Benign prostatic hyperplasia (BPH)

Background Benign prostatic hyperplasia (BPH) is a medical condition closely related to

ageing. It is not life threatening, but its clinical manifestation as lower urinary tract symptoms (LUTS) reduces patients' quality of life. Bothersome LUTS can occur in 30% of men older than 65 years of age. Mild urinary symptoms are very common in men aged over 50 years and generally cause little bother. Moderate and severe urinary symptoms result in higher levels of inconvenience and interference with daily living activity. The same urinary symptoms can cause different bothersome and daily living interference's. There is a relatively low correlation between urinary symptoms, prostate size and urinary flow rate.

The prevalence of clinical BPH remains difficult to determine and an

epidemiological definition of BPH is lacking. The aetiology of BPH is multi-factorial, with age and hormonal status being the true factors related to the development of the disease. The need for surgery to treat BPH increases with age and with the degree of clinical symptoms at baseline. Nocturia and changes in the urinary flow

Symptom scores

Several urinary symptom score systems such as the International Prostate

Symptom Score (I-PSS), the Clinical Prostate score and the Danish Prostate Symptom Score (Dan-PSS) describe and quantify BPH symptoms. They were developed to compare patient status before and after BPH treatment. The I-PSS system is recommended here and consists of 8 questions, 7 of which explore urinary symptoms and 1, which investigates quality of life.

Prostate-specific antigen (PSA) measurementThe conclusions of the 1997 International Consensus Meeting are

recommended here. • PSA measurement should be offered to men with LUTS and a life

expectancy of over 10 years in whom the diagnosis of prostate cancer, once established, would change the treatment plan.

• The benefits and risks, including the likelihood of a false-positive or false-negative PSA test and the potential need for a transrectal ultrasonography (TRUS)-guided biopsy, should be discussed with the patient.

• It has been suggested that newer concepts, such as PSA density, PSA velocity and age-specific reference ranges, may enhance the statistical performance of PSA as a cancer-screening test. Until the results of definite studies are available, physicians must use clinical judgement to determine which patient should or

should not undergo TRUS and TRUS-guided biopsy.• New assays separating free and complexed PSA are being developed. These

are believed to enhance the statistical performance of PSA as a cancer-screening test in the critical range of total PSA values between 2.0 and 10.0 ng/ml.

PSA density, PSA velocity and PSA free/total ratio might offer valuable information in a subgroup of patients.

Creatinine measurementBladder outlet obstruction due to BPH may cause hydronephrosis and renal

failure. A recent study of 264 men presenting with BPH symptoms found that approximately 1 in 10 (11%) had renal insufficiency. While it is difficult to select those BPH patients with renal insufficiency these guidelines recommend the measurement of serum creatinine levels in all BPH patients. Proper therapy can be provided and the costs of long-term renal damage and post-surgical complications avoided.

Digital Rectal Examination A DRE has to be performed as it helps determine the presence of prostate

cancer and the size of the prostate gland.

Imaging of the Urinary TractThe imaging modality used for patients with LUTS should provide an image

of the urinary tract and demonstrate the morphological effects of prostate pathology on the lower and/or upper urinary tract. Intravenous urography (IVU) or sonography and plain films are the procedures routinely used for imaging the upper urinary tract, prior to prostate surgery.

However, these guidelines recommend a renal ultrasound as the imaging modality for the upper urinary tract. Imaging of the lower urinary tract with a urinary bladder voiding cystourethrogram gives limited urodynamic information and is not recommended in the routine diagnostic work-up of elderly men with LUTS. A retrograde urethrography gives indirect information on the effect of benign prostatic enlargement (BPE) on adjacent structures, it is not recommended here.

The prostate is viewed to assess size and shape, the presence of occult carcinoma and for tissue characterisation.

Imaging of the prostate can be done be transabdominal ultrasound, TRUS,

computed tomograpy (CT) and magnetic resonance imaging (MRI). TRUS has been documented as the most accurate way to calculate the size of the prostate. It is necessary to calculate prostate size when surgery, medical and thermotherapy are considered as treatment options.

Voiding ChartsVoiding charts (diaries) are simple to complete and can provide useful

objective clinical information. There is no standard frequency volume chart but the 7-day Abrams and Klevmark chart is the simplest. Recording a 24-hour frequency

volume chart prior to initial consultation helps identify patients with idiopathic nocturia or excessive fluid intake.

Flow RatesUroflowmetry is recommended as a diagnostic assessment in the work-up of

patients with LUTS and an obligatory test prior to patients receiving surgical treatment. It is a simple, non-invasive test that can reveal abnormal voiding.

Flow rate machines provide information on voided volume, maximum flow (Qmax), average flow (Qave) and time to Qmax, and this information should be interpreted by the physician to exclude artefacts. Serial flows (two or more) are recommended to get a representative flow test (Qmax). Obstruction can only be diagnosed with a pressure flow test, however flow rates should be interpreted with caution as elderly patients with LUTS have age-related urodynamic changes.

Post-void residual urine volumePost void residual (PVR) urine volume measurement is recommended in these

guidelines. It should be calculated by measurement of the bladder height, width and length obtained by transabdominal ultrasonography. This is a simple, accurate and non-invasive method.

Urodynamic studiesPressure-flow studies are regarded as an additional diagnostic test in these

guidelines. Flow rates only determine the probability of obstruction, whereas pressure-flow studies can categorize the degree of obstruction and identify patients in whom a low flow rate may be due to a low-pressure detrusor contraction. These guidelines recommend that pressure-flow studies remain optional tests in straightforward cases, presenting for the first time with LUTS. These studies are the most useful investigation available for the purpose of counseling patients regarding the outcome of surgical therapies for BPH. The International Continence Society (ICS) nomogram should be used for the diagnosis of obstruction in order to standardize data for comparative purposes.

A urethrocystoscopy is the standard endoscopic procedure used for evaluating

the lower urinary tract (urethra, prostate, bladder neck and bladder). It can provide information as to the cause, size and severity of obstruction, patency of bladder neck, prostatic occlusion of the urethra and estimated prostate size.

