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Cancer of the prostate gland
Renal and urology
Cancer of the prostate gland
risen steadily over the last twenty years. This statistic should be interpreted with caution because of increased detection due to the prostate-specific antigen serum test (though an increase in clinically significant cancer appears to have occurred). Prostate cancer kills >9,000 UK men each year. There is significant variation in the incidence of clinical prostate cancer worldwide. It is relatively high in northern Europe and North America, intermediate in southern Europe and South America, and low in the Far East and Asia. The highest incidences are found in African-American men and the lowest in Chinese men.
Thomas Swallow Roger S Kirby
Abstract
Aetiology and risk factors
Prostate cancer constitutes a major health problem. It is estimated that the lifetime risk of western men having prostate cancer is about 30%, with the risk of dying from the cancer being 3%. Increasing age is the strongest pre-determinant for the development of prostate cancer. Virtually all cancers are adenocarcinomas with the grade being indicated by the Gleason score. Often, there are no presenting symptoms. Investigations such as, the serum prostate-specific antigen level, digital rectal examination and biopsies via a trans-rectal ultrasound probe, are required for diagnosis. Staging, if required, consists of MRI/CT for locally advanced disease and/or a bone scan for detection of bony metatstases. Management depends largely on the stage of the disease. For localised prostate cancer, radical prostatectomy can offer a cure. Side effects include erectile dysfunction and incontinence. Prostate cancer is also radio-sensitive and can be given as external beam radiotherapy or in the form of brachytherapy. Hormonal therapy, such LHRH analogues and anti-androgens are used in locally advanced and metastatic disease. Hormones do not cure, but slow the progression of the cancer. Follow-up consist of PSA surveillance and other therapeutic options can be considered if the PSA starts to rise. Cytotoxic chemotherapy is increasingly being used for hormone escaped prostate cancer. The survival rate at ten years may be as high as 90% for a well-differentiated, localized prostate cancer.
A direct cause of prostate cancer has not been identified, but a number of risk factors have been identified. Familial: several studies have shown the prevalence of prostate cancer within certain families. This familial or hereditary form of cancer is characterized by either: • three successive generations being affected with the disease • a clustering of three or more men with the disease in a nuclear family • two men with early-onset prostate cancer (i.e. age <55 years) in the same family. The hereditary form of prostate cancer starts about ten years before that of the sporadic type. No single gene has been found (although the HPC-1 gene has been implicated) nor what influence the environment has to play with its expression identified. Age is the strongest predetermining factor for the development of prostate cancer. It is rarely found in men aged <50 years, but it is increasingly common with advancing age. The probability of prostate cancer developing in a man aged <40 years is 1 in 10,000; it is 1 in 8 for men aged 60–79 years.
Keywords brachytherapy; Gleason score; hormonal therapy; prostate Diet appears to have a significant influence on the risk and prevention of prostate cancer. The amount of dietary fat consumed seems to be a risk factor for the development of prostate cancer. The diet is rich in dairy products and red meat in areas with a high incidence (e.g. USA). Studies have indicated that vitamins E and D, as well as the trace element selenium, may protect against prostate cancer.
cancer; prostatectomy; PSA
Prostate cancer is becoming an increasingly significant international health problem; it may soon overtake lung cancer as the leading cause of cancer-related mortality in men in ‘developed’ countries. For a western male, the lifetime risk of: • developing microscopic prostate cancer is 30% • developing clinical disease is 10% • death from the disease is 3%.
Testosterone and its main metabolite, dihydrotestosterone, are the principal hormones regulating the growth and function of the prostate gland. Cancer of the prostate is rarely found in castrated men. Conversely, relatively high concentrations of circulating testosterone has been found in African-American men, possibly explaining the higher incidence of prostate cancer compared to Caucasian men.
Epidemiology Prostate cancer is diagnosed in about 30,000 and 200,000 men each year in the UK and USA, respectively. These figures have
Other risk factors have been suggested, including vasectomy, environmental (e.g. exposure to cadmium) and viral factors.
Thomas Swallow MRCS is a Clinical Research Fellow in Urology at St George’s Hospital, London, UK. Conflicts of interest: none declared.
Pathology
Roger S Kirby FRCS(Urol) is a Honorary Professor of Urology at St George’s Hospital, and University College London, London, UK. Conflicts of interest: none declared.
SURGERY 26:5
Adenocarcinoma is responsible for >95% of prostate cancers; the remainder are due to neuroendocrine tumours or sarcomas. The 213
© 2008 Elsevier Ltd. All rights reserved.
