As the prostate enlarges, it can compress the urethra (Fig. 48.2) and this, together with increased adrenergic tone, can lead to bladder outflow obstruction (BOO) and lower urinary tract symptoms (LUTSs). Therefore, the term BPH includes benign prostatic enlargement (BPE), the clinical features associated with urinary obstruction and LUTSs.

Fig. 48.2 Diagrammatic representation of the impact of prostate hyperplasia on the urethra demonstrating overgrowth of cells in the inner zone of the prostate.

Symptoms

Men with BPH can develop bothersome LUTSs that can impact negatively on their quality of life. It is important to emphasise that not all men who experience LUTSs have BPH. LUTSs can have different aetiologies including bladder cancer or stones, urinary tract infection (UTI) or urethral stricture. Furthermore, a histological diagnosis of BPH does not mean the patient will suffer from LUTSs.

LUTSs can be divided into symptoms of failure of urine storage (irritative) and those caused by failure to empty the bladder (obstructive or voiding).

Irritative symptoms

• Frequency

• Nocturia

• Urgency and urge incontinence

Obstructive symptoms

• Poor urinary flow

• Hesitancy in initiation of micturition

• Post-micturition dribble

• Sensation of incomplete emptying

• Occasional acute retention of urine requiring emergency treatment

Examination and investigations

There is a range of investigations and diagnostic tests available for the evaluation of patients with suspected BPH. Some tests are standard during the assessment of all men with LUTSs. Other investigations are optional and are only performed depending on the patient’s presentation and the clinician’s judgement.

History

A focussed medical history of all men with LUTSs should be taken to elucidate the aetiology of their symptoms. As part of the process, LUTSs should be evaluated using a validated scoring tool such as the international prostate symptom score (IPSS). This can be used to monitor the severity and progression of the disease and assess the impact of therapy on LUTSs.

Physical examination

All patients who present with suspected BPH should undergo a digital rectal examination (DRE) which involves the examiner palpating the prostate with a finger through the rectum wall. A DRE is performed to exclude the presence of prostate cancer (PC) and can also be used to estimate the shape and size of the prostate, although transrectal ultrasonography (TRUS) provides a more accurate measurement of prostate volume.

Urodynamic studies

Simple non-invasive urodynamic studies provide a surrogate measure of BOO. These include maximum flow rate and post-void residual (PVR). Large PVRs of 300 mL, for example, are indicative of bladder dysfunction and predict a poor response to therapy. Definitive proof of BOO requires invasive pressure flow studies.

Imaging

In the past, upper tract imaging involving an ultrasound scan and intravenous urography were used routinely to evaluate LUTSs associated with BPH. These tests are not normally undertaken except in patients with abnormal renal function and LUTSs who should have an ultrasound scan of their kidneys. The following represent the imaging options used for the assessment of men with BPH.

Flexible cystoscopy

Flexible cystoscopy provides an endoscopic image of the bladder for the assessment of prostatic obstruction and informs possible management options. For example, if the prostate has grown and there is intravesical extension, each time the patient tries to void the internal urethral meatus is obstructed. This type of tissue requires surgical removal, whereas simple lateral lobe enlargement may well respond to non-surgical measures.

Prostatic ultrasound scan

Prostatic ultrasound or TRUS uses high-frequency scanners to produce images of the prostate. This imaging is used to obtain an accurate evaluation of the prostate volume and to detect malignant change. TRUS is also used to guide the placement of the needle when obtaining prostatic biopsies.

Other investigations

Other investigations may be carried out to facilitate the diagnostic assessment of patients with LUTSs due to BPH, and these include urinalysis, urine cultures if infection is suspected, and serum creatinine to assess renal function and establish possible upper urinary tract damage. The measurement of serum prostate-specific antigen (PSA) can be considered after counselling the patient, particularly if DRE reveals a nodular or hard prostate.

Treatment

Most men over the age of 50 years exhibit some of the symptoms of BPH. The range of treatment options for the management of BPH includes watchful waiting, medical therapies and surgical interventions. The key issue, therefore, is deciding who should be treated and when.

The British Association of Urological Surgeons has published guidelines for the management of BPH in primary care (Speakman et al., 2004), focussing on when urological referral is required and when non-invasive treatment can be initiated (Fig. 48.3).

Fig. 48.3 Algorithm for the treatment of lower urinary tract symptoms (LUTSs) in males in primary care (from Speakman et al., 2004) (DRE, digital rectal examination; MSU, mid-stream urine sample; PSA, prostate-specific antigen).

Watchful waiting

Men with mild or moderate and not significantly bothersome LUTSs should be offered a trial of watchful waiting. This management strategy does not include any medical or surgical treatment but involves regular active monitoring. In some cases, symptoms remain unchanged for years and no further interventions are necessary since disease progression is minimal. Patients that adopt this modality should be offered education and lifestyle advice (Box 48.1) to manage their urological symptoms together with a review of their medication, particularly diuretics or other medicines known to affect the urinary system.

Box 48.1 Advice for the management of lower urinary tract symptoms

Limit fluid consumption before going out and before going to bed (to reduce urinary frequency and nocturia)

Reduce alcohol and caffeine intake

Schedule toilet visits

Manage constipation

Review medication (including diuretics and other medicines that can affect the urinary system)

Bladder training (encourage patient to go longer between voiding and increase the volume voided)

Use distraction techniques (practice breathing exercises and penile squeezing to control symptoms of irritation)

Therapeutic management

The principal treatment options are α-adrenoceptor blocking drugs, 5α-reductase inhibitors and combination therapy. Phytotherapy is also used in the management of BPH, although the benefits remain unproven.

