Fast Facts: Prostate Cancer

By Manish I. Patel and Darren M.C. Poon

Prostate cancer is the second most common cancer in men worldwide, but it is unusual among solid tumors in that many men die with, rather than of, the disease. This raises challenges in terms of deciding if, when, and how to intervene to control tumor growth and spread in order to extend survival without compromising quality of life. The many developments in the field since the last edition of this book include continuing studies to improve detection and monitoring of the disease, with the evaluation of MRI for screening and prostate-specific membrane antigen (PSMA)-PET/CT for staging. Treatment options have also continued to improve and expand for all stages of the disease with the development of ultrahypofractionated radiotherapy, oral LHRH antagonists, PARP inhibitors and lutetium-177 PSMA-617 radioligand therapy.

• Language: English
• Publisher: S. Karger
• Release date: Feb 27, 2024
• ISBN: 9783318072396

Book preview

Introduction

Prostate cancer is the second most common cancer in men worldwide, but it is unusual among solid tumors in that many men die with, rather than of, the disease. This raises challenges in terms of deciding if, when, and how to intervene to control tumor growth and spread in order to extend survival without compromising quality of life.

The many developments in the field since the last edition of this book in 2020 include continuing studies to improve detection and monitoring of the disease, with the evaluation of MRI for screening and prostate-specific membrane antigen (PSMA)-PET/CT for staging. Treatment options have also continued to improve and expand for all stages of the disease.

Ultrahypofractionated radiotherapy regimens and technologies to improve focal delivery of radiotherapy are being investigated for men with localized disease. For men with advanced disease, the first oral luteinizing hormone-releasing hormone (LHRH) antagonist has been approved. Studies are also ongoing to determine optimum combinations of androgen deprivation therapy (ADT), chemotherapy, and androgen-receptor pathway inhibitors (ARPIs).

For men with metastatic castrate-resistant prostate cancer (mCRPC), several poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated significant clinical benefit in patients with deleterious mutations in homologous recombination repair (HRR) pathway genes, and lutetium-177 PSMA-617 radioligand therapy has also recently been approved in this setting.

The 11th edition of this concise, fully up to date, and evidence-based resource is ideal for urologists, urology trainees, specialist nurses, primary care providers, and allied healthcare professionals who want to get up to speed quickly in this fast-moving field, and we hope it will help both healthcare professionals and men with prostate cancer to feel more fully informed when navigating the complexities of shared clinical decision-making.

Acknowledgments. We gratefully acknowledge the contribution of Professor Roger Kirby who initiated the first edition of this book and co-authored all previous editions.

1Epidemiology and risk factors

Global patterns

Prostate cancer is the most frequently diagnosed cancer in men in many countries, particularly those in the Americas, Northern and Western Europe, the Caribbean, sub-Saharan Africa, and Australia and New Zealand, and the second most common cancer in men overall.¹ The lifetime risk of developing clinical prostate cancer in Western countries is around 1 in 8.²

More than 50% of men aged 90 years or older have prostate cancer at postmortem examination.³ However, many of these cancers are small, low grade, and rarely locally advanced or metastatic. In the USA, the lifetime risk of developing clinically detectable cancer is 12.6%, whereas the risk of dying from the disease is around 2.4% (2017–2019 data),⁴ 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)⁵ 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. This guidance was updated in 2018 to support shared decision-making between men aged 55–69 years and their clinicians based on a discussion of the potential benefits and harms of testing.⁶,⁷

Figure 1.1 Incidence and mortality of prostate cancer in the USA from 1975 to 2020. 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.⁵

In regions in which the use of PSA testing has increased more recently, such as sub-Saharan Africa, the incidence of prostate cancer has continued to climb.¹

The incidence of prostate cancer remains low in Asia and Northern Africa (Figure 1.2).¹ Despite these low levels, more men are now starting to be diagnosed with prostate cancer. From 2008 to 2020, the incidence of prostate cancer rose from 13.8 to 28.6 per 100 000 in Western Asia, for example.¹,⁸ 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.

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 because 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.

Figure 1.2 Age-standardized incidence and mortality rates for prostate cancer. Data are from the GLOBOCAN database, published by the Global Cancer Observatory 2020.¹

Mortality from prostate cancer in many high-income European countries rose to a peak in 1993, reached a plateau, and then started to decrease. Mortality in the USA showed a similar trend, though the US rate has not fallen in recent years.⁵

In contrast, mortality rates have risen during the same period in several Central and Eastern European, Asian (except in the more developed Asian countries), and African countries.¹ 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, several risk factors have been identified.

Age is the greatest factor that influences the development of prostate cancer. Clinical disease is rare in men under 50 years old, but incidence increases markedly beyond 60 years. In the USA, 41% of new cases of prostate cancer are diagnosed in men aged 65–74 years,⁵ while in the UK one-third of new cases are diagnosed in men over 75 years old.⁹ Incidence also peaks in men aged 75 and older in Eastern Europe and Asia.¹⁰

Race and ethnicity. Marked variations in the incidence of clinical prostate cancer are seen geographically and in different racial and ethnic groups (Table 1.1). In the USA, the risk is higher in Black men than in White men,⁵ and Black men also appear to be at greater risk of developing more aggressive disease earlier in their lives.¹¹ 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. While environmental influences, such as diet and lifestyle factors, may affect the development of prostate cancer and progression of latent to clinically detectable cancer, it is difficult to separate the effect that more PSA screening has had on increased diagnosis of prostate cancer in these areas.