Renal and urology
cytological characteristics of prostate adenocarcinomas include hyperchromatic, enlarged nuclei with prominent nucleoli and abundant cytoplasm. The basal cell layer is absent in prostate cancer, but present in normal glands and the glands of benign prostatic hyperplasia.
serum. A screening programme for prostate cancer and the measurement of prostate-specific antigen is not present in the UK. The advantages are: • an initial increase in incidence rates as more cancers are detected, followed by a fall as they are treated • detection of the disease at earlier stages and decrease in mortality from advanced disease • an increase in relative survival rate as compared to other causes of death • detection of disease at a younger age and at lower concentrations of prostate-specific antigen. The disadvantages include the: • specificity of the prostate-specific antigen test • potential unnecessary treatment of disease that would have otherwise been harmless • fact that the concentration of prostate-specific antigen may be high due to other causes (e.g. infection (prostatitis), prostatic hyperplasia, acute urinary retention, vigorous digital rectal examination). The upper limit of normal prostate-specific antigen is usually 4 ng/ml, but this value will include some patients with benign prostatic hyperplasia and some with prostate cancer. The prostate-specific antigen increases with age, so the value must be adjusted for age. Hence, further refinements of the prostatespecific antigen have been employed. • The speed of the rise of the concentration of prostate-specific antigen during the year before the diagnosis of cancer is strongly associated with the risk of death from prostate cancer. • The ratio of free:total concentration of prostate-specific antigen can indicate whether a rise is due to benign prostatic hyperplasia or cancer. A value of <18% suggests cancer and biopsy is indicated.
Prostatic intraepithelial neoplasia is the precursor of prostate cancer. Cells show similar characteristics to that of prostate cancer cells, but the basal cell layer is present. Prostatic intraepithelial neoplasia is often found adjacent to areas of prostate cancer, and its identification in biopsy specimens warrants further investigation for concurrent invasive carcinoma. The areas of prostate adenocarcinoma within the prostate are often multifocal. About 70% are found in the peripheral zone, 20% originate in the transition zone, and 10% are within the central zone.
Grading and staging Prostate cancer is graded using the Gleason grading system, which is based on the microscopic appearance of the glandular architecture of the prostate. The staging is in two parts: a grade between 1 and 5 is given to the most dominant pattern; then a grade between 1 and 5 is given to the second commonest pattern. The two are added together to give the Gleason score. Thus, a Gleason score ranges from 2 to 10, and is usually annotated (e.g. 3+4 = 7). The grade indicates the degree of glandular differentiation: grade 1 indicates a well-differentiated tumour, whereas grade 5 is a poorly differentiated tumour. The Gleason score gives an indication of prognosis and tumour progression. The staging of prostate cancer is assessed using a number of diagnostic tools, including digital rectal examination, bone scinti-graphy and MRI. Not all are always essential; the decision is guided by the concentration of prostate-specific antigen in serum, Gleason score and the clinical stage. Imaging is often unnecessary in patients who are at low risk of metastases using these parameters.
The digital rectal examination is an essential part of the urological examination, enabling the size of the prostate gland to be assessed, and nodules or lumps to be detected. The digital rectal examination alone can determine the need for further investigation. The cancer can be staged by assessing whether the tumour extends to the seminal vesicles or invades adjacent structures.
Tumour progression
Transrectal ultrasound and biopsy are indicated if cancer is suspected due to a raised prostate-specific antigen and the findings of the digital rectal examination. This procedure is done under local anaesthesia and biopsies of the prostate are taken via a transrectal ultrasound probe. Ultrasound-guided biopsy: • provides more accurate staging than the digital rectal examination • allows lesions to be identified • enables the volume of the prostate gland to be measured. The biopsies are taken with a Tru-Cut needle and 6–12 cores are removed. This process samples a small percentage of the prostate gland, but the urologist or radiololgist can focus on taking samples from lesions that look suspicious on ultrasound. Occasionally, despite a high prostate-specific antigen, the biopsies are negative for cancer, or only prostatic intraepithelial neoplasia is found. Most urologists recommend repeat biopsies or even saturation biopsies (20 biopsies are taken) if suspicion remains high. In general, transrectal ultrasound and biopsies have a low morbidity. Infection is seen in <5% (providing antibiotic prophylaxis
The likelihood of local extension outside the prostate capsule or invasion into the seminal vesicle and distant metastases increases with increasing tumour volume and Gleason score. Invasion into the seminal vesicle is associated with regional or distant spread. Metastatic spread usually involves the lymphatics and the axial skeleton. The obturator lymph node chain is the most common site for lymphatic spread.
Diagnosis Early low-grade prostate cancer is usually asymptomatic. Locally advanced or metastatic disease is usually the cause if men present with symptoms. Local growth can cause obstructive or irritative urinary symptoms. Metastatic spread can present as bone pain and even compression of the spinal cord. The main investigations to diagnose prostate cancer are discussed below. Prostate-specific antigen: most cancers are discovered by routine measurement of the concentration of prostate-specific antigen in
SURGERY 26:5
214
© 2008 Elsevier Ltd. All rights reserved.
