BPH and prostate cancer Anatomy (structure and functions) of prostate Prostate gland, or prostate (from a Greek word - to be coming to be issued forward) is one of glands of sexual system of man's organism. Placing in the bottom third of a small pelvis, under bladder, between pubic articulation and rectum, it represents unpaired, has the form of a chestnut anatomical formation (table № 1). Through its thickness passes prostatic part of urethra (figure № 1). Prostate has two surfaces - forward and back, and also two shares - left and right, between which on a back gland surface there passes blurry expressed groove (fig. № 1). The size of prostate changes in rather significant limits depending on age and individual features organism. At adult men it length becomes 2,5 - 4,2 см, width - 2,2 - 5 см and thickness - 1,7 - 2,3 см, weight - 17 – 28 gr. Prostate gland consists of a glandular body making from 1/2 up to 3/4 its volumes and prostatic muscles. The glandular body includes 20 - 50 separate tubulo-alveolary glandules of pear- shaped or sphenoidal form, each of which has own ductus. These ductuses merge and hereinafter open on a back wall of prostatic part of urethra. Glandular lobules are connected among themselves by connective tissue containing elastic fibres and powerful smooth muscles bunches, making a ring muscle of prostate, which reduction causes of a secret throw out. Outside prostate gland is covered of a capsule, which consists from a dense connective tissue with elements of smooth muscle fibres. The main function of prostate is in produce of a specific secret which containing diverse products has various functional properties: fibers, immunoglobulins, enzymes, vitamins, ions of metals etc. Such set of substances provides power requirements of spermatozoons, participates in processes of ejaculate dilution, and carries protective function. The initial function ensuring making of a secret is motor, the contraction function. It is provided of smooth muscles fibres that are taking place in glandular capsule and in prostatic part of urethra. Structure and function of prostate supervise by androgens, estrogens, hypophysic hormones and steroid hormones (fig. № 2). Various parts of the prostate have unequal sensitivity: androgens stimulate a back part of the gland, estrogens – its forward areas. As hormonodependence organ, prostate gland is a main target of testis androgens; dihydrotestosterone is activest in it. The existence of functional dependence between prostate and testis is convincingly proved. At a bilateral castration its function is sharply reduced, volume of the gland decreases at the expense of destruction of glandular epithelium crates. On the contrary, at various pathological processes, on a background of the reduced function of prostate the function of testis is infringed also, that is reflected in sexual activity of man. Thus, the anatomy functionally features of prostate give conception about complex regulation of functional activity of the gland, about its close interrelation with other organs, and not only small pelvis. А. Benign prostatic hyperplasia (BPH) Introduction: the urgency of BPH is stipulated by that this disease is most often at men of elderly age. Until recently term "adenoma of prostate" widely was used, however today overwhelming majority of the experts in the world recognizes definition of BPH, as most full reflecting morphogenetic nature of disease. In the age of 40 - 49 years, BPH meets at 11-12 % of cases, in the age of 80 years at 81-82%. Is established, that up to 30 % of men of 40-year's age living till 80 years, are exposed to operative treatment concerning BPH. The social importance and urgency of a problem is emphasized by demographic researches of the World Health Organization which are indicative of significant growth of the planet population till 60 years, which essentially outstrip the growth of the population as a whole. Epidemiology researches have shown, that despite of a number of the revealed features and deviations, now it's considered universally recognized, that race, nationality, the features of a feed and smoking have not basic significance in quality of the BPH etiology factors. Also is not revealed of obvious dependence between a degree of sexual activity of men and frequency of development BPH. Etiology and pathogenesis of BPH: In a basis of the modern concept of the BPH' development theory lays embryological and morphological distinction of reaction of separate zones of the prostate on endocrine stimulus. So, the peripheral zone submitted mainly of prostatic acinuses, develops and adjusts under the control of androgens but the central zone in experiment more sensitive to influence of estrogens. The importance of androgens for growth and maintenance of normal prostate function and participation of these hormones in BPH development is well known now. According to modern submissions, the main circulating androgen is testosterone, which arrives in cellules of the prostate and turns to the