Tamsulosin

Tamsulosin is a selective inhibitor of the α_1A– and α_1B-adrenoceptor. It has an elimination half-life of about 13 h and is available as a prolonged release formulation that allows once-daily dosing. There is no requirement to titrate the dose upward when initiating treatment. Although the side-effect profile of tamsulosin is similar to other α₁-adrenoceptor antagonists, it is normally well tolerated (O’Leary, 2001). Intraoperative floppy iris syndrome (IFIS) has been reported during cataract surgery in men treated with tamsulosin, as it is highly selective to iris dilator muscle (Chaim et al., 2009). IFIS can lead to complications and poor outcomes during cataract surgery. As a result, it is essential that patients inform their cataract surgeon that they are taking tamsulosin during the pre-operative assessment. It has been recommended to avoid starting treatment and to discontinue treatment with tamsulosin 1–2 weeks before cataract surgery.

Alfuzosin

Alfuzosin displays a higher selectivity for the prostate compared with tamsulosin or doxazosin. It has a half-life of 5 h, but it is available as a once-daily formulation. It has a rapid onset of action and good tolerability (MacDonald and Wilt, 2005). It reduces the overall clinical progression of BPH and it appears to have a sustained beneficial effect on quality of life (Roehrborn, 2006). Alfuzosin has the least effect on ejaculatory function. Alfuzosin should not be co-administered with potent inhibitors of cytochrome P450 3A4 such as itraconazole, ketoconazole and ritonavir, since this can lead to a several fold increase to exposure in alfuzosin.

5α-Reductase inhibitors

The primary androgen responsible for the development and progression of BPH is DHT. There are two isoenzymes of 5α-reductase: type 1 is found in most 5α-reductase producing tissues such as the liver, skin and hair; type 2 is predominant in genital tissue, including the prostate. 5α-Reductase inhibitors downregulate prostate growth by blocking the conversion of testosterone to the more potent DHT.

The two agents currently available in this group are finasteride and dutasteride. Both have been shown to reduce prostate volume, to improve symptom scores and flow rates, and reduce the incidence of complications such as acute urinary retention (AUR) and the need for surgical intervention to treat BPH (Roehrborn et al., 2000, 2002). Improvements in LUTSs are normally seen after the first 6 months of treatment and are sustained during continuous treatment (Lam et al., 2003).

Finasteride

Finasteride is a type 2, 5α-reductase inhibitor that can reduce prostate size by about 30%, improve symptom scores and increase urinary flow. Those most likely to benefit are men with a prostate larger than 40 mL. Side effects include decreased libido, impotence, reduced ejaculatory volume and, less commonly, gynaecomastia and breast tenderness. Serum concentrations of PSA may be reduced by 50% in the first year of treatment with finasteride, a fact which must be taken into account when attempting to interpret the PSA concentration in men with suspected PC.

Dutasteride

Dutasteride inhibits both type 1 and type 2 isoenzymes of 5α-reductase. Although the clinical significance of this is unclear, this double inhibition can reduce serum dihydotestosterone levels by about 90%. Dutasteride decreases prostate volume by up to 26% and reduces the risk of progression to serious complications of BPH. LUTSs also improve after 6 months of treatment. Dutasteride is well tolerated although side effects which include erectile and ejaculatory dysfunction and breast enlargement occur with similar frequency to finasteride.

Combination therapy

It is well established that α-adrenoceptor antagonists are best for managing acute symptoms but have no impact on reducing the risk of complications such as AUR or progression to prostate surgery. In contrast, 5α-reducatase inhibitors have little impact on short-term acute symptoms but reduce prostate size, improve urinary flow and obstructive symptoms in the long-term. Furthermore, α-adrenoceptor antagonists are effective regardless of prostate volume, whereas the 5α-reductase inhibitors are more suited for the management of LUTSs in men with large prostates. In terms of long-term benefits, continued treatment with 5α-reductase inhibitors decreases the risk of AUR and BPH-related surgery. Therefore, it appears logical to use a combination of an α-adrenoceptor antagonist and a 5α-reductase inhibitor to manage acute symptoms and reduce progression of BPH.

The benefits of using a combination of doxazosin and finasteride compared to monotherapy have been demonstrated in over 3000 men (McConnell et al., 2003). Similarly, the combAT trial (Roehrborn et al., 2010) involved nearly 5000 men with moderate to severe symptoms of BPH and prostate enlargement treated with a combination of dutasteride and tamsulosin. This study demonstrated a significant improvement in BPH symptoms over a 4-year period when compared to either agent used alone. The combination was also found to reduce AUR and progression to BPH-related surgery and, although superior to tamsulosin with respect to these complications, combination therapy was not better than dutasteride. Overall, the adverse events associated with combination therapy were few and treatment was well tolerated.

Combination therapy with an α-adrenoceptor antagonist and a 5α-reductase inhibitor has now been adopted widely into routine practice for the early management of LUTSs and to reduce progression of BPH.

Phytotherapy

A number of plant extracts are reputed to be effective in the management of symptoms of BPH. They include saw palmetto berry (Serenoa repens), African plum tree (Pygeum africanum), stinging nettle (Urtica dioica) and rye grass pollen. Their mechanism of action remains unclear but may exert an anti-inflammatory effect by inhibition of prostanoid formation and perhaps produce some degree of inhibition of 5α-reductase. Most of the data available to support the use of plant extracts derive from poorly designed studies. As evidence to assess efficacy and safety is lacking, phytotherapy remedies are not currently recommended by international guidelines for the management of BPH.