Renal and urology
is used) and <2% have significant bleeding. Anticoagulants should be stopped before biopsy.
Incidence of death from prostate cancer: watchful waiting versus radical prostatectomy Cumulative incidence of death from prostate cancer (%)
Other investigations MRI or CT of the pelvic area is indicated if the biopsies are positive for adenocarcinoma. This gives anatomical information about the local extension of the cancer and lymph node involvement, which is important if a radical prostatectomy is considered. Whole-body bone scintigraphy is done if the prostate-specific antigen is >10 ng/ml. This gives information on bony metastases that may influence management. New molecular studies that may negate the need for prostate biopsies are available. A specific urine sample assay can detect PCA3, a gene that is overexpressed in prostate cancer tissue. A prostate massage is done so that prostate cells are shed which are then caught via a urine sample for analysis.
40 Watchful waiting Radical prostatectomy
30 20 10 0
0
Number at risk Radical 347 prostatectomy Watchful waiting 348
Differential diagnosis Induration of the prostate on digital rectal examination is also associated with prostatitis, previous transurethral resection of the prostate, needle biopsy or prostatic calculi. The main differentials are benign prostatic hyperplasia, prostatic calculi and prostatitis.
2
4 6 Years of follow-up
8
10
343
332
284
210
118
341
326
279
198
104
Source: Bill-Axelson A, Holmberg L, Ruutu M, et al. Scandinavian Prostate Cancer Group Study No. 4. Radical prostatectomy versus watchful waiting in early prostate cancer. New Engl J Med 2005; 352: 1977–84. Reproduced with permission.
Figure 1
Management Localized prostate cancer Watchful waiting/active surveillance may be the most appropriate course for men aged >70 years and/or those with significant comorbidity, particularly if the cancer is low volume and the Gleason score is low. Careful follow-up with regular digital rectal examination and monitoring of prostate-specific antigen is important. Counselling and implementation of active treatment should occur if the cancer progresses.
disease. Pelvic lymph nodes can be included in the treatment field. Advances in radiotherapy have led to the radiation beam being focused on the prostate gland. This has led to fewer side effects, but proctitis, rectal bleeding and haematuria can occur. There is also a 1–3% risk of incontinence. In carefully selected patients, external-beam radiotherapy offers a 15-year overall survival, similar to that seen in radical prostatectomy. The cancer cannot usually be treated by surgery if recurrence occurs. One study has revealed a doubling of incidence of rectal carcinoma in patients treated with external-beam radiotherapy, so post-treatment rectal bleeding should be investigated.
Radical prostatectomy (Figure 1) has the advantage of removing the entire prostate gland, which reduces the risk of disease recurrence. The procedure is commonly done through a horizontal or vertical incision on the lower abdomen. Although, laparoscopic and robot-assisted laparoscopic removal of the prostate are becoming more common. Particular care is taken to preserve the delicate nerves on either side of the prostate; this reduces the risk of impotency. The seminal vesicles are removed with the prostate gland. The urethra is then anastomosed to the base of the bladder. The obturator lymph nodes are sampled. A catheter is left for two weeks while the urethra and bladder heal. A recent randomized controlled clinical trial showed a significant improvement in mean survival in patients treated by radical prostatectomy compared to those managed by watchful waiting, and a 50% reduction in the development of metastases. Erectile dysfunction may result in up to 50% of patients, but can be greatly improved with phosphodiesterase-5 inhibitors. Stress incontinence is seen in 2–3% and almost invariably improves with pelvic floor exercises, physiotherapy and/or anticholinergics.
Brachytherapy (Figure 2) is the deployment of radioactive seeds directly into the prostate gland. It can be done as a two-stage (two visits to hospital; to be measured and then implanted with the seeds) or a one-stage procedure. Brachytherapy can be combined with external-beam radiotherapy in patients considered at high risk of recurrence. Brachytherapy is most suitable for patients with smaller, lower-risk cancers and for men with small or medium-sized prostate glands. In the one-stage procedure, under general anaesthesia, 15–20 needles are inserted into the prostate gland through the perineum under transrectal ultrasound guidance. The field of radiation is calculated to avoid damage to the urethra and the rectum. Caution should be used in patients with existing bladder outflow obstruction because retention is a complication. Men who have had a transurethral resection of the prostate are not eligible because the seeds are not retained satisfactorily. Most men will have α-blocker therapy afterwards. The one-stage technique is a relatively new development in the UK. Recent data from the USA suggest that the outcome of brachytherapy is comparable to that of radical prostatectomy and external-beam radiotherapy.
