6053 CRUK Prostate C.Stats08:298. CRUK Prostate C.Stats08 29/8/08 07:28 Page 1 CancerStats Prostate cancer – UK September 2008 Introduction Prostate cancer is the most common cancer in men in the UKa, accounting for nearly a quarter of all new male cancer diagnoses. Although there has been a huge rise in prostate cancer incidence over the last 30 years, this has not been reflected in the mortality rates. Much of the increase in incidence is due to the incidental discovery of prostate cancer following transurethral resection of the prostate (TURP) and, more recently, the use of prostate specific antigen (PSA) testing. Table One: Number of new cases and rates of prostate cancer, UK by country, 2005 Number of new cases Crude rate per 100,000 European age-standardised rate per 100,000 (95% CI) England Wales Scotland 28,886 117.1 2,249 155.9 2,420 98.5 95.2 113.3 (94.1-96.3) 79.6 (108.6-117.9) N. Ireland UK 747 89.0 (76.4-82.9) 85.7 34,302 116.7 (79.5-91.8) 94.6 (93.6-95.6) Incidence In 2005, there were 34,302 new cases of prostate cancer diagnosed in the UK, that is, around 90 men every day or one man every 15 minutes. Table One shows the numbers and rates of new cases in the UK and its constituent countries.1 Figure One: Number of new cases and rates of prostate cancer, by age, UK, 2005 8,000 900 7,000 800 700 600 Cases 5,000 Rates 500 4,000 400 3,000 Rate per 100,000 Number of new cases 6,000 300 2,000 200 1,000 100 Incidence rates increase steeply with age and the highest rates occur in the oldest age groups. For men aged 55–59 the incidence rate per 100,000 is 143; ten years later, at age 65–69, the rate more than triples to 489 per 100,000 and by 85+ the rate is more than five times higher at 783 per 100,000. 85+ 80-84 75-79 70-74 65-69 60-64 55-59 50-54 45-49 40-44 35-39 30-34 25-29 20-24 15-19 10-14 5-9 0 0-4 0 Age Prostate cancer risk is strongly related to age: very few cases are registered in men under 50 and three-quarters of cases occur in men over 65 years. The largest number of cases is diagnosed in those aged 70–74 (Figure One).1 Age at diagnosis Figure Two: Age-standardised* incidence and mortality rates for prostate cancer by world regions, 2002 estimates Northern America Australia/New Zealand Western Europe Northern Europe Caribbean It is estimated from post-mortem data, that around half of all men in their fifties have histological evidence of cancer in the prostate, which rises to 80% by age 80, but only 1 in 26 men (3.8%) will die from this disease.2, 3 In other words, men are more likely to die with prostate cancer than from it – an important fact when considering population screening of asymptomatic men.4, 5 Histology Nearly all prostate cancers are adenocarcinomas, mainly occurring in the peripheral zone of the prostate gland.4 South America Southern Africa Southern Europe Central America World Deprivation Deprivation incidence gradients have been reported for both England & Wales and Scotland, with higher rates in the least deprived populations.6-8 These deprivation gradients have widened during the 1990s due to the greater relative increase in incidence for men in the most affluent groups and are likely to be influenced by accessibility and uptake of PSA testing.8 Middle Africa Western Africa Incidence Eastern Europe Mortality Eastern Africa Western Asia South-Eastern Asia Northern Africa South Central Asia Eastern Asia 0 20 40 60 80 Rate per 100,000 © Cancer Research UK 2008 Registered charity number 1089464 100 120 140 *to World Standard Population a Excluding non-melanoma skin cancer info.cancerresearchuk.org/cancerstats 6053 CRUK Prostate C.Stats08:298. CRUK Prostate C.Stats08 29/8/08 07:28 Page 2 CancerStats – Prostate cancer – UK Geographic variation Worldwide, an estimated 670,000 men were diagnosed with prostate cancer in 2002, accounting for 1 in 9 of all new cancers in males.9 Unlike the UK, it is the second most common cancer in men after lung cancer worldwide. Recent incidence rates are heavily influenced by the availability of PSA testing in the population and incidence varies far more than mortality. Three-quarters of all new cases are diagnosed in the developed world with the highest rates occurring in North America (specifically the USA) and the lowest rates in Asian countries (Figure Two).9 One reason for the extremely high incidence rate in the USA is the frequent use of PSA testing in that country.10 Within the USA there are also significant differences between racial groups. Incidence ratesb for black Americans are more than 50% higher than for white Americans, while rates for Asian Americans are 40% lower than for white Americans.11 An estimated 301,500 cases were diagnosed in the 25 member countries of the EU (EU25) in 2006.12 The lowest European rates are in southern and eastern Europe, and the highest are found in northern and western Europe (Figure Three).12 page 2 of 10 Figure Three: Estimated age-standardised* incidence and mortality rates for prostate cancer, selected EU countries, 2006 estimates Belgium Sweden Austria France Germany Italy UK EU Portugal Netherlands Hungary Greece Denmark Incidence Spain Mortality Czech Republic Slovakia Poland Bulgaria Romania 0 50 100 Rate per 100,000 150 200 *to European Standard Population Figure Four: Age-standardised* incidence and mortality rates for prostate cancer, Great Britain, 1975–2006 120 Time trends for a longer period (1975–2005) are shown in Figure Four for Great Britainc, when the European age-standardised rates almost trebled from 32 per 100,000 in 1975 to 95 per 100,000 in 2005.1 During the late 1970s and 1980s rates rose consistently, with an acceleration of the trend in the early 1990s followed by a brief levelling off in the mid-1990s and another rising trend in the late 1990s. Incidence trends by age group show a similar pattern but with a fall in the 85+ rate, beginning in the mid-1990s and then steeply since 2001 (Figure Five).1 Between 1975 and 2005 the number of cases in Great Britain more than quadrupled from 8,042 in 1975 to 33,555 in 2005.15 Rate per 100,000 Incidence Mortality 80 60 40 20 Year of diagnosis/death 2006 2005 *to European Standard Population Figure Five: Age-specific incidence rates for prostate cancer, Great Britain, 1975–2005 1,400 1,200 85+ 75-84 65-74 55-64 45-54 1,000 800 600 400 200 b In 2001-2005 the age-standardised (to the 2000 US Standard Population) incidence rate was 249 per 100,000 for black men, 157 per 100,000 for white men and 93.8 per 100,000 for Asian men11 c Northern Ireland data is not available before 1993 Registered charity number 1089464 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 0 © Cancer Research UK 2008 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 1987 1986 1985 1984 1983 1982 1981 1980 1979 1978 1977 1976 0 1975 Trends Substantial increases in incidence have been reported in recent years for many countries around the world, including the UK.14 During the last ten years in the UK, European agestandardised rates have increased by a third from 71 per 100,000 in 1996 to 95 per 100,000 in 2005 while the numbers of cases rose from 23,682 in 1996 to 34,302 in 2005, an increase of 45%. 