Prostate Cancer

 1 in 10 men will develop prostate cancer in their lifetime

 Prostate cancer is the second most common cause of cancer death in men in the USA and the UK

 Early prostate cancer is often completely asymptomatic

 Men over 50 should undergo yearly prostate checks with serum PSA and digital rectal examination

 Cancer localised to the prostate gland is curable by radical prostatectomy or radiotherapy

Metastatic prostate cancer can be controlled by hormonal treatment

Description

Prostate cancer develops in the epithelial cells of the glandular elements of the prostate. 95% of prostate cancers are adenocarcinomas. There is no single cause of prostate cancer. 9% of prostate cancers are caused by a genetic susceptibility, probably inherited via a gene on chromosome 1. Proven risk factors for prostate cancer include old age, a positive family history and black race. Probable risk factors include a high intake of dietary fat and high levels of serum testosterone.

Prostate cancer is the most commonly diagnosed malignancy amongst American men with 250 000 new cases reported annually. It is the second most common cause of cancer death in men in the USA and the UK.

Early prostate cancer is often completely asymptomatic. By the time the disease becomes symptomatic it is usually beyond cure. Screening for prostate cancer can be performed with serum PSA measurement and digital rectal examination. The diagnosis is confirmed by transrectal needle biopsies and histological analysis of the specimens.

Prostate cancer that is confined to the gland itself can be cured by radical surgery or radiotherapy, but the benefit of cure only becomes apparent after 10 years. This paradox is due to the slow growing nature of the disease. Radical prostatectomy provides the best chance of cure but carries a high risk of complications. Metastatic prostate cancer cannot be cured. Most patients with metastatic disease will respond to hormonal treatment that deprives the cancer of male hormones. Prostate cancer is not sensitive to current chemotherapy regimes.

Cause

There is no single cause of prostate cancer. The cancer originates in the epithelial cells of the glandular elements of the prostate. As with most cancers defects in the DNA of the cell are central to the development of prostate cancer. Multiple DNA defects are required for cancer to develop. This multi-step process takes place over time. Some defects can be inherited, while others are acquired during the patient's lifetime.

Prostate cancer is exceedingly rare before the age of 40, but 1 in 8 men between the ages of 60 and 80 years suffer from the disease. 9% of all prostate cancers are caused by a genetic susceptibility, probably inherited via chromosome 1. These genetically related cancers tend to present at a relatively younger age. Testosterone and its active metabolite dihydrotestosterone are essential for prostate cancer to develop, but does not actually cause prostate cancer. Men who are castrated at a young age do not develop prostate cancer.

Symptoms

Related to the primary tumour:

  Asymptomatic

   Poor stream

 Retention of urine

 Urgency

  Frequency

 Hematuria (blood in the urine)

Related to secondary tumour deposits:

  Bone pain (back and pelvis):

 Pathological fractures

  Enlarged lymph glands

  Kidney failure

Related to the general effects of malignancy:

 Weight loss

  Tiredness

Malaise

 Anemia

 Loss of appetite

Early prostate cancer is usually completely asymptomatic. By the time that prostate cancer becomes bothersome or clinically apparent it has usually spread beyond the confines of the prostatic capsule and is no longer amenable to cure. In the first world early prostate cancer is usually diagnosed following screening. Prostate cancer can also be a chance finding in the tissue removed by transurethral resection for suspected benign prostatic enlargement.

The primary tumour can cause lower urinary tract symptoms similar to benign prostatic hyperplasia. Obstructive symptoms include poor stream, incomplete emptying and straining while passing urine. Irritative symptoms include dysuria, frequency, urgency and nocturia. Prostate cancer can also cause blood in the urine but this is not common.

Prostate cancer typically spreads to the bony skeleton and the lymph glands of the pelvis. Bony metastases commonly involve the lower spine and pelvic girdle causing backache. Lymphatic involvement can cause swelling of the legs and obstruction of the drainage tubes of the kidneys (ureters). Prostate cancer can cause renal failure by ureteric obstruction or by bladder outlet obstruction.

Prevalence

One in ten men will develop clinically significant prostate cancer in their lifetime. It is the most commonly diagnosed cancer in American males with 250 000 new cases reported annually. Prostate cancer is second only to lung cancer as a cause of cancer death in both the USA and the UK. Prostate cancer is rare among Orientals. It is more common in black than white Americans. The disease appears to present at a younger age and behave more aggressively in American blacks.