External-beam radiotherapy: radiation therapy provides an definitive treatment approach for localized and locally advanced
SURGERY 26:5
215
© 2008 Elsevier Ltd. All rights reserved.
Renal and urology
Prostate brachytherapy Bladder
Radioactive pellets
Ultrasound probe Needle Prostate Tumour
Rectum
Prostate
Radioactive pellets are implanted into the prostate gland under transrectal ultrasound guidance
Figure 2
Cryotherapy is similar to brachytherapy, but is less commonly used. Liquid nitrogen is passed down needles that have been inserted into the prostate gland via the perineum, creating an ‘ice-ball’ that destroys cancer cells. The urethra is protected by a warming urethral catheter. Side effects include pain, urinary retention and erectile dysfunction. A potential serious complication is formation of a colovesical fistula.
They do not have such a profound effect on potency and libido compared to luteinizing hormone-releasing hormone analogues. Anti-androgens slow the progression of, but do not cure, prostate cancer. Metastatic prostate cancer About 70% of men with metastatic prostate cancer die from their cancer within five years. Progression can be delayed for several years by the treatments discussed below.
Locally advanced prostate cancer Hormonal therapy can be used in combination with externalbeam radiotherapy (usually preceding it) or on its own. Most prostate cancers are dependent on, and are stimulated by, testosterone; 70–80% of men with prostate cancers respond to various forms of androgen deprivation. The testicles are responsible for 95% of the testosterone derived, with the remaining amount originating from the adrenal glands. Stimulation for the production of testosterone is along the pituitary–gonadal axis. Therapy aims to block the production of testosterone at different levels.
Bilateral orchidectomy is the surgical removal of both testicles so that testosterone is no longer produced. Prosthetic testes can be inserted for a better cosmetic appearance. A subcapsular orchidectomy (only the cells of the testes are removed and the capsule is left) can be done. The main side effects are hot flushes, loss of libido and impotence. About 80% of men respond to this treatment, which slows disease progression for about 18 months.
Analogues of luteinizing hormone-releasing hormone are usually given as a depot injection every three months. They act by over-stimulating luteinizing hormone-releasing hormone receptors in the pituitary gland and, via negative feedback, stop the release of luteinizing hormone from the pituitary gland. The concentration of circulating testosterone is reduced to castration levels. The main side effects are a reduction in sex drive and impotence, which are reversible upon ceasing medication; they can also cause hot flushes. These agents reduce the size of the cancer and slow progression, but do not eradicate the disease.
Analogues of luteinizing hormone-releasing hormone: the response to this treatment in metastatic cancer is about 80%, and benefits last for 18–36 months. A large rise in circulating testosterone may be seen when the injection is first given, causing bone pain and even spinal cord stenosis; anti-androgens are given to protect against this ‘tumour flare’. Luteinizing hormone-releasing hormone analogues and antiandrogens in combination confer complete testosterone blockade. It is not clear whether this combination therapy significantly increases the time to progression or overall survival. Combination therapy is probably best suited to younger, relatively fit men with advanced prostate cancer because it may result in a longer period before disease progression.
Anti-androgens block the action of testosterone on the prostate gland. Side effects include breast enlargement and soreness. They can also cause mild stomach upset and damage the liver.
SURGERY 26:5
216
© 2008 Elsevier Ltd. All rights reserved.
Renal and urology
Follow-up
Prognosis
Most patients have regular measurement of prostate-specific antigen. After radical prostatectomy, the prostate-specific antigen should remain at zero if all the cancer has been removed. It should, initially, fall to very low levels in locally advanced and metastatic disease treated with hormones. Prostate cancer eventually becomes insensitive to hormone ablation and the prostate-specific antigen begins to rise (‘hormone escaped prostate cancer’). This rise often brings clinical symptoms, usually bone pain. Whole-body bone scintigraphy must be repeated to see if the cancer has spread. Other therapeutic options are available if the prostate-specific antigen rises: • modifying existing hormonal therapy • cytotoxic chemotherapy • oestrogen therapy • bisphosphonates • palliative radiotherapy.
The natural history of prostate cancer is highly dependent on stage, grade, comorbidity and age. The survival rate at ten years may be as high as 90% for a well-differentiated, localized prostate cancer; it drops to ≤60% for a poorly-differentiated tumour. In general, progression in prostate cancer is slower than for most other cancers and treatment is not required in many cases. Prostate cancer is one of the few solid cancers that is readily curable, providing it is detected early. ◆
SURGERY 26:5
Further reading Kirby RS, Partin A, Feneley M, Parsons K, eds. Prostate cancer: principles and practice. London: Taylor and Francis, 2005.