100 Rate per 100,000 A recent analysis of prostate cancer incidence and mortality within the UK and Ireland showed relatively little geographical variation. The availability and uptake of PSA testing across the country may have obscured the underlying variation in incidence.13 Year of diagnosis 6053 CRUK Prostate C.Stats08:298. CRUK Prostate C.Stats08 29/8/08 07:28 Page 3 CancerStats – Prostate cancer – UK Figure Six: Age-standardised* rates of transurethral resection of the prostate (TURP) and crude rates of PSA testing, Scotland, 1981–1996 1,000 12,000 900 TURP 800 PSA 10,000 700 8,000 600 500 6,000 400 4,000 300 200 2,000 PSA testing rate per 100,000 TURP rate per 100,000 An analysis of prostate cancer incidence trends in Scotland concluded that much of the apparent increase between 1981–1996 was caused by increased detection: before 1989 through increasing rates of TURPd16 and afterwards through the rising use of PSA testing (Figure Six).17 Analyses for other countries including the USA18, 19 and Australia20 have also pointed to increased detection being a factor. In the USA widespread PSA testing on asymptomatic men from around 1986 resulted in dramatic increases in incidence (an 82% rise between 1986 and 1991)19 and it is estimated that more than half of US white men aged over 50 have had their PSA level tested.10 In western Europe the widespread use of PSA tests began a few years later, in around 1989–1990, but the level of population screening is much lower than in the USA.21 In the UK it is estimated that between 5–6% of men over 40 have a PSA test each year.22, 23 page 3 of 10 100 0 0 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 *to European Standard Population Year review of the evidence concluded that foods containing lycopenes and selenium probably have a protective effect while diets high in A strong family history of breast cancer may also calcium may increase risk.38 affect a man’s risk of prostate cancer, particularly if the family members were diagnosed under the Lycopene Lycopene, found principally in tomatoes and Risk factors age of 60. In particular, germline mutations in tomato-based products, may reduce the risk of No modifiable risk factor for prostate cancer the breast cancer susceptibility genes, BRCA1 prostate cancer. Cooked and processed has been identified and therefore, at present, and BRCA2, can predispose men to prostate tomatoes, such as tomato sauce, are a better there is insufficient evidence on which to base cancer (for more detail see Molecular biology source of lycopene than fresh tomatoes. A a prevention strategy. The established risk and genetics section). meta-analysis of 21 studies published from factors are age, family history and ethnicity. Many other factors have been studied but the Recently, genome-wide association studies have 1966–2003, showed that men with the highest intake of cooked tomato products had a 20% evidence is inconclusive. One reason for this identified several genetic variants that each reduced risk of prostate cancer compared to may be that different factors are involved in the slightly increase prostate cancer risk.29-33 men with the lowest intake.39 Since then, three development and promotion of aggressive However, because such genetic variants are studies including the European Investigation disease compared to non-aggressive disease, common in the population, they may into Cancer and Nutrition (EPIC)f study40-42 have making epidemiological studies of prostate contribute to a significant proportion of all 24 cancer particularly complex. Interpretation of prostate cancer cases. Current research in this shown a significant protective effect with higher intake of lycopene, although three other studies risk factors has been further complicated in the area is likely to identify further variants in the showed no association.43-45 PSA era, when identification of many prostate next few years. Genetic profiling is being used cancers is dependent on a threshold PSA level, to inform prostate cancer screening and Selenium which in turn is affected by other exposures treatment. Several studies have shown a protective such as body mass. This blurs the distinction association for selenium, reporting a 30–80% between ‘cases’ and ‘controls’ leading to the Ethnicity risk reduction for prostate cancer.46-48 However, possibility of PSA-detection bias.25 Variation in incidence rates around the world and within countries, suggests that risk is affected at least three studies showed no association.49-51 Age (see also Incidence section) by ethnicity. In the UK, black Caribbean and black Further research is needed and the Selenium and Vitamin E Cancer Prevention Trial (SELECT) The strongest known risk factor is age, with African men have approximately two to three very low risk in men under 50 and rising risk times the risk of being diagnosed or dying from may provide much needed answers.52 with increasing age thereafter (Figure One). prostate cancer than white men, while Asian Calcium and dairy products The older the man, the higher the risk and this men generallye have a lower risk than the Some cohort studies have shown a raised risk ties in with post-mortem results where national average.34-36 These results echo those approximately 80% of men by age 80 were from the USA where black American men have of prostate cancer for men with high intakes of calcium from diet and/or supplementation53-56 shown to have cancer cells in their prostate.2 higher rates than white American men and indeed the highest recorded in the world, while but others have not.57-59 Dairy products, as a source of calcium, have been extensively Family history (see also Molecular biology and Asian American men have much lower rates. genetics section) However, migration studies show an increase in studied in relation to prostate cancer. Several cohort studies show a small significant increase A family history of prostate cancer is one of risk as men move from low-risk to higher-risk the strongest known risk factors for this countries, suggesting that lifestyle factors play an in risk but findings differ by whether it affects advanced or localised tumours.56-58, 60, 61 The EPIC disease. It has been estimated that 5–10% of all important role. For example, South Asian men study showed overall a 32% increased risk for prostate cancer cases and 30–40% of earlyliving in the UK have a higher risk of prostate 35g/day higher intake of dairy protein and a 7% onset cases (men diagnosed <55 years) are cancer than men living in South Asia.37 26, 27 risk increase for an 0.3g/day intake of dairy caused by inherited susceptibility genes. calcium. Protein and calcium from non-dairy Diet sources were not associated with risk.62 Risk increases two to three times for men with Diet has been extensively researched because a first-degree relative diagnosed with prostate of the large variation in prostate cancer d TURP is a standard surgical procedure for benign prostatic enlargement, a cancer.28 If the relative is <60 years old at incidence between different cultures and their very common non-cancerous condition in older men. Prostate cancer was an incidental finding in the tissue removed by TURP in around 10% of diagnosis or more than one relative is affected traditional diets around the world, particularly men16 (at any age), the individual’s risk is four times the Asian versus ‘western’ diet. A variety of e A study in South East England recorded increased risk for Indian and Pakistani men and a decreased risk for Chinese and Bangladeshi men when the