activer form - dihydrotestosterone (DHT) under action of 5-reductase enzyme, main located in membrane of a nucleus (fig. № 3). The display of DHT activity occurs as a result of its strong linkage with high-affinity androgen receptors, which are in a nucleus of a crate. It results in synthesis of DHT and specific metabolic and proliferative reactions. Thus, the BPH is a DHT- dependent condition. BPH nodes primarily localized in pery- and paraurethral areas, proximally of spermatic tubercle. The further direction of their growth, configuration and the sizes depend on resistance of surrounding tissues of the gland and bladder neck. The bought form and place of hyperplasia nodes defines current features of disease, its symptoms and pathogenesis. They are closely connected as with voiding infringement, development of chronic renal insufficiency (CRI) and infectious inflammation in kidneys and urinary ways, and with irritative symptoms, causing to arterial hypertension, stenocardia, myocardial infarction or cerebral insult. Symptomatology and diagnostics of BPH: In a clinical picture of BPH on the foreground the infringements of urination act. The occurrence and development of the infravesical obstruction caused of BPH is determined by two components: static - as a result of mechanical squeezing of urethra of the prostate hyperplastic tissue (compression) and dynamic - stipulated of hyperactivity of bladder neck, prostatic urethra and prostate adrenoreceptors (constriction). In this connection is possible to allocate two groups of symptoms for analysis of complaints of the patients. First, obstructive symptoms are hesitancy, weak stream, prolonged voiding time, straining, feeling of incomplete bladder emptying, postmicturition dribble, and total urinary retention connected with progressing difficulty of urine outflow in result of prostatic hyperplasia. And secondly, irritative symptoms are daytime frequency, nocturia, urgency, urge incontinence, small voided volumes and suprapubic pain, determined by a degree of functional frustration of bladder neuromuscular apparatus. The earliest symptoms of disease are the micturition frequency, usually at night, weakness of urine stream and reduction of its pressure. Later, with increase of infravesical obstruction, there are complaints on a feeling of incomplete bladder emptying, terminal dribbling, voiding "on drops" etc. At the latest stages, the symptoms stipulated by secondary changes of a bladder and upper urinary ways (pyelonephritis, bladder stones, hydronephrosis, and chronic renal insufficiency) are added. Often complication of clinical current BPH is the acute urinary retention (AUR), which is observed on any stage of disease. Quite often sudden AUR becomes the first clinical manifestation of BPH. On the literary data this complication is observed at 10-50 % of the patients, more often arising in the second stage of disease. The provoking factors of development of this complication can be: infringement of a diet, for example, reception of alcohol or products with a plenty of spices, overcooling, constipations, delayed bladder emptying, stresses etc. Accompanying inflammatory process in prostate gland plays the great role in formation of a clinical picture of BPH. The frequency of the chronic prostatitis at BPH makes up to 70%. The preconditions to development of a chronic inflammation are infringement of venous outflow, acinuses excretory ducts compression by hyperplastic tissue, congesty. The modern clinical classification of BPH is based on the characteristics of functional condition of a bladder, upper urinary ways and kidneys. So, the first stage of BPH is a presence adenoma itself and the dysuric prodromal phenomena. The second stage - presence of residual urine without complications from the part of upper urinary ways and without of an active inflammation in a bladder and upper urinary ways. The third stage - chronic urinary insufficiency with presence of the plenty of residual urine, chronic cystitis and pyelonephritis, bladder stones and CRI. This division on stages is close to classification. Diagnostics of BPH: One of urgent methodological problems at a stage of diagnostics BPH is the standardization of used methods of research and the elaboration of optimum diagnostic algorithm. According to the recommendations of the 3-rd meeting of International Consultation on Benign Prostatic Hyperplasia (BPH) (Monte-Carlo, 1995) were determined obligatory recommended and facultative methods of research. Most comprehension methods of diagnostics BPH is the digital rectal examination (DRE) and the transrectal ultrasonography (USG) which allow to exactly define sizes and the form of prostate growth, presence of accompanying disease of the prostate. Thus it is necessary to mean, that the presence of morphological attributes of BPH, equally, as well as its enlargement determined of palpation or USG, not always corresponds with a degree of clinical displays of disease and degree of infravesical obstruction. A preferable