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Prostate Cancer: Diagnosis and Treatment. Cardiff (UK): National Collaborating Centre for Cancer (UK); 2014 Jan. (NICE Clinical Guidelines, No. 175.)
In May 2019, NICE updated and replaced this guideline with NICE guideline NG131 on prostate cancer: diagnosis and management. Some of the 2014 recommendations have been retained in the new guideline. This document preserves evidence reviews and committee discussions for areas of the guideline that have not been updated in 2019. The PDF has been colour coded as follows: all text without shading is from the original 2014 guideline and has not been amended by subsequent updates. Black shading indicates text from 2014 has been replaced by the 2019 update.
1.1. Introduction
1.1.1. Risk Factors
Age is one of the strongest risk factors for prostate cancer, with around 85% of all cases diagnosed in those aged over 65 years and an estimated incidence of only 0.1% in those aged under 50 years (Patel and Klein 2009). Family history has been shown to be a risk factor for prostate cancer (Goh et al, 2012); approximately 5–10% of cases are thought to have a substantial inherited component. It has been established that strong predisposing genes could be responsible for up to 40% of cases in younger men up to the age of 55 (Elo and Visakorpi 2001; Carter et al. 1992). For example, a recurrent mutation (G84E) in the HOXB13 gene has recently shown to be significantly associated with an increased risk of prostate cancer and is significantly more common in men with early-onset, familial disease. The relative risk to a patient increases with increasing numbers of first-degree relatives diagnosed and the father-to-son relative risk is increased 2.5-fold whilst the relative risk between brothers is increased 3.4-fold (Johns and Houlston 2003). Patients with hereditary prostate cancer are often diagnosed 6–7 years prior to spontaneous cases (Bratt 2002). A link between prostate cancer and a family history of breast cancer has also been established, believed to be due to the BRCA1 and BRCA2 genes (Thompson and Easton 2002; Edwards et al. 2003).
Ethnicity has been shown to be a risk factor for prostate cancer (see section 1.1.2.5). The lowest incidence rates of prostate cancer are observed in Asian men, particularly in India, China and Japan. South Asian men living in England have a lower incidence of prostate cancer than their white counterparts (relative risk of 0.8) (Metcalfe et al. 2008). Higher rates are seen in Black men; African-American men are thought to have 1.3–2.0 times the risk of developing prostate cancer than Caucasian men, and black men (irrespective of black- African or black-Caribbean origin) have been shown to have a 3-times higher risk of developing prostate cancer than white men (Ben-Shlomo 2008).
However, studies suggest a change in risk in men moving from Japan to areas such as the US, indicating that exogenous factors may also affect the risk of progression from latent to clinical prostate cancer (Zaridze et al. 1984). There is inconclusive evidence on the influence of factors such as food consumption, pattern of sexual behaviour, alcohol consumption, exposure to ultraviolet radiation, and occupational exposure on the development of prostate cancer (Kolonel et al. 2004). Obesity has also been linked to prostate cancer, with an association between high-grade disease and increasing body mass index (BMI) (Rohrmann et al. 2003).
1.1.2. Incidence and prevalence
Prostate cancer is now the most common cancer in men in the UK and made up 26% of all male cancers in England and Wales in 2010 (see Figure 1). Prior to 1994 there was a steady rise in the rate of prostate cancer diagnoses which is attributed to the increasing use of transurethral resection of the prostate (TURP) as a treatment of benign prostate hyperplasia (Brewster et al. 2000; Evans et al. 2003). Improved recording of the diagnosis due to improved registration practice may also have contributed to this increase. Following this the rate of diagnoses was relatively stable until 1998 which may reflect the rising number of diagnoses due to increased prostate specific antigen (PSA) testing but a falling number resulting from the performance of TURPs (Evans et al. 2003). The following rapid increase from 1998 until 2001 is thought to be due to more widespread use of PSA testing (Office for National Statistics 2012). Since 2001 the rate of increase has slowed to around 1,000 new cases in England and Wales each year (p<0.001).
Figure 1
Proportion of all malignant male cancers contributed by the three most common cancers in men in England and Wales, 1995–2010 (source: SWPHO, WCISU)*. * Excludes non-melanoma skin cancer (ICD10 code C44)
Figure 2 shows the age-standardised incidence rate of prostate cancer in England and Wales over time. Both England and Wales show a similar trend with steady increases in prostate cancer prior to 1994 and after 1998. This increase in rates slowed from 2001 in England and from 2005 in Wales. Estimates based on 2007 data suggest prostate cancer will stabilise and continue to make up 26% of all male cancers in 2030 (Mistry et al. 2011). However, this was based on an estimated annual increase of 0.3% in the age-standardised rate. In contrast, the age-standardised rate has shown an annual increase of 2.0% between 2007 and 2010 in England.
Figure 2
Age standardised rate (ASR) of prostate cancer incidence in England and Wales (to European standard population), 1986–2010 (source: SWPHO, WCISU).
Incidence of prostate cancer has increased worldwide since the 1960s due to improved diagnosis and an aging population. Substantial increases were reported in most countries during the 1980s, with the exception of Denmark, Ecuador and Japan (Quinn and Babb 2002). Rates in the USA reached a peak in 1992, prior to this they were more than twice that seen in Sweden and Australia, over three times that seen in the UK, and ten times the levels in countries such as Singapore, Japan, India and China (Quinn and Babb 2002).
Bray et al. 2010 report an increasing trend in all of 24 European countries studied. The rate of increase ranged from 3–4% on average per annum since 1990 in The Netherlands, Slovakia, Switzerland and the UK to 6–7% or more in eight countries including France, Germany, Latvia, Spain and the Russian Federation. The highest incidence rates were in Finland, Sweden and The Netherlands, though rates were seen to either stabilise or decrease after 2005.
1.1.2.1. Incidence by Cancer Networkk
Figure 3 shows the variation in incidence of prostate cancer across the Cancer Networks in England and Wales for the time period 2008 to 2010. Each rate is standardised to the European standard population to take into account differences in the structure of the populations. During 2008 to 2010, the incidence rate was lowest in the North of England and highest in North Wales (89 and 129 cases per 100,000 population respectively). Variations in rates are likely to reflect regional differences in PSA testing resulting from differences in local policy or public demand.
Figure 3
Age standardised rate (ASR) of prostate cancer incidence in England and Wales, by Cancer Network (to European standard population), 2008–2010 (source: SWPHO, WCISU).
Twenty-two (73%) Cancer Networks showed an increase in rate of between 0.3% (in Lancashire and South Cumbria) and 44.1% (in Mount Vernon) since 2002–2004 (the beginning of a period of stability). The incidence rate in the remaining eight (27%) Cancer Networks decreased by between 0.5% (in the North of England) and 14.1% (in the Central South Coast). The ASRs for England and Wales showed an increase of 5.8% and 8.2% respectively. This compares to the increase of between 2.0% and 42.1% that was seen in all Cancer Networks between the years 1996–1998 and 1999–2001. The ASRs for England and Wales increased by 20.3% and 24.8% during this time period respectively.
1.1.2.2. Incidence by age group
The number of diagnoses of prostate cancer in England and Wales is highest among those aged 65 to 79 years (see Figure 4). A rapid increase in the number of diagnoses is seen among those aged 45 to 59 years. This then tapers off and begins to decrease among those in older age groups. This decline has begun earlier, among those aged 75–79 years, since 2002 and a more rapid increase seen between those aged 50–54 and 60–64 years than previously.
Figure 4
Mean number of prostate cancer diagnoses by 5-year age band, 1996–2010 (source: SWPHO, WCISU).
However, when the population size of these age groups is taken into account, the rate of prostate cancer diagnoses can be seen to increase steadily with age (see Figure 5). From the age of 50 years, the risk of being diagnosed with prostate cancer increases steadily in men, reaching a rate of around 2% of all men in England and Wales in those aged 85 years and over. This trend is seen across four previous time periods: 1996–98, 1999–01, 2002–04 and 2005–09, however, in 2008–10 rates were lower in those aged over 80 years compared to those aged 70–79 years. The largest increase in incidence from one age group to the next is between 45–49 years and 50–54 years for all time periods (> 300% increase). The smallest percentage increase was seen between 80–84 years and 85+ years during 1996–98, but between 75–79 years and 80–84 years during later time periods. This may reflect the increased uptake of PSA testing and subsequent higher chance of diagnosis in the younger age groups. The younger age bands (< 80 years) show a trend for increasing rates of diagnoses in recent years, while the older age bands (80+ years) show a trend for decreasing rates of diagnoses in recent years.
Figure 5
Rate of prostate cancer diagnoses by 5-year age band, 1996–2010 (source: SWPHO, WCISU).
1.1.2.3. Incidence by cancer grade and stage at diagnosis
The proportion of prostate cancer diagnoses with a Gleason score ≤ 6 has continued to steadily decline over the last 10 years (see Figures 6 and 7). This is primarily due to increasingly rare occurrence of a Gleason score ≤ 5 at diagnosis (1.5% of all known Gleason scores at diagnosis in 2009). It is thought to be the result of a shift in pathological reporting practice and general agreement that the lowest Gleason grade that can be assessed at needle biopsy is a growth pattern of 3. This suggests that a Gleason score of 6 is the lowest possible on peripheral zone needle biopsy (University of Liverpool 2003; Epstein 2000).
Figure 6
Proportion of new cases of prostate cancer by Gleason score at diagnosis, where known, 2000–2009 (source: SWPHO, WCISU).
Figure 7
Proportion of new cases of prostate cancer by Gleason score at diagnosis, where known, 2000–2009 (source: SWPHO, WCISU).
The proportion of patients with a Gleason score of 7 at diagnosis continued to steadily increase from 17% in 1996 to 39% in 2009. This again reflects the shift in pathological reporting. The proportion of patients with a Gleason score ≥ 8 has remained relatively stable over the last 10 years, varying between 22% and 27% of all diagnoses where the Gleason score is known. Since 2000, the proportion of diagnoses where the Gleason score is unknown has ranged between 27% and 37%.