217
© 2008 Elsevier Ltd. All rights reserved.
Cancer of the prostate gland
risen steadily over the last twenty years. This statistic should be interpreted with caution because of increased detection due to the prostate-specific antigen serum test (though an increase in clinically significant cancer appears to have occurred). Prostate cancer kills >9,000 UK men each year. There is significant variation in the incidence of clinical prostate cancer worldwide. It is relatively high in northern Europe and North America, intermediate in southern Europe and South America, and low in the Far East and Asia. The highest incidences are found in African-American men and the lowest in Chinese men.
Thomas Swallow Roger S Kirby
Abstract
Aetiology and risk factors
Prostate cancer constitutes a major health problem. It is estimated that the lifetime risk of western men having prostate cancer is about 30%, with the risk of dying from the cancer being 3%. Increasing age is the strongest pre-determinant for the development of prostate cancer. Virtually all cancers are adenocarcinomas with the grade being indicated by the Gleason score. Often, there are no presenting symptoms. Investigations such as, the serum prostate-specific antigen level, digital rectal examination and biopsies via a trans-rectal ultrasound probe, are required for diagnosis. Staging, if required, consists of MRI/CT for locally advanced disease and/or a bone scan for detection of bony metatstases. Management depends largely on the stage of the disease. For localised prostate cancer, radical prostatectomy can offer a cure. Side effects include erectile dysfunction and incontinence. Prostate cancer is also radio-sensitive and can be given as external beam radiotherapy or in the form of brachytherapy. Hormonal therapy, such LHRH analogues and anti-androgens are used in locally advanced and metastatic disease. Hormones do not cure, but slow the progression of the cancer. Follow-up consist of PSA surveillance and other therapeutic options can be considered if the PSA starts to rise. Cytotoxic chemotherapy is increasingly being used for hormone escaped prostate cancer. The survival rate at ten years may be as high as 90% for a well-differentiated, localized prostate cancer.
A direct cause of prostate cancer has not been identified, but a number of risk factors have been identified. Familial: several studies have shown the prevalence of prostate cancer within certain families. This familial or hereditary form of cancer is characterized by either: • three successive generations being affected with the disease • a clustering of three or more men with the disease in a nuclear family • two men with early-onset prostate cancer (i.e. age <55 years) in the same family. The hereditary form of prostate cancer starts about ten years before that of the sporadic type. No single gene has been found (although the HPC-1 gene has been implicated) nor what influence the environment has to play with its expression identified. Age is the strongest predetermining factor for the development of prostate cancer. It is rarely found in men aged <50 years, but it is increasingly common with advancing age. The probability of prostate cancer developing in a man aged <40 years is 1 in 10,000; it is 1 in 8 for men aged 60–79 years.
Keywords brachytherapy; Gleason score; hormonal therapy; prostate Diet appears to have a significant influence on the risk and prevention of prostate cancer. The amount of dietary fat consumed seems to be a risk factor for the development of prostate cancer. The diet is rich in dairy products and red meat in areas with a high incidence (e.g. USA). Studies have indicated that vitamins E and D, as well as the trace element selenium, may protect against prostate cancer.
cancer; prostatectomy; PSA
Prostate cancer is becoming an increasingly significant international health problem; it may soon overtake lung cancer as the leading cause of cancer-related mortality in men in ‘developed’ countries. For a western male, the lifetime risk of: • developing microscopic prostate cancer is 30% • developing clinical disease is 10% • death from the disease is 3%.
Testosterone and its main metabolite, dihydrotestosterone, are the principal hormones regulating the growth and function of the prostate gland. Cancer of the prostate is rarely found in castrated men. Conversely, relatively high concentrations of circulating testosterone has been found in African-American men, possibly explaining the higher incidence of prostate cancer compared to Caucasian men.
Epidemiology Prostate cancer is diagnosed in about 30,000 and 200,000 men each year in the UK and USA, respectively. These figures have
Other risk factors have been suggested, including vasectomy, environmental (e.g. exposure to cadmium) and viral factors.
Thomas Swallow MRCS is a Clinical Research Fellow in Urology at St George’s Hospital, London, UK. Conflicts of interest: none declared.
Pathology
Roger S Kirby FRCS(Urol) is a Honorary Professor of Urology at St George’s Hospital, and University College London, London, UK. Conflicts of interest: none declared.
SURGERY 26:5
Adenocarcinoma is responsible for >95% of prostate cancers; the remainder are due to neuroendocrine tumours or sarcomas. The 213
© 2008 Elsevier Ltd. All rights reserved.