method of definition of degree of infravesical obstruction is urofloumetry, which represents the important information on character of voiding infringement and in a number of cases allows allocating the group of the patients for further urodynamic researches. Significance of maximum flow rate, exceeding 15 ml/sec, usually considered normal. A basic stage of the diagnostic program is the definition of the level of prostate-specific antigen (РSА) in the blood serum with the purpose of revealing a latent prostate cancer. For diagnostics BPH also are used roentgenurologic methods – excretory urography with descending cystography in two projections and ascending uretrocystography (demonstration of set roentgenograms). Treatment of BPH: The set of methods of the BPH treatment, finding a use in clinical practice now can be submitted by the following classification: Surgical treatment of BPH: - Open prostatectomy (tab. 2) - Transurethral resection of the prostate (tab. 3) – Transurethral incision of the prostate - Transurethral vaporization of the prostate – Methods of transurethral laser surgery of the prostate (vaporization, ablation, coagulation, incision). Minimally invasive (alternative) methods of treatment: А. Endoscopic transurethral laser therapy: - Interstitial laser coagulation of BPH (tab. 4); - Transurethral laser coagulation of the prostate. B. Transurethral thermal methods: - Transurethral microwave hyperthermia; - Тransurethral microwave thermotherapy; - Transurethral microwave thermodestruction of the prostate; - Transurethral ultrasonic thermoablation of the prostate; C. Balloon dilatation of the prostate; D. Prostatic stents. Medication therapy of BPH: - -adrenoblockers (doxazosin, terazosin, alfuzosin, terazosin the fig. № 4). - 5-reductase inhibitors (finasteride the fig. № 5). - Phytoextracts (tadenam etc.). The absolute indications to operative treatment according to the recommendations of the 3-rd meeting of International Consultation on Benign Prostatic Hyperplasia is: - Acute urinary retention; - Repeated massive hematuria, caused by prostatic hyperplasia; - Bladder stones; - Repeated infection of urinary ways owing to BPH; - Large bladder diverticulum; - Intravesical growing of medium share of the prostate. The choice of the listed methods of treatment is determined by balance of the factors of efficiency and safety in aggregate ensuring maintenance of a necessary degree of quality of life of a patient. B. Prostate cancer: Introduction: the cancer of the prostate is considered, as one of most frequently meeting malignancies in men of average and elderly age. Prostate cancer advances on the second place in structure of oncologic diseases at man's group of the population is now observed. According to the data of epidemiological researches conducted in USA and Europe, the cancer of the prostate most frequently meets among common malignant tumors after a lung cancer. More often cancer of the prostate is observed at men is more than 50 years old. About 50 % of the prostate cancer patients, in connection with the features of the clinical current, to time of an establishment of the diagnosis already have metastases. Etiology and pathogenesis of prostate cancer: At the present stage, etiology of prostate cancer remains one of the most urgent questions. Series of researches prove the communication of occurrence of a prostate cancer with infringements of an endocrine regulation of sexual hormones balance at a hypothalamopituitary level, adrenal gland and sexual glands. The cancer of prostatic gland is classified according to International System of classification ТNМ. At stages Т1 and Т2 tumor does not overstep the bounds of the prostatic gland. At Т3 - the tumor occupies prostatic gland, extends outside the prostate capsule. Occur expressed metastases in regional lymphatic nodes. At Т4 - the tumor invades surrounding tissues and organs, gives numerous metastases. Hystomorphology characteristic of prostate cancer on classification of the International Anticancer Association includes 3 types of histologic gradation: 1 - high degree of differentiation, 2 - moderate degree of differentiation, 3 - low degree or absence of differentiation. In most cases, an adenocarcinoma originally develops in prostatic acinuses or canaliculus. It frequency makes about 90 % of all histological forms. The sarcoma of prostatic gland meets in 0,5 - 1 % of cases and more often in young age. Diagnostics of prostate cancer Diagnostics is based on complex inspection of the patients. The digital rectal examination and definition of serum prostate-specific antigen level are the primary diagnostics tools. Then follows the roentgenurologic examination - survey and excretory urography, transrectal ultrasonography, computed tomography, bones scanning with the help of radiosfumacevtic agents, and also magnetic resonance examination, which allows alongside with roentgenodiagnostics and a computed tomography to reveal metastases in pelvic bones. РSA serum level testing (at