Figure 8 shows an increase in patients diagnosed with prostate cancer stage II over the last 10 years, reaching 66% of diagnoses where stage is known in 2010. Diagnoses of stage IV declined from 22% in 1999 to 12% in 2010. Diagnoses of stages I and III remained relatively constant ranging between 0.2% and 1.2%, and 20.1% and 24.7% over the last 10 years respectively. It should be noted that the proportion of diagnoses reported through this registry whose stage is unknown increased from 19% in 1999 to 48% in 2010. Figure 8 should therefore be treated with caution.
Fourcade et al. (2009) compared the proportion of patients with known stage at diagnosis in 2005 from databases in several European countries (see Figure 9). The proportion of patients diagnosed with stage I was higher in France, Germany and Italy (12–14%) than that seen in the UK or Spain (1%). This was predominantly due to a greater proportion of patients being diagnosed as stage II in the latter two countries (64% and 74% respectively compared to 39–42%). The proportion of patients diagnosed at stage III ranged from 13% to 28%, being lowest in Spain and highest in France. The proportion of patients diagnosed at stage IV was lowest in Spain and the UK (12% and 13% respectively compared to 17–26%) and highest in Germany. However, stage at diagnosis was unknown for varying proportions of patients and reporting was not mandatory for all databases used. Results should therefore be interpreted with caution.
1.1.2.4. Incidence of prostate cancer by socioeconomic status
Figure 10 shows the age-standardised incidence rate of prostate cancer to vary significantly by income deprivation quintile, decreasing as deprivation increases. These differences in rates between deprivation quintile groups have also increased since 1995–1997, to a gap of 18.9 new cases per 100,000 population between the most and least deprived quintiles in 2007–2009.
Figure 10
Age-standardised incidence rate of prostate cancer (per 100,000 population) for 3-year cohorts by income quintile domain, 1995–2009 (source: NCIN).
Studies have also found more deprived patients to be significantly more likely to have an advanced stage at diagnosis. With those in the most deprived quintile estimated to have an odds ratio of an advanced stage at diagnosis of 1.37 (95% CI 1.23–1.52) compared to those who were considered affluent (Lyratzopolous et al. 2013).
1.1.2.5. Incidence of prostate cancer by ethnicity
For the years 2002–2006 cancer registration data was linked with Hospital Episode Statistics (HES) to derive information on the ethnicity of prostate cancer patients. However, the availability and accuracy of ethnicity data was limited and the ethnic group of 37% of cases remained unknown. Where known, the ASR were 97 in the White ethnic group, 203 were Black, 49 for Asian, and less than 37 were Chinese, and 80 for mixed ethnicity or other per 100,000 population (National Cancer Intelligence Network 2009).
1.1.3. Mortality
Prostate cancer is the second most common cause of death due to cancer in men in England and Wales, below only lung cancer (see Figure 11). However, while lung cancer has shown a slow decline in men over the past 30 years, deaths from prostate cancer have remained relatively consistent since 2001 with a slight increase in 2009 and 2010.
These figures only include deaths where prostate cancer is recorded as the underlying cause. However, if deaths where prostate cancer was mentioned on the death certificate were included, the number in England would increase from an average of 8,596 to 11,768 deaths per year during 2001–2010, and from approximately 1.8% to 2.5% of all deaths in England (National End of Life Care Intelligence Network 2012).
Since reaching a peak of 30.7 per 100,000 population in 1992, the age standardised mortality rate for prostate cancer in England has shown a decline to 23.8 per 100,000 population in 2010 (see Figure 12). Despite much greater variability the mortality rate in Wales suggests a similar trend. As the number of deaths remains relatively constant it is likely the declining mortality rate is counteracted by an aging population.
Figure 12
Directly age standardised mortality rate (ASR) from prostate cancer in England and Wales (to European standard population), 1985–2009 (source: ONS, WCISU).
Worldwide mortality rates for prostate cancer have seen an overall decrease since 1990, by about 24% in the US and some Western-European countries including the UK, Austria, France and Germany show annual declines of 2–4% per annum since 1990 (Jemal et al. 2009; Bray et al. 2010).
1.1.3.1. Prostate cancer mortality by Cancer Network
Figure 13 shows the variation in mortality due to prostate cancer across the Cancer Networks in England and Wales for the time period 2008 to 2010. Each rate is standardised to the European standard population to take into account differences in the structure of the populations. During 2008 to 2010, the mortality rate was lowest in North West London and in North East London (21.1 deaths per 100,000 population in both). It was highest in Merseyside and Cheshire and in Peninsula (26.1 deaths per 100,000 population in both).
Figure 13
Age standardised rate (ASR) of prostate cancer mortality in England and Wales, by Cancer Network (to European standard population), 2008–2010 (source: ONS, WCISU).
All cancer networks showed a decrease in the mortality rate since 2002 to 2004, ranging from a 20.0% decrease in South Wales to a 0.7% decrease in Dorset. The exception to this was in Merseyside and Cheshire which saw no change. The age-standardised mortality rates for England and Wales showed a decrease of 11.5% and 17.7% respectively.
1.1.3.2. Mortality by age group
During 2001–2010 deaths from prostate cancer made up 0.7% of all deaths in men aged under 65 years, 2.3% in men aged 65–84 years, and 1.5% of all deaths in men aged 85 years and over (National End of Life Care Intelligence Network 2012). The number of deaths due to prostate cancer in England and Wales has increased almost linearly with age in recent years (see Figure 14). In comparison, the time periods 1996–1998 and 1999–2001 show a more rapid increase up to the age of 75–79 years, then a much slower increase. The number of deaths continues to be highest in those aged 85 years and over and the proportion of all prostate cancer deaths in those aged 85+ years has increased steadily from 23% in 1996–1998 to 32% in 2008–2010.
Figure 14
Mean number of prostate cancer deaths by 5-year age band, 1996–2010 (source: SWPHO, WCISU).
Once the population size of these age groups is taken into account, the mortality rate of prostate cancer can be seen to increase at a slower rate until the age of 60–65 years then follows a rapid increase with age (see Figure 15). This trend can be seen in all time periods from 1996 to 2010. The largest increase in mortality from one age group to the next is between 80–84 years and 85+ years for all time periods. While the smallest percentage increase is seen between 45–49 years and 50–54 years for all time periods. All age groups show a decline in mortality over time, with the exception of those aged 85+ years during 1999–2004.
Figure 15
Prostate cancer mortality rate by 5-year age band, 1996–2010 (source: SWPHO, WCISU).
Many deaths from prostate cancer occur at an advanced stage when the probability of death from other causes is high. Therefore any treatment which delays death may result in an apparent reduction in prostate cancer mortality.
1.1.3.3. Mortality by socioeconomic status
Figure 16 shows the proportion of deaths due to prostate cancer which occurred in each quintile of income deprivation during three time periods. For all time periods, the proportion of deaths is lowest in the most deprived quintile. This may be due to better case ascertainment in more affluent groups of men and a greater likelihood of diagnosis (see section 1.2.1).
Figure 16
Proportion of deaths due to prostate cancer by quintile of income deprivation, 2002–2010 (source: SWPHO).
The age standardised mortality rate has decreased in all quintiles of income deprivation since 1995–97, with the largest decrease seen in quintile 3. A narrowing of the mortality rates in the different quintiles has occurred in recent years (see Figure 17). This is due primarily to the mortality rate in the least deprived quintile decreasing at a slower rate. However, no significant association between income deprivation quintile and the mortality rate was found during any of the time periods.
Figure 17
Age standardised mortality rate by quintile of income deprivation, 1995–2009 (source: SWPHO).
1.1.3.4. Mortality by ethnicity
Data up to 2008 suggests an age-standardised mortality rate in White men of 70.5 per 100,000, compared to 24.2 per 100,000 in the whole population (based on broad age bands). The mortality rate in Black men was found to be 30% higher than in White men (p<0.01) at a rate of 91.6 per 100,000. The mortality rate in men from India, Pakistan and Bangladesh was found to be only a quarter of that in White men, at 17.2 per 100,000 (p<0.01). This is consistent with a low mortality rate in India, Pakistan and Bangladesh as found by the GLOBOCAN project and may be due to the shorter life expectancy in these countries with many men dying of other causes (National Cancer Intelligence Network 2012).
1.1.3.5. Mortality by place of death
In 2010, the greatest number of deaths due to prostate cancer occurred in hospital, followed by the patient’s own residence (3,611 and 2,351 deaths respectively) (see Figure 18). Deaths due to prostate cancer were most likely to occur in hospital in those aged <65, 65–84 and 85+ years (37%, 39% and 43% of all prostate cancer deaths respectively). The proportion of deaths due to prostate cancer which occurred in a hospice decreased with increasing age (28%, 18% and 8% in those aged <65, 65–84 and 85+ years). While the proportion occurring in a nursing home or old people’s home increased with age (4%, 13% and 29% respectively).
Figure 18
Number of deaths due to prostate cancer by place of death, 2010 (source: SWPHO).
Since 2002–2004 there has been a decline in the proportion of prostate cancer deaths which occur in hospitals (from 47% to 42%) and a slight decline in the proportion occurring in hospices (see Figure 19). This is a result of an increase in the proportion of prostate cancer deaths which occurred the patient’s own residence (from 21% to 26%) and a slight increase in the proportion occurring in old people’ homes. The proportion of prostate cancer deaths occurring in nursing homes has remained at 10%.
Figure 19
Proportion of all deaths due to prostate cancer by place of death, 2002–2010 (source: SWPHO).
1.1.4. Survival
Prostate cancer prevalence is predicted to increase at the fastest rate of all cancers among males in the UK, even when assuming incidence rates from 2009 remain static. The number of prostate cancer survivors is estimated to reach 831,000 by the year 2040 with an average annual increase of 5.0% between 2010 and 2020 (assuming dynamic incidence rates) (Maddams et al. 2012).