TABLE 1.1

Incidence of prostate cancer according to race in the USA

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, studies have suggested the existence of genetic mutations that increase susceptibility to prostate cancer.

Family history of prostate cancer is a strongly positive risk factor for the disease: the risk of a man developing prostate cancer is increased approximately 2.5-fold if he has one first-degree relative who is affected and over fourfold if he has two or more first-degree relatives who are affected (Table 1.2).¹²

Family history of breast cancer is also associated with an increased prostate cancer risk. In a large prospective study of 37 000 men followed up for 16 years, those with a family history of breast cancer had a 21% higher risk of developing prostate cancer and a 34% greater risk of lethal disease, and those with a family history of both prostate and breast cancer were at even higher risk (60%) of developing prostate cancer.¹³

TABLE 1.2

Risk of developing prostate cancer in relation to family history of the disease

Gene mutations. Familial prostate cancer is a far more heterogeneous condition than familial breast cancer, with contributions from many more gene loci.¹⁴ The predictive value of any one allele is low; hence, a clinically useful genetic test has not yet been identified, though research is ongoing.

The strongest evidence for direct causality comes from families who develop cancer syndromes such as Lynch syndrome, caused by a mutation in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2). The risk of developing prostate cancer is elevated up to fivefold in men with Lynch syndrome.¹⁵ In the IMPACT study, the first round of PSA screening in men from families with MMR gene variants has shown that carriers of MSH2 and MSH6 pathogenic variants have a higher incidence of prostate cancer than age-matched non-carriers.¹⁶

Mutations in the BRCA2 breast cancer susceptibility gene are rare in men with prostate cancer, but they appear to be associated with earlier diagnosis and more aggressive disease – with a higher Gleason score (see pages 27–9), PSA level, and tumor stage and/or grade at diagnosis.¹⁷ Furthermore, carriers of BRCA2 mutations may have lower overall survival and prostate-cancer-specific survival than non-carriers. Knowledge of a man’s BRCA2 status therefore has prognostic value.

The US National Cancer Institute web pages on the genetics of prostate cancer provide a thorough review of this fast-changing field and are updated regularly (cancer.gov/types/prostate/hp/prostate-genetics-pdq).

Hormones. Testosterone and its more potent metabolite dihydrotestosterone (DHT) are essential for normal prostate growth, and also play a role in the development of prostate cancer (Figure 1.3). Prostate cancer almost never develops in the rare case of men who, for some reason, are castrated before puberty, or in men deficient in 5α-reductase – the enzyme with type I and II isoforms that converts testosterone to DHT. Trials have shown that the type II 5α-reductase inhibitors finasteride and dutasteride reduce the development of prostate cancer by about 25%, suggesting a key role for DHT. These drugs are effective in the treatment of benign prostatic hyperplasia (BPH), but no trials have demonstrated an impact on overall or prostate-cancer-specific mortality and neither drug has been approved for the chemoprevention of prostate cancer.¹⁸

Figure 1.3 Testosterone, which is converted to DHT by 5α-reductase, supports prostate cell function and stimulates cell division.

Paradoxically, the incidence of prostate cancer increases with age, while serum testosterone levels decrease. In addition, men diagnosed with advanced prostate cancer often have a lower average testosterone level than men of a similar age who do not have prostate cancer.

Obesity. The prevalence of obesity is increasing almost everywhere in the world, and obesity-induced disease, insulin resistance, cardiovascular disease, and malignancies are an ever-increasing problem. Epidemiological studies have shown that obesity is associated with advanced prostate cancer and that obese men with prostate cancer have a poorer prognosis. Obesity is associated with an increased risk of a number of malignancies.

In prostate cancer, a high-fat diet or obesity appears to change the local profile of immune cells such as myeloid-derived suppressor cells and macrophages. Inflammatory cells appear to play important roles in tumor progression. Tumor-associated neutrophils, B cells and complement, as well as procarcinogenic pathways such as the insulin-like growth factor (IGF) axis, and deregulation of the insulin axis, sex hormone secretion, adipokine signaling, and oxidative stress may potentially promote prostate cancer in obese men.¹⁹–²¹

Diet and dietary supplements. A large number of studies have evaluated the association between various dietary factors and prostate cancer but there is still a lack of quality evidence. The current picture is summarized in recently updated guidelines from the European Association of Urology (EAU) and other European organizations (Table 1.3).²² Western diets tend to be high in animal fat, protein, red meat, and refined processed carbohydrates, and low in plant foods and fiber. Some studies support links between the development of prostate cancer and the intake of dairy products, saturated fat, and red meat (particularly processed meats), while coffee may be associated with a reduced risk of prostate cancer.²³

Although randomized clinical trials have provided some indication that selenium and vitamin E have a protective effect, SELECT, a large study