Surgical treatments

Surgical interventions are commonly performed in men with LUTSs caused by BPH that have failed to respond to medical treatment. Surgery is also indicated in patients who develop complications such as intractable or recurrent urinary retention, renal impairment, persistent haematuria, recurrent UTIs or bladder stones.

Transurethral resection of the prostate

Transurethral resection of the prostate (TURP) is a common and effective procedure which achieves a high level of improvement in symptoms and flow rate. It is the preferred surgical intervention in men with a prostate volume between 30 and 80 mL. Sections of prostate are removed using electrical wire loops attached to a tube-like telescope (resectoscope) inserted into the urethra. The tissue removed is collected for histological assessment. There is a small incidence of perioperative mortality associated with TURP along with complications such as bleeding, UTIs and epididymitis. Long-term complications include stress incontinence, urethral and bladder neck strictures and erectile dysfunction.

Open prostatectomy

Open prostatectomy involves the surgical removal of an enlarged prostate. Typically, an incision is made through the lower abdomen although sometimes the incision is between the rectum and the base of the penis. This procedure is now performed infrequently and restricted to very enlarged prostate glands (larger than 100 mL) and those with large bladder stones or bladder diverticula (Stoevelaar and McDonnell, 2001). Open prostatectomy requires a longer hospital stay than transurethral resection and is associated with a higher incidence of bleeding and other complications.

Minimally invasive techniques

Various treatment modalities have been tried as alternatives to TURP to reduce the risks associated with resection. Thermotherapy and laser technology are the most commonly used. Thermotherapy uses techniques such as electrovaporisation and transurethral microwave heat treatment (TUMT), which heats the prostate to cause vaporisation of the tissue. Various types of laser energy can also be used to destroy prostatic tissue mainly by coagulation or vaporisation.

Patient care

Patients generally seek medical help for BPH because of the impact of symptoms on their quality of life. Most men tolerate a high degree of symptoms and impact on daily activities before they seek help. Table 48.1 lists some common therapeutic problems in the management of BPH. Patients should receive information about the management options available, the investigations that they need to undergo and possible treatment outcomes and adverse effects. Patients receiving drug therapy should receive specific information about their treatment, including potential benefits, timeline of expected outcomes and possible side effects.

Table 48.1 Common therapeutic problems and proposed management strategies in benign prostatic hyperplasia

Problem	Solution
Patient taking α-blocker still symptomatic after 2 weeks	Patients should be advised that it may take 2–6 weeks before symptomatic treatment relief is seen
Patient taking an α-adrenoceptor blocker complains of cardiovascular adverse effects such as dizziness, syncope, palpitations, tachycardia or angina	These side effects are more likely in elderly patients. They are most common after the first dose and reflect the hypotensive effects of the drugs. They can be reduced by titrating the dose or using more uroselective drugs such as tamsulosin
Sexual dysfunction	Decreased libido or impotence can occur in patients taking finasteride and dutasteride. Abnormal ejaculation can be caused by α-blockers. Tamsulosin in particular can cause a dry climax (retrograde ejaculation). Patients should be forewarned when discussing treatment options
Patient taking finasteride notices breast enlargement	Unilateral or bilateral gynaecomastia is a frequently reported side effect with finasteride and patients need to be counselled accordingly when discussing treatment options
Patient taking finasteride or dutasteride has a sexual partner who is pregnant	Exposure to semen should be avoided as both drugs can cause abnormalities to genitalia in a male fetus. The patient should be advised to use a condom

There are two websites which produce particularly useful educational material on prostatic disease: the Men’s Health Forum (http://www.menshealthforum.org.uk/) and the Prostate Research Campaign (http://www.prostateuk.org/index.htm).

Prostate cancer

Epidemiology

PC is the second most common cancer in the world and the most common form of cancer in men. Incidence varies from country to country with the highest rates in America, Canada and Scandinavia and the lowest rates in China and other Asian countries (Quinn and Babb, 2002; Gronberg, 2003). In the UK, nearly a quarter of all new male cancer diagnoses are of the prostate. The lifetime risk of PC is 1 in 10 in males in the UK.

The aetiology of PC is multi-factorial. Testosterone and DHT have an important role in the disease as males who undergo castration before puberty do not develop PC. Other factors which can influence the risk of developing PC include the following:

Age

PC is rare before 50 years in Caucasians and before 40 years in Africans, but after this age, the incidence and mortality increase exponentially with every passing decade. Most cases are detected around the age of 70.

Race

Incidence and mortality is high among Caucasians and African Americans and lowest in Chinese males. Environmental factors may play a role in this variation as studies have found an increased incidence in East Asian men who relocate to western countries.

Family history

Presence of PC in a first-degree relative or in multiple family members who need not be first-degree relatives increase risk. Inheritance of a susceptible gene or polymorphism of gene may be responsible for this.

Diet

Although there is no compelling evidence to prove the direct influence of diet, high intake of fat, red meat and dairy produce, typically the main sources of dietary fatty acids in a Western diet, have individually been linked with PC. The low incidence of PC in China and Japan may be due to their use of soya bean products which contain isoflavones and inhibit protein tyrosine kinases responsible for cell proliferation.