The 1-, 5- and 10-year survival rates for adults in England aged between 15 and 99 years are estimated to be 94%, 81% and 69% respectively for patients diagnosed between 2005 and 2009l. The 5-year age standardised survival for prostate cancer patients diagnosed between 2005 and 2009 is the third highest in men of the 21 most common cancers. Only cancer of the testis, melanoma of the skin, and Hodgkin lymphoma have higher survival rates at 97%, 84% and 82% respectively (Office for National Statistics 2013). Figure 20 shows a steady improvement in survival rates since 1971 at 1, 5 and 10 years, with 5- and 10-year survival improving at a greater rate since 1990.
Between-country differences in survival in Europe have been shown to be some of the widest for any cancer (Sant et al. 2009). This may be due to wide differences in stage at diagnosis as some parts of Europe are diagnosing asymptomatic cancer. Figure 21 shows data from the Eurocare-4 project which aims to standardise cancer survival data across Europe to enable meaningful comparisons between countries. It is important to be aware that while countries such as the UK have population-based cancer registries approaching 100% coverage, others use regional registries with population coverage of less than 10% and data may not be representative of the country as a whole. There are also variations in data collection and diagnostic practices across Europe.
Figure 21
Age standardised relative survival of prostate cancer patients diagnosed 1995–1999 at 1 and 5 years by European country (source: Eurocare-4). Yellow bars represent 1 year survival and purple bars 5 year survival
Survival at 1 year was highest in Switzerland and lowest in Malta (97.1% and 83.0% respectively). Survival at 5 years was highest in Austria and lowest in Denmark (86.7% and 47.7% respectively). The overall survival rate for Europe at 1 and 5 years was 92.7% and 76.4% respectively. The greatest decrease in the estimated proportion of prostate cancer patients surviving between 1 and 5 years was in Denmark and the smallest decrease seen was in Austria (38.3% and 7.2% respectively). The overall survival rate for Europe decreased by 16.3%.
1.1.4.1. Survival by Cancer Network
Figure 22 shows the variation in relative survival of prostate cancer patients across the Cancer Networks in the UK. Relative survival at 1 year was highest in Arden and lowest in North Trent (98.3% and 92.4% respectively). Relative survival at 5 years was highest in Dorset and lowest in North Trent (91.8% and 75.5% respectively). These were significantly different from the overall relative survival rate for the UK at 1 and 5 years (95.4% and 83.8% respectively; p<0.05). The greatest decrease in the estimated proportion of prostate cancer patients surviving between 1 and 5 years was in North Trent and the smallest decrease seen was in Dorset (16.9% and 4.7% respectively). The overall relative survival rate for England decreased by 11.5%.
Figure 22
Prostate cancer relative survival of patients diagnosed 2001–2005 and 2005–2009 at 1 and 5 years respectively in the UK by Cancer Network (source: NCIN). Rates are adjusted for age, sex and geographical region
1.1.4.2. Survival by stage at diagnosis
Based on a cohort of men diagnosed with prostate cancer in England 2003–2005, the 5-year relative survival was found to be 95%, 96%, 87% and 69% for those diagnosed with stage I, II, III and IV respectively (see Figure 23). The largest decrease in relative survival over the 5 years following diagnosis was seen in those with stage IV; decreasing from 92% at 1 year to 69% at 5 years.
Figure 24 shows relative survival by stage of those diagnosed during different time periods. Over time there has been a significant increase in the proportion of patients diagnosed with stages II and IV who survive to 5 years (p<0.02). This is most notable in those diagnosed with stage IV disease with the proportion surviving to 5 years having increased by 10% between 2000–02 and 2003–05.
1.1.4.3. Prostate cancer survival by age
Studies have shown age at diagnosis to be a significant predictor of overall survival in men with prostate cancer (Bechis et al. 2011). This is likely to reflect the impact of other variables such as comorbidities, increased susceptibility to major illness, and decreased immune response. Figure 25 shows 5-year relative survival to be highest in those aged 50–69 years (91–92%), dropping to only 60% in those aged 80–99 years.
Figure 25
Relative survival of prostate cancer patients diagnosed 2005–2009 in England at 5 years (source: Cancer Research UK 2012).
1.1.4.4. Survival by socioeconomic deprivation quintile
Survival estimates based on patients diagnosed between 2002 and 2006 show decreasing survival rates with increasing income deprivation at both 1 and 5 years (p=0.001) (see Figure 26). This difference equates to 86% of those in least deprived quintile surviving at 5 years compared to 81% in the most deprived quintile.
Figure 26
Relative survival of prostate cancer patients diagnosed 2002–2006 in England at 1 and 5 years by quintile of income deprivation (source: NCIN).
1.1.4.5. Survival by ethnicity
Survival estimates for different ethnic groups show no statistical difference due to the high proportion of patients whose ethnic group is not reported (see Figure 27). It is therefore difficult to determine any trends.
Figure 27
Relative survival of prostate cancer patients diagnosed 2002–2006 in England at 1 and 5 years by ethnic group (source: NCIN).
1.1.5. Quality of life of prostate cancer survivors
The patient-reported outcome measures (PROMs) study of cancer survivors 1–5 years following diagnosis reported that 38.5% of prostate cancer respondents had some degree of urinary leakage, 12.9% reported difficulty controlling their bowels, and 58.4% were unable to have an erection. A further 11.0% reported significant difficulty in having or maintaining an erection. The presence of urinary leakage was found to be significantly associated with lower quality of life scores (Glaser et al. 2013).
The PROMs study also found that patients with two or more long-term conditions or who were in the most deprived quintile (based on the IMD) were significantly associated with lower quality of life scores and increased social distress and difficulties (odds ratios of 4.28 and 2.57 respectively). However, prostate cancer survivors were shown to have significantly lower overall social distress scores and reported fewer problems in everyday living, money matters, and interaction with others compared with other types of cancer (Glaser et al. 2013).
1.1.6. Financial cost of prostate cancer
The impact of prostate cancer in an aging population is expected to increase, even if the incidence rate were to remain constant. The financial burden of treatment will therefore increase as the number of patients diagnosed increases. There will also be an increased need for resources such as treatment facilities and trained specialists. The mean direct costs per patient for initial treatment for prostate cancer have been estimated at around £2,505 in the UK. This compares to £2572 in Spain, £3,205 in Germany, £4,129 in Italy, and £4,622 in France (Fourcade et al. 2009). The total estimated costs for all patients in the first year from diagnosis were estimated to be £94.1 million in the UK (compared to £92.5, £196.9, £163.0 and £310.6 million in the other countries respectively). However, this does not include indirect costs, such as time and productivity lost through cancer-related illnesses, the impact of the physical and mental suffering of both patients and relatives during diagnosis and follow-up, or end-of-life costs.
Prostate cancer patients have also been shown to have more emergency than elective admissions during their last year of life (National End of Life Care Intelligence Network 2012). In those dying from prostate cancer, the average final admission cost is nearly half (47%) of the average total last year of life cost (National End of Life Care Intelligence Network 2012). The estimated total cost of inpatient care per person during their last year of life is reported to be £6,931 for prostate cancer (see Table 6).
Table 6
Admissions, length of stay and cost in the last year of life, for men dying from prostate cancer in 2006–08 (source: National End of Life Care Intelligence Network 2012).
1.2. Diagnosis and investigations
The four procedures which are commonly used as diagnostic tests for prostate cancer are digital rectal examination (DRE), the PSA blood test, transrectal ultrasound (TRUS), and needle biopsy. DRE procedures are very common but information on this is not routinely collected. Most prostate cancers are located in the peripheral zone of the prostate and may be detected by DRE when the volume is about 0.2 mL or larger (European Association of Urology 2011). A suspect DRE is usually an indication for prostate biopsy which commonly involves needle biopsy in conjunction with TRUS. Radiological screening, including computerised tomography (CT) and magnetic resonance imaging (MRI) are also often used to aid diagnosis and staging.
1.2.1. Prostate-specific antigen (PSA) testing
Men in the UK can request a PSA test at their general practice, however, the level of PSA testing is not currently centrally monitored. Surveys of general practices and pathology labs carried out in recent years have suggested a testing rate of around 6% per year among 45–89 year-old men with no previous diagnosis of prostate cancer (Williams et al. 2011; Pashayan et al. 2006; Mokete et al. 2006; Melia et al. 2004). The consistency of survey results suggest that rates of PSA testing have varied little over the last decade.
Testing rates vary by age and by geographical location; testing rates of 1.4% have been found in those aged 45–49 years, rising to 11.3% in those aged 75–79 years (Williams et al. 2011). The rate of PSA testing has also been shown to independently decrease with increasing proportion of either black or Asian populations (Melia et al. 2004). In black populations the incidence of prostate cancer is higher than the average for England while in Asian populations it is lower.
Men attending general practices in more affluent areas have been shown to be more likely to undergo a PSA test, which suggests that uptake may not reflect clinical need (Williams et al. 2011). For example, Williams et al. 2011 found a strong inverse relationship between PSA testing rate and the relative social deprivation of the area surrounding that practice. However, the link itself between testing rate and social deprivation is unclear. Studies have found no correlation with educational status or monthly household income after controlling for age (Haidinger et al. 1999). It may be that higher testing rates reflect more screening requests by asymptomatic men. There is evidence to suggest that men from higher socioeconomic backgrounds are more likely to be aware of the PSA test and to have discussed prostate cancer screening with a healthcare professional (The Prostate Cancer Charity 2009). A survey by Melia et al. 2004 between 1999 and 2002 reported testing rates of 2.0% in asymptomatic men, 2.8% in symptomatic men, and 1.2% for re-testing. This suggests that a third of PSA tests conducted in general practice may be on asymptomatic men.
The Prostate Cancer Risk Management Programme (PCRMP) has performed two surveys of 210 laboratories that participate in the UK National External Quality Assessment Service (NEQAS) scheme (UK NEQAS). A subgroup of 79 laboratories responded to the survey in both 2000–01 and 2003–04 and reported an increase of 39% in the number of PSA tests conducted. The origin of samples for PSA testing varied significantly between laboratories. However, the mean proportion of test samples collected by General Practitioners in 2003–04 was 52%, with 31% of samples submitted by a Urologist and 16% by other Consultants (Prostate Cancer Risk Management Programme, accessed 2012; Prostate Cancer Risk Management Programme, accessed 2012). There was a small but statistically significant increase in the proportion of tests which were requested by GPs between the two surveys.