average. These factors combine so that if factors have been looked at but much of the compared to ‘All White’ men34 more than one relative is affected by earlyresearch is at present inconclusive. A recent f EPIC is a prospective study of diet and health involving over half a million onset prostate cancer, the risk is increased by seven-fold.27 people in ten European countries © Cancer Research UK 2008 Registered charity number 1089464 6053 CRUK Prostate C.Stats08:298. CRUK Prostate C.Stats08 29/8/08 07:28 Page 4 CancerStats – Prostate cancer – UK Fat and meat Extensive research into fat intake has been inconclusive. One difficulty is measurement of the different types of fat intake including saturated and unsaturated fat as well as fatty acids such as α-linolenic acidg, an omega-3 polyunsaturated fatty acid. A recent large multi-ethnic cohort study found no increase in prostate cancer for any source of fat and therefore did not support earlier studies that showed a raised risk.63 Further studies are needed, especially as α-linolenic acid may protect against cardiovascular disease and therefore its role for prostate cancer needs to be clarified.64 dayk.75 Findings since these meta-analyses have been inconsistent. page 4 of 10 2005 meta-analysis reporting a 40% increased risk of prostate cancer in men with a history of gonorrhoea, and a 50% increased risk with human papilloma virus infection.94 However, increased detection or recall bias may have influenced the result. Since then a large cohort study found no such association.95 A higher risk of fatal prostate cancer in smokers compared to non-smokers has been shown in some studies.76-77 However, no clear trends were shown with number of cigarettes smoked per day or between current, ex- and never-smokers. Two large studies concluded Endogenous hormones that smoking is not likely to be linked to either It has long been suggested that high circulating the incidence or mortality of prostate cancer.78, 79 levels of sex hormones are associated with an increased risk of prostate cancer as most prostate cancers respond favourably to Bodyweight and physical activity androgen-deprivation and castrated men do not Obesity is a major health problem in the UK and has been linked to several major cancers.80, 81 develop prostate cancer.96 However, the most recent worldwide re-analysis of 18 prospective However, it is not yet proven to be an studies, including the EPIC study,97 has shown no important risk factor for prostate cancer. A Meat intake, particularly red and processed meath, has been studied in relation to prostate recent meta-analysis reported a small association between endogenous sex hormones borderline significant increase in prostate cancer and risk of prostate cancer overall.98 cancer but findings are inconsistent. risk with increasing body mass index (BMI).82 Fruit and vegetables Some cohort studies indicate that obese men Insulin-like growth factor (IGF-1) is an easily are at greater risk of dying from prostate cancer measurable protein that is involved in normal Some studies65-67 have shown a lower risk of 83-85 cell proliferation and death. Both a recent prostate cancer for men consuming high while others have reported a reduced risk quantities of cruciferous vegetables but this was of localised prostate cancer in men with a high meta-analysis and a large Swedish study found not confirmed in the EPIC study which studied BMI.86, 87 Although the evidence is far from clear that higher concentrations of IGF-1 were 130,000 men and found no association between for prostate cancer, general health advice would associated with an increased risk of prostate cancer with a clear dose-response total fruit and vegetable intake or cruciferous be for men to maintain a healthy BMI. relationship.99,100 However, other studies vegetables and risk of prostate cancer.68 Physical inactivityl88 has been linked to several including EPIC have shown no association.101-103 serious diseases such as diabetes and heart Vitamin E, green tea and soy IGF-1 levels may mediate the effects of many disease as well as some cancers, particularly environmental exposures as its levels are The Alpha-Tocopherol, Beta-Carotene Cancer regulated by other cancer risk factors such as Prevention (ATBC) Study in smokers showed a colon cancer, but there is no strong link with bodyweight, diet and physical exercise. The 32% reduction in risk of prostate cancer in men prostate cancer.81 relationship between several components of receiving daily alpha-tocopherol (the major the IGF system and prostate cancer is form of vitamin E in supplements).69 Other Medications, medical procedures and infections studies have shown little or no association. Non Steroidal Anti-inflammatory Drugs (NSAIDs) undergoing further investigation.104, 105 Further research is underway to clarify the There is some evidence that aspirin use equivocal results, in the SELECT trial.52 particularly, may reduce the risk of prostate Diabetes mellitus cancer.89 Results from other studies have been The risk of prostate cancer was significantly lower, by 16% in the most recent meta-analysis, Green teai has been studied due to its regular mixed. among men with diabetes mellitus than among consumption by Japanese and Chinese men those without this condition but why this is so Statins whose prostate cancer risk is low. Green tea is not clear.106, 107 A number of possible contains high level of polyphenols which have In the laboratory, cholesterol-reducing statins 70 71 anti-oxidant effects. One cohort and one have shown possible chemopreventive mechanisms are discussed in the latest metaproperties against cancers. However, a analysis107 and recent research suggests that case-control study72 showed a reduced risk of systematic review of observational studies and prostate cancer with green tea consumption there may be a genetic link between diabetes randomised controlled trials found that statinand a dose-response relationship with the and prostate cancer.108 quantity drunk, although a third study found no use was not associated with short-term cancer risk but an association with reduced longer-term Molecular biology and genetics effect.73 More research into the possible risk cannot yet be ruled out.90 Further research Research into prostate cancer genetics aims to chemopreventive properties of green tea is needed. improve our understanding of men’s risk of on the effects of statin-use on prostate cancer disease and the factors that drive cancer risk or the course of the disease is needed.91 East Asian diets have higher soy content than progression. This knowledge has the potential western diets, for example, with the to improve diagnosis and guide the Vasectomy consumption of tofu, soymilk and miso. As the development and use of targeted treatments. A 2002 meta-analysis reported a small incidence of prostate cancer is lower in these increased risk of prostate cancer following countries, soy and isoflavonesj have been vasectomy, with risk ratios increasing with time Prostate cancer often clusters in families and studied to see if they are protective factors but since vasectomy, from 1.07 in the first 10 years 5–10% of all prostate cancers may have a to 1.23 after 30 years.92 However, a subsequent substantial inherited component. Searches for findings are inconsistent. high-risk prostate cancer