Other factors

These include exposure to cadmium (found in cigarette smoke), pesticides, alkaline batteries, radionuclides and heavy metals.

Pathophysiology

The growth and differentiation of cells in the prostate is under androgen control. In the prostate, free testosterone diffuses into the epithelial cells where it is converted to DHT. Various growth factors are present in stromal cells, and the interaction of these with epithelial cells can play a role in cell proliferation and growth. The development of PC is generally a slow, gradual process where cellular structure changes from normal through dysplastic to cancer. High-grade prostatic intra-epithelial neoplasia (HGPIN) represents the precancerous stage of cellular proliferation in prostate cells and can be detected by biopsy. It can predate carcinoma by 10 years or more. There is no link between PC and BPH but they can coexist.

Screening

Population-based screening based on PSA levels is prevalent in the USA, and the annual incidence here has doubled due to this. In the UK, screening is not advocated as the prevailing view is that there is a lack of evidence to support it. Due to the aetiology and nature of PC, most patients will not be symptomatic in their lifetime and screening may increase the risk of overtreatment.

Symptoms

Clinical symptoms of PC are similar to those for BPH, and there are no symptoms which correlate specifically to early PC. As more than 50% of men above the age of 50 years have prostate-related symptoms, it is difficult to detect early PC. Advanced PC typically presents with symptoms of urethral and bladder outlet obstruction, anaemia, weight loss, haematuria or bone pain.

Examination and investigation

Physical examination

A DRE is an important diagnostic tool for PC with an estimated sensitivity of more than 60%. A palpable tumour will have a distinctive texture, but the accuracy of detection may depend on the experience of the clinician. False-positive results can occur in the presence of BPH or cysts.

Imaging

TRUS of the prostate is commonly used to aid the diagnosis of PC. Sensitivity ranges from 48% to 100%. Cancer in the anterior and central region of the prostate can, however, be missed. Computerised tomography, MRI scan of the pelvis and isotope bone scan are also useful to stage PC, but they are not effective as screening methods.

Prostate-specific antigen

Measurement of PSA is an accurate and clinically useful biochemical marker because it is specific to prostate tissue and produced by the columnar epithelial cells in the prostate gland. Unfortunately, PSA is not cancer specific as any damage to the internal architecture of the prostate can result in release. As a consequence, it is not a useful tool for diagnosing cancer on its own, but it is useful in monitoring the effect of treatment or tumour progression in untreated patients. Generally, PSA is high in PC, but it can sometimes be low in high-grade malignancy. The standard assay for PSA measures total prostate-specific antigen (tPSA) and includes all molecular forms. Age-specific ranges are available (Table 48.2) and help make it a better predictor, but this is only a rough guide as variations occur due to racial difference. There is no threshold for PSA below which PC cannot be found.

Table 48.2 Age-specific levels of prostate-specific antigen

Age	Prostate-specific antigen (ng/mL)
40–49	≤ 2.5
50–59	≤ 3.5
60–69	≤ 4.5
>70	≤ 6.5

Prostate biopsy

This is a definitive method to detect PC. TRUS guided biopsy will help obtain samples from the peripheral and transitional zones of the prostate and other suspicious areas. The peripheral zone of the prostate is the location where the majority of the PC occurs and the most common location for HGPIN. It is difficult to identify PC from trans-urethral resection of the prostate specimens as not much of it occurs in the transitional zone. In the UK, USA and Europe, the most widely accepted histological grading system, which corresponds to biological malignancy, is based on the Gleason scale (Gleason and Mellinger, 1974). Histological examination of biopsy tissue is undertaken to identify cancer cells and these are scored from 1 to 5 depending on the different pattern of glandular tissue (Fig. 48.4). A score of 1 corresponds to well-differentiated cells, while a score of 5 corresponds to poorly differentiated cells. The higher the score, the more aggressive the cancer. The number for the two most common types of cell in the sample are added together to get a Gleason score. The score ranges from 2 to 10. This is an important prognostic factor as it can help predict the future behaviour of the tumour and determine the treatment required.

Fig. 48.4 Gleason scale.

Cancer staging

Results from a DRE, biopsy and scan are used to identify the extent of the cancer. The tumour volume, whether there is invasion into or through the capsule, and spread to lymph nodes or bone are all taken into consideration for staging. Staging based on the tumour, node, metastasis (TNM) system is a classification accepted worldwide (Epstein et al., 2005). Based on the TNM classification, PC can be classified into localised disease, locally advanced disease and advanced/metastased disease.

Treatment

The factors that must be considered to aid the treatment decision relate to the tumour and the patient:

Tumour: Staging result, histology, Gleason score and the PSA concentration.

Patient: Age at diagnosis, life expectancy and the presence of co-morbidities such as cardiovascular disease, chronic obstructive pulmonary disease and diabetes (Fig. 48.5).

Fig. 48.5 Diagrammatic representation of the site of action of some treatments used in prostate cancer.

Localised prostate cancer

Established treatments with curative intent

Active surveillance

It is difficult to distinguish PC which may not cause any problems to that which may grow and spread aggressively. Curative treatment can improve longevity but has side effects which include impotence and incontinence and can affect the quality of life of the individual. Patients on active surveillance are monitored closely by repeated testing of PSA levels, DRE and biopsy with the intention to make a radical intervention to treat if there is disease progression. A 20-year outcome study following conservative management of localised PC found that the annual mortality rates did not support aggressive treatment (Albertsen et al., 2005). Although active surveillance can spare side effects of treatment without compromising survival, regular biopsies used to monitor the disease can also be uncomfortable and carry a risk of infection. The optimal schedule for measuring PSA and repeating biopsies is unclear.

