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Sun 1 Oct 2006 12:00 AM

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Carcinoma of the prostate

A review of diagnostic and treatment advances.

A review of diagnostic and treatment advances.

Over the last decade, prostate cancer has emerged as one of the most common cancers in men worldwide, second only to lung cancer.

Globally, more than 650,000 men are diagnosed each year, a number that is set to rise further in view of increased lifespans, making this malignancy even more prevalent than it is today.

Success rates for prostate cancer are excellent while the tumour is confined to the prostate (T1/T2). In contrast, once the cancer advances beyond the prostate capsule (T3), success rates drop by 30 -70%.

Once the cancer has invaded adjacent organs such as the bladder (T4), or metastasis to the lymph nodes or skeletal system has occurred, cure is – unlike in other cancers - almost impossible.

Prostate cancer will not produce any symptoms (such as pain, voiding dyscomfort, or bleeding) unless it is advanced and therefore less likely to be curable.

Consequently, timely intervention is essential to reduce mortality rates.

In this article, we will provide an overview of the key features of early detection and treatment to minimise the risk of metastatic prostate cancer.
Risk factors and preventionThe impact of risk factors has been well defined in many cancers; smoking for lung or bladder cancer, diet for cancers of the gastrointestinal tract and viral origins for cervical and liver cancer.

But few factors have been demonstrated for prostate cancer.

To date, only three firm risk factors have been established; age, a positive family history and ethnicity.

It is important to note that the only proven risk factors for prostate cancer cannot be avoided or influenced by lifestyle changes and that consequently there is no proven method of prevention.

- Age

While most malignancies become progressively more common as people age, for prostate cancer, the trend is particularly striking.

Less than 1% of all prostate cancers are found in men younger than 40 years, but this steadily increases to about 40% for men in their 60s to 70s.

- Family history

Men with a positive family history of the prostate cancer are at increased risk of developing the disease.

For example, an individual whose brother developed prostate cancer has a two to three-fold greater risk of developing the disease.

More strikingly, the risk for an individual with two first-degree relatives with prostate cancer is increased by a factor of 5.1.

The risk appears to be higher if the relative is a brother rather than a father, suggesting that the disease is recessive or linked to the X chromosome.

- Ethnicity

Ethnic background also plays a role in determining prostate cancer risk.

The highest incidence of the disease has been found in the African America population, whereas in Asian countries, the incidence is reported to be between 10 to 40-fold lower. Early detectionEarly detection of prostate cancer relies on three basic examinations that should be carried out annually. These are:

- Digital rectal exam (DRE)

Digital rectal examination (DRE) is the principle method of examination of the prostate.

The procedure involves palpation of the prostate to check for irregular, nodular, or indurated areas that may be suspicious for malignancy.

Because prostate cancer usually grows slowly, tumours large enough to be felt on palpation are more likely to have spread beyond the prostate capsule.

Success rates are therefore worse than in non-palpable prostate cancers.

It is important to note that the procedure fails to detect a significant number of tumours, as not all prostatic malignancies are palpable on DRE.

- Transrectal

ultrasound (TRUS) of the prostate TRUS allows evaluation of the prostate in search of hypoechoic areas that may suggest the presence of a carcinoma.

Sonographically, the normal prostate gland has a homogenous, uniform echo pattern.

In contrast, and particularly within the peripheral zone, prostatic malignancies most commonly appear as hypoechoic regions.

However, this is not a firm rule.

A hypoechoic peripheral-zone lesion can reflect anything from normal prostate, to prostatitis, to infarct; but it does warrant further investigation.

It should also be noted that up to 40% of prostate cancers may be isoechoic on ultrasound, and therefore ‘invisible’ to TRUS.

- Prostate-specific antigen in blood

By far the most essential tool in the early detection of prostate cancer is the measurement of prostate-specific antigen (PSA).

Since PSA testing became widespread in the early 90s, it has undisputedly become the most important tumour marker in the field of urology, despite much debate about its strength as a diagnostic tool.

PSA is an enzyme produced by the glandular epithelium of the prostate.

Increased quantities are secreted when the gland enlarges; consequently, elevated levels of PSA in the blood can indicate cancer.

PSA is superior to DRE as an early detection tool, as a rise in levels due to prostate cancer may preceed a palpable lesion by more than six years.

When testing was introduced into clinical use, the upper limit for a ‘normal’ PSA measurement was set at 4.0 ng/ml, below which the risk of prostate cancer was assumed to be minimal.

However, this limit is currently the subject of debate.

Recent data have shown that no PSA concentration excludes prostate cancer, and that a significant number of life-threatening cancers are found despite recorded PSA levels below 4.0 ng/ml.

