Monday, November 28, 2011

Prostate Cancer: The Truth


For some of us, ‘Movember’ has been a hairy month (Figure 28.1). The Movember Foundation was set up, in 1999, to draw attention to men’s health problems. Throughout the world, men, including myself, stopped shaving on October 31st and let facial hair run riot. (A friend of mine claims to have grown a moustache in memory of his late grandmother, who, he insists, resembled Magnum PI.)

Figure 29.1: Check out 'No Shave November' at

Copyright 2011 Paul Spradbery

One of the foundation’s main concerns is prostate cancer (PCa), which is the second most common malignancy (after lung cancer) among men in Western Europe. In the USA, it is second to none. The current estimate is that there are more than 20,000 new diagnoses per year in the UK alone (Lane, Strefford & Oliver, 2006, pp. 3-5). Given its approximate population of 60,975,000 (Office for National Statistics, 2009), this level of occurrence implies that approximately 1 in 300 British men will be positively diagnosed within the next decade.

Such high incidence is a recent phenomenon. A three-fold (age-adjusted) increase has been observed over the past 20 years. Despite this, however, mortality rate has remained constant (Cancer Research UK, 2008). Several theories for the sudden increase have been postulated. These refer to both genetic and environmental factors (Ekman, 1999), in addition to changes in detection methods (Tannock, 2002).


Signs and symptoms of PCa are manifold, although the majority of sufferers are symptom-free when the initial diagnosis is made. As a consequence of the periurethral anatomy of the gland, the most common symptom is urethral obstruction, frequently resulting in impaired urinary flow and nocturia. If symptoms are severe, then it is likely that the tumour is well established. Associated spinal or pelvic pain is usually indicative of metastasis (Zisman, Twardowski, Liebovici & Figlin, 2008, pp. 320-322).


Neoplasia occurs as a consequence of DNA mutation. The affected cell then fails to respond to normal stimuli and its progeny proliferate autonomously. Therefore, PCa is, by definition, a genetic disease (Raskó & Downes, 1995, p. 331). Hsing and Chokkalingam (2006) estimated that more than 40% of the associated risk was genetic, caused by genes of both high and low penetrance and, also, gene-gene interactions. Twin studies suggest that this figure is higher than those relating to tumours of the pancreas, stomach, breast and lung (Carpten & Trent, 2008, p. 54).

Some tumours have an inherited predisposition (Strachan & Reed, 2004, p. 488). They can be investigated by examining family histories. Carter (2007, p. 28) reported that the risk of PCa is doubled if an individual’s father or brother are similarly affected, and the probability of monozygotic twins contracting the disease (19-27%) is significantly higher than that for dizygotic twins. Similar conclusions were reached by Parnes, Hoque, Albanes, Taylor and Lippman (2006, p. 378).

Evidence does not, however, suggest that polymorphism at a single locus is responsible for PCa aetiology (Coughlin & Hall, 2002). Research into a variety of genetic markers, including single-nucleotide polymorphisms (SNPs), is ongoing. Most recently, Eeles et al. (2008), Kiermeney (2008) and Salinas et al. (2009) suggested that a combination of SNPs (at 8q24, 17q12 and 17q24.3) was highly significant, particularly when considered alongside family history. It is likely that additional markers will eventually be identified.

Perhaps the most well-researched locus is Hereditary Prostate Cancer I (HPCI) at 1q24-q25 (Klein, 2004, pp. 59-62). However, results regarding its significance are inconclusive (Carter, 2007, p. 28) and, furthermore, there is no evidence that the frequency of the crucial trimeric short tandem repeat (CAG) polymorphism has increased in recent years.

The proven existence of genetic aetiology does not imply that germline mutations have been responsible for recent statistics. (20 years represents barely a single reproductive cycle.) However, modulation of gene expression can result from environmental changes (Waghray et al., 2001) which take place more rapidly. Ornish et al. (2008) studied untreated, low-risk PCa sufferers and detected, using quantitative real-time polymerase chain reaction amplification, 48 up-regulated and 453 down-regulated transcripts following controlled environmental intervention.

Race is another causative factor (Tanagho, Smith & McAninch, 2007, p. 355). Incidence for white men is lower than for blacks but higher than for Asians (Carter, 2007, p. 29). In the UK, for example, net migration has been inward since the mid-1980s. In 2006, it was estimated that almost 20% of all foreign-born UK nationals were Asian, a greater percentage than any other racial group (Somerville, 2007, p. 2). Black Africans, too, have immigrated en masse (Kohnert, 2007, p. 37). Demographic changes of this magnitude could, therefore, have affected PCa incidence either positively or negatively. This factor alone, however, is unlikely to have caused a three-fold increase in such a short period.