Radical prostatectomy

This is the treatment of choice and the procedure involves the total removal of a prostate, seminal vesicle, distal vasa, ejaculatory ducts and prostatic urethra. In the open procedure, it is performed by the retro pubic or perineal approach based on the surgeon’s choice. Laparoscopic prostatectomy, and more recently robotic-assisted laparoscopy, has been developed. The most common complications of prostatectomy are blood loss, post-operative thromboembolism, urinary incontinence, impotence and rectal injury. Systemic review and meta-analysis have shown that the laparoscopic and robotic methods are associated with less blood loss and transfusion, but oncological outcomes, incontinence and erectile dysfunction rates are similar with all three types of prostatectomy.

Radical external-beam radiotherapy

Radiotherapy is used for locally confined disease and more recently for locally advanced disease state as well. In this treatment, high-energy photons produced by a linear accelerator are targeted at the prostate. Sometimes, special particles such as protons and heavy ions are used and have advantages over photons in terms of dose distribution. The side effects of radiotherapy include impotence, genitourinary stricture, rectal bleeding, haematuria and incontinence.

Interstitial brachytherapy

With interstitial brachytherapy radioactive isotope seeds are placed in the prostate under ultrasound or fluoroscopic control. These implants can emit radiation of low energy over several weeks and can be temporary or permanent. This treatment has the potential advantage of less erectile dysfunction than other treatment.

Minimal invasive procedures

The minimal invasive procedures are in the development stage and, although they may be used in some centres, there are no medium- or long-term follow-up data to prove efficacy. The various procedures include:

Cryosurgical ablation of prostate (CSAP)

Cryosurgical ablation involves freezing the prostate which results in cell death by protein denaturation, direct rupture of cellular membranes and apoptosis. Freezing is achieved by placing 12–15 cryoneedles into the prostate guided by a transrectal ultrasonograph and using the cryoneedles to create freeze thaw cycles using temperatures of −40 °C.

High-intensity focussed ultrasound (HIFU)

In this technique, ultrasound waves from a transducer are focussed on the prostate tissue to cause damage to the cells by mechanical and thermal effects. The malignant tissue is subjected to temperatures above 65 °C and hence is destroyed by coagulative necrosis.

Radio-frequency interstitial tumour ablation (RITA)

A needle electrode is placed inside the prostate and radio-frequency waves are delivered through it to heat the tissue up to 100 °C thereby causing necrosis.

Watchful waiting

This approach implies that the patient is observed for symptomatic progression and will only receive palliative treatment when clinical symptoms develop. Since the disease often progresses slowly, watchful waiting is an option for patients with early disease as it maintains their quality of life and avoids complications related to surgery or radiation therapy. On the downside, it is not a curative option, the cancer can metastasise and be a source of pain and reduce life expectancy.

Locally advanced prostate cancer

Hormonal therapy/androgen deprivation therapy

In locally advanced disease involving areas outside the capsule, there is an increased risk of relapse and lymph node metastasis after prostatectomy.

Androgens are produced both in the testes (95%) under the stimulation of luteinising hormone (LH) and luteinising hormone-releasing hormone (LHRH) from the pituitary gland, and in the adrenal glands (5%) under the stimulation of adrenocorticotropic hormone (ACTH). The androgens produced by the adrenal gland are hormone precursors that are enzymatically converted to testosterone and DHT in prostatic and peripheral tissue. Since testosterone is a well-known etiologic factor associated with PC, it follows that testosterone deprivation can be utilised as part of treatment. In practice, this can be achieved by either surgical or medical castration with the response time varying from a few months to years.

Surgical castration

This is further discussed under metastatic disease.

Medical castration

A number of drugs can be used to reduce the levels of testosterone to those achieved by castration.

LHRH agonists

LHRH is released in the hypothalamus and stimulates the secretion of LH by binding to the LHRH receptors in the pituitary. This LHRH receptor complex is normally broken down by enzymes which lead to the release of lutenising hormone and frees the receptors for further binding with LHRH. LHRH agonists are synthetic analogues that bind to the LHRH receptor and the complex formed is resistant to enzymatic action. Thus, they maintain a continuous presence on the receptor and render the pituitary gland refractory to hypothalamic regulation compared to the pulsatile release in normal individuals. Continuous administration of LHRH agonists exhibits a biphasic response. There is an initial increase in LH, and testosterone release referred to as ‘tumour flare up’ followed by a fall over the following 1–2 weeks due to the down regulation and decrease in LHRH release as the receptors are continuously occupied. ‘Tumour flare up’ is prevented by first initiating treatment with an anti-androgen before the use of LHRH agonist. The anti-androgen is then continued for a further 3–4 weeks. Currently available LHRH analogues include buserelin (nasal spray), goserelin, triptorelin and leuprorelin. Goserelin is administered subcutaneously at monthly or 3 monthly intervals, whereas triptorelin and leuprorelin are administered intramuscularly at monthly or 3 monthly intervals.

In advanced PC, therapy with an LHRH agonist is comparable in efficacy to surgical orchiectomy or diethylstilboestrol but with reduced physical and psychological discomfort of the former or the cardiovascular risks of the latter. There would appear to be little difference between the various formulations of LHRH agonists. UK, U.S. and European guidelines support the use of LHRH agonists as first-line agents in the treatment of advanced PC.