As a guideline, PSA concentrations above 2.5 ng/ml in younger men aged between 45-55, particularly those with a positive family history, should be considered suspicious and invite further examination.

PSA concentrations may fluctuate over time, so one ‘normal’ value does not guarantee absence of prostate cancer.

Instead, it is advisable to monitor PSA velocity (the rate of PSA increase) over time.

If several measurements show a rapid increase, it is more likely that prostate cancer is behind the rise.

There is no strict definition on how fast PSA should increase to be considered suspicious.

However, an increase of 0.75ng/ml per year or more should raise concern.

If such an increase is noted, even if the absolute PSA-concentration is below recommended levels, further diagnostic tools should be employed.

Despite its merits for improved early detection, PSA is not a perfect tumour marker.

Other common disorders such as benign prostatic enlargement (also called benign prostatic hyperplasia, or BPH) can raise PSA levels, explaining why not every man with elevated PSA suffers from prostate cancer.

BPH and PCa also frequently coexist in the same prostate.

Nevertheless, despite it’s imperfections, PSA is the best marker available today and any early detection programme would be incomplete without it.

If any of these three parameters (palpation of the prostate, ultrasound of the prostate or elevated PSA-levels) raises concern, the next step is to obtain tissue from the prostate by means of a TRUS-guided biopsy.

- Transrectal ultrasound-guided biopsy TRUS-guided prostate biopsy is the current standard for diagnosis of prostate cancer.

The traditional strategy has been to obtain a set of six biopsy specimens in a sextant pattern, but recent studies suggest that this approach results in a residual probability of cancer of at least 10%.

As a result, the optimal number and pattern of biopsy specimens and the number of times biopsies should be repeated are now hotly debated.

In our institute, at least eight to 10 separate cores are taken from the lateral parts of the prostate.

If performed by experienced urologists under local anaesthesic and antibiotic protection, TRUS-guided prostate biopsy is a well-tolerated, safe procedure that can be performed on an ambulatory basis.

In the 1,500 men biopsied in our clinic in 2005, significant complications (bleeding that required intervention, acute prostatitis,) leading to hospitalisation occurred in 0.7%.

A short increase in temperature to 38C° was seen in 2.1 % of all patients.

Minute traces of blood, such as in urine, were seen in about 50% of all patients but this subsided without the need for further intervention.

The likelihood of finding prostate cancer on biopsy is directly related to PSA-levels and DRE findings.

In case of a negative initial biopsy, a repeat biopsy may be performed within three to six months if suspicion for prostate cancer remains due to a persistently elevated PSA-concentration.

It is estimated that this second biopsy will reveal prostate cancer in 5 to 25% of cases.

Diagnosis: the next stepOnce prostate cancer is diagnosed, it is critical to determine whether the cancer is clinically localised or advanced.

Imaging guidance, indispensable for virtually all other cancers, is needed only in those patients who have a very aggressive, palpable cancer and / or a PSA above 10 - 20 ng/ml.

The majority of prostate cancers identified in early detection programs will be non-palpable and have a PSA below 10ng/ml.

For these cancers, a CT scan of the pelvis or a bone scintigraphy is rarely necessary, as the risk of skeletal metastasis in this setting is less than 1%.Treatment options for clinically localised prostate cancerIf prostate cancer is clinically localised, the challenge for both the urologist and patient is to agree a course of treatment.

Few other malignancies have such a wide array of adequate treatment options as prostate cancer.

Through discussion, the urologist and patient should decide which treatment option is most suitable considering the features of the cancer, potential side-effects, any comorbidities, the age of the patient and, crucially, the patient’s preference.

Established therapeutic options include:

- Surgical removal of the prostate

- Various radiation techniques

- Hormonal therapy

- Observation (‘wait and see’or ‘watchful waiting’) strategies.Surgical removal of the prostate (radical prostatectomy)The radical prostatectomy (RP) involves complete removal of the prostate and seminal vesicles.

Principally, the prostate can be removed using the approach from the lower abdomen (radical retropubic prostatectomy) or the perineum (radical perineal prostatectomy).

The most widely used procedure is the open radical retropubic prostatectomy (RRP).

Urologic centers worldwide use this approach for its superior exposure of the prostate, improved surgical technique to preserve urinary continence and, if cancer characteristics

permit, bilateral preservation of the nerves to regain sexual function after therapy.

In the appropriate patient, RRP may be curative.

Data from our own department shows that patients with an early-detected, low-risk prostate cancer may remain free of recurrent cancer in more than 80% of cases.

However, the procedure is not for everyone.

Suitability is based on several criteria; the tumour must appear to be confined to the prostate, as defined by Gleason grade, TMN stage, and serum PSA level; the patient should not have significant comorbidities, such as restricted cardiac or pulmonary function, neurological disorders (e.g history of stroke), morbid obesity or severe vascular or uncorrected hemorragic diseases; and he should be medically fit to withstand anaesthesia and surgery.