PCa incidence rate increases with age. Most significantly, it increases five-fold from men’s late 50s to late 80s (Cancer Research UK, 2008). Moreover, it is higher than for many other sites of primary malignancy (Nelen, 2007, p. 6). As life expectancy in Western Europe increased by 11 years from 1950 to 2005 (World Health Organization, 2008, p. 24), it follows that longevity could be an additional determinant. If men continue to live longer, then the effect will be enhanced.


Many environmental causes of PCa have been postulated. The main categories are diet, lifestyle and pollution (Nelen, 2007, p. 6).

The effect of dietary animal fat dominates research findings. Japanese men consume only half as much of it as do American counterparts, and the former experience significantly less PCa (Carter, 2007, p. 30). However, correlation does not necessarily imply causation. In contrast, though, a diet in which vegetables predominate has been associated with a risk reduction (Chan, Lok & Woo, 2008), as has the inclusion of various vitamins, minerals and antioxidants (Carter, 2007, p. 31). Incidentally, chimpanzees, from which the lineage of Homo sapiens split only a few million years ago, eat mainly fruit and vegetables and do not experience PCa (Coffey, 2001). Again, though, sequence and consequence must not be confused.

Coffey (2001) implicated the recent shift in Western dietary patterns and stated that biological defence mechanisms would evolve too slowly to counteract the onslaught from such rapid change. This view would appear to have merit: the fast-food revolution was a late 20th-century phenomenon (Challem, 2003, pp. 46-47), and fat intake has increased substantially.

In spite of the conclusions of many dietary studies, Pruthi, Swords, Schultz, Carson and Wallen (2009) published current data which cast doubt on the impact of obesity and, hence, high fat intake.

The relationship between PCa and excessive alcohol consumption is contentious. Stanford et al. (1999) and Nelen (2007, p. 6) reported a weak positive association, whereas Lund Nilson, Johnsen and Vatten (2000) stated that there was no effect either way. Given its estimated hereditability of 50-60% (Dick & Bierut, 2006), it would seem improbable that alcohol dependence could produce such a marked increase in PCa incidence.

Carcinogenic effects of several environmental pollutants on PCa incidence have been investigated. For instance, exposure to the heavy metal cadmium has been linked (Timiras & Leary, 2007, p. 310). Sources include food and contaminated water (Agency for Toxic Substances and Disease Registry, 2008). Pesticides and other industrial waste have also been blamed (Puga & Wallace, 1999, p. 287). While it could be argued that industrial processes in Western Europe are more tightly regulated presently than previously, given that cadmium has a biological half-life of 20 years (Friberg, 1983), it would be reasonable to suggest that exposure when young might still have contributed to the development of disease during middle and old age.

Cigarette smoking has also been linked with PCa (Timiras & Leary, 2007, p. 310). However, its prevalence throughout Western Europe has declined within the last 20 years (British Heart Foundation, 2008). This would imply a negligible contribution, unless its effect is either delayed or cumulative — that is, smoking when young causes PCa when much older.

Epidemiological research on migrant populations has been useful when apportioning genetic and environmental contributions to disease incidence. Men from (low-risk) China and Japan, having immigrated to the (high-risk) USA, have been found to have increased rates (Tanagho et al., 2007; Zisman et al., 2008). Furthermore, first-generation migrants have had lower rates than those of subsequent generations (Greenberg, Daniels, Flanders & Eley, 2005, p. 179). These data would emphasize environmental, rather than genetic, causation.


PSA is a prostate-secreted serine protease and the most widely-used PCa marker (Balk, Ko & Bubley, 2003). Serum concentration is, generally, less than 4 ng/ml, but when the gland is either inflamed or cancerous, the value increases (Ellsworth, Wein, Heaney & Gill, 2008, pp. 2-10). This forms the basis for PSA screening.

In the USA, during the late 1980s, a national screening programme began. No such equivalent was introduced in the UK. Hence, cross-sectional transatlantic comparisons could subsequently be drawn. Within a decade, there had been an 80% rate increase among (white) Americans but a far less dramatic rise among Britons (Shibata, Ma and Whittemore, 1998). It was concluded that the sharp increase was caused solely by this new diagnostic test (Amling, 2006). Other populations in Western Europe yielded similar findings (Brewster, Fraser, Harris & Black, 2000).


