The Hallmarks of BPH Progression and Risk Factors

European Urology Supplements European Urology Supplements 2 (23) 2 7 The Hallmarks of BPH Progression and Risk Factors M. Emberton * Institute of Urology and Nephrology, University College London, 48 Riding Street, London W1P 3AA, UK Abstract A review of selected literature from population studies and also from the placebo arm of large, randomised, double-blind clinical trials was conducted in order to identify evidence for progression of benign prostatic hyperplasia (BPH), and to identify possible markers for the risk of progression. Population studies reported that, overall, the severity of lower urinary tract symptoms and prostate size increases with patient age, with a concomitant diminution in peak urinary flow rates. Similarly, the risk of acute urinary retention (AUR) increases with age. These changes are often accompanied by a reduction in the quality of life of both the patient and his family. Data from the placebo arm of the Proscar Long-term Efficacy and Safety Study have shown that all of these changes are correlated with increases in serum prostate-specific antigen (PSA) levels. It has also been shown that serum PSA levels are a reliable predictor of BPH progression and, as such, can be used to guide treatment decisions. Other predictors of BPH progression include prostate size, obstructive symptom score and peak urinary flow rates. Effective management of BPH will become increasingly important as its prevalence rises in line with the ageing population. More information is required on the value that men place on reducing the long-term progression of BPH and thus, to what extent they are willing to trade off the speed of symptom relief for a reduction in AUR or surgery. # 23 Elsevier B.V. All rights reserved. Keywords: BPH; Disease progression; Risk factors; PSA; Age; Quality of life 1. Introduction It is well established from a large number of studies that the prevalence of benign prostatic hyperplasia (BPH) increases linearly with age. In these studies, BPH was defined histologically by micronodularity in the transitional zone of the prostate gland, although this is not directly linked to the downstream consequences of progression. Where the condition occurs, it is likely to increase over time, resulting in an age-related impact of symptoms requiring pharmacological or surgical intervention [1]. The increase in life-expectancy that has been observed over the last 5 years has resulted in the ageing of the global population. It is expected that the world population aged over 65 years will double between 198 and 25 [2] and that approximately 15% of the population (1 million people) worldwide will be elderly by 25. This increase in the ageing * Tel. þ44-27-38-9852; Fax: þ44-27-637-776. E-mail address: memberton@dial.pipex.com (M. Emberton). population will, therefore, have a significant impact upon the incidence and prevalence of BPH. 2. The evidence for BPH progression A number of studies have provided a good evidence base to chart the process of change in downstream consequences of BPH, and have established the progressive nature of the disease [3]. The most comprehensive of these is the ongoing Olmsted County Study. An important feature of this study is the provision of continual updates, which improve the quality of the data as the study matures. Other sources of data on the progression of BPH are the placebo arms of large, randomised clinical studies, such as the Proscar Longterm Efficacy and Safety Study (PLESS), and also cross-sectional studies. These studies have used a number of different parameters as evidence for the progression of BPH, including increased symptom severity, reduced urinary flow, increased prostate volume, increased prostate-specific antigen (PSA) 1569-956/$ see front matter # 23 Elsevier B.V. All rights reserved. doi:1.116/j.eursup.23.9.8