It can confirm causes of outflow obstruction and eliminate intravesical abnormalities. It is recommended as an optional diagnostic test in these guidelines however, it should be performed if patients are to receive surgical treatment.

Recommended Guidelines for the Diagnosis of Benign Prostatic Hyperplasia

1. Among all the different urinary symptom score systems currently available, the use of I-PSS is recommended because of its world-wide distribution and use.

2. In patients undergoing investigation for LUTS, the minimal requirement is to assess the upper urinary tract function with a creatinine measurement and or an ultrasonographic examination.

3. There is a consensus that if imaging of the upper urinary tract is performed, ultrasonography is the method of choice.

4. Imaging of the upper urinary tract is recommended in patients with LUTS and a:

• History of or a current urinary tract infection• History of urolithiasis• History of urinary tract surgery• History of urothelial tumour (including IVU)• Haematuria (including IVU)• Urinary retention5. Routine imaging of the urinary bladder cannot be recommended as a

diagnostic test in the work-up of patients with LUTS. Ultrasound of the bladder, however, is a valuable diagnostic tool for the detection of bladder diverticula or bladder stones.

6. Routine imaging of the urethra is not recommended in the diagnostic work-up of patients with LUTS.

7. DRE is a minimal requirement in patients undergoing investigation for LUTS.

8. The method of choice for the determination of prostate volume is ultrasonography, preferably via the transrectal route. However, imaging of the prostate by transabdominal ultrasound and TRUS is optional.

9. Prostate size should be assessed when considering open prostatectomy and TUIP, and prior to finasteride therapy.

10. If the voided volume is less than 150 ml or Qmax is greater than 15 ml/sec, pressure flow studies should be considered before surgical intervention, particularly in elderly men. Pressure-flow studies should be considered for patients prior to surgical treatment in the following subgroups:

• Younger men (e.g. < 50 years of age)• Elderly patients (> 80 years of age)• Post-void residual urine volume over 300 ml• Suspicion of neurogenic bladder dysfunction• After radical pelvic surgery• Previous unsuccessful invasive treatment11. Measurement of residual urine volume is a recommended test in the

assessment of patients with LUTS suggestive of benign prostatic obstruction.12. Endoscopy is recommended as a guideline at the time of surgical

treatment to rule out other pathology and to assess the shape and size of the prostate, which may have an impact on the treatment modality chosen.

Treatment of Benign Prostatic HyperplasiaThe aim treatment is to improve patients' quality of life and it depends on the

severity of the symptoms of BPH. These guidelines recommend that a minimal assessment should be done in all patients seeking consultation for BPH before deciding on an appropriate treatment modality. This must include an evaluation of

urinary symptoms, measurement of post-void residual urine volume and peak flow rate. There are several types of treatment commonly used for BPH; surveillance, medical, surgical and non-surgical.

• Watchful Waiting (WW)The watchful waiting (WW) treatment option is recommended for patients

with a symptom score of less than 7, i.e. mild symptoms that do not interfere with daily life activities. A multi-factorial approach, combining the presence of symptoms, their bothersomeness and their influence on daily life, as well as cost-efficacy, should be taken into account before deciding on the WW treatment option.

• Medical Treatment 5α-reductase inhibitors Finasteride was the first 5α-reductase inhibitor used for the treatment of BPH.

Several clinical trials have demonstrated that finasteride can reduce the size of the prostate gland by 20 - 30%, improve symptom scores by approximately 15% and cause moderate improvements in urinary flow rates. While the maximum effects of finasteride are seen after 6 months, long-term benefits have been reported for up to 6 years. Side effects are minimal and are related to sexual function. Finasteride is more effective in men with enlarged prostates (greater than 40 ml) and should be considered as an acceptable treatment option. No additional patient benefits have been seen when finasteride is combined with α1-blockers. Although finasteride lowers serum PSA levels it does not mask the early detection of prostate cancer.

α-blockersUse of the a-pblockers, alfuzosin, doxazosin, indoramin, prazosin and

terazosin and the α1-blocker, tamsulosin, for the symptomatic relief of BPH has increased in the past 10 years. These drugs relax the smooth muscle of the prostate gland and bladder neck to improve urine flow and to reduce balder outlet obstruction. Reductions of 20-50% in symptom scores and improvements of 20-30% in urinary flow rates have been reported. Improvements are seen within 48 hours and maintained for up to 42 months. While they all have similar efficacy and side-effect profiles they differ in their pharmacokinetic properties and cost. The most commonly reported side-effects are headaches, dizziness, postural hypotension, asthenia, drowsiness, nasal congestion and retrograde ejaculation.

Patients with specific indications for surgery such as urinary retention, recurrent urinary tract infections, chronic renal impairment and recurrent prostatic bleeding should not be considered for a-blocker therapy. Patients on anti-hypertensive therapy and those with postural hypotension should be carefully monitored when receiving a-blocker therapy.

PhytotherapyThe treatment of BPH with phytotherapeutic agents has gained popularity in

recent year's. While their mode of action is unclear, encouraging results using Serenoa repens have been reported in clinical trials. The efficacy of phytotherapeutic agents has to be demonstrated before their introduction into clinical practice.

Surgical SurgeryThe best long-term solution for patients with BPH is probably surgery, which

removes the enlarged part of the prostate and usually relieves the obstruction and incomplete emptying caused by BPH.

Transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP) and open prostatectomy are the three surgical treatment options for BPH.

Surgery is recommended for patients with bothersome BPH symptoms refractory to medical treatment. Refractory urinary retention, recurrent urinary tract infection, recurrent haematuria, renal insufficiency and bladder stones are the complications of BPH which require surgery. TUIP is recommended for patients with a small prostate gland, no median lobe and a low risk of associated prostate cancer (normal DRE and serum PSA levels). TURP is the most frequently performed surgical procedure and is recommended for moderately enlarged prostate glands, provided it can be completed within 60 minutes. Open prostatectomy is recommended for severely enlarged prostate glands. Urinary tract infections should be treated before surgery. The number of patients experiencing complications and morbidity due to surgical interventions has decreased during the past decade.