1.2.2. Initial biopsy
Diagnosis of prostate cancer in the UK is confirmed using a needle biopsy. Biopsy is recommended for men with a serum PSA above a diagnostic threshold currently set at 3 ng/ml for men in their 50s, 4 ng/ml for those in their 60s and 5 ng/ml for those in their 70s (NHS Cancer Screening Programmes 2012; Oesterling et al. 1993). The biopsy is an outpatient procedure which is most often conducted as a transrectal needle biopsy under TRUS guidance and antibiotic prophylaxis to gain 10–12 cores of prostate tissue for a histopathological diagnosis. The number of needle biopsies conducted in England has shown a relatively steady increase over the last 10 years and numbers follow the same trend seen in incidence (see Figure 28).
The majority of tumours are located in the peripheral zone of the prostate, however, some do occur elsewhere such as in the transitional or central zone. TRUS is poor at detecting anterior, apical and central lesions which limits its usefulness (Norberg et al. 1997). At present, approximately 25% of men undergoing biopsy with PSA levels above threshold will have cancer detected (Ramsey et al. 2012), though this varies depending on the biopsy protocol used. Detection rates are estimated at 14–22% for first biopsy, 10–15% for second biopsy, and 5–10% for third biopsy (Djavan et al. 2005; Mian et al. 2002; Lujan et al. 2004).
Current European Association of Urology (EAU) guidelines recommend an extended scheme as the initial biopsy strategy and reserving saturation protocols to repeat biopsy (European Association of Urology 2011). The role of saturation schemes involving more than 20 cores and including additional lateral peripheral and midline peripheral sampling remains controversial, as some studies demonstrated (Guichard et al. 2007; Scattoni et al. 2010) while others failed to demonstrate diagnostic advantages of saturation over extended schemes (Eichler et al. 2006; Jones et al. 2006; Pepe and Aragona 2007). For example, Cormeo et al. 2012 found no significant difference in the detection rate of 10-, 14- or 18-core schemes (39%, 42% and 42% respectively), however, there was a significant difference between these and a 6-core scheme (33% detection rate). There is no routinely-collected information on the number of cores collected at biopsy in the UK, however, standard agreed practice is to take 10–12 cores.
1.2.2.1. Transperineal biopsy
There was a significant reduction in the proportion of biopsies undertaken in England which were transperineal from 29% in 2000 to 8% in 2007 (p<0.001), since then there has been a significant increase to 13% of all prostate biopsies in cancer patients (p=0.04) (see Figure 28). Sampling in the anterior zone of the prostate is thought to be improved with transperineal template biopsies, though some studies report similar rates to rectal biopsies (Takenaka et al. 2008; Hara et al. 2008).
Most sampling and imaging techniques have been introduced at a local level based on facilities available, rather than a systematic approach and use of transperineal template biopsy is varied. A survey of current guidelines for the use of template biopsy held by the Cancer Networks in England and Wales was undertaken November 2012 to January 2013; the response rate was 60%. It was assumed that all transperineal biopsies are perfeormed using a template. Of the Cancer Networks who responded, eight (44%) stated that there was no written Network guidance or policy relating to template biopsy, six (33%) provided details of their template biopsy policy, six (33%) provided details of a template biopsy policy specific to a particular Hospital or Trust, two (11%) reported that they used the EAU guidelines in the absence of their own policy, two (11%) reported standard practice in their Network (in the absence of a policy), and one (6%) provided their Urology Clinical Guideline which made no reference to template biopsy.
Of the ten template biopsy policies received, one (10%) did not recommend its use while another Network without a policy stated that this was because there was no funding for template biopsy. In eight (80%) of the policies, template biopsy was recommended for patients who had had a previous negative or equivocal transrectal TRUS biopsy but in whom prostate cancer was still suspected (in three of the policies this was specified as a rising PSA and in two suspicious areas on the MRI). The two Networks which reported standard practice also followed this policy. However, one of the policies required at least two negative TRUS biopsies before template biopsy was used. Further requirements for a template biopsy included: patients who were suitable for radical therapy only (20%); and a risk level > 12 based on PSA, DRE, appearance on TRUS, and TRUS calculated volume (10%).
Three (30%) of the policies and the two Networks reporting standard practice also allowed for the use of template biopsy in patients on or beginning an active surveillance (AS) regime. In one policy patients on active surveillance were required to be at low-risk, while in another a previous Gleason score of 6, volume < 5%, static PSA, and suitability for radical therapy was required. The third policy was to offer template biopsy to those considering AS with minimal amounts of prostate cancer on prior TRUS biopsy and to those on AS with suspicion of progression. Standard practice in one Network was to use template biopsy in men with localised disease who wished to undertake AS but were regarded as having high risk of under-staging by the transrectal biopsy. Standard practice in another was to perform template biopsy on all men being considered for AS following a diagnosis of low risk disease or low volume intermediate disease on prior TRUS biopsy.
One of the policies also allowed for template biopsy on men with a suspicion of prostate cancer who were unsuitable or unwilling to undergo transrectal TRUS biopsy, for example, those with inflammatory bowel disease or perianal sepsis. Standard practice in another Network was to undertake template biopsy in men with a prostate > 70 cc, with significant lower urinary tract symptoms (LUTS), who had received recent antibiotic therapy, had a lack of tolerance for transrectal biopsy, or who had any other complicating factor.
1.2.2.2. Repeat biopsy
Of those patients with a cancer diagnosis undergoing prostate biopsy as inpatients or day cases, the proportion which are the first recorded biopsy for that patient has decreased steadily from 93% in 1998 to 75% in 2011. This decrease can be seen for both transrectal and transperineal biopsies despite an overall increase in the number being undertaken (see Figure 29). However, this may reflect changes in recording practices rather than a large increase in the proportion undergoing repeat biopsies.
Where age is reported, the proportion of prostate biopsies which are the first recorded for that patient is highest in those aged under 40 or over 80 years (91% and 92% respectively) and lowest in those aged 60–69 years (77%) (see Figure 30). This trend can be seen for both transrectal and transperineal biopsies.
1.2.3. Radiological screening
1.2.3.1. Magnetic resonance imaging (MRI)
Due to the high false negative rates associated with TRUS guided biopsy, if there is an interval rise in PSA following a negative biopsy, further investigation may be undertaken using MRI. The accuracy of staging of the disease may also be improved by MRI which can reduce unnecessary treatment-related morbidity when there is no possibility of cure (Sanchez-Chapado et al. 1997; Bates et al. 1997). Multiparametric MRI (mpMRI) may add additional information and can help to gauge suitability for active surveillance or feasibility of nerve-sparing surgery in low risk patients. In intermediate risk patients it can aid in identifying stage T3 disease, while in high risk patients an MRI of the spine may detect the degree of metastases.
A survey of current practice was conducted during January and February 2013. Details of the survey were sent to Cancer Networks and a contact at the Royal College of Radiology for escalation to all Consultant Radiologist members of the urological cancer multi-disciplinary teams (MDTs). Fifty-three Consultants from 47 different organisations responded, however, only 36 (68%) completed the full survey. The majority (94%) of respondents were employed by NHS Trusts or hospitals. Most (81%) worked in the NHS alone, while the remaineder were employed by both the NHS and private sector.
Thirty-six respondents (73% of those answering this question) reported using MRI for the detection of prostate cancer. Eighteen (50% of those using MRI for detection) used MRI prior to first biopsy, 14 (39%) prior to second biopsy, and 21 (58%) prior to a subsequent biopsy (10 used MRI at multiple points).
Forty-seven (89%) respondents reported using MRI at staging post-biopsy. Of these, 34 (72%) reported using PSA, in combination with other criteria, as the basis for their decision to undertake MRI, 21 (45%) reported using DRE findings with other criteria, 34 (72%) used the Gleason score (alone or in combination with other criteria), 15 (32%) used the number of positive cores, and 14 (30%) used the proportion of cores involved. Thirty-five (74%) used a combination of these methods, while 11 (23%) did not report using any of these five methods.
Of those that reported using PSA to help determine whether to use MRI for staging post-biopsy, 24 (71%) provided further information on their PSA threshold. Of these, 14 (58%) used a threshold of ≥ 10 ng/ml, four (17%) used a threshold of ≥ 15 ng/ml, and three (13%) ≥ 20 ng/ml. In three (13%) cases, no threshold was given as either all patients were considered for radical treatment or AS were given an MRI or the decision was based on multiple factors and likely treatment options.
Of those that reported using Gleason score to help determine whether to use MRI for staging post-biopsy, 23 (68%) provided further information on their threshold. Of these, 16 (70%) used a threshold of ≥ 7, though in two (9%) cases this was lowered to 6 if multiple cores involved and patient was aged < 65 years or if apices were involved. In two (9%) cases, no threshold was given as the decision was based on multiple factors and likely treatment options.
Of those that reported using the number of positive cores to help determine whether to use MRI for staging post-biopsy, seven (47%) provided further information on the threshold used. This ranged from > 3 to > 10–12 and is likely to be dependent on the number of cores taken at biopsy in practice. One respondent also reported a threshold of > 2 mm of a single core. Of those that reported using the proportion of cores involved to help determine whether to use MRI for staging post-biopsy, three (21%) provided further information on the threshold used. In two (67%) this was ≥ 50%, the other did not use a specific threshold but relied on multiple factors and likely treatment options.
Thirty-two (76% of those answering this question) respondents reported using MRI at follow-up. Of these, 26 (81%) reported using MRI during active surveillance (AS), 24 (75%) following deep x-ray therapy (DXT), and 23 (72%) following radical prostatectomy. Twenty-two (85%) of those using MRI during AS provided further information on when MRI was used; 11 (34% of those using MRI at follow-up)) respondents reported undertaking MRI during AS following a rise in PSA, two (9%) undertook MRI annually, three (13%) if there was a possible change of management, three (13%) reported it to be variable, and three (13%) prior to next biopsy.