M. Emberton / European Urology Supplements 2 (23) 2 7 3 levels, decreased quality of life and increased risk of acute urinary retention (AUR) with or without the requirement for surgery. The Olmsted County Study, which was initiated in 199, has studied outcomes in a randomly selected cohort of 2115 community-dwelling men (aged 4 79 years) in Olmsted County, Minnesota, USA, and data are now available from 12 years of follow-up. The study has recorded an average increase in scores on the American Urological Association Symptom Index (AUA-SI) of.18 points per year [4]. However, the most dramatic increase in symptom severity has been observed among men aged 6 69 years (Fig. 1). The apparent decrease in the rate of change that has been observed in men over 7 years of age may be due to either accommodation, failure or decompensation of the bladder at this time, with the result that urge is not manifested in the same way as at younger ages. Other noteworthy findings from the Olmsted County Study include a diminution of 2% per year in peak urinary flow rates with increasing age [5], and a median increase in prostate size of 1.9% per year related to baseline prostate volume [6]. PLESS involved a total of 34 men with an enlarged prostate, moderate-to-severe lower urinary tract symptoms (LUTS) and a decreased urinary flow rate, who were treated in a randomised, double-blind manner with finasteride 5 mg/day or placebo for 4 years [7]. For those men who were assigned to the placebo arm, prostate volume increased by 14% over the 4-year study period (Fig. 2); however, no deterioration in LUTS or urinary flow rate was observed during this time. This linear change from baseline might be extrapolated to the life-expectancy of the patient. The painful condition of AUR may occur spontaneously in men with BPH or be precipitated by surgery, anaesthesia or certain drugs. Among men with BPH in the Olmsted County Study, the cumulative incidence of AUR increased linearly with increasing age, and a dramatic 1-fold increase was seen when men aged 7 79 years with moderate-to-severe symptom scores were compared with their counterparts aged 4 49 years [8]. Long-term consequences of BPH may include variables other than outlet resistance or obstruction. For example, residual urine after mictruition or increased bladder wall thickness may develop as a consequence of BPH. Blood flow and oxygen delivery to the bladder may also be diminished, particularly in the last third of voiding against an obstructed outlet, and this in turn can result in reperfusion injury [9] to the bladder and lead to detrusor instability. Changes in renal function and urodynamic profile may prove useful in assessing BPH progression. 3. The economic and personal impact of BPH The symptoms and complications of BPH account for a large proportion of the workload of urologists, and they also interfere in the daily activities of patients to produce a negative impact on quality of life. The economic impact of BPH progression via loss of 2. Change in AUA Symptom Index from baseline 1.8 1.6 1.4 1.2 1..8.6.4.2 * 4 49 5 59 * 6 69 * 7 79 4 79 Age (years) Fig. 1. Changes in BPH symptom severity with age in the Olmsted County Study [4] (*p < :1 vs. baseline).

4 M. Emberton / European Urology Supplements 2 (23) 2 7 2 Prostate volume (mean % change from baseline) 1 1 2 Baseline* 1 2 Years 3 4 Fig. 2. Mean percentage increase in prostate volume over 4 years among men in the placebo arm of the PLESS trial (*mean prostate volume ¼ 41.4 ml). Reproduced with permission from McConnell JD et al. N Engl J Med 1998:338;557 563. productivity can be severe. For example, it has been estimated that a man with hourly urinary frequency, taking 1 minutes per visit, will lose 1 hour per day or 15% of his working time. Increasing symptom severity is associated with a decrease in several aspects of quality of life, particularly disease-specific measures such as bother and interference with daily activities (Fig. 3) [1]. In a study performed in Scotland, Garraway et al. [11] found that men with LUTS resulting from BPH were twice as likely to report alterations in the activities of daily life, such as limiting fluid intake before travel and bedtime, having insufficient sleep, avoiding places without toilets, restricted participation in outdoor sports and in visits to places like theatres, cinemas and churches. While BPH is not in itself a life-threatening condition. One of its established symptoms, nocturia, although seemingly benign, is associated with increased morbidity in the elderly due to fractures incurred when falling [12]. Chronic conditions such as BPH also affect individuals other than the patient. For example, the partners of men with BPH may suffer greater impairment of their quality of life than the patient himself, as the condition disrupts normal family life and potentially disrupts sleeping patterns for the patient s partner. The impact increases with severity and nearly all partners experience fatigue, worry and social inconvenience, together with anxiety about cancer and surgery [13]. 