Renal and urology
cytological characteristics of prostate adenocarcinomas include hyperchromatic, enlarged nuclei with prominent nucleoli and abundant cytoplasm. The basal cell layer is absent in prostate cancer, but present in normal glands and the glands of benign prostatic hyperplasia.
serum. A screening programme for prostate cancer and the measurement of prostate-specific antigen is not present in the UK. The advantages are: • an initial increase in incidence rates as more cancers are detected, followed by a fall as they are treated • detection of the disease at earlier stages and decrease in mortality from advanced disease • an increase in relative survival rate as compared to other causes of death • detection of disease at a younger age and at lower concentrations of prostate-specific antigen. The disadvantages include the: • specificity of the prostate-specific antigen test • potential unnecessary treatment of disease that would have otherwise been harmless • fact that the concentration of prostate-specific antigen may be high due to other causes (e.g. infection (prostatitis), prostatic hyperplasia, acute urinary retention, vigorous digital rectal examination). The upper limit of normal prostate-specific antigen is usually 4 ng/ml, but this value will include some patients with benign prostatic hyperplasia and some with prostate cancer. The prostate-specific antigen increases with age, so the value must be adjusted for age. Hence, further refinements of the prostatespecific antigen have been employed. • The speed of the rise of the concentration of prostate-specific antigen during the year before the diagnosis of cancer is strongly associated with the risk of death from prostate cancer. • The ratio of free:total concentration of prostate-specific antigen can indicate whether a rise is due to benign prostatic hyperplasia or cancer. A value of <18% suggests cancer and biopsy is indicated.
Prostatic intraepithelial neoplasia is the precursor of prostate cancer. Cells show similar characteristics to that of prostate cancer cells, but the basal cell layer is present. Prostatic intraepithelial neoplasia is often found adjacent to areas of prostate cancer, and its identification in biopsy specimens warrants further investigation for concurrent invasive carcinoma. The areas of prostate adenocarcinoma within the prostate are often multifocal. About 70% are found in the peripheral zone, 20% originate in the transition zone, and 10% are within the central zone.
Grading and staging Prostate cancer is graded using the Gleason grading system, which is based on the microscopic appearance of the glandular architecture of the prostate. The staging is in two parts: a grade between 1 and 5 is given to the most dominant pattern; then a grade between 1 and 5 is given to the second commonest pattern. The two are added together to give the Gleason score. Thus, a Gleason score ranges from 2 to 10, and is usually annotated (e.g. 3+4 = 7). The grade indicates the degree of glandular differentiation: grade 1 indicates a well-differentiated tumour, whereas grade 5 is a poorly differentiated tumour. The Gleason score gives an indication of prognosis and tumour progression. The staging of prostate cancer is assessed using a number of diagnostic tools, including digital rectal examination, bone scinti-graphy and MRI. Not all are always essential; the decision is guided by the concentration of prostate-specific antigen in serum, Gleason score and the clinical stage. Imaging is often unnecessary in patients who are at low risk of metastases using these parameters.
The digital rectal examination is an essential part of the urological examination, enabling the size of the prostate gland to be assessed, and nodules or lumps to be detected. The digital rectal examination alone can determine the need for further investigation. The cancer can be staged by assessing whether the tumour extends to the seminal vesicles or invades adjacent structures.
Tumour progression
Transrectal ultrasound and biopsy are indicated if cancer is suspected due to a raised prostate-specific antigen and the findings of the digital rectal examination. This procedure is done under local anaesthesia and biopsies of the prostate are taken via a transrectal ultrasound probe. Ultrasound-guided biopsy: • provides more accurate staging than the digital rectal examination • allows lesions to be identified • enables the volume of the prostate gland to be measured. The biopsies are taken with a Tru-Cut needle and 6–12 cores are removed. This process samples a small percentage of the prostate gland, but the urologist or radiololgist can focus on taking samples from lesions that look suspicious on ultrasound. Occasionally, despite a high prostate-specific antigen, the biopsies are negative for cancer, or only prostatic intraepithelial neoplasia is found. Most urologists recommend repeat biopsies or even saturation biopsies (20 biopsies are taken) if suspicion remains high. In general, transrectal ultrasound and biopsies have a low morbidity. Infection is seen in <5% (providing antibiotic prophylaxis
The likelihood of local extension outside the prostate capsule or invasion into the seminal vesicle and distant metastases increases with increasing tumour volume and Gleason score. Invasion into the seminal vesicle is associated with regional or distant spread. Metastatic spread usually involves the lymphatics and the axial skeleton. The obturator lymph node chain is the most common site for lymphatic spread.