Prostate cancer is common in South Africa and probably underreported as a cause of death. The exact incidence in South Africa is not known as no large-scale epidemiological studies have been performed. It is uncertain whether prostate cancer is more common in South African blacks as compared to whites.

In very old men prostate cancer is not always clinically significant. Autopsy data indicate a 70% incidence of prostate cancer in 80 year old men. The majority of these men died with rather than from prostate cancer.

Course

1. Prostatic intra epithelial neoplasia (PIN)
2. Localised prostate cancer
3. Locally advanced prostate cancer
4. Metastatic prostate cancer
5. Hormone independent prostate cancer
6. Death

Prostate cancer is very slow growing. The natural history of the disease is long and variable. The time from early cancer at a cellular level to eventual death from metastatic disease may be as long as 20 years. The course of the disease will be influenced by the general health and immune status of the host, as well as by the treatment modalities that the cancer is subjected to.

Most prostate cancers are slow growing but not all behave in the same manner. Poorly differentiated cancers tend to follow an aggressive course and have often spread beyond the prostate by the time of diagnosis. On the other hand well-differentiated cancers often follow an indolent course and may not bother the patient for many years.

The precursor to cancer develops in the epithelial cells of the prostate gland and is called prostatic intraepithelial neoplasia or PIN. Once the cancerous cells breach the basement membrane of the epithelium it is no longer PIN but prostate cancer proper. Cancer that is confined within the prostatic capsule is called localized prostate cancer. At this stage the disease is still potentially curable. Cancer that has spread locally beyond the confines of the prostatic capsule is called locally advanced disease. Once the cancer has spread to the lymph glands, bones or other organs it is called metastatic cancer. Metastatic prostate cancer is currently not curable. Metastatic prostate cancer is usually hormone sensitive. This means that the cancer will respond to treatment depriving it of male hormones (see treatment). This response to hormonal treatment is of variable duration, but on average lasts about 2 years. Once the cancer becomes resistant to hormonal manipulation it is called hormone independent disease. Hormone independent prostate cancer is usually followed by death within months.

Many patients only develop prostate cancer late in life. Due to the very slow growth rate of the disease many of these patients will outlive their prostate cancer and die from other causes before the cancer has had time to run its course. The implications of early prostate cancer are completely different for a healthy 50 year old as compared to an 80 year old man with other co-morbid disease.

Risk Factors

Proven:

 Old age

 Family history of prostate cancer

 Race

Probable:

 High intake dietary fat

 High levels of male hormones

Possible (unproven):

Vasectomy

Cadmium intake

Vitamin D

Vitamin A

The prostate needs time and male hormones to develop cancer. One in 10 000 men under the age of 40 develop prostate cancer, whereas 1 in 8 men between the ages of 60 and 80 suffer from the disease. Testosterone does not cause prostate cancer but is essential for prostate cancer to develop. Men who are castrated at a young age do not develop prostate cancer.

9% of all prostate cancers and 55% of prostate cancers in men under the age of 55 years are related to a genetic susceptibility. A man with three first degree relatives with prostate cancer has a 10 times increased risk of developing prostate cancer himself. A family history of breast cancer also carries an increased risk for developing prostate cancer.

The high intake of dietary fat in the western diet may explain the relatively high incidence in the west as compared with oriental countries. Blacks appear to have a higher incidence of prostate cancer than whites subjected to the same environmental factors. One possible explanation for this is the higher levels of testosterone found in black men.

A link between vasectomy and prostate cancer has been suspected but probably does not exist. High intake of cadmium, vitamin D and vitamin A have been implicated, but probably play no role in the development of prostate cancer.

When to see a doctor

Need to see a doctor urgently:

 Inability to pass urine (retention)

Severe difficulty passing urine

Blood in urine

Unexplained backache or bone pain

Enlarged lymph glands

Unexplained weight loss

Suspected kidney impairment

 Need to see a doctor at a convenient time:

Any man over 50 years should have a yearly prostate check to rule out prostate cancer

Black men and men with a positive family history of prostate cancer should start their prostate checks at age 40 years

Visit preparation

No specific preparation is needed for the first visit. The health professional will take a detailed medical history and perform a physical examination. The physical examination should include a digital rectal examination of the prostate gland. The health professional will almost certainly require a urine sample. It is a good idea not to empty the bladder shortly before the appointment. A blood sample will be taken to measure the level of PSA.