loci have identified the cohort study showed an association only for Alcohol and smoking localised tumours, suggesting an increased g Sources of α-linolenic acid include nuts, seeds, vegetables oils, green leafy Two meta-analyses of alcohol consumption and likelihood of detection of early prostate cancer vegetables such as spinach and grass-fed meat such as beef h Including cured meat, sausages, hamburgers and meat-balls prostate cancer have been carried out. The in men who have undergone vasectomy.93 i Obtained from the plant Camellia sinensis largest study found no association74 whilst the j Isoflavones are found in a number of plant foods but the main source is other showed only small risk increases, although Infections the soy bean. The main soy isoflavones are daidzein and genistein k One unit contains 8 grams of alcohol dose-related, of 5%, 9% and 19% with Sexually-transmitted diseases and prostatitis l Government recommendations are that people undertake 30 minutes of consumption of 25, 50 and 100 grams per may increase the risk of prostate cancer with a moderate or vigorous physical exercise five times a week but only 40% of men and 28% of women achieved this in 200688 © Cancer Research UK 2008 Registered charity number 1089464 6053 CRUK Prostate C.Stats08:298. CRUK Prostate C.Stats08 29/8/08 07:29 Page 5 CancerStats – Prostate cancer – UK familial breast cancer gene BRCA2 as an important susceptibility factor. Carriers of germline mutations in BRCA2 have at least five times greater risk of prostate cancer and frequently develop a more aggressive form of the disease.109, 110 The current IMPACT study is evaluating the benefits of PSA screening in this high-risk population.111 However, BRCA2 mutations account for only 2% of all early-onset cases (<55years) indicating that further susceptibility loci exist.109 Mutations in the BRCA1 gene have a smaller effect, increasing a man’s risk of prostate cancer by less than two-fold.112 Current evidence indicates that prostate cancer inheritance is complex with numerous lowerpenetrance gene variants contributing to disease progression. Several studies highlight ELAC2, MSR1 and RNASEL as candidate genes for hereditary prostate cancer.113 MSR1 and RNASEL encode proteins involved in innate immunity, which fits well with the recent hypothesis that inflammation plays a key role in prostate carcinogenesis.114 The International Consortium for Prostate Cancer Genetics has also identified a novel susceptibility locus on chromosome 22.115 Genetic variants common in the wider population may also contribute to sporadic cases of prostate cancer. For example, single nucleotide polymorphisms (SNPs) in the Androgen Receptor (AR) gene, inflammatoryrelated genes and hormone metabolising genes have all been linked to increased risk of disease.116, 117 Strong evidence also links polymorphisms on chromosomes 8 and 17 with prostate cancer and a combination of five of these SNPs can increase an individual’s risk by more than five-fold.118 Three large international studies have identified a further 10 important prostate cancer susceptibility loci and highlighted candidate genes within these regions that may contribute to this disease including MSMB, KLK3 and LMTK2.29, 31, 119 page 5 of 10 Figure Seven: Diagram of the prostate Bladder Prostate gland Penis Urethra Testis Table Two: Treatment and management options for men with localised disease Watchful waiting Active surveillance Brachytherapy Prostatectomy High dose conformal radiotherapy Cryotherapy High intensity focused ultrasound Low-risk men (PSA < 10ng/ml and Gleason score <6 and T1-T2a) Intermediate-risk men (PSA 10-20ng/ml or Gleason score 7 or T2b-T2c) ◊ ◊ ◊ ◊ ◊ ◊ ◊ X* X* † X* X* ◊ X X * *† X* X* (adapted with permission from NICE (2008) CG58. Prostate cancer: diagnosis and treatment. London). Preferred treatment X Not recommended ◊ Treatment option X* Not recommended unless as part of a clinical trial comparing use with established interventions * Offer if there is a realistic prospect of long term disease control † neo-adjuvant ± adjuvant hormone therapy (for Gleason score >8) is recommended frequently underlie the onset of androgenindependent disease that fails to respond to hormone deprivation strategies. Alterations to other pathways involving PI3K, ERBB2 and BCL2 are also linked to the transition to hormoneindependence.124, 125 Genetic profiling is likely to become more important in the future providing valuable prognostic information and guiding the use of different treatment options. Patients with two copies of the TMPRSS2-ERG fusion gene have been linked with worse prognosis.126 Key genes such as LMTK2 are also being considered as targets for novel prostate cancer treatments. In addition to germline faults, mutations in key oncogenes and tumour suppressor genes have been detected in prostate cancer cells per se, including amplification of MYC and loss of NKX3.1, TP53, CDKN1B and PTEN.120 Chromosomal translocations have also been found to fuse 5’ regulatory elements of genes upstream of ETS transcription factors.121, 122 Epigenetic events such as DNA hypermethylation affect the expression of several genes in prostate cancer including GSTP1, a gene involved in carcinogen detoxification.123 This alteration occurs in nearly all prostate cancers and may prove useful as a diagnostic marker. Symptoms The prostate gland lies at the base of the bladder surrounding the upper part of the urethra (Figure Seven).127 Localised prostate cancer is often asymptomatic but some symptoms can arise from enlargement of the prostate gland. The symptoms for localised prostate cancer may be the same as those for benign prostatic enlargement (BPE)m, namely frequency and difficulty in urinating, and occasionally blood in the urine. If untreated, bladder obstruction may eventually occur. Men with more advanced disease may present with pain from widespread skeletal metastases, especially back pain. Much research is now focussing on the faulty molecular pathways that contribute to prostate cancer progression. AR signalling in particular, plays a crucial role at different stages of the disease. Overexpression and mutation of the AR gene can alter both the ligand sensitivity and specificity of the receptor. These changes Stage and grade Tumours are usually staged using the TNM system.4, 128 In brief, T1 and T2 tumours (‘early stage’) are confined within the prostatic capsule. T3 tumours have grown through the prostatic capsule and are known as ‘locally advanced’. T4 tumours are also regarded as locally advanced, © Cancer Research UK 2008 High-risk men (PSA >20ng/ml or Gleason score 8-10 or T3-T4) Registered charity number 1089464 assuming spread is confined to lymph nodes or nearby tissues. The most common site of distant metastasis is the bones. Tumours are graded according to the histology of the malignant cells. The most widely used grading system for prostate cancer is the Gleason system.129 To assess the Gleason score, biopsies must be obtained which are given scores. As prostate cancer may be histologically heterogeneous a primary (most common pattern) and secondary score are given and then added together. It is now recommended that the worst score is always included even if present in only a small proportion of the cancer. Gleason score effectively ranges from 6–10. Tumour size also