Diagnosis Early low-grade prostate cancer is usually asymptomatic. Locally advanced or metastatic disease is usually the cause if men present with symptoms. Local growth can cause obstructive or irritative urinary symptoms. Metastatic spread can present as bone pain and even compression of the spinal cord. The main investigations to diagnose prostate cancer are discussed below. Prostate-specific antigen: most cancers are discovered by routine measurement of the concentration of prostate-specific antigen in
SURGERY 26:5
214
© 2008 Elsevier Ltd. All rights reserved.
Renal and urology
is used) and <2% have significant bleeding. Anticoagulants should be stopped before biopsy.
Incidence of death from prostate cancer: watchful waiting versus radical prostatectomy Cumulative incidence of death from prostate cancer (%)
Other investigations MRI or CT of the pelvic area is indicated if the biopsies are positive for adenocarcinoma. This gives anatomical information about the local extension of the cancer and lymph node involvement, which is important if a radical prostatectomy is considered. Whole-body bone scintigraphy is done if the prostate-specific antigen is >10 ng/ml. This gives information on bony metastases that may influence management. New molecular studies that may negate the need for prostate biopsies are available. A specific urine sample assay can detect PCA3, a gene that is overexpressed in prostate cancer tissue. A prostate massage is done so that prostate cells are shed which are then caught via a urine sample for analysis.
40 Watchful waiting Radical prostatectomy
30 20 10 0
0
Number at risk Radical 347 prostatectomy Watchful waiting 348
Differential diagnosis Induration of the prostate on digital rectal examination is also associated with prostatitis, previous transurethral resection of the prostate, needle biopsy or prostatic calculi. The main differentials are benign prostatic hyperplasia, prostatic calculi and prostatitis.
2
4 6 Years of follow-up
8
10
343
332
284
210
118
341
326
279
198
104
Source: Bill-Axelson A, Holmberg L, Ruutu M, et al. Scandinavian Prostate Cancer Group Study No. 4. Radical prostatectomy versus watchful waiting in early prostate cancer. New Engl J Med 2005; 352: 1977–84. Reproduced with permission.
Figure 1
Management Localized prostate cancer Watchful waiting/active surveillance may be the most appropriate course for men aged >70 years and/or those with significant comorbidity, particularly if the cancer is low volume and the Gleason score is low. Careful follow-up with regular digital rectal examination and monitoring of prostate-specific antigen is important. Counselling and implementation of active treatment should occur if the cancer progresses.
disease. Pelvic lymph nodes can be included in the treatment field. Advances in radiotherapy have led to the radiation beam being focused on the prostate gland. This has led to fewer side effects, but proctitis, rectal bleeding and haematuria can occur. There is also a 1–3% risk of incontinence. In carefully selected patients, external-beam radiotherapy offers a 15-year overall survival, similar to that seen in radical prostatectomy. The cancer cannot usually be treated by surgery if recurrence occurs. One study has revealed a doubling of incidence of rectal carcinoma in patients treated with external-beam radiotherapy, so post-treatment rectal bleeding should be investigated.
Radical prostatectomy (Figure 1) has the advantage of removing the entire prostate gland, which reduces the risk of disease recurrence. The procedure is commonly done through a horizontal or vertical incision on the lower abdomen. Although, laparoscopic and robot-assisted laparoscopic removal of the prostate are becoming more common. Particular care is taken to preserve the delicate nerves on either side of the prostate; this reduces the risk of impotency. The seminal vesicles are removed with the prostate gland. The urethra is then anastomosed to the base of the bladder. The obturator lymph nodes are sampled. A catheter is left for two weeks while the urethra and bladder heal. A recent randomized controlled clinical trial showed a significant improvement in mean survival in patients treated by radical prostatectomy compared to those managed by watchful waiting, and a 50% reduction in the development of metastases. Erectile dysfunction may result in up to 50% of patients, but can be greatly improved with phosphodiesterase-5 inhibitors. Stress incontinence is seen in 2–3% and almost invariably improves with pelvic floor exercises, physiotherapy and/or anticholinergics.
Brachytherapy (Figure 2) is the deployment of radioactive seeds directly into the prostate gland. It can be done as a two-stage (two visits to hospital; to be measured and then implanted with the seeds) or a one-stage procedure. Brachytherapy can be combined with external-beam radiotherapy in patients considered at high risk of recurrence. Brachytherapy is most suitable for patients with smaller, lower-risk cancers and for men with small or medium-sized prostate glands. In the one-stage procedure, under general anaesthesia, 15–20 needles are inserted into the prostate gland through the perineum under transrectal ultrasound guidance. The field of radiation is calculated to avoid damage to the urethra and the rectum. Caution should be used in patients with existing bladder outflow obstruction because retention is a complication. Men who have had a transurethral resection of the prostate are not eligible because the seeds are not retained satisfactorily. Most men will have α-blocker therapy afterwards. The one-stage technique is a relatively new development in the UK. Recent data from the USA suggest that the outcome of brachytherapy is comparable to that of radical prostatectomy and external-beam radiotherapy.