Diagnosis

The diagnosis of prostate cancer can be made on clinical suspicion of the disease, following screening, or as an incidental finding during transurethral resection for suspected benign disease (TURP).

Clinically suspected prostate cancer

Prostate cancer can be completely asymptomatic or present with symptoms similar to benign prostatic enlargement (see symptoms). It can also present with the symptoms of metastatic disease.

On digital rectal examination prostate cancer feels rock hard and nodular. Invasion into the surrounding structures may be palpable as a hard mass. Spread to the lymph glands may be palpable in the groins or pelvis. Bony metastases to the lumbar spine or pelvis are often tender to palpation.

PSA (Prostate Specific Antigen) is a substance excreted by all prostate cells. The blood level of PSA is elevated in prostate cancer and the level of elevation correlates with the extent of disease. The PSA level can also be elevated by benign diseases such as prostatitis and benign prostatic hyperplasia. The normal range for PSA is 0 - 4 ng/ml. The higher the PSA the greater is the chance of having prostate cancer. Somebody with a PSA of 4 - 10 ng/ml has a 25% chance of having prostate cancer, while a PSA of greater than 10 carries a 50% risk of the disease. Very high levels of PSA (>100ng/ml) almost invariably indicate widespread metastatic disease.

The diagnosis of prostate cancer is confirmed by needle biopsy and histological analysis of the biopsy specimens. A transrectal ultrasound scan is performed via a probe inserted into the rectum, and ultrasound guided needle biopsies of the prostate are taken. The procedure is performed under local anaesthetic

Screening

All healthy men over the age of 50 years should have annual prostate cancer checks. Black men and men with a positive family history should start at age 40. The aim of screening is to diagnose the disease at an early stage while it is still potentially curable. By the time prostate cancer becomes symptomatic it is usually beyond cure. The screening tests consist of a digital rectal examination and a PSA blood test. The prostate gland may feel entirely normal despite the presence of an early cancer. The combination of PSA and digital rectal examination is more sensitive than either test alone. If one or both of these tests are abnormal a transrectal ultrasound and needle biopsies of the prostate gland are performed.

 Incidental finding following TURP

Whenever a transurethral resection of the prostate gland is performed for suspected benign disease the removed tissue is sent for histological analysis. Occasionally evidence of unsuspected prostate cancer is found in the tissue. In a young man with an otherwise long life expectancy this is obviously significant. A tiny focus of cancer in an elderly man is probably not significant, since the prostate cancer will not have sufficient time to become bothersome.

Staging and Grading

Once the diagnosis of prostate cancer has been made the disease has to be staged and graded. The stage refers to the extent and spread of the disease while the grade refers to the nature (aggressiveness) of the particular tumor. Staging will determine the extent of disease and provide important prognostic information that will influence the management decisions.

Staging investigations

 PSA

 X-rays of lumbar spine and pelvis

Chest X-ray

Radionuclitide bone scan

 MTI scan of pelvis

TNM Staging system

T stage (extent of primary lesion)

 T1 - tumour confined to prostate, not palpable or visible on TRUS

T2 - tumour palpable or visible on TRUS but confined to prostate

T3 - spread beyond the prostatic capsule

T3a - extracapsular spread only

T3b - involvement of the seminal vesicles

 T4 - invasion into rectal wall, bladder neck or pelvic wall

N (Nodal) status

  N0 - regional nodes not involved

 N1 - regional nodes involved by tumour

M (Distant Metastases)

 M0 - no distant metastases

  M1 - distant metastases present

Grading

Grading refers to what the cancer looks like under a microscope. The most commonly used system is the Gleason grade and score. The glandular pattern is compared to that of a normal prostate and scored out of 5, where 1 resembles a pattern very close to normal and 5 resembles severely distorted glandular architecture. The two predominant glandular patterns within the cancer are graded out of 5 and the combined score calculated out of 10. The higher the Gleason score, the more aggressive is the tumour and the worse is the prognosis.

Patients with cancers confined to the prostate (T1 and T2) and no involvement of the lymph nodes or other organs (N0 and M0) are potentially curable by surgery or radiotherapy. Patients with disease beyond the prostate are not curable.

