Fast Facts: Prostate Cancer: If, when and how to intervene

Introduction

Prostate cancer is the most commonly diagnosed cancer in men. However, it is unusual among solid tumors in that many men die with, rather than of, the disease – the lifetime risk of developing clinical prostate cancer in western countries is about one in eight, but as many cancers grow slowly, the lifetime risk of actually dying as a result is approximately 2.5% throughout the developed world. This raises many challenges for both healthcare professionals and patients in terms of deciding if, when and how to intervene in order to control tumor growth and spread, thereby extending survival but without compromising quality of life. Survivorship after treatment is therefore an increasingly important issue, and this is discussed in the final chapter.

This is the tenth edition of this Fast Facts handbook since the first was published in 1996 – the many iterations are testament to the rapid changes in the field and steadily improving outlook for patients. This new edition introduces the Gleason grade grouping (Chapter 1), which has important prognostic value, and nomograms that are used to evaluate risk (Chapter 3). Our understanding of the genetics and underlying pathogenesis of prostate cancer is growing apace, leading to the identification of germline mutations and the development of genomic tests to help identify and direct therapy for those at greatest risk of developing clinically significant disease. They also provide reassurance for those patients who have opted for active surveillance (Chapters 3 and 5). Imaging techniques are also improving rapidly, particularly multiparametric MRI (Chapter 4). By identifying specific target areas, these techniques are improving biopsy accuracy and reducing not only the number of negative biopsies but also the identification of tiny foci of well-differentiated cancer that may well be destined never to progress and therefore require no treatment.

The androgen receptor is central to the pathogenesis of prostate cancer – as is the estrogen receptor in breast cancer – and manipulation of the hormone milieu is key in treatment; however, androgen deprivation has unfortunate side effects that have a considerable effect on quality of life, prompting continued exploration of the optimal timing and sequencing of treatment, including the concept of intermittent androgen blockade (Chapters 7 and 8).

Methods for detecting and monitoring the disease are also improving. The role of prostate-specific antigen (PSA) in the screening, detection and monitoring of prostate cancer and its treatment is still controversial, with advocates for and against. Nevertheless, measurement of serum PSA continues to provide valuable information to inform clinical decisions, though it is hoped that other markers, whether complementary or alternative, will emerge with time. Different measures of PSA, such as the doubling time and velocity, are being explored. The Prostate Health Index, a combined measure, has been approved in the USA (Chapter 3).

Novel molecular imaging techniques are now providing new opportunities to both detect and characterize sites of prostate cancer involvement and are entering into clinical practice, particularly in the setting of recurrent or advanced metastatic disease. Based on biochemical, clinical or imaging criteria, these approaches can define disease burden, guide locoregional salvage therapies and support the selection and monitoring of systemic treatment. An exciting and emerging role of molecular imaging is in the selection of patients for radionuclide and stereotactic therapy.

The debate over the merits of surgery versus radiotherapy for patients with localized but high-risk disease continues, especially as robot-assisted surgery, low-dose seed brachytherapy and CyberKnife targeted radiation therapy continue to improve accuracy and precision (Chapter 5). Chemotherapy with docetaxel at initiation of androgen-ablation therapy has become the standard of care for men with metastatic prostate cancer, and either enzalutamide or abiraterone acetate for men with castrate-resistant prostate cancer (CRPC). Immunotherapies and vaccines are now also being explored, and these offer further hope to men with CRPC (Chapter 8).

With this tenth edition of this popular Fast Facts handbook, we hope to help those who provide support and care for men with prostate cancer to feel more fully informed in navigating the complexities of clinical decision making. As the book is concise, fully up to date and evidence based, we believe it is an ideal resource for those general urologists, primary care providers, specialist nurses, trainees and allied healthcare professionals who want to get quickly up to speed in this fast-moving and ever-expanding field. You can swiftly test your knowledge after reading this book by taking our Fast Test at karger.com/fastfacts, and please do send an email to [email protected] if you have any specific feedback.

Global patterns

Prostate cancer is the most frequently diagnosed cancer in men in many countries, particularly those in the Americas, northern and western Europe and SubSaharan Africa, as well as Australia and New Zealand.¹ Overall, it is the second most commonly occurring cancer in men.¹ The lifetime risk of developing clinical prostate cancer in western countries is around one in eight.

Approximately 80% of men aged 80 years have prostate cancer at autopsy. However, many of these cancers grow slowly and the risk of developing clinically detectable cancer is about 13%; the lifetime risk of actually dying from prostate cancer is around 2.5%, but death from this disease is often preceded by a long and debilitating illness.