The use of laser surgery to treat BPH has been rapidly developed within the past decade. Clinical studies using side-firing Nd:YAG and ILC lasers have demonstrated equivalent improvements in symptom scores and urinary flow when compared with TURP. However the long term effects of laser surgery are unknown and eagerly awaited. Holmium laser resection of the prostate (HoLRP) is a relatively new technique with only a few studies completed. These guidelines advise laser prostatectomy for patients who are: on anticoagulant medication, unfit for TURP (side-fire or ILC) or desire to maintain ejaculation (side-fire or ILC).

Transrectal HIFU is the only technique that provides non-invasive tissue ablation. Clinical data are only available for one device Sonablate®. Transrectal HIFU is well tolerated but requires general anaesthesia or heavy intravenous sedation. Urinary symptom improvement in the range 50-60% and mean Qmax increases of 40-50% have been shown. Long-term efficacy is limited, with a treatment failure rate of approximately 10%/year. Clinical data from randomised trials is limited and transrectal HIFU should be considered as investigational therapy.

Transurethral Needle Ablation (TUNA®)TUNA® is a simple and safe technique that delivers low-level radiofrequency

energy to the prostate gland. It can be performed under local anaesthesia in a significant number of patients. It results in an improvement of urinary symptoms in the range of 50-60% and mean Qmax increases of 50-70%. Clinical efficacy has been proven in randomised, controlled trials, although there is limited evidence of long-term efficacy.

TUMT uses computer-regulated microwaves to deliver heat through a catheter to selected portions of the prostate gland and destroy excess prostate tissue. A cooling system protects the urinary tract during the procedure. Morbidity is relatively low and can be performed without anaesthetic; patients in poor health are particularly good candidates for thermotherapy. These guidelines recommend low-energy TUMT for patients with smaller prostates and lower grades of bladder outlet obstruction. It has an excellent subjective response and minimal morbidity. High-energy TUMT is recommended for patients with larger prostates and higher grades of bladder outlet obstruction. It has excellent subjective and objective responses but has a higher morbidity than low-energy TUMT New TUMT procedures aim to reduce morbidity and treatment time with sustained objective results and durability. A recent report of a shorter treatment has demonstrated similar results as seen with one-hour high-energy TUMT protocols.

Recommended Guidelines for the Treatment of Benign Prostatic Hyperplasia

1. The WW policy should be recommended to patients with mild symptoms that have minimal or no impact on their quality of life.

2. Finasteride is an acceptable treatment option for patients with bothersome LUTS and an enlarged prostate (> 40 ml). It can be used when there is no absolute indication for surgical treatment.

3. Alpha-blocker therapy is a treatment option for patients with bothersome LUTS, irrespective of prostate volume, who do not have an absolute indication for surgical treatment.

4. Surgical management (TURP, TUIP, or open prostatectomy) is recommended as first-line treatment for patients with (an absolute indication for the treatment of) LUTS.

5. Significant post-operative morbidity, disappointing long-term data and high costs have resulted in a substantial decline in the clinical use of side-fire and ILC. It is not recommended as a first-line surgical treatment for patients with LUTS. It may have a role in the treatment of high-risk patient subgroups.

6. HoLRP is a promising new technique with outcomes in the same range as those of TURP.

7. Transrectal HIFU therapy is currently not recommended as a therapeutic option for elderly patients with LUTS and is considered as an investigational therapy.

8. Due to a significant treatment failure rate, TUNA® is not recommended as a first-line therapy for patients with LUTS.

9. TUMT should be reserved for patients who prefer to avoid surgery or who no longer respond favourably to medication.

Follow upAll patients who receive treatment for BPH need follow-up. Follow-up

schedules depend on the type of treatment administered. Patients who subsequently develop chronic retention will require evaluation of their upper urinary tract by serum creatinine measurement and/or renal ultrasound. They may also be candidates for urodynamic assessment and surgical treatment.

Watchful WaitingPatients on the WW treatment option should be followed-up at 6 months and

then annually, provided that there is no deterioration of symptoms or the development of absolute indications for surgical treatment.

Medical Treatment 5α-reductase inhibitorsPatients should be reviewed at 12 weeks and 6 months to determine their

response to 5a-reductase inhibitors. Thereafter, these patients should be followed-up annually, provided that there is no deterioration of symptoms or the development of absolute indications for surgical treatment.

α-blockersAfter the first 6 weeks of therapy with a-blockers, patients should be reviewed

to determine their response. If these patients gain symptomatic relief without any troublesome side-effects, treatment with a-blockers may be continued. Patients should be followed-up at 6 months and then annually, provided that there is no deterioration of symptoms or the development of absolute indications for surgical treatment

Surgical treatmentPatients who received surgical treatment should be seen within 6 weeks to

discuss histological findings and to identify early post-operative morbidity. Long-term follow-up should be scheduled at 3 months to determine the final outcome. Any patients who fail surgical treatment should have urodynamic studies with pressure flow analysis.

Alternative therapiesLong-term follow-up is recommended for patients who receive alternative

therapies (HIFU, TUNA® and TUMT). For minimally invasive therapies follow-up is recommended at 6 weeks, 3 months, 6 months and then annually.

Epidemiology of prostate cancerDescriptive EpidemiologyIn 1995, were approximately 244 000 new cases and 44 000 deaths from

prostate cancer (PC)-numbers that will continue to rise as the population ages. Ninety-five percent of prostate cancer is diagnosed in men between 45 and 89 years of age with a median age of diagnosis of 72 years.