More recently, a novel agonist called histrelin was introduced. This is a 1-year subcutaneous preparation which is surgically implanted.

Anti-androgens

Anti-androgens competitively inhibit the effect of androgens peripherally by competing with testosterone and DHT for binding sites in the prostate. This results in inhibition of cell growth and apoptosis. Based on their chemical structure, the anti-androgens can be further divided into steroidal agents, which include cyproterone acetate, megesterol acetate and medroxyprogesterone, and non-steroidal agents such as nilutamide, flutamide and bicalutamide.

The steroidal agents also possess progestational activity and inhibit leutinising hormone secretion by acting centrally on the pituitary thereby reducing serum testosterone levels. The non-steroidal agents do not possess this additional property. Cyproterone is the most widely used steroidal agent normally administered in two or three daily doses of 100 mg despite having a half-life of 30–40 h. It can be used to treat the hot flushes associated with LHRH agonists or orchiectomy. Side effects include hepatoxicity, loss of libido and potency, fatigue and depression. Use of medroxy progesterone and megestrol is limited because of less favourable outcomes in clinical trials compared to cyproterone.

Non-steroidal anti-androgens are used in patients who wish to preserve their quality of life as they do not suppress testosterone and hence preserve libido, physical performance and bone mineral density. The disadvantage of nilutamide, flutamide and bicalutamide is a reduced survival when used as monotherapy because of a gradual rise in testosterone. All three agents have side effects of gynaecomastia, gastro-intestinal upsets, idiopathic hepato-cellular toxicity and haematuria. Bicalutamide has a better safety and tolerability profile compared to nilutamide and flutamide (Inverson, 2002). Some trials show that non-steroidal anti-androgens used in combination with surgical castration or LHRH agonists bring about complete or total androgen blockade by also reducing the production of androgens from the adrenal glands, which normally accounts for 5% of the body’s production, thereby conferring a small survival advantage.

LHRH agonists and the non-steroidal anti-androgen flutamide have been used as neoadjuvant (treatment to reduce tumour size before further surgery or other treatment) or adjuvant (treatment given in addition to primary/initial treatment to reach a treatment goal) with radiotherapy to improve disease-free and overall survival in patients with locally advanced disease.

Metastatic prostate cancer

LHRH agonists

Patients with metastatic cancer of the prostate usually respond to treatment with LHRH agonists and use is as described above for locally advanced disease.

Surgical castration

Surgical castration by bilateral orchiectomy is the treatment of choice for metastatic disease. Advantages include its low cost and morbidity with testosterone levels falling to castration levels within 5–12 h of surgery. The disadvantages include psychological trauma, its irreversible nature and the fact that nearly half experience side effects including loss of libido and potency, hot flushes and bone and muscle loss.

Other palliative treatments

LHRH antagonists

LHRH antagonists, which include abarelix and degarelix, work by competitively binding to LHRH receptors in the pituitary thereby suppressing LH release and creating a rapid and sustained decrease in testosterone levels. They do not cause an initial surge in testosterone levels and hence there is no ‘tumour flare up’ or need for short-term treatment with anti-androgens unlike the LHRH agonists. Abarelix requires an induction regimen followed by monthly injections and use is associated with anaphylactic reactions. Degarelix is given as a monthly depot injection; the most common side effect is a local reaction at the injection site such as swelling and erythema. Degarelix has a place in high-risk PC where the patient is acutely symptomatic with impending spinal cord compression, ureteric obstruction and urinary retention. Degarelix reduces testosterone, LH and PSA levels faster than LHRH agonists and reduces microsurges of testosterone.

The European Association of Urology (EAU) guidelines on PC recommend the use of LHRH antagonists in patients with metastasis and impending spinal cord compression (Heidenreich et al., 2009).

Bisphosphonates

Skeletal involvement in PC can be disease related or due to androgen depletion therapy. Bisphosphonates are pyrophosphates that inhibit osteoclast activity in bones and hence prevent and treat bone lesions. Pamidronate prevents bone loss but zolendronate not only increases bone mass while on androgen depletion therapy but also reduces skeletal complications in patients with bone metastasis secondary to PC (Saad and Schulman, 2004). Bisphosphonates are also recommended for pain relief when analgesics and palliative radiotherapy to bone have failed. Dental examination needs to be carried out before commencing treatment with a bisphosphonate due to the risk of osteonecrosis of the jaw in those with a history of dental trauma, infection or surgery.

Ketoconazole

This broad-spectrum, imidazole, anti-fungal can be used at a higher dose than is normal for its anti-fungal effect to inhibit the testicular and adrenal cytochrome P-450 enzyme synthesis of sex sterols. It has a rapid onset of action and is usually prescribed at a dose of 400 mg three times daily. As it causes adrenal suppression, hydrocortisone supplementation is necessary. Side effects of ketoconazole include drug-induced toxicity, adrenal suppression and hepatotoxicity.

Dexamethasone

Dexamethasone is used if spinal cord compression is suspected.

Castrate resistant prostate cancer

Androgen deprivation therapy can fail to control disease progression. The reasons for this are unclear but include the clonal selection hypothesis or adaption hypothesis. In the clonal selection hypothesis, the premise is that the basal cells are the stem cells of the prostate and generate secretory epithelial cells. Whilst the secretory epithelial cells undergo apoptosis upon androgen withdrawal, this is not the case with basal or stromal cells. As a consequence, there is selective survival of these androgen independent cells within the tumour. With the adaption hypothesis, there is the assumption that androgen independence may be an intrinsic, but dormant property of some prostate cells that is activated by androgen deprivation. Whatever the explanation, when there is failure of first-line therapy, quality of life can be improved by using single or combination therapy that includes a second-line hormone treatment (oestrogens), corticosteroids, ketoconazole, chemotherapy and bisphosphonates for short-term palliative response.