Twenty-one (88%) of those using MRI following DXT provided further information on when MRI was used; 17 (53%) respondents reported undertaking MRI following a rise in PSA, two (6%) following a risk in PSA or clinical symptoms, and one 3% following clinical symptoms. Twenty-one (91%) of those using MRI following radical prostatectomy provided further information on when MRI was used; 14 (44%) respondents reported undertaking MRI following a rise in PSA, five (16%) following a risk in PSA or clinical symptoms, and one (3%) following clinical symptoms.
Thirteen (25%) respondents reported that the use of MRI had reduced the number of biopsies undertaken while four (8%) reported that it had increased the number of biopsies. Seven (13%) reported that it had reduced the number of cores taken while three (6%) reported that MRI had increased the number of cores taken.
The survey found that of those who responded to the question (68%), all (100%) used T2, as well as either a T1 or a diffusion weighted sequence or both (see Figure 31). Seven respondents (19%) used T1 and T2, seven (19%) used T1, T2 and diffusion weighted, and 17 (47%) reported using T1, T2, diffusion weighted, and dynamic contrast-enhanced sequences. One (3%) reported using all four and proton magnetic resonance spectroscopy. Three (8%) reported using T2 and diffusion weighted sequences (without T1), while one (3%) used T2, diffusion weighted, and dynamic. Of those that responded to the question regarding the magnetic field strength used (68%), 34 (94%) reported using a field strength of 1.5-T. This included eight (22%) who reported using both 1.5-T and 3.0-T. Two (6%) respondents reported using <1.5-T field strength.
Figure 31
Proportion of survey respondents by MRI sequence used, 2013 (source: NCC-C).
Eighteen (34%) respondents reported using a 16-channel phased array coil to improve staging performance. Twelve (23%) reported using an 8-channel phased array coil and one (2%) reported using an endorectal coil (it was unclear how many respondents chose not to answer this question). Of those that responded to the question on where the MRI was directed for detection (62%), all (100%) reported directing it at the prostate. Four (12%) also reported directing it at the abdomen and one (3%) at the lumbar spine (see Figure 32). Of those that responded to the question on where the MRI was directed for staging (68%), the majority (75%) reported directing it at both the prostate and the pelvis. This includes 14 (39%) who also directed the MRI at the abdomen and six (17%) who also directed it at the lumbar spine. One (3%) respondent reported directing the MRI at the prostate alone and four (11%) at the pelvis alone. Two (6%) reported directing the MRI at the prostate and the abdomen and one (3%) at the prostate and the lumbar spine. One (3%) respondent reported directing the MRI at the pelvis, lumbar spine and abdomen (but not the prostate), and one (3%) reported directing the MRI at the whole spine together with the prostate and pelvis.
Figure 32
Proportion of survey respondents by direction of MRI during detection and staging (source: NCC-C).
It is important to note that two (4%) respondents commented that the answer options were too restrictive in the survey. It is also important to note that while some respondents reported using more than one MRI sequence or directing the MRI at more than one area, some choices are likely to be limited to intermediate or high risk populations.
1.3. Current treatment options
Current evidence suggests that any benefit to an individual undergoing radical treatment for prostate cancer can take at least 10 years to accrue. Therefore these options may be best used for men whose comorbidity and age suggests a life expectancy of > 10 years (Ramsey et al. 2012). There is also evidence that more aggressive cancers, categorised by a Gleason score of ≥ 8 out of 10 and a PSA of > 20 ng/ml, are likely to already have developed metastases and therefore such patients are considerably less likely to benefit from radical treatment alone (Ramsay et al. 2012).
Current treatment consists of four main options: active surveillance, surgery, radiotherapy or androgen deprivation therapy (ADT) (also known as hormone therapy). Radical prostatectomy (surgical removal of the prostate), radiotherapy (RT), and ADT accounted for 61% of all patients diagnosed with prostate cancer in 2009 (see Figure 33). ADT was given to 39% of patients, though 15% of patients received hormone therapy in combination with external RT. Radiotherapy was given to 26% of men, most commonly in combination with ADT, with 9% of men receiving external RT alone and 1% receiving brachytherapy alone. Radical prostatectomy was used to treat 12% of men diagnosed in 2009, with only 1% of men undergoing radical prostatectomy and ADT or radiotherapy. The ‘no treatment’ group made up a large proportion (22%) of patients and included patients treated at private hospitals or where treatment was not recorded. Therefore these results should be treated with caution.
Data from BAUS on men diagnosed in England in 2005 demonstrate the variation in treatment by stage at diagnosis (see Figure 34) (BAUS 2012). Patients diagnosed with stage I disease were most likely to undergo radiotherapy (39%), followed by radical prostatectomy (30%), hormone therapy (26%), and active monitoring (14%). Similar proportions of patients with stage II disease underwent radiotherapy and hormone therapy (43% and 38% respectively), with 19% undergoing radical prostatectomy and 4% active monitoring. For those with stage III disease, hormone therapy was the most common initial treatment (41%) followed by radiotherapy (31%), with ≤ 4% of patients receiving the other treatments. A similar trend was seen in patients with stage IV disease; with 35% receiving hormone therapy and 17% undergoing radiotherapy. More patients with stage IV disease underwent chemotherapy or orchidectomy than in any other stage.
Hormone therapy has been found to have significantly lower uptake in those of Asian ethnicity than in White men diagnosed for prostate cancer in England in 2009 (National Cancer Intelligence Network 2012). While the proportion of men undergoing radical prostatectomy was found to be significantly higher in Black or Asian ethnicity than in White men. The proportion of Black men receiving external radiotherapy was also significantly higher than the proportion of White men. However, reporting of ethnicity was poor and only 63% of men had a valid ethnicity assigned. Therefore results should be treated with caution.
There are no clear trends in treatment variation by quintile of income deprivation in patients diagnosed with prostate cancer in England (see Figure 35). The data suggest an increase of the use of hormone therapy with increasing deprivation. This may reflect earlier presentation of the disease in the least deprived patients as hormone therapy is generally reserved for advanced or relapsed cases. The proportion of patients undergoing radical prostatectomy or brachytherapy is slightly higher in the two least deprived quintiles which may again reflect more localised disease in these groups (National Cancer Intelligence Network 2012).
Figure 35
Proportion of men diagnosed with prostate cancer in 2009 in England by treatment type and quintile of income deprivation (source: NCIN). * Alone or in combination with another treatment type
Figures for 2009 suggest that the likelihood of receiving ADT, alone or in combination, increases with increasing age and is highest in those aged 70 years and over (see Figure 36). This is likely to reflect more advanced disease at presentation in older age groups and their reduced life expectancy. In contrast, the proportion of men undergoing radical prostatectomy, alone or in combination, decreases with age. This is likely to reflect more localised disease and greater life expectancy and benefit in the younger age groups. Use of brachytherapy also shows a slow decline with age which is consistent with the recommendation not to use this treatment in those with high risk localised disease.
Figure 36
Proportion of men diagnosed with prostate cancer in 2009 in England by treatment type and age group (source: NCIN). * Alone or in combination with another treatment type.
No correlation between treatment type and region of residence was found which suggests that personal and disease-related factors are of greater influence in treatment decisions (see Figure 37) (National Cancer Intelligence Network 2012).
Figure 37
Proportion of men diagnosed with prostate cancer in 2009 in England by treatment type and geographical region (source: NCIN). * Alone or in combination with another treatment type.
1.3.1. Active surveillance
Active surveillance (AS) and watchful waiting are observational follow-up strategies which avoid immediate therapy in patients with prostate cancer. AS is curative in intent and suitable in men where the disease is believed to be indolent and does not require therapy. It involves the close monitoring of patients to avoid unnecessary treatment, which can be associated with significant short- and long-term complications, until disease progression occurs (or the patient requests treatment). In contrast, watchful waiting is palliative in intent and suitable for men in whom treatment is inappropriate due to comorbidity. Men with serious comorbidities which affect life expectancy, such as severe chronic pulmonary obstructive disease, end stage renal disease, or life limiting cancer, are unlikely to benefit from active treatment but may, at some stage, need intervention for disease control.
The previous NICE guidance on prostate cancer diagnosis and treatment (2008) recommended that men with low-risk localised disease who are considered suitable for radical treatment should first be offered active surveillance and that active surveillance should also be discussed as an option with men who have intermediate-risk localised disease (National Institute for Health and Clinical Excellence 2008). There are various ways of following up men with low risk prostate cancer. These include regular examination such as a DRE or the measurement of the PSA to look at PSA velocity (PSAv), PSA doubling times (PSAdt) or PSA density (PSAd). Repeat biopsy may also be used. The previous clinical guideline GD58, recommended use of the follow-up protocol from the PROSTART study (examination and PSA testing at 3-monthly intervals for 2 years, and 6-monthly thereafter, with repeat TRUS-guided biopsies at 1, 4, 7 and 10 years), although no evidence was given to support this approach.
1.3.1.1. Eligibility for active surveillance
A survey of AS protocols currently in use by the 30 Cancer Networks in England, Wales and Northern Ireland was undertaken by NCC-C in 2012. A total of 24 protocols from 19 networks were received; a response rate of 63%. Of the protocols received which specified eligibility criteria for engaging in AS, all (19 in total) used clinical T-stage as a criterion but varied widely in their definition. One (5%) protocol only included patients with stage T1a; three (16%) required patients to have stage T1c disease; four (21%) only included patients with either T1c or T2 disease; three (16%) required patients to have stage T2a or lower; another three (16%) protocols required patients to have stage T2b or lower; and three (16%) only included patients with stage T2c or lower. Two protocols (11%) required patients to have any stage T1 or T2.
Seventeen (89%) of the protocols also used Gleason score as a criterion. In one (5%) protocol patients were required to have a Gleason score < 6; in three (16%) patients had a score < 7; in five (26%) protocols any patients with a Gleason score < 8 were included. Five (26%) protocols required patients to have a Gleason score of 6, though they varied in their T-stage criteria, and two (11%) required patients to have a score of 6 or 7.