The age-adjusted incidence and death rates from prostate cancer vary from country to country as well as between racial-ethnic groups. In 1989, the incidence rates were highest in blacks (149/100 000 person-years), intermediate in U.S. whites (107/100 000 person-years), and lowest in Orientals (Japanese [39/100

000/person-years] and Chinese [28/100 000 person-years])). While the incidence rates are increasing yearly, these variations continue to persist. Clinically apparent disease is rare under the age of 50 and increases dramatically with age. The age-adjusted incidence rate is 21 per 100 000 person-years for U.S. whites under age 65 and 819 per 100 000 for those over 65. Between 1973 and 1989, the age adjusted U.S. incidence rates of PC have increased at approximately 2.7 per 100 000 yearly. This rise was attributed to an ageing population and in part to the increased use of transurethral resection of prostate yielding more stage A disease. Improvements in ultrasound and biopsy techniques may have contributed to finding more PC in the community. Between 1989 and 1991, incidence rates rose by 23,5 per 100 000.

The introduction of new and more efficient diagnostic procedures, such as prostate-specific antigen (PSA) testing and improved biopsy techniques, in addition to an increased public awareness has caused a dramatic increase in the incidence of prostate cancer during the last decade, particularly in the USA. The evolving trends in PC mortality are less clear-cut. Although there has been an increase of prostate cancer mortality in most Western countries up to now, it is not the same magnitude as the change in incidence. The disparity between reported incidence and mortality rates leads to the probable conclusion that only a minority of the small, localised prostate cancers diagnosed in the "PSA-era" will progress to a life-threatening disease during the lifetime of the patient.

The number of elderly people will increase in Western countries over the next decades. Since prostate cancer is strongly associated with increasing age, the prevalence of clinical prostate cancer will continue to increase. So even in the age-specific rates remain unchanged or even decrease, the ageing of the population will lead to a substantial increase in the burden of prostate cancer as well as other age-related cancers. The need for primary prevention of prostate cancer is obvious and further research identifying risk factors for the development of the disease is ur-gently needed.

Symptomatology and natural history of prostatic malignanciesSymptomatology of prostatic malignanciesSymptoms observed in patients with prostatic malignancies depend on the

stage of the desease.Among the patients with localised prostatic cancer no specific symptoms are

observed. This causes significant delay in establishing the diagnosis and radical treatment.

Carcinoma of the prostate localised to the organ causes symptoms like those in patients suffering from benign prostatic hyperplasia (BPH). Reduction of the flow, hesitancy, dribbling, urinary frequency, nycturia and feeling of incomplete emptying are observed in both diseases. These symptoms develop more rapidly in patients with prostatic malignancies compared to those with BPH. Micro- and

macrohaematuria is sometimes seen as well as recurrent infections of urinary system, which are resulted from poor emptying of bladder. Locally advanced carcinoma doesn't affect sexual potency. It is impossible to distinguish carcinoma of the prostate and BPH relying only on patients history and symptoms.

Generalisation of the neoplasmatic disease most often is manifested with bone pain. Pathological fractures are recognised, especially in the group of patients, who don't pay the attention on these symptoms. The fracture of backbone sometimes leads to spinal cord compression. Rarely palsies of cranial nerves are observed as the result of basilar skull metastases. Oedemas of lower extremities are the symptoms of pelvic nodes metastases. Enlargement of supraclavicular or inguinal lymph nodes may be the first sign of the widespread cancer of the prostate. Metastases in tissues other then lymph nodes are seldom as the only symptom of generalised malignancies of prostate.

Natural history of prostate cancerCarcinoma of the prostate is one of the most common cancer among men.

Incidence is strongly correlated with age. In men in the age below 40 years the incidence of the disease is very low, it rises at the age of 50 and in the population of men of 80 or more years it can be diagnosed even in 80% examined persons. The overwhelming majority of prostatic cancers are adenocarcinomas.

Natural history of the disease is the description of it course in non treated patients. It is important to establish course and prognosis depending on the stage of the cancer. This allows to estimate critically efficacy of the undertaken treatment.

There are 4 phases in natural history of any malignancy:1. induction phase - lasting till 30 years2. in situ phase - lasting from 5 to 10 years3. invasive phase - lasting from 1 to 5 years4. dissemination phase - lasting from 1 to 5 years.Carcinoma of the prostate in phase 2-4 is met usually at clinical practice.

Using staging scale TNM, in situ phase corresponds with stage Tl.T2, NO, MO, invasive phase corresponds with T3-T4, NO,MO and dis-

seminated phase stage with N+, M+.Accidentally diagnosed carcinoma of the prostate in the stage Tl, NO, MO is

predominately symptomless. The real occurrence of prostate malignancies is a few times greater then diagnosed one. It is estimated, that in 1 among 10 patients in this group, clinical symptoms will develop and in 1 among 1000 - 3000 metastases will be present. The risk of death as the result of prostate tumour in stage Tla in a period of 10 years is less then 5%. The risk of progression in the period of 5 years is 2% to 32% (Tla versus Tib). In the evaluation of the presumable course of the disease one must take into account staging and grading, that are for long time in use as prognostic factors, as well as newer ones - cells ploidy, activity of growth factors, presence of factors expressing proliferation activity of tumours. Nevertheless, prognosis in patients with tumour at stage Tl a is so good, that only watchfull waiting is recommended for them.

Patients with carcinoma localised to prostate (T2, N0, M0) are usually symptomless. This group represents about 10% of patients with clinically diagnosed neoplasma. The course of disease is slow. In the group of untreated men 5-years survival is observed in 89% of cases and 10-years in 51% of cases. Progression in the period of 5 years may occur in 33% of cases. The prognosis mainly depends on the volume of the tumour.

Patients with locally advanced carcinoma (T3-4, N0,M0) make 30-50% all diagnosed prostate carcinomas. The median survival time in untreated group of patients is 2,5 year. Metastases to regional lymph nodes are detected in 50% cases and the presence of them depends on the tumour's volume and grading.

