Prostate cancer is a fast-changing field, and recent advances have significantly improved both the survival and quality of life of many men diagnosed with the disease. As well as providing comprehensive information on the diagnosis, staging and management of the disease, the eighth edition of this ever-popular handbook is an invaluable update on new developments, including: Evidence for the debate surrounding PSA screening A better understanding of molecular and genetic advances The latest methods of delivering radiotherapy New drug treatments for castrate-resistant prostate cancer Important discussion of survivorship issues This superbly illustrated handbook is a practical resource for all those who provide support and care for men with prostate cancer - including GPs, nurses and allied health professionals - as well as a refreshingly readable source of information for patients wanting to know more about their condition and its treatment.
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Fast Facts: Prostate Cancer
By Roger S Kirby, Manish I Patel
Health Press LimitedCopyright © 2014 Roger S Kirby, Manish I Patel
All rights reserved.
Epidemiology and pathophysiology
In most developed and, increasingly, in developing countries, prostate cancer is the most common malignancy to affect men of middle age and beyond, and is second only to lung cancer as a cause of cancer deaths in men. It has been estimated that, in western countries, the lifetime risk of developing microscopic prostate cancer is 30%. At autopsy, the prevalence of microscopic prostate cancer is approximately 80% in men aged 80 years. However, as many of these cancers grow slowly, the risk of developing clinically detectable cancer is about 8%; the lifetime risk of actually dying from prostate cancer is approximately 3%.
Worldwide, there has been a steady increase in the incidence of clinically significant disease but, in the USA at least, the data indicate that incidence is now plateauing (Figure 1.1). However, because prostate cancer is primarily a disease affecting men over the age of 50 years, the worldwide trend towards an aging population means that the number of men diagnosed with prostate cancer is predicted to increase substantially over the next two decades. Mortality from prostate cancer in Europe rose to a peak in 1993, reached a plateau, and has now started to decrease. Mortality in the USA has recently shown similar trends and has also started to decline (see Figure 1.1). The rate of decline has increased significantly in recent years and is now four times faster than the rate in the UK. Some have attributed this drop to the efforts made in North America to detect prostate cancer early, though several other factors such as changes in lifestyle and better treatment outcomes may also have contributed.
Despite the high incidence of prostate cancer, relatively little is known about the underlying causes of the disease. However, a number of risk factors have been established (Table 1.1).
Age is the greatest factor influencing the development of prostate cancer. Clinical disease is rare in men under the age of 50 years, and the incidence increases markedly in men over 60 years of age (Figure 1.2).
Race. There are marked geographic and ethnic variations in the incidence of clinical prostate cancer (see, for example, Figure 1.2). The risk is highest in North America and northern European countries, and lowest in the Far East. In the USA, the risk is higher in blacks than in whites, and black men also appear to develop more aggressive disease earlier. Chinese and Japanese races show the lowest incidence of prostate cancer, though the prevalence is now increasing in both. The incidence of latent, clinically insignificant disease, however, is similar in all populations studied. In migration studies, the incidence of prostate cancer in men emigrating from a low- to a high-risk area increases to that of the local population within two generations. This suggests that environmental influences such as diet and nutrition may have a profound effect on the development of prostate cancer and on the progression of histological cancer to a clinically detectable cancer.
Family history/genetic risk. Overall, epidemiologic studies show that heritable factors account for a small proportion of prostate cancer risk, but a higher proportion of early-onset disease. However, the existence of prostate cancer susceptibility genes is suggested by a host of studies, and family history is a strong risk factor for prostate cancer. The risk of a man developing prostate cancer if he has a first-degree relative affected is increased approximately 2.5-fold. The relative risks for developing prostate cancer based on family history are given in Table 1.2.
Linkage analyses, which screen for genetic traits in high-risk groups in whom prostate cancer has been detected, have identified many prostate cancer susceptibility loci (physical locations of genes/DNA on a chromosome). However, the high 'background' incidence of sporadic prostate cancers can make statistical analyses of these results difficult. It appears that many of the loci are associated with cancer in a small group of families, and currently there is no single genetic marker that indicates increased susceptibility to prostate cancer. Researchers are looking at combining single nucleotide polymorphisms in multiplex assays, but more research is needed before tests become routinely available. The US National Cancer Institute's webpages on the genetics of prostate cancer are regularly updated and provide a thorough review of the current status of this fast-changing field (www.cancer.gov/cancertopics/pdq/genetics/prostate).
Mutations in the BRCA breast cancer susceptibility genes are rare in men with prostate cancer, but appear to be associated with features of more aggressive disease, such as higher Gleason score, and higher PSA level and tumor stage and/or grade at diagnosis. Furthermore, carriers of BRCA mutations may have lower overall survival and prostate cancer-specific survival compared with non-carriers. Knowledge of a man's BRCA status is, therefore, of prognostic value.