Sixteen (84%) of the protocols also set PSA level criteria; half (42%) of these only included patients with PSA < 10 ng/ml; three (16%) included patients with PSA < 20 ng/ml; two (11%) included patients with PSA < 0.15 ng/ml (both of which required patients to have stage T1c and Gleason 6); and one (5%) protocol each included patients with PSA < 11, < 15 and < 16 ng/ml.
Twelve (63%) of the protocols set further eligibility criteria; in six (32%) these were based on predicted survival and in six (32%) they were based on the number of cores positive or involved. Two (11%) protocols included certain exceptions to their eligibility criteria such as older frail patients, those with serious medical conditions, those that were asymptomatic, or who had a preference for AS.
1.3.1.2. Undertaking active surveillance
Twenty-three protocols for the follow-up of patients on AS were received from the 19 Cancer Networks which responded to the survey. Over half (57%) of the protocols recommended PSA testing at 3-monthly intervals initially for a period of between 12 and 24 months or until stable. Five (22%) recommended PSA testing at 4-monthly intervals initially for between 12 and 24 months. One (4%) protocol recommended PSA testing ≤ every 3 months for an initial period of 24 months; while one recommended testing between every 3–6 months, and another every 4–6 months.
Following the initial testing period of 12–24 months, 15 (65%) of the protocols recommend testing PSA at 6-monthly intervals thereafter though three (13%) specify 3-monthly if PSA is stable. One (4%) protocol recommended ongoing 3-monthly testing and one (4%) recommended ongoing 4-monthly testing. Eleven (48%) of the protocols specify a time period for the frequency of DRE testing of patients on active surveillance. In five (22%) of these DRE is recommended annually, in five (22%) DRE is recommended at the same frequency as PSA testing (3- or 4-monthly initially reducing to 6-monthly), and one (4%) recommended DRE testing 6-monthly.
There is greater variation in the frequency at which biopsy should be reconsidered; twenty of the protocols provided guidance in this area. Five (25%) recommended considering re-biopsy annually, three (15%) recommended considering re-biopsy at between 1 and 2 years, and two (10%) recommended re-biopsy at 1 year and at 2 years. One (5%) each of the remaining protocols recommended re-biopsy at ≤ 6 months; at 9 months and 2 years; at ≤ 1 year and at 2 years; at 1 year; at 1, 4 and 7 years; at 1 and 5 years; between 12 and 18 months; at 18 months and at 3 years; at 18 months then following clinical discretion; and at 2 and 5 years.
Two protocols also made a recommendation regarding measurement of PSA doubling time; one recommended measuring this at 6-monthly intervals (at the same frequency as PSA testing following the initial 3-monthly period). The other recommended measuring PSA doubling time after 1 year of follow-up. One protocol also recommended undertaking MRI annually (alongside continuous 4–6 monthly PSA testing).
1.3.2. Surgery
Total removal of the prostate, known as radical prostatectomy, is the primary curative surgical procedure for prostate cancer. Studies have reported significant reductions in deaths from prostate cancer and risk of metastases in those undergoing radical prostatectomy compared to AS or watchful waiting (Bill-Axelson et al. 2005). However, sometimes the tumour cannot be completely removed and disease can reccur.
The number of prostatectomies undertaken in England and Wales has more than doubled over the last 10 years, reaching 5,341 in 2010–11 (see Figure 38). The mean age at which prostatectomies were performed has remained at 63 years since 2003. Prostatectomies are most commonly performed in those aged between 60 and 74 years, with the proportion performed in this age group showing a slow increase from 65.4% in 2000 to 68.6% in 2011–12 (p=0.01). In contrast, prostatectomies performed on those aged 75+ years have decreased from 11.0% in 2000–01 to 2.4% in 2011–12 (p=0.001).
Figure 38
Number of prostatectomies and orchidectomies performed in England and Wales, 2000–2011 (source: HES; PEDW).
Of those reporting to the Radical Prostatectomy Dataset held by BAUS in 2011, most reported no previous treatment (62%), with 2% reporting previous management by TURP and 1% by radiotherapy (35% did not report this information) (BAUS 2012). The reason for undergoing radical prostatectomy was given in 72% of procedures reported; in 60% of procedures it was the primary treatment with 12% having undergone prior active surveillance. Salvage therapy was reported as the reason for radical prostatectomy in 0.5% of cases. Of those who had previously been on active surveillance, 43% were undergoing radical prostatectomy due to PSA progression, 17% due to clinical progression, and 13% due to Gleason progression. In 25% of cases it was the patient’s decision to move from active surveillance to radical prostatectomy.
Surgical removal of the testes, known as orchidectomy, is sometimes used for the treatment of metastatic disease. Orchidectomy suppresses the level of testosterone in the body and retards the growth of prostate tumours. However, the number of orchidectomies performed in England and Wales has decreased steadily over the last 10 years, from 645 in 2000–01 to 279 in 2010–11 (p<0.001). This is due to the increasing use of medical castration using hormonal therapy in place of surgical castration (see section 1.3.4). Orchidectomies are most commonly performed in those aged 75 years and over. However, there has been a slow increase in the proportion of patients undergoing orchidectomy who were aged less than 60 years, from 11.8% in 2000–01 to 22.9% in 2010–11 (p<0.001). This increase is reflected in a steady decrease in the proportion of patients who were aged 60–74 or 75+ years (p<0.001 and p=0.03 respectively).
1.3.2.1. Radical prostatectomy by type
Of 2,163 prostatectomies reported voluntarily to the Radical Prostatectomy Dataset in 2011, 47% were laparoscopic, 17% were robotic, and 22% were open (15% did not report this information) (Bristish Association of Urological Surgeons 2012). Of the 992 laparoscopic procedures, 16 (2%) were converted to open procedures; reasons included failure to progress, haemorrhage, and adhesions.
However, these estimates differ from HES data which show retropubic, transvesical and perineal to make up 11.9%, 0.3% and 0.8% of all prostatectomies performed in 2010–11 respectively (see Figure 39). All specified types of open excision have also decreased in frequency since 2000–01 (p<0.05). This data suggests that non-open procedures made up 69.1% of all prostatectomies in 2010–11. Laparoscopic prostatectomy can be recorded as either ‘total excision of prostate and capsule’ or ‘other specified open excision of prostate’ with additional codes. Therefore it was not possible to estimate the proportion of prostatectomies which were laparoscopic in nature. The former category represents the greatest proportion of prostatectomies in England and has increased significantly since 2000–01, reaching 69.1% in 2010–11 (p=0.004). However, NHS England reference cost data recorded 1816 laparoscopic/robotic procedures in the year 2009–10, suggesting that these options were used for 46% of all radical prostatectomies (Ramsay et al. 2012).
Figure 39
Proportion of prostatectomies undertaken in England by type, 2000–2011 (source: HES).
1.3.2.2. Radical prostatectomy by patient age group
The number of radical prostatectomies performed on prostate cancer patients has increased significantly since 1997 in all age groups (p≤0.01) (see Table 7). The number performed has risen fastest in those aged 45–69 years; in 2011–12 this group accounted for 86% of all prostatectomies performed. Once the size of the population in that age group is taken into account using the ASR, rates of radical prostatectomies have been consistently highest in those aged 65–69 years (see Table 8). The overall ASR of prostatectomy in England has increased from 50 in 1997–98 to 281 per 100,000 men diagnosed with prostate cancer in 2011–12.
Table 7
Number of radical prostatectomies (OPCS code M61) undertaken in men diagnosed with prostate cancer in England (source: HES).
Table 8
Age standardised rate (ASR) of prostatectomies (OPCS code M61) undertaken in men diagnosed with prostate cancer in England per 100,000 men in England (source: HES).
1.3.2.3. Prostatectomy by NHS Trust
The number of NHS Trusts in England performing prostatectomies on patients diagnosed with prostate cancer has decreased significantly in recent years, from 118 in 2002–03 to 67 in 2011–12 (p<0.001). In contrast the total number of prostatectomies being performed by the Trusts in this time period has more than doubled, from 2,565 in 2002–03 to 5,165 in 2011–12 (p<0.001). The geometric mean number of prostatectomies performed by an NHS Trust during 2011/12 was 44 (95% CI 31–57), however, the number performed by a Trust during 2011–12 ranged from one to 292 (see Figure 40).
The NICE manual for improving outcomes in urological cancer, published in September 2002, states that ideally all radical prostatectomies undertaken in each network should be carried out by a single MDT and that radical prostatectomy should not be carried out by MDTs which carry out fewer than 50 radical operations per year (National Institute for Clinical Excellence 2002).
1.3.2.4. Radical prostatectomy by Gleason score
The BAUS collect data on prostatectomies undertaken and the Gleason score at diagnosis. However, reporting to BAUS is voluntary and the data only represent a subset of all prostatectomies undertaken in England and Wales. Since 2004 the number of prostatectomies reported to BAUS has varied between a third and half the number of all procedures recorded in HES. Figure 41 should therefore be interpreted with caution.
Figure 41
Proportion of prostatectomies performed by Gleason score at diagnosis, 2004–2010 (source: BAUS).
Prior to 2010 radical prostatectomies were most commonly reported to have been performed on patients with a Gleason score of 5–6 at diagnosis. However, the proportion of patients with this score has decreased steadily since 2004 (p<0.001), while the proportion of patients with a Gleason score of 7 at diagnosis has increased (p=0.001). In 2010, more patients with a Gleason score of 7 underwent prostatectomy than those with any other score. The proportion of reported prostatectomies whose Gleason score at diagnosis was unknown has increased from 6% in 2004 to 18% in 2010 (p=0.004).
1.3.2.5. Prostatectomies performed per Consultant
There has been a significant decrease in the total number of Consultants performing prostatectomies on prostate cancer patients in England since 1999–00, decreasing from 411 to 358 in 2011–12 (p<0.001). In 2011–12, around half (51%) of all Consultants performed less than ten prostatectomies with 17% performing more than 40. This compares to 78% of all Consultants in 1999–00 performing less than ten prostatectomies and only 1% performing more than 40. Figure 42 shows the change in the number of consultants performing prostatectomies over time. There has been a significant decrease in the number of consultants performing 0–9 prostatectomies (p<0.001) but a significant increase in the number of consultants performing 20–29, 30–39, 40–49 and 50+ (p≤0.02).]