In 50% of patients, who are affected with prostatic cancer, disease is diagnosed in the phase of dissemination, when metastases are presented in lymph nodes, bones or other organs. The disease is the reason of the death of most patients at this stage. The median survival rate, from the moment of establishing the diagnosis, is about 30 months and after 5 years only 15% of them are alive. Bone metastases will appear on an average in 5 years in patients with lymph node metastases. In the group of patients with metastases in two, different organs, 66% will die in one year.

There are no spontaneous regressions in the course of prostatic carcinoma. The course of the illness is not linear in the aspect of TNM classification, hence, the most advanced forms can developed itself from the small, confined to the prostate tumours (carcinoma ocultum).

Methods of diagnosis of prostatic malignancies

The diagnosis of prostate cancer is usually made as well on the basis of subjective symptoms as physical examination, biochemical tests or radiological and ultrasound imagings.

SymptomsBecause the majority of adenocarcinomas of the prostate arise in the

periphery of the gland, distant from the urethra, they rarely cause symptoms early in the course of the disease. Most often the presence of symptoms as a result of prostate cancer suggests locally advanced or metastatic disease.

Growth of prostate cancer into the urethra or bladder neck can result in obstructive voiding symptoms. Local progression of the disease and obstruction of the ejaculatory ducts can result in hematospermia and the finding of decreased ejaculate volume. Impotence can be a manifestation of prostate cancer that has spread outside the prostatic capsule to involve the branches of the pelvic plexus.

Metastatic disease involving the axial or appendicular skeleton can cause

bone pain or anemia from replacement of the bone marrow. Lower extremity edema can result from cancerous involvement of the pelvic lymph nodes and compression of the iliac veins. Less common findings from metastatic disease may include malignant retroperitoneal fibrosis from dissemination of cancer cells along the periureteral lymphatics, paraneoplastic syndromes from ectopic hormone production and disseminated intravascular coagulation.

The majority of men diagnosed with prostate cancer are initially suspected of having the disease based on digital rectal examination (DRE) abnormalities or serum PSA elevations. Approximately 50% of suspicious lesions on DRE actually represented cancer on prostate biopsy. The positive predictive value for DRE ranges from 21% to 53%. The significant risk of prostate cancer causes that prostate biopsy is recommended for all men who have DRE abnormalities, regardless of PSA level, because 25% of men with cancer have PSA levels less than 4 ng/ml. DRE misses from 23% to 45% of the cancers that are subsequently found with prostate biopsies performed because of serum PSA elevations or TRUS abnormalities. Additionally prostate cancers detected by DRE are pathologically advanced in more than 50% of men.

DRE and serum PSA are the most useful first-line tests for assessing the risk that prostate cancer is present in an individual. Serum PSA elevations occur as a result of disruption of the normal prostatic architecture that allows PSA to diffuse into the prostatic tissue and gain access to the circulation. This can occur in the setting of prostate disease and with prostate manipulation. The presence of prostate disease (prostate cancer, BPH, prostatitis) is the most important factor affecting serum levels of PSA.

PSA elevations may indicate the presence of prostate disease but not all men with prostate disease have elevated PSA levels. Furthermore, PSA elevations are not specific for cancer. Routine use of PSA increases the detection of prostate cancer over that of DRE, improves the predictive value of DRE for cancer and increases the detection of prostate cancers that are organ confined yet significant in terms of size and grade. PSA is the single test with the highest positive predictive value for cancer. Although PSA has the highest positive predictive value for prostate cancer use of PSA without DRE is not recommended because 25% of men with prostate cancers have PSA levels less than 4 ng/ml. The most effective method for early detection of prostate cancer is the combined use of DRE and PSA to assess prostate cancer risk.

Recognizing that PSA elevations are common in aging men because of the high prevalence of BPH investigation has focused on methods of improving the ability of the PSA test to distinguish between men with BPH and men with cancer. So it was introduced:

* age-specific PSA* PSA density (PSAD, adjusting PSA for prostate volume)* PSA velocity (PSAV, rate of change in PSA)* ratio between free (unbound) to total PSA (f/t PSA)

* PSAD of transition zone (PSATZ)

Ultrasound imaging Ultrasound

imagingThe enthusiasm for using ultrasound imaging to identify early prostate

cancers by detection of hypoechoic lesion has not been proven with longer follow-up. Studies has confirmed the inability of TRUS to localize early prostate cancer. It was revealed that 17% of hypoechoic sectors contain cancer, whereas 37% of sectors containing cancer were not suspicious by ultrasound. The limitations of TRUS in prostate cancer detection are that most hypoechoic lesions found on TRUS are not cancer and 50% of nonpalpable cancers more than 1 cm in greatest dimension are not visualized by ultrasound. Although hypoechoic areas on TRUS are more than twice as likely to contain cancer as isoechoic areas 25% to 50% of cancers would be missed if only hypoechoic areas were biopsied. Therefore any patient with a DRE suspicious for cancer or a PSA elevation should undergo prostate biopsy regardless of TRUS findings if an early diagnosis of cancer would result in a recommendation for treatment. Because TRUS is not an accurate method for localizing early prostate cancer it is not recommended as a first-line screening tool. The major role of TRUS is to ensure accurate wide-area sampling of prostate tissue in men at higher risk of harboring cancer.

Computed tomography and magnetic resonance imaging failed to improved significantly the assessment of local extent of prostate cancer. None of these radiological procedures possess sufficient sensitivity and specificity to determine precisely, on an individual basis, which patients have extracapsular spread or lymph node involvement. Intravenous pyelography (IVP) has only limited value in prostate cancer diagnosing.

Staging and strategy of the treatment of prostatic malignanciesStaging of prostate cancer includes the determination of the size and local

extent of the tumour and the detection of distant foci either in lymphatics, bone or soft tissues. Although accurate staging is a necessary part of evaluation of any tumour, it is of great importance especially in prostate cancer, a disease in which aggressive local therapy may not be indicated for all patients. In some patients with tumours detected at early, localized stages and the prediction of sufficiently slow progression rate, especially in older men or with short life expectancy, aggressive therapy with curative intent may not be justified. On the other hand local tumour progression or the finding of metastatic disease may be the indication for palliative modes of treatment.