Incidence. In the 1980s, intensive testing using the newly available commercial tests for prostate-specific antigen (PSA) led to an increase in diagnoses in many countries. The picture emerged first in the USA (Figure 1.1) but soon also became apparent in Europe, Australia and Canada. In the USA, the number of incidental diagnoses then fell as the US Preventive Services Task Force issued guidance against PSA-based screening for all men in 2012 (updated in 2018).³,⁴ In the Nordic countries, some of which adopted intensive strategies for PSA testing early on, a rise in incidence has been followed by a decline or stabilization since the mid 2000s, as the pool of men with undetected disease has reduced.¹ In countries in which the use of PSA testing has increased more recently, such as the UK and Brazil, the incidence of prostate cancer has continued to climb.¹

Figure 1.1 The incidence and mortality of prostate cancer in the USA from 1975 to 2016. The temporary rise in incidence coincides with the introduction of PSA screening in about 1990. The US Preventive Services Task Force guidelines issued in 2012 discouraged screening in all men. Data are from the Surveillance, Epidemiology, and End Results (SEER) Program, National Cancer Institute.²

In contrast to western countries, the incidence of prostate cancer remains low in Asia (Figure 1.2).¹ Despite these low levels, more men are now starting to be diagnosed with prostate cancer. From 2008 to 2018, the incidence of prostate cancer rose from 13.8 to 26.9 per 100 000 in western Asia, for example.¹,⁵ Such an increase could be attributed to the increased prevalence of risk factors associated with economic development, enhanced public awareness of prostate cancer leading to more PSA-based screening and the development of cancer registration systems.

Figure 1.2 Age-standardized incidence and mortality rates for prostate cancer. Data are from the GLOBOCAN database, published by the Global Cancer Observatory 2018.⁶

As prostate cancer predominantly affects men over the age of 50 years, the number of men diagnosed with prostate malignancy is predicted to increase substantially over the next two decades simply as a result of the worldwide trend toward an aging population. The debate around the use of PSA as a screening tool is discussed in detail in Chapter 3.

Mortality from prostate cancer in many European countries rose to a peak in 1993, reached a plateau and then started to decrease. Mortality in the USA showed a similar trend (see Figure 1.1), though the US rate has not fallen in recent years.⁷

In contrast, mortality rates are rising in several Central and South American, Asian (except in the more developed Asian countries) and central and eastern European countries.⁸ These trends highlight the growing challenges involved in managing prostate cancer in developing countries, many of which have limited access to effective treatments, lack of awareness among the public and inconsistent approaches to workup and intervention.

Risk factors

Despite the high incidence of prostate cancer, relatively little is known about the underlying causes. However, a number of risk factors have been identified.

Age is the greatest factor that influences the development of prostate cancer. Clinical disease is rare in men under the age of 50 years, but incidence increases markedly beyond 60 years.

Race/ethnicity. Marked variations in the incidence of clinical prostate cancer are seen geographically and in groups of different ethnic background (Table 1.1). In the USA, the risk is higher in black men than in white men, and black men also appear to be at greater risk of developing more aggressive disease earlier in their lives.⁹ The incidence of latent (clinically insignificant) disease seems to be similar in all populations studied.

In men who emigrate from a low- to a high-risk area, the incidence of prostate cancer increases to that of the local population within two generations. This suggests that environmental influences, including diet and lifestyle factors, may have a profound effect on the development of prostate cancer and on the progression of latent to clinically detectable cancer.

Family history/genetic risk. Epidemiological studies show that heritable factors account for a relatively small proportion of prostate cancer risk but a higher proportion of early-onset disease. However, a host of studies have suggested the existence of genetic mutations that increase susceptibility to prostate cancer.

Family history is a strongly positive risk factor for prostate cancer: the risk of a man developing prostate cancer is increased approximately 2.5-fold if he has a first-degree relative who is affected (Table 1.2).¹⁰

The significant incidence of familial prostate cancer prompted a search for germline mutations. Early linkage analyses suggested the human prostate cancer 1 gene (HPC1), located at 1q24–25, and studies in men with familial prostate cancer but without male-to-male transmission led to the identification of the X-linked human prostate cancer X gene (HPCX) at Xq27–28. Further loci have also been identified on multiple chromosomes. Familial prostate cancer is a far more heterogeneous condition than familial breast cancer, with contributions from many more gene loci.¹¹ The predictive value of any one allele is low; hence, a clinically useful genetic test has not yet been identified, though research is actively ongoing.

The strongest evidence for direct causality comes from families who develop cancer syndromes such as Lynch