During the same period there has been a significant increase in the total number of prostatectomies on prostate cancer patients in England since 1999–00, increasing from 2,554 to 6,866 in 2011–12 (p<0.001). In 2011–12, 43% of all prostatectomies were performed by a Consultant who undertook more than 50 per year, while only 7% were performed by Consultants who undertook less than ten per year. This compares to only 2% of prostatectomies being performed by Consultants who undertook more than 50 annually in 1999–00 and 41% being performed by Consultants who undertook less than ten annually.
Following the recommendation in 2002 that radical prostatectomy should not be carried out by MDTs which carry out fewer than 50 radical operations per year, surgeons carrying out fewer than five radical prostatectomies per year were required to refer patients to designated surgeons who were more specialised (National Institute for Clinical Excellence 2002). Figure 43 shows the change in the number of prostatectomies being performed by Consultants over time. There has been a significant decrease in the number of prostatectomies performed by Consultants who perform less than ten annually (p<0.001) but a significant increase in the number of prostatectomies performed by Consultants who perform 20 or more annually (p≤0.02).
Of 78 NHS Trusts reporting this information, 11 (14%) had an average of one radical prostatectomy per Consultant, six (8%) had an average of two prostatectomies per Consultant, 52 (67%) averaged more than 50 per Consultant, 27 (35%) averaged 100 or more per Consultant, and five (6%) performed an average of 200 or more per Consultant.
1.3.2.6. Treatment-related morbidity
Data voluntarily submitted to BAUS suggests a steady decrease in the overall morbidity rates associated with radical prostatectomy since 2004, with 9.4% of patients experiencing morbidity in 2010 (see Figure 44). However, this data represents only a small sample of prostatectomies undertaken in the UK and may be biased.
Figure 44
Proportion of patients experiencing complications during or following radical prostatectomy, 2004–2010 (source: BAUS).
The proportion of patients experiencing post-operative complications has also decreased steadily since 2004, to 5.9% in 2010. This is due to a decrease in the proportion of patients experiencing leaks, wound infections, or ileus post-operatively. The proportion of patients experiencing intra-operative complications has remained at 4–5% since 2007. Where reported, these complications predominantly involved bleeding or rectal injury.
In 2010, 33% of intra-operative and 7% of post-operative complications delayed discharge of the patient, 35% and 5% required medical treatment, and 8% and 3% required surgery respectively. However, the significance of the complications was not reported in 14% and 73% of intra-and post-operative cases respectively. In no cases were the complications thought to contribute to the death of the patient.
1.3.3. Economic cost of surgery
Although the number of radical prostatectomies performed per year is known, reliable data to accurately determine the overall costs of these are not available.
1.3.4. Radiotherapy
Radiotherapy can be delivered to the prostate in two ways; either using external x-ray beams from a linear accelerator or via brachytherapy where radiation sources are placed directly into the prostate gland. Since April 2009 it has become mandatory to submit a dataset for every patient receiving radiotherapy in the NHS in England. In 2011–12, 20,805 radiotherapy episodes were given to patients with a primary diagnosis of prostate cancer. This is an increase of 10% from the previous year and of 18% from 2009–10 (Ball 2012).
1.3.4.1. Radiotherapy by Cancer Network
Figure 45 shows the proportion of new cases of prostate cancer which received radiotherapy in 2010–11 in each of the Cancer Networks in England. On average 35% of newly diagnosed cases received radical radiotherapy in England and 25% received palliative radiotherapy. The highest proportion of newly diagnosed patients receiving radical radiotherapy was in North East London whilst the lowest was in Yorkshire (48% and 25% respectively). The highest proportion of newly diagnosed patients receiving palliative radiotherapy was in Three Counties and the lowest was again in Yorkshire (38% and 11% respectively). All Cancer Networks provided radical radiotherapy to a greater proportion of new cases than palliative, with the exception of Three Counties and the Peninsula who provided palliative radiotherapy to a greater proportion of new cases than radical radiotherapy (38% versus 35% and 35% versus 29% respectively).
Figure 45
Proportion of new cases of prostate cancer receiving radiotherapy (RT), 2010–2011 (source: RTDS – NATCANSAT). Dark green represent radical radiotherapy and the light green represent palliative radiotherapy
1.3.4.2. Radiotherapy by provider
During 2010–11 there were 49 providers of radiotherapy in England. Individual Cancer Networks used a median of eight providers (range 3 – 13) (see Figure 46). Of the 28 Cancer Networks, 14 (50%) used one main provider who undertook more than 80% of all treatment episodes, with between two and 12 other providers undertaking less than 20% each. Two (7%) Networks used one provider for 60–80% of all episodes and 7–10 other providers for less than 20% of treatment episodes. Eight (29%) of the Cancer Networks used between five and 11 separate providers, each providing less than 60% of all episodes. Four (14%) Cancer Networks used between nine and 13 separate providers, each providing less than 40% of all episodes.
Figure 46
Number of providers used by Cancer Networks in England 2010–11 (source: RTDS – NATCANSAT).
1.3.4.3. Radiotherapy by tumour grade
The tumour grade at radiotherapy is not reported for a large proportion of patients diagnosed with prostate cancer (47% to 55%; see Figure 47). The proportion which were low grade tumours at radiotherapy has decreased from 11% to 1% from 1999 to 2010. Those which were medium grade ranged between 25% and 35% over this time period. Those which were high grade tumours have increased from 13% to 22%. However, these figures should be interpreted with caution due to the high numbers of unknown grade.
1.3.4.4. Variation in dose and fractionation
The most frequently prescribed dose fractionation for prostate cancer in England is 74 Gy in 37# (see Figure 48). This made up 63%, 59% and 67% of all prescribed dose fractionations in 2009–10, 2010–11 and 2011–12 respectively. Other fractionations schemes are likely to be part of closed or ongoing trials (Department of Health Cancer Policy Team 2012).
Figure 48
Radiotherapy episodes with a primary diagnosis of prostate cancer by prescribed dose and fractionation, April 2009 to March 2012 (source: RTDS - NATCANSAT).
1.3.4.5. Brachytherapy
Data suggests that 1.3% of men diagnosed with prostate cancer in 2009 were treated with brachytherapy (Bates et al. 1997). This represented 5.2% of all men who received some form of radiotherapy. There are two different radiation sources used in prostate cancer; low dose rate I125 seeds which are permanent implants to the prostate or high dose rate Ir192 temporary implants delivered using an after-loading machine. HES data show figures for low dose rate brachytherapy to have increased by 91% since first reported in 2006–07, reaching 1,174 procedures in 2010–11. In comparison, implantation of high dose rate brachytherapy was first reported in 2009–10 at 112 procedures. This increased to 142 procedures in 2010–11.
1.3.4.6. Combination external beam followed by HDR brachytherapy boost
Mandatory reporting of brachytherapy episodes to RTDS began in April 2011. The number of patients receiving external beam radiotherapy (EBRT) followed by a high dose rate (HDR) brachytherapy boost in England in 2011–12 is estimated to be 270, based on the number of patients receiving 37.5–38.0 Gy in 15 teletherapy episodes. However, this is thought to be an underestimate as it is difficult to predict the number of brachytherapy boosts delivered from patients in the higher fractionation (45–46 Gy) group and there is known under-reporting of brachytherapy in RTDS due to technical difficulties with nine providers. Also, only brachytherapy given with an automatic aftercare loading machine is captured by RTDS (Ball 2012).
In comparison, collection of the same data was begun through a National database in September 2010. For the fiscal year 2011–12 there were an estimated 323 HDR brachytherapy boosts given following EBRT. However, this is also thought to be an underestimate (Hoskins 2012).
1.3.5. Economic cost of radiotherapy
Although the total number of courses of radical radiotherapy for prostate cancer delivered per year is known, reliable data to accurately determine the overall costs of these are not available.
1.3.6. Hormone therapy
The function of hormone therapy on prostate cancer is to stop testosterone feeding prostate cancer and encouraging growth. ADT blocks the production of androgens including testosterone, with the aim of slowing the growth of prostate cancer cells. Most men who receive ADT for prostate cancer will receive the treatment for anything between a few months up to a few years (Bill-Axelson 2005). The Prostate Cancer Charity estimate that around 9,000 newly diagnosed men in the UK will receive ADT each year; around 26% of all new diagnoses (The Prostate Cancer Charity 2009). However, this does not include those men previously diagnosed who convert to ADT as their disease progresses or if their initial treatment is unsuccessful. It also does not include men who have been receiving ADT for several years. NICE clinical guidelines for prostate cancer recommend ADT as a treatment option for men with locally advanced and advanced (metastatic) prostate cancer, although it can also be offered to men with high risk localised disease (Bill-Axelson 2005). A survey conducted by The Prostate Cancer Charity found 43% of respondents had received ADT for localised disease, 33% for locally advanced, and 22% for advanced disease. Of all respondents, 73% were currently receiving ADT (The Prostate Cancer Charity 2009). GPs (53%) and practice nurses (40%) were most commonly cited as the healthcare professional involved in the provision of ADT.
Androgen blockade can be administered in one of three ways: (i) orchidectomy; (ii) injection of a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist; and (iii) oral anti-androgen or oestrogen tablets (which may also be used in combination with an orchidectomy or LHRH agonist). Data on the number of prescriptions for ADT for prostate cancer in England and Wales is not routinely collected. The Health and Social Care Information Centre (HSCIC) provides information on the number and cost of community-based prescriptions in England by drug but not details of the condition that they are being prescribed for.
Figure 49 shows the total numbers of prescriptions for hormone therapy which are licensed for prostate cancer. These include a number of drugs which are also indicated for other conditions; therefore this is an overestimate and may be seen as an upper bound estimate. Only those prescriptions which were dispensed in England are included; this includes prescriptions written in Wales, Scotland, Northern Ireland and the Isle of Man but dispensed in England. It does not include prescriptions written in England but dispensed outside of England, items dispensed in hospital, or on private prescriptions.