The selected mode of treatment for men with prostate cancer is directly dependent upon stage of the tumour. For patients with a sufficiently long life expectancy and disease confined to the gland the aggressive therapy with curative intent e.g. radical surgery or radical radiotherapy should be proposed. The patients with metastatic disease or locally advanced will not benefit from such treatment and should be spared from morbidity always connected with aggressive therapy.

After the histopathological confirmation of adenocarcinoma of the prostate has been made, an accurate assessment of the stage i.e. extent of the disease should be made. The principles in staging of prostate cancer are twofold: to evaluate accurate prognosis and to direct therapy rationally based on extent of disease. The prognosis in men with newly diagnosed prostate cancer directly correlates with extent of the disease. The modes of treatment directed at eredication of the primary tumour are not likely to affect prognosis when the disease is no longer confined to the gland because so far an adjuvant therapy is not capable to eredicate extra-prostatic disease. Thus an accurate assessment of disease extent is pivotal when counseling the patient with newly diagnosed prostate cancer. The available modalities for assessing the disease extent in men with prostate cancer are: DRE, serum tumour markers, histologic grade, radiographic imaging and pelvic lymphadenectomy. Pretreatment staging, although not always uniformly reproducible, provides a means of distinguishing among clinically localized, locally advanced and metastatic disease.

Because the treatment selection of prostate carcinoma is based on extent of disease, it is appropriate to ascertain the extent of disease prior to treatment selection. Multiple staging systems have been proposed so far. In 1992 the American Joint Committee on Cancer and the International Union Against Cancer adopted the new TNM classification system for prostate cancer. Clinical stage refers to an assessment of the extent of disease determined by DRE, serum tumour markers, tumour grade and imaging modalities. The pathologic stage as a more accurate representation of the extent of disease within and beyond the prostate is performed following histologic examination of the pelvic lymph nodes and prostate gland after removal them at radical surgery. The pathologic staging is ore useful than clinical in the prediction of prognosis because tumour volume, surgical margin status, extent of extracapsular spread and involvement of seminal vesicles and pelvic lymph nodes can be well determined. For this reason alone accurate survival comparison between palliative and radical therapies is difficult to perform.

The important pathologic criteria that are predictive for the prognosis after radical prostatectomy are tumour grade, surgical margin status and presence of extracapsular disease, seminal vesicle invasion or involvement of pelvic lymph nodes. The presence of positive surgical margin or the presence of high-grade tumour in the setting of extraprostatic disease is associated with a higher probability of residual disease, biochemical, local, distant progression and survival after surgical removal of the prostate. In many statistical analysis the Gleason histologic grade or score has independent prognostic significance for those men with extracapsular disease. The finding of seminal vesicle invasion or lymph node metasta-ses on pathologic evaluation after radical surgery is associated with a low probability of total eredication of tumour and a high probability of distant failure. For this reason some investigators recommend the biopsy of seminal vesicles to improve staging before treatment.

Bone scintigraphy, intravenous urography, magnetic resonance imaging, computed tomography and TRUS have been evaluated as methods or staging prostate cancer. For an imaging modality to be clinically useful for staging prostate

cancer, the modality must reliable distinguish organ-confined disease from disease that has spread beyond the confines of the prostate gland (locally or distantly) and is thus not amenable to a curative approach.

The modern staging of prostate cancerClassic radiological procedures failed to improve significantly the staging of

localized prostate cancer. Prostate specific antigen has been used successfully to improve the clinical staging of clinically localized prostate cancer. Only in patients with a serum PSA value greater than 10 ng/ml is radionucleotide bone scan indicated. Bilateral pelvic lymphadenectomy is necessary only in men who have a high serum PSA value or a poorly differentiated tumour or both. The newest field of investigation in the staging of prostate cancer involves systematic prostate biopsies. Some of their features are used routinely by themselves or in combination with PSA and digital rectal examination to predict the final pathological (pT) stage of the tumour.

Recently, emphasis has been placed on the relevance of biomolecular methods to determine the presence of PSA positive cells in the blood stream which could indicate early metastatic extent and be linked to the pT stage.

Capsular perforation on biopsyThere is, on observation, no well-defined capsule in the prostate and

a,,capsular perforation" is evident only if carcinomatous tubes are present among the fat cells that characterize periprostatic soft tissue. The predictive value of capsular perforation is debated widely. This feature may be powerful in association with the percentage of positive biopsies (>66,7%) and serum PSA (>15 ng/ml) to predict biological progression defined by a detectable serum PSA level after radical prostatectomy (if two of three criteria are present, 85% of the patients will progress vs 14% if no criterion is present).

Gleason score on biopsy The Gleason score on biopsy is identical to that of the specimen in only 35%-48% of the cases, underscored in 40%-80% and over scored in %-14% of the cases. The best correlation is obtained with high Gleason scores (>8) but the frequency of poorly differentiated carcinomas remains lower in biopsies than in specimens. The correlation between biopsy grading and pathological stage is poor except for very low or very high Gleason score.

Percentage of cancer in biopsy coresThe observation of the amount of biopsy tissue invaded by cancer should be

used in conjunction with other preoperative features. It would appear to be preferable to use the number of positive biopsies to assist staging. A large number of positive biopsies (more than three out of six) has been shown to be highly predictive for high-volume tumours and to be a significant predictor both of positive surgical margins in radical prostatectomy specimens and of stage.

Principles of hormonotherapy of prostatic malignanciesThe aim of hormonal manipulation is to deprive the tumor cells of androgens

or their byproducts. Any treatment that decreases production or interferes with delivery of androgens to the cell is likely to produce an objective and subjective

response to most patients with prostate cancer. There are multiple points along the pathway between production and metabolism at which the cycle may be broken.