norm is not higher 4,0 ng/ml) has high sensitivity and specificity, low frequency of false-positive or false-negative results and both high positive and negative prognostic importance. The American Urological Association (AUA) recommends realization of this test annually for all healthy men is more senior 50 years, at which the expected duration of life not less than 10 years. In case of the presumable diagnosis of prostate cancer on the data of clinical symptoms, DRE and data РSA serum level, a biopsy of the prostate gland is making. At a positive result of a biopsy, the further step of diagnostic algorithm is the definition of prevalence of malignant process. At stages Т3 and Т4 the tumor is distributed in tissues, which surround prostatic gland. In process of tumor growth, there are signs of diseases poorly distinguished from clinical symptoms of BPH (under condition of absence of metastases). To them concern: dysuria, impairment of urinary stream force to complete urinary retention, pain in an anus, sacrum, loin, legs, feeling of gravity in a perineum. Late manifestations of cancer are the symptoms of defeat of the upper urinary ways, which is connected to extending tumor growth in area of ostium ureteris exposed to a mechanical squeeze. The treatment of prostate cancer till now remains a difficult and inconsistent problem, that is explained by features of clinical current of disease and various character of a tumor reaction on the certain medical influence. In case of early diagnostics of a prostate cancer, when the tumor is circumscribed of prostate gland, the recovery can be achieved in overwhelming majority of cases. The parameter of a 5-year's survival rate in similar cases makes 90%. At a metastatic defeat of separate organs or bones, even at use of the best modern ways of treatment, the survival does not exceed three years. At stages Т1 - Т2 - localized cancer of a prostate - the basic ways of treatment are surgical method and radiotherapy (tab. № 5). The surgical treatment - radical prostatectomy - consists in complete ablation of prostatic gland, seminal vesicles and frequently, pelvic lymphatic nodes. The radiotherapy is made by outside irradiation with the focus on prostatic gland or implantation radioactive capsules in the prostate (brachytherapy). A prevailing method of palliative treatment of advanced prostate cancer is the hormonal therapy, which purpose - achievement of disease remission by suppression of androgen-dependent tumors. The standard position of modern hormonal therapy of prostate cancer is the concept of the maximal androgen blockade. According to this conception, it is necessary to completely remove influence of man's sexual hormones (fig. №№ 6,7). Androgen deprivation can be attained by three pharmaceutical approaches as well as by surgical castration (orchiectomy): - Administration of exogenous estrogens such as diethylstilbestrol; - Use of analogues of luteinizing hormone-releasing hormone (LHRH), which inhibit the release of pituitary gonadotropins (zolodex or decapeptyl); - Elimination of androgens influences on target tissues with antiandrogens (cazodex, androcur) or combined androgen blockade using LHRH agonists plus antiandrogens. The hormonal therapy is applied to treatment both localized and metastatic cancer of the prostate. Also can be applied the combination of various medical methods: surgical, radial or hormonal treatment. The absolute indications to operative treatment according to the recommendations of the 3 rd Meeting of International Consultations on Benign Prostatic Hyperplasia is: - Acute urinary retention; - Repeated massive hematuria caused by prostatic hyperplasial; - Bladder stones; - Repeated infection of urinary ways owing to BPH; - Large bladder diverticulum; - Intravesical growing of medium share of the prostate. The choice of the listed methods of treatment is determined by balance of the factors of efficiency and safety in aggregate ensuring maintenance of a necessary degree of quality of life of a patient. Microwave hyperthermia The use of hyperthermia to promote healing has been recognized and practised since the times of Hippocrates. Numerous studies have since confirmed that the artificial elevation of body temperature to 41 to 45°C may selectively induce irreversible damage to malignant cells while leaving normal cells intact. Rapid advances in material and electronic technology in our century have made it possible to apply local hyperthermia to the prostate in a relatively controlled, safe and noninvasive procedure. The modern hyperthermia unit, described by Servadio, consists of a skirt- type rectal antenna connected to a microwave generator. Computer control facilitates continuous monitoring of temperature variations in the rectal wall and prostatic urethra. Using such a system, Steg and colleagues have reported encouraging results. Servadio and associates have studied the long-term effects of rectal hyperthermia in 124 patients. One year after treatment, 51 percent of patients