Old age is not an automatic disqualification for RRP, but unless the patient has a life expectancy of at least 10 years, surgery is unlikely to improve overall survival.

As a result, RRP is usually performed only in patients under the age of 70, who are otherwise in good health.

Studies have demonstrated that, in men undergoing RRP, variations in surgical technique and follow-up care have a substantial effect on postoperative morbidity.

Complications, such as urinary incontinence and postoperative impotence, are significantly reduced if the procedure is performed in a high-volume hospital and by a surgeon who performs a high number of such procedures.

Data from our institute reports that men who underwent radical retropubic prostatectomy achieved full continence rates of >90%.

Preservation of erectile function depends on both the age of the patient and whether or not one or two neurovascular bundles have been preserved.

In the ideal setting, men who are potent preoperatively, who are younger than 55 years and receive a bilateral nerve-sparing prostatectomy will be able to perform intercourse (IC) in more than 70% of cases without, and more than 90% with, the aid of PDE5-inhibitors.

Alternatives to the open radical prostatectomy are laparoscopic and robotic assisted prostatectomies.

Both approaches are less established than the open technique.

These surgical techniques are strongly promoted by some urologic surgeons, in an attempt to reduce hospital time, postoperative pain and blood loss.

It should be noted however, that both minimally invasive surgical techniques have yet to prove that their long-term functional results, most importantly in continence and potency, are better than results obtainable with the open radical retropubic prostatectomy. Radiation techniquesRadiation offers a completely different approach to treating prostate cancer.

There are several available therapies, including:

- External beam radiation (EBRT)

- Low-dose-rate brachytherapy (LDR-BT)

- High-dose rate brachytherapy (HDR-BT).

Not every technique is suitable for all clinically localised prostate cancers.

Advantages of radiation therapy over surgery include the lower affection of the cardiovascular system (EBRT is a non-invasive, and LDR-BT and HDR-BT are minimally invasive, procedures).

Therefore, there is no (with EBRT) or virtually no (with HDR-BT and LDR-BT) blood loss and no or only minimal acute trauma to the patient.

For patients with comorbidities too severe for the anaesthesia required for surgical procedures, radiation therapy is an appropriate treatment option.

EBRT can be performed without the need for anaesthesia on an ambulatory basis.

HDR-BT and LDR-BT require a maximum of one to two nights in the hospital.

It should be noted that, because many of the newer forms of radiation therapy (such as brachytherapy) have been developed during the PSA era, most cancer-control outcomes reported for men with early-stage disease are based on PSA measurements rather than survival rates.

Longer follow-up will be necessary to determine whether radiation therapies demonstrate an equally effective treatment outcome compared to the surgical removal of the prostate in early detected prostate cancers.

Radiation may not be suitable for patients with large glands (>50 cubic centimeters) and / or obstructive voiding symptoms, patients with a history of pelvic radiation due to other malignancies, or those with chronic inflammatory bowel disease such as ulcerative colitis or Crohn´s disease.

- External beam radiation

With EBRT, the radiation source is completely external to the patient’s body.

After scanning of the pelvis to locate the prostate, an external beam is focused on the prostate and seminal vesicles from various directions.

The standard technique utilises three-dimensional conformal radiation therapy, which permits the 3D visualisation of both the target and the normal tissue.

This technique improves delivery of EBRT to the prostate while more efficiently sparing the surrounding normal tissue, resulting in an overall increase in the total dose that can be safely administered.

Short-term side effects, such as radiation-induced inflammation of the rectum and bladder, and long-term side effects, such as strictures of the urethra, loss of potency and decreased continence, are higher with increased doses.

EBRT is a suitable therapy for early stage and locally advanced prostate cancer.

In more advanced cases, it may be combined with an antihormonal treatment to improve long-term success rates.

- Low-dose-rate (LDR) brachytherapy

LDR brachytherapy refers to the permanent implantation of radioactive seeds in the prostate.

The implants need only have a low activity, hence the name ‘low-dose-rate’.

LDR-B is currently indicated only for patients who have small, non-palpable cancers, a PSA of 10 ng/ml or less and a life expectancy of at least ten years.

In general, patients who are candidates for either radical prostatectomy or EBRT are also suitable candidates for brachytherapy.

Side effects may include the risks of general anaesthesia, as well as specific side effects from the radiation.

Irritative voiding symptoms (urgency, frequency, dysuria) are relatively common, while a small percentage of patients will experience urinary retention due to swelling of the prostate from the radiation.

