constitute the main treatments for advanced disease. Surgery may be used to assist in staging. The usefulness of hormonal treatments, or anti-androgens, may be enhanced by strategies employing intermittent administration. Bone pain may respond specifically to parenteral strontium.

An extensive review of stage-specific treatment approaches is beyond the scope of this Monograph Series. The reader is referred to existing comprehensive reviews.^20,27 Although there is general agreement on some parameters for initial treatments of men with various stages of the cancer, major areas of uncertainty exist. These include whether surgery, radiation or delayed therapy is best in early stage disease, whether androgen blockade is warranted in minimal metastatic disease and how best to manage advanced disease resistant to anti-androgen therapy. All active treatments carry an associated morbidityófor example, impotence (at least 20-40%) and incontinence (5-25%) are common with both radiation and surgery for early stage disease,²³⁸ and erectile dysfunction is certain when hormonal treatments are used for later stage cancers.

Thus men with prostate cancer face several uncertainties regarding treatment options, all of which carry significant attendant risks of negative health effects.

Conclusions and Recommendations

Prostate cancer control is problematic. In part because prostate cancer incidence and mortality vary dramatically internationally and because of the findings of migrant studies, there is widespread belief that behavioural factors play a key role in the etiology of prostate cancer. Unfortunately, with the possible exception of animal fat consumption, no known widespread modifiable risk factors have been identified, notwithstanding numerous epidemiology studies of prostate cancer. Why has epidemiology failed?

One possibility is that epidemiology is a relatively crude tool to examine, what may prove to be, an unusually complex etiology. Most epidemiologic studies of prostate cancer have considerable problems with both exposure and disease characterization. Perhaps an understanding of the interplay between many genetically determined factors (such as 5-alpha-reductase) and environmental factors (such as dietary fat, vitamin A and cigarette smoking) will be necessary before consistency is achieved across epidemiologic studies. Appropriate staging information on prostate cancer cases, absent in most epidemiologic studies, should allow for the control of biases that may occur from the mixing of clinically inconsequential cancers from those that may provide etiologic clues.

Screening remains controversial, as does whether or not treatment extends or improves quality of life. Clearly, further research efforts are warranted. To address the issues concerning prostate cancer, the National Prostate Cancer Forum was held in early 1997 in Toronto.²³⁹ The Forum's recommendations included the development of a comprehensive research program that reflects the importance of the disease. As a first step, it was proposed that a Canadian randomized controlled trial of screening for prostate cancer with PSA be conducted to resolve the debate over the use of PSA for screening. Tools are necessary to monitor the outcomes of changes in practices of screening, increasing earlier diagnosis and changes in treatment. To accomplish this, the Forum recommended the creation of a registry of outcomes data, as well as a serum bank and a tissue bank on prostate cancer.

The implementation of these recommendations would help to increase our understanding of the epidemiology of prostate cancer and to resolve the controversy over screening.

APPENDIX Classification of prostate cancer: tumour, node, metastases (TNM) and Jewett systems
TNM	Description	Jewett
T	Primary tumour
TX	Primary tumour cannot be assessed
TO	No evidence of primary tumour
T1	Clinically unapparent tumour, not palpable or visible by imaging	A
T1a	Tumour an incidental histological finding in 5% or less of tissue resected	A1
T1b	Tumour an incidental histological finding in more than 5% of tissue resected	A2
T1c	Tumour identified by needle biopsy (e.g. because of elevated prostate--specific antigen [PSA])
T2	Tumour confined within the prostate	B
T2a	Tumour involves half a lobe or less	B1
T2b	Tumour involves more than half a lobe but not both lobes	B2
T2c	Tumour involves both lobes	B2
T3	Tumour extends through the prostatic capsule	C
T3a	Unilateral extracapsular extension	C1
T3b	Bilateral extracapsular extension	C1
T3c	Tumour invades seminal vesicle	C1
T4	Tumour is fixed or invades adjacent structures other than seminal vesicles	C2
T4a	Tumour invades bladder neck and/or external sphincter and/or rectum
T4b	Tumour invades levator muscles and/or is fixed to pelvic wall
N	Regional lymph nodes
NX	Regional lymph nodes cannot be assessed
NO	No regional lymph node metastasis
N1	Metastasis in a single regional lymph node, <2 cm in greatest dimension	D1
N2	Metastasis in a single regional lymph node,  >2 cm <5 cm in greatest dimension, or multiple regional lymph nodes, none  >5 cm in greatest dimension
N3	Metastasis in a regional lymph node  >5 cm in greatest dimension
M	Distant metastasis
MX	Presence of distant metastasis cannot be assessed
MO	No distant metastasis
M1	Distant metastasis	D2
M1a	Nonregional lymph nodes(s)
M1b	Bone(s)
M1c	Other site(s)
Source: Modified from References 24, 25

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