Figure 49
Number of prescriptions for in England, for hormone treatments known to be used for prostate cancer, 1998–2011 (Data source: HSCIC).
Prescriptions for hormone treatment for prostate cancer have continued to increase since 1998, with prescriptions of anti-androgens almost doubling from 143,900 in 1998 to 285,335 in 2011. LHRH agonists and antagonists have also shown a similar increase, from 248,600 in 1998 to 460,384 in 2011 (an increase of 85%). Anti-androgens and LHRH agonists were first introduced in 1984 and 1987 respectively and have shown almost continuous increases since. However, prescriptions of oestrogens maintained a relatively steady rate since 1998.
Bicalutamide and flutamide are only indicated for prostate cancer in the UK and therefore are representative of prescriptions for prostate cancer. Cyproterone acetate is also indicated for severe hypersexuality and sexual deviation, and for acne and hirsutism in women. The majority of the rise in anti-androgen prescriptions in recent years is due to the increased use of bicalutamide. Since it was introduced in 1994, bicalutamide has made up an increasing proportion of all anti-androgens prescribed, reaching 79% in 2011 (see Figure 50). Prescriptions of cyproterone acetate have fallen from a peak of over 85,000 per year in 1993 (National Collaborating Centre for Cancer 2008) to 55,550 in 2011 and now represent only 19% of anti-androgens indicated for prostate cancer. Prescriptions of flutamide have also fallen from a peak of around 40,000 prescriptions in 1996 (National Collaborating Centre for Cancer 2008) to less than 4,000 in 2011. Abiraterone acetate and enzalutamide are also indicated for prostate cancer but none had yet been prescribed as of December 2011.
Figure 50
Number of anti-androgens prescribed for ADT in England, for treatments known to be used for prostate cancer, 1998–2011 (source: HSCIC). * Also indicated for conditions other than prostate cancer
The majority of LHRH agonists indicated for prostate cancer are also prescribed for other conditions and figures are therefore an overestimate. For example, buserelin, goserelin acetate, leuprorelin acetate, and triptorelin are prescribed for other conditions including endometriosis, uterine fibroids, assisted reproduction, endometrial thinning, breast cancer, precocious puberty, and male hypersexuality with severe sexual deviation.
Goserelin acetate makes up the largest proportion of all LHRH agonists prescribed, though this has decreased from 84% of all LHRH agonists prescribed in 1998 to 68% in 2011. Some forms of goserelin acetate (Zoladex LA and Novgos) are known to be prescribed only for prostate cancer and these can be seen to make up a substantial proportion of the prescriptions (see Figure 51), leading the increasing trend. The proportion of goserelin acetate prescriptions which are known to be for prostate cancer increased from 39% in 1998 to 72% in 2011.
Figure 51
Number of LHRH agonists prescribed in England, for treatments known to be used for prostate cancer, 1998–2011 (source: HSCIC). * Also indicated for conditions other than prostate cancer
Degarelix was introduced in 2009 and histrelin acetate in 2010, both of which are currently only prescribed for prostate cancer. Degarelix made up 0.3% of all LHRH agonists/antagonists in 2011, there were only 29 prescriptions for histrelin acetate in 2011 in total.
Of the two oestrogens prescribed for prostate cancer in the UK, diethylstilboestrol (previously stilboestrol) is also prescribed for breast cancer and figures are therefore an overestimate. However, ethinylestradiol is only indicated for prostate cancer in the UK. Prescriptions for diethylstilboestrol increased steadily from around 16,800 in 1998 to around 47,800 in 2009, but have begun to slightly decline since (see Figure 52). Prescriptions of ethinylestradiol have decreased steadily from around 32,200 in 1998 to around 11,300 in 2011. The exception to both these trends occurred in 2004, when prescriptions of diethylstilboestrol dropped dramatically and prescriptions of ethinylestradiol increased by a similar amount. This may have been linked to the renaming of stilboestrol to diethylstilboestrol that year.
Figure 52
Number of oestrogen prescriptions in England, for treatments known to be used for prostate cancer, 1998–2011 (source: HSCIC). * Also indicated for conditions other than prostate cancer
Of the prescriptions for oestrogens which are indicated for prostate cancer, the proportion which were ethinylestradiol has decreased steadily from 68% in 1998 to 20% in 2011, with the exception of 2004 when it reached 63% of all prescriptions. In contrast, diethylstilboestrol has increased steadily from 34% to 80% of prescriptions, with the exception of 2004 when it dropped to 37%.
1.3.6.1. Economic cost of ADT
Table 9 lists all androgen deprivation therapies indicated for prostate cancer in the British National Formulary (BNF), with the number of prescriptions and cost per prescription in 2011. Again, it is important to highlight the fact that many of these therapies are also indicated for other conditions, as shown in the table, and do not represent the cost associated with treating prostate cancer alone.
Table 9
Hormone therapy licensed for prostate cancer in England and Wales; number of prescriptions in England in 2011 and associated cost.
The annual cost of anti-androgen prescriptions for prostate cancer has decreased rapidly in the last few years (see Figure 53). This is primarily due to a rapid decline in the cost of bicalutamide prescriptions since its peak in 2008.
Figure 53
Annual cost of anti-androgen prescriptions in England, for treatments known to be used for prostate cancer (source: HSCIC). * Also indicated for conditions other than prostate cancer
The annual cost of goserelin acetate prescriptions has also seen a decline since its peak in 2004. Though goserelin acetate is also indicated for a number of other conditions, including breast cancer, formulations which are indicated only for prostate cancer (Zoladex LA and Novgos) make up the majority of the cost each year and lead this trend (see Figure 54). Leuprorelin acetate and triptorelin historically have a much lower annual cost than goserelin but appear to be increasing in cost. However, these medications are also indicated for other conditions (such as endometriosis and uterine fibroids) which may contribute to this rise. Prescriptions for the remaining LHRH agonists and antagonists which are indicated for prostate cancer (buserelin, histrelin acetate, and degarelix) have never reached an annual cost over £0.5 million. The annual cost of prescriptions for buserelin has decreased from around £299,600 in 1998 to around £7,049 in 2011. Degarelix and histrelin acetate were both first prescribed in 2010 and cost around £218,000 and £29,000 in 2011 respectively.
Figure 54
Annual cost of LHRH agonist prescriptions in England, for treatments known to be used for prostate cancer (source: HSCIC). * Also indicated for conditions other than prostate cancer
1.3.6.2. Treatment-related morbidity
In a survey conducted by The Prostate Cancer Charity in 2009, the most common side effects experienced by men undergoing ADT for prostate cancer were hot flushes (85%), erectile dysfunction (83%), loss of libido (80%), and fatigue (71%) (The Prostate Cancer Charity 2009). The most common effects experienced on the mental health of men with prostate cancer were cognitive effects (47%), becoming more emotional (43%), and mood swings (39%). Other potential physical side effects are breast tenderness, weight gain, muscle loss, and osteoporosis (McLeod et al. 1997; Isbarn et al. 2009; Eastham 2007). There may also be an increased risk of developing diabetes and heart disease (Smith 2007; Hakimian et al. 2008).
However, adverse events associated with ADT vary by the type of therapy given. Orchidectomy and LHRH agonists are commonly associated with erectile dysfunction (in around 70% of men), hot flushes (in 55–80% of men), and loss of sexual desire (in around 50% of men) (Mulhall 2009; Higano 2003; Potosky et al. 2001). While around half of men taking anti-androgen therapy are thought to develop gynecomastia to some degree (McLeod et al. 1997).
1.3.6.3. Hormone-relapsed prostate cancer
Current approved licensed drugs for management of hormone-relapsed prostate cancer (HRPC) recommended by NICE include docetaxel and more recently abiraterone acetate. Docetaxel in combination with prednisolone is considered first line treatment for HRPC with an improvement in median survival of 2.4 when compared to the previous standard, mitoxantrone (Tannock et al. 2004). A newer generation taxane, cabazitaxel, has been licensed by the FDA and EMA but not approved by NICE (National Institute for Health and Clinical Excellence 2013) for use in HRPC that has previously been treated with a docetaxel-containing regime (FDA Centre for Drug Evaluation and Research Approval Package for: Jevtana 2010). A head-to-head trial (FIRSTANA) comparing docetaxel with cabazitaxel is due for completion in 2015.
Abiraterone acetate is an inhibitor of androgen biosynthesis which blocks androgen synthesis in the adrenal glands in addition to the testes. Abiraterone acetate, which was approved by NICE in May 2012, used in combination with prednisolone is recommended as an option for HRPC if the disease has progressed after one docetaxel-containing chemotherapy regimen. Abiraterone acetate with prednisolone offers a median survival benefit of 4.6 months when compared to prednisolone alone (Fizazi et al. 2012).
Drug development for HRPC is a fast growing field with many phase III trials either completed or due for completion in the next few years for novel agents. There are several agents currently undergoing appraisal by NICE.
1.3.7. Other treatments
High intensity focused ultrasound (HIFU) consists of focused ultrasound waves emitted from a transducer, which cause tissue damage by mechanical and thermal effects as well as by cavitation. The goal of HIFU is to heat malignant tissues above 65°C so that they are destroyed by coagulative necrosis (Glaser et al. 2013). Figures for high intensity focused ultrasound treatment of the prostate were first reported by HES in 2007–08, since then they have varied between 168 and 216 procedures per year.
Cryotherapy is another potential primary or salvage treatment. During cryotherapy gas is delivered at temperatures below −40°C though needles placed in the prostate with the aim of targeted destruction of prostatic tissue. HIFU and cryotherapy are not currently recommended for men with localised prostate cancer other than in the context of controlled clinical trials comparing their use with established interventions (Bates et al. 1997).
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Footnotes
- k
Cancer Networks became part of Strategic Clinical Networks, serving larger populations, in April 2013.
- l
1- and 5-years survival rates are based on those diagnosed between 2005 and 2009 in England. The 10-year survival rate is based on those diagnosed in 2007 in England and Wales
- Epidemiology - Prostate CancerEpidemiology - Prostate Cancer
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