has a bearing on prognosis. Treatment Treatment options should be fully discussed with each patient. Many treatments have serious side-effects and men need access to evidencebased information in order to make informed decisions, alongside health professionals.130 Localised disease There is no consensus on best treatment for early prostate cancer. Treatment decisions may be based on the risk of disease progression, categorised into low, intermediate and high risk131 (Table Two).130 Low risk early tumours can be monitored with ‘watchful waiting’ or ‘active surveillance’. Watchful waiting is based on the premise that many patients are elderly with a relatively short life expectancy. Their prostate cancer is likely to progress very slowly, may not cause symptoms and will not cause their death. m Also called benign prostatic hyperplasia (BPH) 6053 CRUK Prostate C.Stats08:298. CRUK Prostate C.Stats08 29/8/08 07:29 Page 6 CancerStats – Prostate cancer – UK Figure Eight: Rates of radical prostatectomy and orchidectomy, England, 1991–2004 (Adapted with permission from Hussain S et al. BJU Int 2008;101(5):547–55) 14 12 Radical prostatectomy All ages Rate per 100,000 Active surveillance is for low-risk men, suitable for radical treatment should their disease progress. If it does not, then over-treatment is avoided. Monitoring consists of PSA testing, digital rectal examination (DRE) and repeat biopsy as necessary - the optimum monitoring protocol has not been identified.132-134 Radical treatment is an option, if the patient prefers. page 6 of 10 10 Orchidectomy All ages 8 6 4 2 A randomised trial comparing radical prostatectomy and watchful waiting management for men with clinically localised prostate cancer predominantly not detected by PSA testing, reported a statistically significant reduction in overall mortality and prostate-specific mortality at 12 years for men receiving surgery who were younger than 65 years.136 There have been no adequate comparative trials between the different types of prostatectomy, or between surgical and radiotherapy approaches. A recent systematic review of treatments for localised prostate cancer suggests from cohort studies that there are likely to be, at most, small differences between the different radical treatment options.137 Clinical trial entry should always be considered to help answer treatment uncertainties. The UK Prostate Testing for Cancer and Treatment (ProtecT) trial completes recruitment in 2008. It is evaluating treatment effectiveness (‘active monitoring’ vs radical surgery vs radiotherapy) for clinically localised prostate cancer in men aged 50–69 years identified through population-based PSA testing.138 The increasing use of radical prostatectomy in England is shown in Figure Eight.139 1992 1991 1993 1994 1996 1995 1998 1997 Year 2000 2002 2001 2003 2004 1,200 (Adapted with permission from Hussain S et al. BJU Int 2008;101(5):547–55) 1,000 LH-RH analogues Anti-androgens Oestrogens 800 600 400 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 1987 1986 1985 1984 1983 1982 1981 1980 1979 1978 1977 0 1976 200 Year Some men, previously thought to have localised disease, are found to have involved margins at radical prostatectomy. Adjuvant radiotherapy has been shown to reduce the rate of biochemical and clinical recurrence but follow-up is presently too short to assess the impact on survival.141 The widespread usage of super sensitive PSA assays to detect biochemical recurrence at an early time point has led to the establishment of the RADICALS Trial. This will compare immediate adjuvant radiotherapy with early salvage radiotherapy following a rise in PSA levels. If the latter is as effective, approximately half the men may avoid radiotherapy and its associated toxicities.142 Treatment developments Treatment efficacy in prostate cancer is complicated by side-effects that may profoundly affect quality of life, such as erectile dysfunction and urinary incontinence.143, 144 Both are common following radical treatment. Bowel toxicity can occur following radiotherapy to the prostate or pelvic nodes. For both early and locally advanced disease, conformal radiotherapy is standard. It delivers high, effective doses of radiation to the tumour Locally advanced disease while minimising damage to the healthy Radiotherapy is the standard of care for locally surrounding tissue, thereby reducing side-effects, advanced disease which approximates to disease in men who have two or more high risk particularly to the bowel.145 Intensity modulated factors using the National Cancer Collaborative radiotherapy (IMRT) ‘shapes’ the radiotherapy dose, as well as the field, and is in research. Network (NCCN) classification131 as shown in Table Two. Neo-adjuvant hormone therapy can Recruiting until at least 2011, the CHHiP trial is currently investigating hypofractionated IMRT shrink tumours prior to radiotherapy. Postfor both efficacy and side-effect incidence.146, 147 radiotherapy adjuvant hormone therapy is advocated for men with a Gleason score above Brachytherapy using radioactive prostatic implants is an alternative to external beam 7. An international trial investigating whether radiation for localised prostate cancer: main hormone therapy alone can produce similar side-effects are impotence and urinary results to radiotherapy (MRC PRO7140) symptoms. Brachytherapy is approved by NICE completed recruitment in 2005. © Cancer Research UK 2008 1999 Figure Nine: Hormone treatment for prostate cancer, UK, 1975–2004 1975 Radical treatment options for curing localised disease include prostatectomy or radiotherapy. Erectile dysfunction and urinary incontinence are issues for both approaches but more likely with radical prostatectomy compared to external beam radiotherapy.135 For intermediate and high risk disease, neo-adjuvant and/or adjuvant hormone therapy is an additional option. 0 Number of prescriptions per 100,000 There is no standard approach for intermediate risk tumours. Radical treatment is generally preferred, with active surveillance a viable alternative. High risk tumours are usually treated radically. Watchful waiting is acceptable in some circumstances, with fully informed patient consent. Registered charity number 1089464 as a monotherapy148 or as a booster dose, alongside external beam radiotherapy.149 Surgical developments include laparoscopic (keyhole) surgery and intra-operative nerve sparing surgery (IONS). The latter aims to preserve erectile function where possible. Laparoscopic surgery may or may not be carried out with the assistance of a robotic device (robotic-assisted laparoscopic prostatectomy). Both approaches result in less blood loss during surgery than during open surgery150 but meta-analyses indicate that urinary incontinence and erectile dysfunction rates are similar to that of open surgery.151, 152 Side-effect profiles between treatments are not clear. Brachytherapy may provide better sexual function than either external beam radiotherapy or surgery but can cause more urinary problems.153-155 Radiotherapy generally produces more bowel toxicity than surgery.154, 155 Long term quality of life may be better overall with surgery than with either brachytherapy or external radiotherapy although to some extent it evens out over time.156 Metastatic disease In the UK, approximately 20–30% of men with primary prostate