The major circulating androgen in men is testosteron, 90% of which is produces by testes. Testosterone released from the testes is regulated by the hypothalamic-pituitargonadal axis. Stimulated by the neurotransmitter norepinephrine, gonadotropin releasing hormone is released in a pulsatile fashion from the median eminence of the hypothalamus. In turn, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are produced by the anterior pituitary. Direct action of LH upon the Leydig cells of the testis causes the release of testosterone into the bloodstream. Most circulating testosterone is bound to blood proteins, either albumins or testosterone/estrogen binding globulin, a specific sex steroid binding protein. The functionally active form of testosterone is the approximately 3%, that remains unbound to protein. Testicular production of testosterone amounts to about 6,6 mg/day leading to serum concentration of 5,72 ± 1,35 ng/ml (19,8 ± 4,7 nmol/1) in the adult. After castration serum testosterone decreases to 5% to 10% of the original values.

Prolactin is a hypophyseal hormone which acts on the prostate in two ways: 1) indirectly, by stimulating the formation of testosterone and androgen by the testes and adrenals, 2) directly, by potentiating the action of testosterone on the prostatic tissue by promoting the binding of testosterone to epithelial cells.

The role of growth factors and their potential in prostate growth control has been proved. There is interaction between steroid hormones, growth hormones, the natural growth hormone antagonist somatostatin and growth factors that have been shown to be active on prostate and prostate cancer cells, including the epithelial growth factor family, the fibroblast growth factor family, insulin-like growth factor 1 and 2, and the transforming growth factor beta family, which plays an important physiologic role in suppressing the proliferation of prostatic epithelial cells. Growth factors act through membrane receptors and through binding he-paran sulfate, which is part of the extracellular matrix.

It has been proven, that prostate cancer tissue shrinks if androgen is withdrawn. Even normal androgen-dependent tissue has the capability of regrowth if the androgenic stimulus is reactivated. The endocrine treatment of human prostate carcinoma leads to the shrinkage of cancerous tissue can best be shown by the decrease and disappearance of metastatic deposits. The primary tumor volume decreases by an average of 30% to 40%.

Some 80% of patients with prostate cancer can be expected to have a favourable response to adequate hormonal therapy. Also approximately 80% of prostate cancer patients achieve symptomatic and objective response following androgen suppression and serum PSA levels decrease in almost all patients. However cure of prostate cancer by means of endocrine treatment is highly unlikely.

Rates of response of clinical prostate cancer under endocrine treatment depend on type of criteria used for the evaluation. Objective and subjective response may vary between 40% as in most studies of the European Organization for Research of Treatment of Cancer (EORTC) and 80% if the criteria of the

National Prostatic Cancer Project (NPCP) are applied. Hormone refractory prostate cancer has been defined as a progressive disease despite castration serum level of testosterone. The development of hormonal resistance predictable occurs after androgen deprivation. The median time to progression is 18 months. Median survival after progression has been described as approximately 6 months.

With the recognition of the purely palliative nature of endocrine treatment, subjective parameters related to the quality of life under endocrine treatment are more frequently and more seriously considered. The potential advantages and disadvantages of different types of endocrine treatment and of different regimens, such as early versus delayed and intermittent treatment, as well as minimally aggressive forms of treatment should be taken to the attention.

Hormonal treatment of prostatic adenocarcinoma is based on the assumption that malignant prostatic epithelia is androgen dependent as is nonmalignant prostatic tissue. Reduction of androgenic support of prostatic epithelia can be accomplished therapeutically by:

• removal of the primary source of circulating androgens (surgical castration),• removal or suppression of hypothalamic luteinizing hormone and reduction

of testicular testosterone production (estrogens, LHRH analogs, cyproterone acetate, LHRH antagonists),

• direct inhibition of androgen synthesis at the cellular level (aminogluthetymide, cyproterone acetate, spironolactone),

• blocking of androgens or their effect at a cellular level - antian-drogens (steroidal - cyproterone acetae, megestrol acetate, nonsteroidal -flutamide, nilutamide, bicalutamide).

Surgical treatment of the prostatic tumoursSurgery of prostatic malignancy can be divided into four distinct areas: (1)

surgery for establishing diagnosis, (2) surgery for staging, (3) surgery for primary control, (4) surgical palliation of extended disease. In this lecture surgery for primary control i.e. radical surgical removal of malignant tissue and surgical palliation will be discussed.

Methods of definitive local therapyTraditionally the definitive therapy is directed to localized form of prostate

cancer. It includes radical surgical operation and radical radiotherapy. There are, perhaps, fewer areas in medicine that generate more disagreement than the appropriate management of localized prostate cancer. To a great extent, the confusion surrounding this subject is due to variable natural history of the disease and its occurrence in a patient population that generally is of advanced age and with many competing causes of death. Very view randomized studies have been conducted comparing the various forms of treatment for localized prostate cancer. Comparisons between retrospective series often are invalid because of variability in patient selection and staging as well as other prognostic parameters. Therefore, there are no definitive data that allow the clinician to make dogmatic recommendations regarding selection of therapy.

Radical prostatectomyRadical prostatectomy should be reserved for men who are likely to be cured

and will live long enough to benefit from the cure. Because of the protracted course of prostate cancer, the age and cormobid conditions of the patient are critical determinants of the benefits of treatment.

Radical prostatectomy implies surgical removal of entire prostate gland and prostatic capsule as well as the seminal vesicles. In selected patients, good long-term disease free survival rates have been demonstrated after radical prostatectomy. The role of radical prostatectomy as curative therapy for some prostatic cancers is well established. Recent technical innovations that have decreased the overall morbidity of the procedure have increased interest in the operation and have led to more frequent application of the procedure.

Patients' selectionPatients with tumour, that apparently is confined within the capsule of the

prostate gland, are candidates for radical prostatectomy. This includes patients with Ti.2N0M0 stage prostate cancer. Since the margin of surgical dissection in radical prostatectomy follows closely along the prostatic capsule, it seems logical that surgical margins are inadequate in patients with extracapsular extension of tumour. Therefore, the procedure does not seem indicated in patients with obvious tumour extension beyond the capsule of the prostate. In locally advanced prostate cancer (TisNoMo) radical prostatectomy is traditionally not recommended, although some trials proved its oncological efficacy, especially with connection with some forms of maximal androgen blockade, comparing to androgen ablation alone.