External-beam radiotherapy: radiation therapy provides an definitive treatment approach for localized and locally advanced
SURGERY 26:5
215
© 2008 Elsevier Ltd. All rights reserved.
Renal and urology
Prostate brachytherapy Bladder
Radioactive pellets
Ultrasound probe Needle Prostate Tumour
Rectum
Prostate
Radioactive pellets are implanted into the prostate gland under transrectal ultrasound guidance
Figure 2
Cryotherapy is similar to brachytherapy, but is less commonly used. Liquid nitrogen is passed down needles that have been inserted into the prostate gland via the perineum, creating an ‘ice-ball’ that destroys cancer cells. The urethra is protected by a warming urethral catheter. Side effects include pain, urinary retention and erectile dysfunction. A potential serious complication is formation of a colovesical fistula.
They do not have such a profound effect on potency and libido compared to luteinizing hormone-releasing hormone analogues. Anti-androgens slow the progression of, but do not cure, prostate cancer. Metastatic prostate cancer About 70% of men with metastatic prostate cancer die from their cancer within five years. Progression can be delayed for several years by the treatments discussed below.
Locally advanced prostate cancer Hormonal therapy can be used in combination with externalbeam radiotherapy (usually preceding it) or on its own. Most prostate cancers are dependent on, and are stimulated by, testosterone; 70–80% of men with prostate cancers respond to various forms of androgen deprivation. The testicles are responsible for 95% of the testosterone derived, with the remaining amount originating from the adrenal glands. Stimulation for the production of testosterone is along the pituitary–gonadal axis. Therapy aims to block the production of testosterone at different levels.
Bilateral orchidectomy is the surgical removal of both testicles so that testosterone is no longer produced. Prosthetic testes can be inserted for a better cosmetic appearance. A subcapsular orchidectomy (only the cells of the testes are removed and the capsule is left) can be done. The main side effects are hot flushes, loss of libido and impotence. About 80% of men respond to this treatment, which slows disease progression for about 18 months.
Analogues of luteinizing hormone-releasing hormone are usually given as a depot injection every three months. They act by over-stimulating luteinizing hormone-releasing hormone receptors in the pituitary gland and, via negative feedback, stop the release of luteinizing hormone from the pituitary gland. The concentration of circulating testosterone is reduced to castration levels. The main side effects are a reduction in sex drive and impotence, which are reversible upon ceasing medication; they can also cause hot flushes. These agents reduce the size of the cancer and slow progression, but do not eradicate the disease.
Analogues of luteinizing hormone-releasing hormone: the response to this treatment in metastatic cancer is about 80%, and benefits last for 18–36 months. A large rise in circulating testosterone may be seen when the injection is first given, causing bone pain and even spinal cord stenosis; anti-androgens are given to protect against this ‘tumour flare’. Luteinizing hormone-releasing hormone analogues and antiandrogens in combination confer complete testosterone blockade. It is not clear whether this combination therapy significantly increases the time to progression or overall survival. Combination therapy is probably best suited to younger, relatively fit men with advanced prostate cancer because it may result in a longer period before disease progression.
Anti-androgens block the action of testosterone on the prostate gland. Side effects include breast enlargement and soreness. They can also cause mild stomach upset and damage the liver.
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Renal and urology
Follow-up
Prognosis
Most patients have regular measurement of prostate-specific antigen. After radical prostatectomy, the prostate-specific antigen should remain at zero if all the cancer has been removed. It should, initially, fall to very low levels in locally advanced and metastatic disease treated with hormones. Prostate cancer eventually becomes insensitive to hormone ablation and the prostate-specific antigen begins to rise (‘hormone escaped prostate cancer’). This rise often brings clinical symptoms, usually bone pain. Whole-body bone scintigraphy must be repeated to see if the cancer has spread. Other therapeutic options are available if the prostate-specific antigen rises: • modifying existing hormonal therapy • cytotoxic chemotherapy • oestrogen therapy • bisphosphonates • palliative radiotherapy.
The natural history of prostate cancer is highly dependent on stage, grade, comorbidity and age. The survival rate at ten years may be as high as 90% for a well-differentiated, localized prostate cancer; it drops to ≤60% for a poorly-differentiated tumour. In general, progression in prostate cancer is slower than for most other cancers and treatment is not required in many cases. Prostate cancer is one of the few solid cancers that is readily curable, providing it is detected early. ◆
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Further reading Kirby RS, Partin A, Feneley M, Parsons K, eds. Prostate cancer: principles and practice. London: Taylor and Francis, 2005.
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