cancer present with incurable metastatic disease.157, 158 Hormone treatment can give good short-term disease control by lowering androgen levels, principally testosterone. Options for androgen withdrawal are surgical castration (bilateral orchidectomy)n or drug therapy with luteinising hormone-releasing hormone (LH-RH) analogueso. These show similar efficacy and siden In 1941 Higgins and colleagues discovered the beneficial effects of castration on prostate cancer and won a Nobel prize for this work in 1966 o These affect the levels of luteinising hormone produced by the pituitary gland, which leads to a reduction in testosterone produced in the testes. They are also called gonadotrophin hormone-releasing analogues 6053 CRUK Prostate C.Stats08:298. CRUK Prostate C.Stats08 29/8/08 07:29 Page 7 CancerStats – Prostate cancer – UK The effect on survival of intermittent androgen withdrawal (as opposed to continuous therapy) is being investigated. Short periods of treatment are followed by periods of monitoring, with treatment restarting following PSA progression or should symptoms occur. This can preserve potency during periods off treatment. Figure Ten: One-, five- and ten-year age-standardised relative survival for prostate cancer, men aged 15-99 diagnosed in England and Wales, 1971–2001 100 80 % survival effect profiles.130 Side-effects include impotence, hot flushes, osteoporosis, gynaecomastia, tiredness and metabolic alterations.159 Androgen deprivation achieves an overall median survival time of approximately two and a half years and around 80% of patients have symptomatic relief.160 Hormonal treatment trends over time are shown in Figure Nine.139 The fall in orchidectomy rates can be seen in Figure Eight. page 7 of 10 One year Five years Ten years # 60 40 20 * period analysis ** 0 1971-1975 1976-1980 1981-1985 1986-1990 1991-1995 Year of diagnosis 1996-1999 2000-2001* ** data not available # not agestandardised Figure Eleven: Five-year age-adjusted relative survival, selected countries in Europe 1990–99 and the US 1996–2003 US White US All races US Black A third hormonal therapy option is antiandrogen treatmentp. This is not as effective in controlling metastatic cancer, but is less likely to affect sexual function. The most troublesome side-effects are gynaecomastia and breast pain. A single radiotherapy fraction to the breasts or the anti-oestrogen tamoxifen is a useful preventative measure. Combining anti-androgens with androgen deprivation (medical or surgical) is known as maximum androgen blockade or MAB. This may give a modest survival advantage but increases morbidity.161-163 Additional hormonal treatments include low dose corticosteroids or oestrogen (stilboestrol). Austria Switzerland Germany Netherlands Finland Iceland Italy France Sweden Spain Norway England Wales 1996–2003 Scotland Northern Ireland 1995–99 Poland 1990–94 Slovenia Czech Republic Metastatic prostate cancer will nearly always become refractory to hormone therapy. The main treatment option is then chemotherapy with docetaxel and steroids.130 This is not recommended for men with a Karnofskyq performance status below 60%.164 Denmark 0 20 40 60 80 100 % survival Figure Twelve: Five-year relative survival for prostate cancer patients, by age, England and Wales, 1999–2003 100 Future treatments Various biological therapies are in trials, including cancer vaccines and monoclonal antibodies. Other research is investigating treatment combinations such as chemotherapy, bisphosphonates and strontium 89, or hormone therapy with or without chemotherapy, bisphosphonates and Cox-2 inhibitor. Recently the CYP17 inhibitor, abiraterone acetate, which ablates androgen and oestrogen synthesis from all tissue sources has shown significant activity in castrate resistant disease and is entering phase III trials.169 For localised disease, though both are approved by NICE, high-intensity focused ultrasound (HIFU) and cryotherapy are not recommended outside clinical trials. Research continues into their use as primary therapy or © Cancer Research UK 2008 % survivall 80 Bone pain is the biggest problem with castrate resistant metastatic disease. Radiotherapy and analgesics should be tried first for palliation.130 Radiotherapy provides effective pain relief while surgery may be necessary for pathological fractures.165 Bisphosphonates may be used if these treatments fail.130 The precise role of bisphosphonates in treating advanced prostate cancer is under investigation.166-168 60 40 20 0 15–49 50–59 60–69 Age at diagnosis salvage following prior radiotherapy. NICE assert that evidence is sufficient regarding safety but lacking in long term efficacy and effect on quality of life.170-172 Survival Survival rates for prostate cancer have been improving for more than 30 years. However, interpretation of these trends is difficult as the case-mix on which they are based is likely to have changed over time with earlier diagnosis following the advent of TURP and PSA testing. The detection of a greater proportion of latent, earlier, slow-growing tumours in more recent time periods will have the effect of raising survival rates due to lead-time bias, that is, the difference in time between screen detection and clinical detection in the absence of screening.173 Lead-time bias is estimated to be Registered charity number 1089464 70–79 80–89 between 5–12 years, varying with a man’s age at screeningr.23, 174 There may also have been genuine improvements in survival due to more effective treatment, both for early, aggressive prostate cancers and for advanced cases.175 The five-year relative survival rate for men diagnosed with prostate cancer in England and Wales in 2000–2001 was 71%, compared with only 31% for men diagnosed in 1971–1975 (Figure Ten).176, 177 The one and 10-year rates have also risen dramatically. Similar increases have occurred in Scotland: five-year relative p These block the binding of testosterone and dihydrotestosterone (DHT) in the prostate cancer cells and therefore block the action of androgens produced by both the testes and the adrenal glands q The Karnofsky scale measures physical ability and scores normal health as 100%. A person with a performance status of 60% would require occasional help with physical needs r Data from the European Randomized Study of Prostate Cancer (ERSPC) estimated for a single screening test, mean lead times of 12 years at age 55 and six years for a man aged 75174 6053 CRUK Prostate C.Stats08:298. CRUK Prostate C.Stats08 29/8/08 07:29 Page 8 CancerStats – Prostate cancer – UK Table Three: Number of deaths and mortality rates for prostate cancer, UK by country, 2006 Number of deaths Crude rate per 100,000 European age-standardised rate per 100,000 (95% CI) England Wales Scotland 8,506 34.3 546 37.7 779 31.9 24.9 25.0 (24.4-25.5) 24.3 (22.9-27.1) N. Ireland UK 207 24.6 (22.6-26.0) 22.0 10,038 34.0 (19.0-25.0) 24.8 (24.3-25.3) Figure Thirteen: Number of deaths and mortality rates for prostate cancer, by age, UK, 2006 3,000 800 700 2,500 2,000 Deaths 500 Rate per 100,000 600 Number of deaths survival rates increased from 47% for patients diagnosed in 1980–1984 to 80% for patients diagnosed in 2000–2004.178 The increase in survival rates is particularly pronounced in the 1990s when PSA testing became more prevalent.179 The same problems of interpretation apply to