Treatment

Treatment options for localised disease (T1-2, N0, M0)

Radical prostatectomy

External beam radiotherapy

 Brachytherapy (radiotherapy seeds)

Watchful waiting

The treatment of localised prostate cancer is fraught with difficulty and each individual case needs to be considered on its own merits. Organ confined disease is potentially curable by radical treatment with surgery or radiotherapy. Due to the slow-growing nature of the disease the benefit of cure usually only becomes apparent after 10 - 15 years. The radical treatment of prostate cancer carries a high morbidity. The younger patient who will gain the most from the survival benefit of radical treatment also stands to suffer the greatest from the potential complications of erectile dysfunction and incontinence. Patients with less than 10 years life expectancy due to their age or other co-morbid disease should not be offered radical treatment for prostate cancer.

Radical prostatectomy involves the surgical removal of the prostate and surrounding structures. Radical prostatectomy provides the best chance of cure for early prostate cancer. Cure rates are quoted at 70 - 80% in the literature. The main complications are incontinence and erectile dysfunction. 5% of patients suffer total incontinence and 30% suffer a degree of wetness needing some protection. The incidence of erectile dysfunction varies with age and is quoted at 30 - 70%.

Radiotherapy can be delivered via external beam or seeds implanted into the prostate. External beam radiotherapy is not quite as effective as radical surgery in providing a cure, but has a slightly lower incidence of complications. Brachytherapy with radioactive seeds has the lowest incidence of complications. The results of brachytherapy are comparable to surgery in patients with well-differentiated cancers and low PSA levels. Brachytherapy is not suitable for patients with PSA levels above 10 and high Gleason grades.

After treatment with curative intent with either surgery or radiotherapy the PSA should drop to an undetectable level. A PSA that fails to reach nadir level or rises after an initial drop indicate residual disease or metastases. The main cause of treatment failure is inaccurate staging prior to embarking on radical treatment.

Watchful waiting involves regular surveillance of the tumor, but no active treatment initially. It is a suitable option for patients with less than 10 years life expectancy and some patients with very early low-risk cancers.

Locally advanced disease without metastases (T3a, N0, M0)

The overall results of treatment of patients with disease beyond the prostate are not good. Some patients with early disease beyond the prostatic capsule, and no evidence of metastases, benefit from radical treatment. The most widely used treatment regimens consist of a combination of radiotherapy and hormonal treatment.

Treatment options for locally advanced and metastatic disease (T3b, T4, N1, M1)

Early hormonal treatment

Watchful waiting with hormonal treatment once symptoms develop

Disease that has spread to the seminal vesicles and beyond is not curable. Prostate cancer is dependent on the male hormone testosterone. 80% of patients will respond to hormonal treatment that deprives the tumour of testosterone. This response usually involves the shrinkage of metastases and symptomatic improvement for the patient. The response to hormonal treatment is not a cure but can last for many years in some patients. The average duration of response is 2 years. Most cancers eventually escape hormonal manipulation. This is referred to as hormone independent disease and is usually followed by death within a few months.

Controversy exists regarding the timing of hormonal treatment. Most studies indicate a survival benefit for early rather than late hormonal maneuver. Testosterone deprivation has side effects like erectile dysfunction, breast enlargement and osteoporosis. The earlier hormonal treatment is instituted the greater the chance of complications. Once again treatment has to be individualized to the needs of the specific patient.

Hormonal treatment options

Surgical castration by orchidectomy

LHRH-analogues

 Estrogen

Anti-androgens

Surgical castration is the simplest and cheapest way to treat metastatic prostate cancer. The obvious disadvantage is the psychological effect of the loss of the testicles. LHRH-analogues and estrogen achieve a "medical castration" by stopping the testicular production of testosterone. LHRH-analogues are injections that have to be given monthly or three monthly for the rest of the patient's life. They are effective but very expensive. Estrogen can be taken orally on a daily basis. It has a high incidence of thrombotic complications such as stroke and myocardial infarction.

Anti-androgens oppose the action of testosterone by blocking the androgen receptors. The incidence of erectile dysfunction is less than with surgical or medical orchidectomy because testosterone levels are maintained in the bloodstream. Anti-androgens alone are probably not adequate treatment for metastatic disease. Total androgen blockade by a combination of anti-androgens and LHRH-analogues or orchidectomy has never been shown to be better than LHRH-analogues or orchidectomy alone.

Prevention

Unfortunately the only certain way of preventing prostate cancer is castration at a young age. A diet low in animal fat and high in phyto-estrogens is probably beneficial although this has not been proven beyond doubt. Regular intake of free-radical scavengers such as selenium, vitamin E, and vitamin A have been associated with a lower incidence of prostate cancer.