Oestrogen

Diethylstilboestrol (DES) is a synthetic oestrogen which acts by producing negative feedback on the hypothalamus and anterior pituitary, thereby down regulating the secretion of LHRH and hence the production of testosterone. Diethylstilboestrol is the least expensive of the synthetic oestrogens and causes fewer hot flushes and psychological trauma compared to the surgical option. Side effects include gynecomastia, loss of libido and potency, oedema, nausea and vomiting, and increased risk of thromboembolism. It is usually used in a dose of 1 mg once daily to reduce the risk of cardiovascular side effects as it is associated with increased cardiovascular mortality.

Corticosteroids

Both prednisolone and hydrocortisone are anti-inflammatory and can alter the body’s immune response to various stimuli and are used in combination with other treatments.

Chemotherapy

Chemotherapy inhibits cell growth and proliferation; it has a variable response rate and is used as a last resort. In the USA, a regimen using mitoxantrone and prednisolone is approved for use in palliation of advanced PC. In the UK, it is recommended that docetaxel is used within its licensed indication to treat men with hormone refractory metastatic disease. Repeat courses of treatment are not recommended if the disease reoccurs when the planned course is complete.

Chemoprevention

Chemoprevention is defined as the administration of micronutrients, dietary products or drugs to prevent or delay the progression of PC.

Diet

There has been interest in a variety of products and numerous studies have been conducted. Currently in favour are soya-containing foods, green tea, pomegranates and omega-3 fatty acids. Selenium and vitamin E are no longer considered favourable. Similarly, vitamin D and lycopene found in tomatoes are also out of favour due to the lack of positive outcomes.

Drugs

5α-Reductase inhibitors which are currently used in BPH to reduce prostate size due to their inhibitory effect on the production of DHT are thought to have potential for chemoprevention.

Studies with dutasteride have shown it can reduce the risk of PC and improve outcomes in BPH by reducing AUR. On the down side, it appears to increase the risk of cardiac failure and consequently is not routinely used in chemoprevention.

Patient care

Treatment is decided after discussing the various options and side effects with the individual. Urinary and sexual function related problems are common side effects of most treatments in PC and need to be discussed in detail with the patient. Emotional factors like depression may also need to be addressed as they can adversely affect the quality of life of the individual. Some of the common problems associated with PC are listed in Table 48.3. Patients can also be referred to http://www.nhs.uk/prostatecancer for facts, information and details of choices available in the diagnosis and treatment of PC. Information on how to cope with the disease and live with PC together with details of various support organisations are available from http://www.cancerhelp.org.uk, whilst http://www.prostate-link.org.uk describes various patient experiences.

Table 48.3 Common problems associated with prostate cancer

Problem	Solution
Loss of erectile function after prostatectomy	Phosphodiesterase 5 inhibitors such as sildenafil have shown efficacy in prevention and help improve chance of spontaneous erection. If medication fails or is contraindicated a vacuum device, intraurethral inserts or penile prosthesis may be used
Advanced disease with impending spinal cord compression	Treat with oral dexamethasone and either cyproterone or ketoconazole with external-beam radiotherapy. LHRH agonist treatment is not advisable as the tumour flare up in the initial stage can stimulate tumour growth and exacerbate the condition
Bleeding and coagulation disorder	Prostate cancer can cause disseminated intravascular coagulation as a pathological response to the disease. This is a rare condition where small blood clots are formed in the body, disrupt the normal coagulation process and cause bleeding. This can be further complicated if the patient has co-morbidities which require treatment with anti-coagulants. Prompt treatment of the cancer with hormones and in some cases replacement of blood, platelets and clotting factors may be required
Hot flushes during androgen deprivation therapy	The hypothalamus is the centre for thermoregulation. Orchiectomy and LHRH agonists inhibit some of the peptides involved in thermoregulation. This increases central adrenergic activity and inappropriate stimulation of thermoregulatory centres, causing peripheral body vasodilatation and hot flushes. Low dose cyproterone acetate (100 mg a day) has been used to suppress hot flushes

Prostatitis

Epidemiology

The term prostatitis comprises a range of disorders that have been defined and classified (Table 48.4) by the International Prostatitis Collaborative Network (IPCN) into four categories (Krieger et al., 1999).

Table 48.4 International Prostatitis Collaborative Network (IPCN) classification of prostatitis

IPCN classification	Comment
I. Acute bacterial prostatitis	Acute infection of the prostate
II. Chronic bacterial prostatitis	Chronic infection of the prostate
III. Chronic prostatitis/chronic pelvic pain syndrome	No evidence of infection
A. Inflammatory	Leucocytes in prostatic secretions, post prostate massage urine, or semen
B. Non-inflammatory	No evidence of inflammation
IV. Asymptomatic inflammatory prostatitis	Lack of genitourinary symptoms

Prostatitis has been estimated to affect up to 16% of adult men. Unlike BPH and PC, which are more prevalent in older men, prostatitis affects men of all ages.

In most instances (between 90% and 95%), the aetiology of prostatitis is unknown with bacteria isolated in only 5–10% of men presenting with prostatitis.