4. Predicting BPH progression The major risk factors for the progression of BPH that have been validated are age, prostate volume and PSA levels [3]. Other predictors include reduced urine flow, increased symptom score and increased bother, which drive the health-seeking behaviour. However, a reliable single predictor of the development of bothersome LUTS, AUR or other complications, such as urinary tract infections, bladder stones or renal decompensation would be of obvious value to urologists, and would reduce the need to measure prostate volume and other variables. A good predictor of risk would alert the physician to the presence of an enlarged prostate or of a prostate that was likely to increase in size, as well as to identify patient likely to develop LUTS, poor flow or to suffer AUR and/or require surgery. It would also provide patients with information that may help in making decisions on treatment. PLESS has demonstrated that PSA is an indicator of all these, albeit with differing degrees of sensitivity and with age as an important covariate [14]. Strong evidence for the relationship between PSA and prostate volume has been demonstrated in PLESS. This study of 4627 patients showed that prostate volume is strongly correlated with serum PSA in men with BPH but with no evidence of prostate cancer, in an age-dependent log-linear relationship [14]. It was concluded that this correlation is close enough for serum PSA to be used for accurate estimation of

M. Emberton / European Urology Supplements 2 (23) 2 7 5.5 Symptom score None = Mild = 1 7 Mod/severe = 8 35 Age-adusted means on 1 scale.4.3.2.1 Degree of bother Degree of interference Degree of worry PGWB scale Sexual worry Sexual satisfaction Fig. 3. Correlation between symptom severity and poor quality of life in men with BPH. Reproduced with permission from Girman CJ et al. Urology 1994;44:825 831. prostatic enlargement as a guide for therapeutic decisions. PSA can also be used as a predictor of future prostate growth [15]. Thus, for men in the placebo arm of the PLESS, those with PSA values in the first tertile (.2 1.3 ng/ml) showed increases from baseline of less than 3% over the 4 years of the trial, whereas those in the third tertile (3.3 12 ng/ml) had an increase in prostate volume of over 13% (Fig. 4) [15]. Serum PSA is less precise when used as a predictor of peak urinary flow. Nevertheless, those men in PLESS with low PSA levels maintained their flow rate well, whilst those with higher levels showed a trend towards decreasing flow over 48 months [16]. Similarly, PLESS found some evidence of a relationship between serum PSA and symptom outcomes in the placebo arm, assessed using a quasi-aua-si. There was a statistically significant decrease in symptom scores in all groups at 12 months, and this effect was maintained with a continuing downward trend in symptom scores in those with low baseline PSA values (<1.2 ng/ml) [16]. However, in subjects with serum PSA levels 1.3 ng/ml, there was a steady increase in symptom scores toward baseline values at 4 years. A clear correlation exists between serum PSA levels and the risk both of experiencing AUR or requiring BPH-related surgery [17]. Thus, in the placebo arm of the PLESS, 6.2% of men in the low PSA tertile required surgery, compared with 9.9% and 14.6% of men in the middle and upper tertiles, respectively, during the 4 years of the study [17]. Similarly, an episode of AUR was experienced by 2.9% and 5.8% of men in the low and middle tertiles, respectively, but by 11.6% of those in the high serum PSA tertile, thereby establishing PSA as a powerful predictor of AUR. Models for predicting progression include algorithms and single risk factors, as well as the fivevariable model, which encompasses the indices of serum PSA, symptom problems, peak urinary flow, urinary frequency 2 hours and hesitancy. When these are compared using the area under the receiver operating characteristic curve for logistic regression analysis, cross-validation shows that the sensitivity of PSA alone is comparable to the five-variable model and the use of an algorithm in predicting the progression of BPH. Serum PSA levels alone are therefore an appropriate guide for treatment decisions [18].