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 men castrated before puberty, or in men deficient in 5α-reductase (the enzyme, existing in type I and II isoforms, that converts testosterone to DHT). Trials of type II 5α-reductase inhibition with finasteride and dutasteride have shown that the development of prostate cancer can be reduced by around 25%, suggesting a key role for DHT. However, 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 suggested link between body mass index and incidence of prostate cancer has been controversial. Early studies showed an increased risk of prostate cancer in obese men, while more recent studies have suggested that obese men actually have lower levels of detected prostate cancer. This may be because levels of PSA and androgens are lower in obese men, so fewer obese men may be being biopsied and diagnosed with prostate cancer in the PSA era. There is, however, a clear increase in prostate cancer mortality in men who are obese. The mechanism by which obesity increases the likelihood of death from prostate cancer is not known; it may be through the activation of pro-carcinogenic pathways such as the insulin-like growth factor (IGF) axis.
Western diets are high in animal fat, protein, meat and processed carbohydrates, and low in plant foods. A link between dietary fat, saturated fat and meat intake and the development of prostate cancer has been supported by a number of studies. There is also some evidence that α-linoleic acid, an omega-3 polyunsaturated fatty acid, increases prostate cancer risk and the risk of developing advanced prostate cancer. This may be the result of oxidative stress and subsequent DNA damage or the development of obesity. Omega-3 fatty acids from marine sources may result in a decreased risk of developing prostate cancer.
Sun exposure and vitamin D. The risk of dying from prostate cancer is geographically related to ultraviolet (UV) light exposure. Vitamin D levels in men with prostate cancer are lower than in men without, and vitamin D levels are determined by dietary intake and conversion in the skin by UV light. The mechanism by which vitamin D levels protect against prostate cancer is not known. Calcitriol (vitamin D) has been used to treat advanced prostate cancer, but evidence of efficacy is lacking.
Most prostate cancers are adenocarcinomas that appear to arise in the peripheral zone of the gland (> 70%) (Figure 1.4). Approximately 5–15% arise in the central zone and the remainder from the transition zone, which is the zone where benign prostatic hyperplasia (BPH) also develops.
Microscopic foci of 'latent' prostate cancer are a common autopsy finding and may appear very early in life; approximately 30% of men over 50 years of age have evidence of latent disease. Because of the very slow growth rate of these microscopic tumors, many never progress to clinical disease. Beyond a certain size, however, these lesions progressively de-differentiate, probably owing to clonal selection, and become increasingly invasive. A tumor that has a volume greater than 0.5 cm3 or is anything other than well differentiated is generally regarded as clinically significant.
The Gleason system is the most widely used system for grading prostate cancer (Figure 1.5). It recognizes five levels of increasing aggressiveness.
Grade 1 tumors consist of small, uniform glands with minimal nuclear changes.
Grade 2 tumors have medium-sized acini, still separated by stromal tissue, but more closely arranged.
Grade 3 tumors, the most common finding, show marked variation in glandular size and organization, and general infiltration of stromal and neighboring tissues.
Grade 4 tumors show marked cytological atypia with extensive infiltration.
Grade 5 tumors are characterized by sheets of undifferentiated cancer cells.
Because prostate cancers are often heterogeneous, the numbers of the two most widely represented grades are added together to produce the Gleason score (e.g. 3 + 4). This score (or sum) provides useful prognostic information; Gleason scores above 4 are associated with a progressive risk of more rapid disease progression, increased metastatic potential and decreased survival (Table 1.3). A meta-analysis of patients being managed by active surveillance/watchful waiting (the distinction between the two approaches, as described later, was not clear in the paper), for example, found that the annual rate of developing metastases was 2.1% in patients with Gleason scores below 4, compared with 5.4% in patients with scores between 5 and 7, and 13.5% in patients with scores above 7. The chance of relapse after radical prostatectomy has also been shown to be directly proportional to the percentage of Gleason grade 4 and 5 cancer in the specimen. Occasionally, more than two grades are observed in prostatectomy specimens, the least common being known as the tertiary grade. When the tertiary grade has a high score (4 or 5), the patient has a higher risk of progression, even if the primary and secondary grades are lower.
One study of 767 men with localized prostate cancer reported a highly significant correlation between the Gleason score and the risk of dying from prostate cancer. Patients with a score of 2–4 had a 4–7% chance of dying within 15 years of diagnosis. In contrast, patients with a score of 8–10 had a 60–87% chance of death from prostate cancer.