In order to assess the efficacy of PSA testing, it must, firstly, be acknowledged that PCa progresses slowly and is largely symptomless (Tannock, 2002). Affected men, generally, die with it and not of it (Stamey, 2001).

The test’s sensitivity and specificity are of limited value (Marshall & Bangert, 2008, p. 351). Both false-positive and false-negative results are common (Breskin, 2009). There are multiple causes of elevated serum PSA concentration, including inflammation, benign neoplasms and infection (National Cancer Institute (NCI), 2009). It is also age- and race-dependent. Of further significance is that PCa is frequently detected among men whose serum PSA concentration is below 4 ng/ml (Thompson et al., 2004). Therefore, choice of diagnostic cut-off value has been highly consequential. The more sensitive the test, the greater is the number of false-positive diagnoses. Thus, another possible cause of increased incidence rate is identified.

To compound the sensitivity-specificity dilemma, serum PSA concentration fluctuates physiologically. Causes include sexual activity and, possibly, medical procedures such as cystoscopy and rectal examination (Ellsworth et al., 2008) which are, ironically, carried out to assess prostate pathology (El-Shirbiny, 1994, p. 108). Transurethral resection of the prostate (TURP) involves partial gland removal in order to ease urinary flow (Bupa, 2007). It is carried out frequently to treat benign conditions, and yet, increased treatment has been found to increase PCa incidence (Levy, Gibbons, Collins, Perkins & Mao, 1993; Brewster et al., 2000).

Etzioni, Gulait and Mariotto (2009, pp. 3-13) reported that the introduction of PSA testing has led to an increased detection rate in younger men and at earlier stages of the disease itself. These changes would have had a positive effect on PCa incidence rate.

All such findings have rendered PSA screening controversial. In Germany, Luboldt, Swoboda, Börgermann, Fornara and Rübben (2001) contended that it was ineffective. However, contradictory evidence from the USA has shown that PCa mortality rates have just begun to decline (Bryant & Hamdy, 2009, pp. 15-17). Nevertheless, it is debatable whether sufficient time has passed since the US programme began for it to have produced significant benefit.

Regardless of the intense argument and disputed findings, change in incidence rate depends on the level of uptake of PSA screening which is, in turn, determined by public awareness. In Ireland, Fitzpatrick, Corcoran and Fitzpatrick (1998) claimed that a social divide existed with regard to public understanding of PCa and readiness to undergo medical investigation. This conclusion was endorsed by Rowan (2007) who studied similar effects of social deprivation in England and Wales. It would be logical to suppose that incidence rates would be higher still if men among lower socio-economic classes were as motivated as those belonging to more affluent groups.


Circulatory PSA becomes bound by protease inhibitors. However, some remains unbound as ‘free PSA’ (Balk et al., 2003). A low ratio of free to bound PSA is indicative of PCa (NCI, 2009) and this discovery has been applied to clinical studies. Catalona et al. (1998) demonstrated increased specificity with a negligible reduction in sensitivity. The more this method is used, the more downward pressure on incidence rate might be exerted.

Another recent refinement is the measurement of rate of increase of PSA concentration with time, or ‘PSA velocity’ (Brosman, 2006). One study found that a velocity greater than 0.35 ng/ml/year increased significantly the likelihood of terminal PCa (Carter et al., 2006). However, these data would require confirmation by other studies, and are, in any case, too recent to have had any effect on incidence rates.


Environmental pressures will continue to change with time. Consequently, gene expression will be affected. If, as a result of media coverage, the public concludes that PCa screening is either worthless or potentially harmful, it is conceivable that fewer medical investigations will be carried out. Thus incidence rate might decline. It is clear, then, that increased reliability, of either PSA or a different marker, must be sought.


Substantial evidence has been put forward concerning both genetic and environmental contributions to the recent increase in PCa incidence throughout Western Europe. However, it would be difficult to provide a definitive explanation as to the relative importance of each factor. Probably the most significant change, though, has been the introduction of widespread medical screening. The irony of PSA testing is that it has, undoubtedly, increased the incidence of a disease which is, for the most part, both symptomless and harmless.

Much work remains to be done.

Happy shaving on December 1st.

Copyright 2011 Paul Spradbery


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