Pathophysiology

Acute bacterial prostatitis (ABP) is caused by bacterial infection. The most common isolated uropathogen is Escherichia coli. Other causative agents include Proteus spp., Klebsiella spp., Pseudomonas spp. and, less commonly, enterococci, Bacteroides and Staphylococcus spp. Chronic bacterial prostatitis (CBP) usually involves recurrent bacterial urinary infections caused by the same organism involved in acute bacterial prostatitis. Both syndromes are of infective origin and represent the minority of cases of prostatitis.

In contrast, the aetiology of chronic prostatitis/chronic pelvic pain syndrome is poorly understood. Several possible mechanisms have been proposed including autoimmune disorders, infection, neurogenic inflammation and voiding dysfunction.

Symptoms

In prostatitis, the clinical presentation and symptoms are a strong diagnostic determinant. A validated, nine-point questionnaire, the Chronic Prostatitis Symptom Index (CPSI) quantifies the severity, frequency and location of pain and discomfort. It is also used to assess urinary symptoms and to establish the impact of symptoms on the patient’s quality of life.

Patients with acute bacterial prostatitis usually present with symptoms of a UTI which may include dysuria, urinary frequency or urgency, whilst some may present with pain of penile, lower back or perineal origin. Signs and symptoms of systemic infection can be present in some cases and include pyrexia, rigors, malaise and myalgia. Acute bacterial prostatitis can sometimes precipitate AUR due to prostatic inflammation.

In chronic bacterial prostatitis, symptoms of UTI and pain can also be present. Typically, men with chronic bacterial prostatitis remain asymptomatic between infective episodes.

The main feature in chronic prostatitis/chronic pelvic pain syndrome is urological pain (perineum, lower abdomen and back, rectum, penis and testicles). These symptoms are usually present for at least 3 months before a diagnosis can be made. LUTSs and ejaculatory dysfunction can also affect men with chronic prostatitis/chronic pelvic pain syndrome.

Patients with asymptomatic inflammatory prostatitis have no symptoms. The condition is usually diagnosed when patients undergo investigation to assess other genitourinary complaints. For example, prostatitis may be found in biopsies taken from patients investigated for elevated PSA or when leucocytes are found in semen samples from men being investigated for infertility.

Examination and investigations

If acute bacterial prostatitis is suspected, a urine dipstick and culture are performed to reveal the presence of pathogens and leucocytes. Depending on the clinical picture, a blood culture may be indicated to diagnose concomitant bacteraemia. An ultrasound scan of the bladder can be conducted to evaluate the residual volume of urine and problems with voiding and urinary retention.

Chronic bacterial prostatitis is diagnosed in men with a history of recurrent or relapsing UTIs. A positive urine dipstick and culture is a common finding during acute episodes. Microscopy and culture of lower tract urinary secretions (urine and prostatic) between symptomatic periods can be performed and will help identify the prostate as the main focus of infection. Imaging of the urinary tract can be conducted to rule out any structural abnormalities.

Chronic prostatitis/chronic pelvic pain syndrome is a diagnosis of exclusion. Typical disorders which must be excluded include the presence of active urethritis, urogenital cancer, urinary tract disease, functionally significant urethral stricture or neurological disease affecting the bladder (Krieger et al., 1999). The main component of this syndrome is the presence of genitourinary pain. After taking a detailed medical history, the evaluation of symptoms can be done using the Chronic Prostatitis Symptom Index. Other investigations include a DRE, urinalysis, urine culture and cytology, screening for sexually transmitted diseases, urodynamic studies, prostatic TRUS and serum PSA.

Treatment

Acute bacterial prostatitis can present as a serious infection and therapy normally includes empirical treatment with parenteral antibiotics. Commonly used agents include broad-spectrum penicillins, fluoroquinolones or third-generation cephalosporins usually in combination with aminoglycosides. Urine culture and sensitivities will inform the choice of future antibiotic treatment, which is recommended to be continued for 2–4 weeks. General supportive measures such as maintenance of appropriate hydration and pain relief are important. Suprapubic catheterisation may be required if AUR is present.

The treatment of chronic bacterial prostatitis involves long courses (at least 4 weeks) of antibiotics. Fluoroquinolones are used as first-choice agents because of good prostatic penetration, their spectrum of anti-bacterial activity and favourable safety profile. If infective episodes are frequent, patients can be offered prophylactic antibiotics for several months with periodic follow-up to monitor progress (McNaughton-Collins et al., 2007).

Since the aetiology of most cases of chronic prostatitis/chronic pelvic pain syndrome is unknown, management often involves empirical treatment. Despite not being considered to have an infective nature, up to 50% of patients with chronic prostatitis/chronic pelvic pain syndrome respond to long courses of fluoroquinolones (Nickel et al., 2001), especially men with symptoms of relatively recent onset (a few weeks). Patients with longstanding symptoms refractory to treatment are less likely to benefit from fluoroquinolones. α-Adrenoceptor antagonists are also used alone or in combination with antibiotics in the management of chronic prostatitis/chronic pelvic pain syndrome. The evidence for efficacy is conflicting but remains an option for patients with persistent symptoms. There are also limited data describing the use of other therapies in chronic prostatitis/chronic pelvic pain syndrome such as fluoxetine, pollen extract, quercertin, finasteride, mepartricin and pelvic electromagnetic therapy.

No treatment is necessary for patients with asymptomatic inflammatory prostatitis since the condition is characterised by the lack of symptoms.