international comparisons of survival rates (Figure Eleven).180,181 The 99% five-year survival rate recorded for white American men is likely to reflect the stage distribution of registrations in that country due to PSA testing.182 page 8 of 10 © Cancer Research UK 2008 Registered charity number 1089464 85+ 80-84 75-79 70-74 65-69 60-64 55-59 50-54 45-49 40-44 35-39 30-34 25-29 20-24 15-19 5-9 10-14 0-4 Rates Survival from prostate cancer is strongly related 1,500 400 to the stage of the disease at diagnosis. For 300 disease which is confined to the prostate, five1,000 year relative survival is 90% or more, but if 200 500 disease is metastatic at presentation five-year 100 relative survival is lower at around 30%.s183 For 0 0 most cancers survival rates decrease with age of patient, but five-year relative survival rates Age at death for men diagnosed with prostate cancer in their 60s are higher than rates for either younger or 2. Lack of specificity. Conditions other than External Quality Assessment Service (UK older men (Figure Twelve).183, 184 NEQAS) are used. prostate cancer, such as BPE, prostatitis and lower urinary infections, can give rise to PSA testing, the Prostate Cancer Risk Mortality elevated levels of PSA. About two-thirds of Management Programme and informed In the UK, prostate cancer is the secondt most men with an elevated PSA level (measured consent as >4ng/ml) will not have prostate cancer common cause of cancer death in men after Prostate cancer affects many men and the but will suffer the anxiety, discomfort and risk lung cancer.1 In 2006 there were 10,038 deaths disease is incurable when diagnosed at a late of follow-up investigations.3, 4 from prostate cancer in the UK, accounting for stage. An accurate method of detecting early, 12% of all male cancer deaths.194-196 The number treatable disease is therefore highly desirable. of deaths and the mortality rates for prostate 3. The natural history of prostate cancer is cancer in the UK and its constituent countries poorly understood. At present it is not Three tests for prostate cancer are available, in 2006 are shown in Table Three.1 The possible to reliably predict which tumours Digital Rectal Examination (DRE), Prostate will be aggressive and which will require little majority of deaths (93%) occur in men aged 65 Specific Antigen (PSA) measurement and or no treatment. A proportion of patients and over as Figure Thirteen shows.1 In men transrectal ultrasound (TRUS) biopsy but all with early, localised disease detected through aged 85 and over, prostate cancer overtakes have drawbacks.4, 157 Of the three, the PSA test PSA testing and then biopsy, will receive lung cancer to become the most common is the most acceptable but there are problems. unnecessary treatment, with considerable cause of cancer death. PSA is an enzyme produced by the prostate side-effects. which can be measured in the blood. It is clear Geography that a number of factors, other than the 4. There is a lack of consensus on the best Mortality rates worldwide (Figure Two) vary presence/absence of cancer, can affect the treatment for early stage prostate cancer. 15-fold and although North America ranks first levels of PSA, such as the age of the man, in terms of incidence, it is eighth for mortality, obesity and the presence of benign prostatic 5. There is no evidence that screening reduces with the highest mortality rates being recorded hypertrophy.185 Research into making the PSA in the Caribbean. The widespread use of PSA mortality. Screening trials are underway in test more accurate is ongoing and includes testing in the USA results in not only higher the US, UK and in Europe but it will be looking at PSA density (takes into account the some years before the results are known.188-192 incidence but also a much higher proportion of size/volume of the prostate gland), velocity early stage cases being diagnosed than in (how fast it rises over time), doubling time and As a result of these problems, population countries with lower levels of testing and this the ratio between two different components of screening is not recommended and instead the naturally leads to higher survival rates overall PSA, ‘free’ and ‘complexed’.3, 186 Free PSA is and lower mortality rates relative to incidence. Department of Health launched the Prostate associated with benign prostatic conditions and Cancer Risk Management Programme For instance, 60–70% of the prostate cancers complexed PSA with cancer so their ratios may (PCRMP) in 2002.186 One of its main aims is to diagnosed in Japanese men have extended help to interpret total PSA levels, alongside beyond the prostate versus only 11% in US provide clear and balanced information about DRE findings, previous biopsy results, ethnicity, white men.197 Significant decreases in mortality the benefits and limitations of PSA testing.3, 186 prostate size and co-morbidities.3 (see Trends below) have been recorded in Asymptomatic men can then make an informed decision about whether they wish to some countries since 2002 which will not be The main reasons why PSA testing is not at reflected in these rankings (Figure Two). have a PSA test or not, after discussion with present suitable for population screening of their primary care physician. Referral guidelines asymptomatic men are summarised below. Trends recommend that PSA levels take age into Overall in GB prostate cancer mortality was account with cut-off values of >3.0ng/ml for 1. Lack of sensitivity. Around 15% of men with fairly stable during the 1970s but began to men aged 50-59, >4.0ng/ml for men aged 60a normal (measured as ≤4ng/ml) PSA level increase in the early 1980s (Figure Four). 69 and >5.0ng/ml for men aged 70+.193 Interwill have prostate cancer.187 In other words, Mortality peaked in the early 1990s when the laboratory variability has also been identified the test will provide them with false European age-standardised death rate reached and the PCRMP recommends that only reassurance.3 laboratories participating in the UK National s based on patients resident in England 1999–2002 t In 2006 there were 19,600 lung cancer deaths responsible for 24% of all male cancer deaths 6053 CRUK Prostate C.Stats08:298. CRUK Prostate C.Stats08 3/9/08 10:11 Page 9 CancerStats – Prostate cancer – UK Figure Fourteen: Age-specific mortality rates, prostate cancer, UK, 1971–2006 1,000 800 Rate per 100,000 30 per 100,000 in 1992. Since then there has been a slight fall in the rates and in 2006 the European age-standardised rate was 25 per 100,000. This was the first sustained decrease in annual death rates for thirty years. A decrease in mortality has also been observed in the USA since 1991198 and in Europe since 1993.199 A comparison of mortality rates in the USA and UK between 1975–2004, reported that mortality peaked in the early 1990s for both countries, but the subsequent fall in mortality until 2004 was much greater in the USA.200 page 9 of 10 85+ 75-84 65-74 55-64 45-54 600 400 200 controlled trials can provide definitive answers about the efficacy of screening.139 Acknowledgements Cancer Research UK wishes to thank Professors D Dearnaley and R Martin and Dr R Eeles for their expert advice on this report and Dr S McPhail for providing the survival by stage analysis. However, the content of this CancerStats report is entirely the responsibility of Cancer Research UK. Cancer Research UK would also like to acknowledge the essential work of the cancer registries in the UK (www.ukacr.org/). 