6 M. Emberton / European Urology Supplements 2 (23) 2 7 14 PSA.2 1.3 (n = 52) PSA 1.4 3.2 (n = 65) 13.3 Change from baseline (ml) 12 1 8 6 4 2 PSA > 3.3 (n = 47) 1.6 8.7 7. 5.5 3.9 2.5 2.5 1.6 1.1 2.8 8.3 12 months 24 months 36 months 48 months Fig. 4. Serum PSA as a predictor of prostate growth in men in the placebo arm of the PLESS [15]. 5. Risk factors for AUR Data from the placebo arms of three dutasteride randomised studies resulted in about 9 episodes of AUR among the 2158 men, giving a crude incidence rate of 4.2%. The continuous variables of prostate volume, PSA and peak flow rate were divided into five equal groups and a model was created to calculate the absolute risk of AUR for an individual man based on measurable baseline characteristics [19]. The risk of AUR increased with increasing prostate volume and PSA levels and with decreasing peak flow rate. A different approach to identifying factors that predict BPH progression was taken by Dr Bob Djavan and co-workers who used a neural network model in patients with mild symptoms of BPH (IPSS 8) [2]. In order of significance, the following were predictors of BPH progression: PSA, obstructive symptom score, age, transitional zone volume, IPSS, quality of life score, peak flow rate and post void residual volume. Using this neural network, three variables were found to be particularly useful for predicting progression: obstructive symptom score, age and PSA. Age-correlated PSA plus obstructive symptom score predicted with 88% accuracy the likelihood of progression [2]. 6. The value of reducing the risk of BPH complications Data currently missing from the literature are those relating to the value patients put on a reduction in the long-term consequences of BPH. To aid appropriate management of the patient it would be useful to know the value patients would place on the 57% reduction in risk of AUR seen with 5a-reductase inhibitors. There is little research on the impact of long-term morbidity associated with BPH and on how men choose a treatment for BPH. Conjoint analysis techniques are used in market research and are increasingly used in healthcare. These techniques allow estimation of the relative Table 1 Patients marginal rates of substitution between out-of-pocket expenses or life expectancy and other attributes [21] Costs (UK ) Life expectancy (months) For a single level improvement Diarrhoea 257 1.8 Moderate to mild, or mild to absent Hot flushes 75.5 Moderate to mild, or mild to absent Loss of libido 391 1.3 Present to absent Moderate erectile dysfunction (<71 years) 537 1.8 Moderate to mild, or mild to absent Moderate erectile dysfunction (>7 years) 261.9 Moderate to mild, or mild to absent Lack of energy 889 3. Present to absent Breast symptoms 265 1.9 Present to absent

M. Emberton / European Urology Supplements 2 (23) 2 7 7 importance of different attributes of care, the trade-offs between these attributes, and the total satisfaction or utility that patients derive from such healthcare services. Table 1 shows the amounts men with prostate cancer are willing to pay, in terms or money or months/ years of life, to reduce the chance of side-effects relating to androgen suppression [21]. 7. Conclusion BPH is recognised as a progressive disorder that is associated with considerable morbidity, including the risk of AUR and the need for surgery. Due to increased life expectancy, the proportion of men at risk of BPH and its progression will increase significantly over the coming years. Effective management of the condition will be essential to reduce the economic cost and increasing the well-being of patients and their families. Consequently, the use of markers to identify those patients at greatest risk of BPH progression is necessary to ensure the timely delivery of appropriate treatment. A large body of evidence has now accumulated to demonstrate that serum PSA levels can be used to identify those patients at greatest risk of progression and, therefore, who will benefit most from treatment. Other important predictors include prostate volume, obstructive symptom score and peak flow rate. Such risk factors should be included in the standard assessment of any man presenting with LUTS. More research is needed on the value patients put on a reduction in the long-term consequences of BPH progression and thus, to what extent they are willing to trade off the speed of symptom relief for a reduction in AUR or surgery. References [1] Jacobsen SJ, Girman CJ, Guess HA, Oesterling JE, Lieber MM. New diagnostic and treatment guidelines for benign prostatic hyperplasia. Arch Intern Med 1995;155:477 81. 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