In choosing therapy for an individual patient with clinically localized prostate cancer, the age and general health of the patient remain critically important because of the well established protracred course of the disease. Mortality from a localized cancer left untreated is not likely to occur for 8 to 10 years, yet the risk of death from cancer continues to increase for at least 15 to 20 years or more. In the last decade the average life expectancy of a 70-year-old man was 12,1 years and for 75-year-old it was less than 10 years. Thus the potential benefits of therapy decrease rapidly as men age. In general, patients should have a reasonable expec-tancy of 10 to 15 years of life in order to justify the operation.

Serum PSA levels increase proportionally with advancing clinical stage. However, considerable overlap is present among all clinical stages. As with clinical stage, there is correlation between advanced pathologic stage and increasing serum PSA levels but with considerable overlap between preoperative PSA and pathologic stage. Higher preoperative serum PSA levels are not always associated with advanced pathologic features (established extracapsular extension, seminal vesicle invasion, positive lymph nodes), and lower values do not necessarily suggest organ confined disease. PSA alone cannot definitively distinguish the stage of the cancer in an individual patient.

The role of neoadjuvant hormonal deprivation before definitive surgical treatment in order to diminish the rate of pathological extracapsular extension of

the cancer, positive surgical margins, rate of biochemical, local or general progression as well as cancer specific and overall survival is not established so far.

Similarly the role of salvage radical prostatectomy made in cases with local progression after radical external beam radiation or brachytherapy seems to be limited.

Pelvic lymphadenectomyLymph node dissection is performed as a staging procedure as an integral part

of radical retropubic prostatectomy or solely, as a laparoscopic procedure before definitive surgery. Accordingly, the operation should be limited in scope, but the surgical dissection should encompass the primary lymphatic drainage of the prostate. Description of lymph node groups in the pelvis is largely a matter of semantics, but the operation is designed to remove the obturator and hypogastric lymph nodes as well as nodes along the medial external iliac chain. Nowadays the anatomical limits of lymphadenectomy often are dimishing. There exists the following kinds of lymphadenectomy:

• Percentage classical - the obturator, internal, external and common iliac nodes are removed,

• widen or broaden - as in classic operation plus presacral and preis-chiac nodes are removed,

• modified - only obturator and hypogastric nodes are removed,• obturator - only oburator nodes are removed.

Radical prostatectomyRadical prostatectomy implies complete removal of the prostate and prostatic

capsule as well as the seminal vesicles. Nowadays usually two approaches are used to remove the gland with surrounding tissues: 1) most often retropubic and 2) more rarely perineal approach. Laparoscopic radical prostatectomy is not performed widely so far. The surgical specimen is similar in all approaches, and neither has been shown to have any therapeutic advantage over the other.

The complications of radical prostatectomy depend on the surgical experience and stage of the tumour. Patients undergoing radical prostatectomy are subject to the same potential complications as any major pelvic operation. However, the incidence of wound infection, deep venous thrombosis, cardiovascular or pulmonary complications is relatively low. Excessive intraoperative blood loss can be avoided by careful and anatomical control of the deep dorsal vein complex. The other complications are: erectile disfunction (10-90%), complete (1-5%) or stress (5-20%) incontinence, anastomotic stricture (5-10%) and rectal injury (1-5%).

It is widely recognized that there are no valid contemporary, prospective, randomized trials with published long-term results comparing the efficacy of radical prostatectomy to either radiation, hormonal therapy or watchful waiting. Retrospective comparisons are statistically invalid. According to data from Mayo clinic, with respect to radical prostatectomy, disease-specific 15-year survivals at 93%, 82% and 71% for Gleason score groups 2-3, 4-6 and 7-10 respectively make

surgery inviting as a treatment choice for operable localized disease in selected patients. The comparable 15-years radiotherapy survivals stand at 85%, 60% and 40% for the same three Gleason score groupings.

Even though radical prostatectomy is an effective treatment, it is associated with considerable morbidity in some cases and efforts are made to provide minimally invasive alternative treatment options with equal efficacy but fewer side effects. Between them are:

• cryosurgical ablation (CSAP),• brachyterapy by transperineal ultrasound-guided radioisotopes implantation,• high-intensity focused ultrasound (HIFU),• radiofrequency interstitial tumourablation (RITA).Surgical palliative treatment of prostate cancerAdvanced prostate cancer (locally, regionally, metastatic) may be associated

with the need of doing life-saving procedures. Between them are:

Transurethral resection of prostate

• transurethral resection of prostate (tunnelisation), urethral stents to facilitae or even make possible voiding in cases of urine retention,• percutaneous nephrostomy, ureteral catheterisation (if possible) in cases of ureterohydronephrosis with anuria and uremia.

References:a) basic literature:1. Donald R. Smith, M.D. General Urology, 11-th edition, 1984, p. 306-4052. Official Journal of the European Association of Urology /2002-2007/.3. Urological Guidelines (European Assosiation of Urology) Health Care

Office /august 2004 edition/.4. Scientific Foundations of Urology. Third Edition 1990. Edited by Geoffrey

D. Chisholm and William R. Fair, MD. Heinemann Medical Books, Oxford, p.516-549

5. Urology edited by N.A.Lopatkin, Moscow, 1982, p292-363

b) supplementary literature:1. Urinary Tract Infection and Inflamation / Jackson E. Fowler, JR. MD. Year

Book Medical Publishers, Chicago 1989. 2. European Urology Supplements /2002-2007/. 3. Urological Oncology. Editors J. Lorens, J. Dembowski, R. Zdrojowy /Dolnoslaskie wydawnictwo edukacyyne, Wroclaw 2002, 2003/, p.11-153. 4. European Urology via www.eropeanurology.com 5. Urology The Gold Jounal /www.goldjournal/net/.