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. Cancer Research UK. News and Resources Centre CancerStats. Prostate cancer. 2008. http://info.cancerresearchuk.org/cancerstats/ Sakr WA, Grignon DJ, Haas GP, et al. Age and racial distribution of prostatic intraepithelial neoplasia. Eur Urol 1996;30(2):138-44. Burford DC, Kirby M, Austoker J. Prostate Cancer Risk Management Programme information for Primary Care; PSA testing for asymptomatic men. Sheffield: NHS Cancer Screening Programmes.; 2008. Selley S, Donavan J, Faulkner A, et al. Diagnosis, management and screening of early localised prostate cancer. Health Technol Assess 1997;1(2). Frankel S, Smith GD, Donovan J, et al. Screening for prostate cancer. Lancet 2003;361(9363):1122-8. Quinn M, Babb P, Brock A, et al. Cancer Trends in England & Wales 19501999: TSO; 2001. Scottish Cancer Intelligence Unit. Trends in Cancer Survival in Scotland 19711995; 2000. Rowan S. Trends in cancer incidence by deprivation, England and Wales, 1990-2002. In: Health Statistics Quarterly 36 Winter; 2007. GLOBOCAN 2002. Cancer Incidence, Mortality and Prevalence Worldwide 2002 estimates. 2006. http://www-dep.iarc.fr/ Gann P. Interpreting Recent Trends in Prostate Cancer Incidence and Mortality. Epidemiology 1997;8:117-9. SEER. Cancer Statistics Review 1975-2005. 2008. http://seer.cancer.gov/csr/1975_2005/ Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007;18(3):581-92. Quinn M WH, Cooper N, Rowan S (eds). Cancer Atlas of the United Kingdom and Ireland 1991-2000: Palgrave Macmillan; 2005. Hsing A, Tsao L, Devesa S. International Trends and Patterns of Prostate Cancer Incidence and Mortality. International Journal of Cancer (PredOncol) 2000;85:60-7. Statistical Information Team Cancer Reseach UK. 2008. Horwich A, Waxman J, Schroder FH. Tumours of the prostate. In: Oxford Textbook of Oncology. Oxford: OUP; 1995. Brewster D, Fraser L, Harris V, et al. Rising incidence of prostate cancer in Scotland: increased risk or increased detection? BJU International 2000;85:463-73. Potosky A, Kessler L, Gridley G, et al. Rise in Prostatic Cancer Incidence Associated with Increased Use of Transurethral Resection. JNCI 1990;82:1624-7. Potosky A, Miller B, Albertsen P, et al. The Role of Increasing Detection in the Rising Incidence of Prostate Cancer. JAMA 1995;273:548-52. Threlfall T, English D, Rouse I. Prostate Cancer in Western Australia: trends in incidence and mortality from 1985 to 1996. MJA 1998;169:21-4. Levi F, Negri E, La Vecchia S. Recent Trends in Prostate Cancer Mortality in the European Union. Epidemiology 2000(11):612. Melia J, Moss S, Johns L. Rates of prostate-specific antigen testing in general practice in England and Wales in asymptomatic and symptomatic patients: a cross-sectional study. BJU Int 2004;94(1):51-6. Pashayan N, Powles J, Brown C, et al. Excess cases of prostate cancer and estimated overdiagnosis associated with PSA testing in East Anglia. BJC 2006;95(3):401-5. Giovannucci E, Liu Y, Platz EA, et al. Risk factors for prostate cancer incidence and progression in the health professionals follow-up study. Int J Cancer 2007;121(7):1571-8. Platz EA, De Marzo AM, Giovannucci E. Prostate cancer association studies: © Cancer Research UK 2008 2005 2003 2001 1999 1997 1995 1993 1991 Year of death Future In 1999, prostate cancer overtook lung cancer to become the most common solid tumour in As yet it is not possible to say what proportion UK men. As a health problem, it will continue to grow due to the ageing of the male of the fall in mortality is the result of improvements in treatment,201 changes in cancer population and the increasing ad hoc use of registration coding,202 the attribution of death to PSA testing. With many more cases of early localised cancer being diagnosed, it is prostate cancer, and the effects of PSA imperative that a method is developed that testing.203 Only the ongoing randomised References 1989 1987 1985 1983 1981 1979 1977 1975 1973 1971 0 The UK mortality rates by age group between 1971–2006 are shown in Figure Fourteen. Rates for men under 84 years reached a peak in 1992 and have declined consistently since then. Recent rates for men over 85 had two peaks: the first in 1996 which was followed by a decline and then a further increase to 2003, since when the rates have fallen. Further information For a list of other CancerStats reports and PowerPoint Presentations, all freely downloadable, visit our Publications website http://publications.cancerresearchuk.org choose ‘Browse by type’ and then select from the list. Or email [email protected] for more information and help. pitfalls and solutions to cancer misclassification in the PSA era. J Cell Biochem 2004;91(3):553-71. 26. Bratt O. Hereditary prostate cancer: clinical aspects. J Urol 2002;168(3):90613. 27. Carter B, Beatty T, Steinberg G, et al. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci 1992;89:3367-71. 28. Johns LE, Houlston RS. A systematic review and meta-analysis of familial prostate cancer risk. BJU Int 2003;91(9):789-94. 29. Eeles RA, Kote-Jarai Z, Giles GG, et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 2008. 30. Amundadottir LT, Sulem P, Gudmundsson J, et al. A common variant associated with prostate cancer in European and African populations. Nat Genet 2006;38(6):652. 31. Thomas G, Jacobs KB, Yeager M, et al. Multiple loci identified in a genomewide association study of prostate cancer. Nat Genet 2008;40(3):310-5. 32. Zheng SL, Sun J, Cheng Y, et al. Association Between Two Unlinked Loci at 8q24 and Prostate Cancer Risk Among European Americans. JNCI 2007;99(20):1525-33. 33. 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Washington: American Institute for Cancer Research; 2007. 39. Etminan M, Takkouche B, Caamano-Isorna F. The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev 2004;13(3):340-5. 40. Zhang J, Dhakal I, Stone A, et al. Plasma carotenoids and prostate cancer: a population-based case-control study in Arkansas. Nutr Cancer 2007;59(1):46-53. 41. Wu K, Erdman JW, Jr., Schwartz SJ, et al. Plasma and dietary carotenoids, and the risk of prostate cancer: a nested case-control study. Cancer Epidemiol Biomarkers Prev 2004;13(2):260-9. 42. Key TJ, Appleby PN, Allen NE, et al. Plasma carotenoids, retinol, and tocopherols and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition study. Am J Clin Nutr 2007;86(3):672-81. 43. Peters U, Leitzmann MF, Chatterjee N, et al. Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 2007;16(5):962-8. 44. Kirsh VA, Mayne ST, Peters U, et al. A prospective study of lycopene and tomato product intake and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2006;15(1):92-8. 45. Bosetti C, Talamini R, Montella M, et al. Retinol, carotenoids and the risk of prostate cancer: a case-control study from Italy. Int J Cancer 2004;112(4):689-92. 46. van den Brandt PA, Zeegers, M. P. A., Bode, P. and Goldbohm, R. A. Toenail Registered charity number 1089464 differentiates between cases which need radical treatment and those that do not.204 Otherwise large numbers of men may receive unnecessary and possibly debilitating treatment and place a significant burden on the NHS. 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