Patterns of disease spread
Prostate cancer can be classified according to the spread of the disease by the tumor–nodes–metastasis (TNM) system (Table 1.4). The tumor stage (T1–T4) describes the pathological development of the tumor.
T1 represents 'incidental' status, in which the tumor is discovered after transurethral resection of the prostate (TURP) or, more commonly, by PSA testing, and is not detectable by palpation or ultrasonography.
T2 represents a cancer which is palpable but still confined to the prostate gland.
T3 represents a cancer which has extended through the prostate capsule into the surrounding fat or seminal vesicles.
T4 represents advanced disease, in which the tumor invades neighboring organs (Figure 1.6).
The nodal stages (N0–N1) and metastatic stages (M0–M1c) reflect the clinical progression of the disease. Metastases are most common in the lymph nodes (N1) and bones (M1); the lungs and other soft tissues are less commonly involved.
Currently, it is not possible to distinguish unambiguously between those tumors that will remain latent throughout the patient's life and those that will definitely progress to clinical disease. Studies of incidental carcinomas diagnosed after TURP suggest that the median time to progression for T1b (high-volume, moderately or poorly differentiated) tumors is 4.75 years, compared with 13.5 years for T1a (low-volume, well-differentiated) tumors (Figure 1.7). Thus, elderly men with T1a tumors are more appropriately managed by active surveillance alone, while younger men with T1b disease may be considered, after informed consent, for more aggressive, potentially curative therapy.CHAPTER 2
Diet, lifestyle and chemoprevention
Effect on development of prostate cancer
Diet and lifestyle are clearly linked to the development of prostate cancer. In Chapter 1, the effect of hormones, obesity and a western-style diet were discussed as risk factors for the development of prostate cancer. A large number of studies have evaluated the effects of dietary manipulation/supplementation or drug treatment to reduce the incidence of prostate cancer. Table 2.1 shows the current evidence for dietary manipulation.
Although randomized clinical trials have provided some indication of a protective effect from selenium and vitamin E, a large chemoprevention study (the Selenium and Vitamin E Cancer Prevention Trial [SELECT]), designed to determine whether they reduced the likelihood of prostate cancer when used singly or in combination, was ended prematurely because of disappointingly negative results. Cohort studies show that lycopene and isoflavonoids – in, respectively, tomatoes and soy products – are possibly associated with a decrease in the incidence of prostate cancer. Evidence for other dietary supplements is weak.
Chemoprevention with drugs. The 5α-reductase inhibitor finasteride has been shown to reduce the incidence of prostate cancer by 24.8% compared with placebo over a 7-year period, though at the cost of a small incidence of sexual side effects. Counterbalancing this observation is the finding that a small proportion of the cancers in the finasteride group tended to be more aggressive in nature than those in the placebo group. The explanation for this is still debated, but it is possibly explained by an artifact of biopsying the smaller prostates that resulted from the shrinkage effect of finasteride in the active treatment arm of the study. A recent report has confirmed no difference in the rates of overall survival, or survival after a diagnosis of prostate cancer, between the placebo-treated and finasteride-treated patients after 18 years of follow-up.
Another 5α-reductase inhibitor, dutasteride, has been evaluated for its effect on the occurrence of prostate cancer in the so-called REDUCE study (Reduction by Dutasteride of Prostate Cancer Events). Dutasteride resulted in a 23% reduction in prostate cancer risk, mainly by suppressing the well-differentiated cancers, with only a slight, statistically insignificant, increase in Gleason pattern 7 or 8–10 poorly differentiated tumors. It also effectively treated the symptoms arising from benign prostatic enlargement in participants.
Significantly, neither of these compounds has been approved by the regulatory authorities for chemoprevention.
Recently, statins have been reported to have some chemopreventative properties. Evidence for this is still weak but it is an intriguing possibility.
Effect on progression
Unfortunately, very few clinical trials have investigated the effect of diet and lifestyle change on prostate cancer progression. Table 2.2 outlines the current body of evidence. In addition to this, a large number of compounds – many of them herbal – have been tested in the laboratory and show possible promise; these include green tea and other polyphenols, resveratrol from red wine, vitamin D, epilobium and Serenoa repens (saw palmetto).
Excerpted from Fast Facts: Prostate Cancer by Roger S Kirby, Manish I Patel. Copyright © 2014 Roger S Kirby, Manish I Patel. Excerpted by permission of Health Press Limited.
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Table of Contents
Glossary of abbreviations,
Epidemiology and pathophysiology,
Diet, lifestyle and chemoprevention,
Screening and early detection,
Diagnosis, staging and prognostic indicators,
Management of clinically localized disease,
Managing recurrence after initial therapy,
Management of metastatic prostate cancer,
Management of castrate-resistant prostate cancer,
Survivorship and treatment complications,