- High-dose rate (HDR) brachytherapy

HDR brachytherapy allows high doses of radiation to be delivered directly to the prostate area, sparing normal tissues.

The high activity of the source means significant doses of radiation can be delivered in minutes.

HDR is administered under general or spinal anaesthesia by inserting multiple plastic flexible catheters interstitially through the perineal area into the prostate gland under transrectal ultrasound guidance.

The catheters help to deliver the highest possible dose to the tumour while minimising morbidity in normal tissue.

Once the catheters are placed, the patient undergoes a CT scan.

The results are entered into a computer-controlled treatment programme that determines the radiation dose given through each catheter.

During the procedure, dose adjustments can be made to ensure the tumour receives the higher dose and surrounding organs receive lower doses.

In our institute, two sessions are administered to the patient in a one-week interval.

Subsequently, 28 courses of ambulatory EBRT are administered to achieve an effective radiation dose.

Hormonal therapy A unique feature of prostate cancer is its dependence on sexual hormones of the male, in particular testosterone.

This feature makes hormonal ablation - by drugs or by surgical castration- a mainstay of prostate cancer treatment.

Hormonal ablation by means of drugs relies on continuous antihormonal drug administration for several years.

While hormonal therapy can slow and partially stop the growth of the cancer, the time that the cancer can be controlled is limited.

This is because prostate cancer consists of two main cell types; while a large proportion of cells are hormone-dependent , a small fraction are hormone-independent.

Under the influence of androgen ablation, hormone-dependent cancer cells will disappear, but hormone-independent cells will continue to grow, spreading beyond the prostate into adjacent organs, lymph nodes and the skeletal system.

The time frame that prostate cancer remains hormone sensitive for under continuous hormonal ablation can be estimated to be between 12 and 60 months.

While more recent data suggest that this time frame can be extended by intermittent hormonal therapy, hormonal ablation is always a time-limited therapy.

Hormonal therapy is indicated in the following settings:

- If the patient has a clinically localised cancer at the time of diagnosis but age or comorbidities preclude other therapies such as radical prostatectomy or radiation therapy.

In short, if the lifespan of the individual is more likely to be limited by concomittant diseases or advanced age rather than the cancer itself.

- If the cancer at the time of diagnosis has already metastasised and therefore cannot be treated by any local therapy.

- In combination with radiation therapy in more advanced cancer stages.Watchful waiting Watchful waiting is a unique feature in genitourinary oncology.

As outlined earlier, while prostate cancer is common, not every case is life threatening.

In its earlier stages, prostate cancer has a growth rate slower than virtually all other known cancers.

It may take more than a decade for a very small, organ-confined cancer to spread beyond the prostatic capsule and metastasise.

Therefore, not every cancer may need to be detected or treated.

These are termed ‘clinically insignificant’ prostate cancers and are not likely to affect the remaining lifespan of the individual.

To date, there is no certain way to tell which cancers are clinically significant and require treatment and which are not.

However, as a guideline, suitable cases for watchful waiting should feature a non-palpable cancer, a PSA below 10 ng/ml and should consist only of well to moderately differentiated cancer cells.

Likewise, the number of cores positive for cancer should be two or less and no single biopsy must contain more than 50% cancer cells.

Finally, the age at diagnosis plays an important role.

Men who can be expected to have a life expectancy of 10 years or more are more likely to develop clinically manifest cancer and its consequences than those with a shorter life expectancy.

The aim of this therapy is not to cure but to outlive the cancer.

Despite the designation ‘watchful waiting’, this treatment option should be considered an active therapy.

If a patient diagnosed with prostate cancer decides to take this option, close monitoring is necessary.

This monitoring consists of semiannual PSA-determinations, prostatic palpation and a yearly prostatic control biopsy.

If any of the parameters changes unfavourably (e.g. the cancer can be palpated, or the PSA exceeds 10 ng/ml or poorly differentiated cancer is found in a subsequent biopsy) the watchful waiting strategy must be checked for its appropriateness and other treatment options should be reconsidered.

The alternative designation ‘deferred therapy’ probably illustates more clearly the true nature of this valuable therapeutic option.ConclusionWith increasing knowledge about prostate cancer, urologists can now inform men more accurately than ever before on risk factors, early detection strategies and diagnostic tools.

Likewise, a wide array of constantly refining therapeutic options is now available for patients.

However, only men who are aware of this most common and life threatening disease will seek out early diagnosis.

To reduce morbidity and mortality from this common male cancer, physicians must ensure men are aware of the importance of an annual full urological screening.

Dr Alexander Haese is associate professor of urology at University Clinic Hamburg Eppendorf, Germany.

Dr Markus Graefen is associate professor of urology and chairman of the Martini Clinic Prostate Cancer Centre in Hamburg, Germany.

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