had sustained symptomatic improvements, the best results being obtained in patients with the most severe symptoms. Despite these findings, rectal hyperthermia is not a panacea for all the problems of retention. Accurate and reproducible positioning of the probe is difficult, and the rectal approach unevenly heats the prostate (the peripheral part of the prostate is heated to a greater degree than is the central region). Transurethral microwave hyperthermia may solve these technical problems. In addition, however, as Servadio has emphasized, little is known of the effect of hyperthermia on the benign enlargement of the prostate. While this remains the case, it is prudent to regard rectal hyperthermia as a remedy, but not a cure, for the symptoms of BPH. Thermotherapy involves elevating the temperature of the prostate to 45°C, producing changes within the periurethral tissue. Baloon dilatation Dilatation of the prostatic urethra was tried during the 18th and 19th centuries, especially by Mercier (1844), but met with limited success. The first successful application dates from 1956, when Deisting developed a dilator consisting of two flat metal plates set on a screw thread. The dilator was introduced into the urethra with the plates held together, once positioned, the plates could be separated by turning the screw thread. Deisting’s method has since been superseded by balloon dilatation of the prostate, a technique with its origins in percutaneous transluminal coronary angioplasty. In prostatic balloon dilatation, a balloon is passed through a catheter to the level of the prostatic urethra and inflated. The optimal period of dilatation is estimated to be between five and 20 minutes. Symptomatic responses to balloon dilatation are excellent although the urodynamic responses tend to be better in patients with smaller prostates. The procedure is safe and relatively simple and may be preferred by younger patients, many of whom fear the retrograde ejaculation that can develop after TURP. The success of balloon dilatation depends in part on careful positioning of the balloon, and a variety of positioning methods ensure that the distal end of the balloon is above the level of the distal sphincter. Patient selection also influences outcome in this procedure. Dilatation should not be used in patients with a large middle prostate lobe, acute urinary retention, carcinoma of the prostate, or with a prostate that weighs more than 30 g. Intraprostatic stents A recent innovation, the intraprostatic stent was first described by Fabian as an alternative to an indwelling catheter in inoperable patients with infravesical prostatic obstruction. Since then, four main types of stent have been devised: the intraprostatic coil, the intraurethral catheter, the Wallstent (a self-expanding stent made of woven stainless steel), and the titanium stent. Large-scale clinical experience with stents has been documented for the prostatic coil only. Of 41 patients, 28 (68 %) showed a satisfactory voiding pattern three months after the coil was inserted. Twelve-month follow-up data from the same series indicated continued success in 61 percent of the patients, based on objective and subjective symptom criteria. Intraprostatic stents may be an alternative to temporary or permanent indwelling catheters and can relieve obstructive voiding symptoms in the elderly. Long-term use has not been associated with urinary infections, but encrustation of the stent may occur. Robotic The long-term mortality and morbidity from TURP are higher than those associated with open prostatectomy, perhaps reflecting the incidence of transurethral syndrome (TUR syndrome), a constellation of hypotension; bradycardia; various neurological signs including twitching and convulsions; cyanosis; and renal failure. As reviewed recently by Krane and Siroky, TUR syndrome appears to be the result of dilutional hyponotraemia and ammonia intoxication caused by absorption of the glycine irrigation fluid. Shorter operating times should reduce the opportunity for irrigant absorption, and one way to achieve this goal may be to develop a robot ‘surgeon’. Davies et al have demonstrated the feasibility of this suggestion. In a pilot study, the prototype robot successfully resected a simulated prostate in approximately 5 minutes. In a subsequent study by the same group of researchers, urinary flow improved from 10.1 ml per second (range, 5.5 to 13.6 ml per second) to 22.2 ml per second (range, 9 to 40.5 ml per second) in 28 patients who underwent robotic TURP. In response to spatial and histological data supplied by the surgeon, these robotic devices can now suggest a cutting programme that the human operator can accept, modify, or reject. The aim is to produce a machine capable of resecting up to 60 g of tissue in 10 minutes or less. This goal is still some way off, however, and the widespread application of robots in urological surgery is years away. TULIP Another system for transurethral surgery is transurethral ultrasound-guided laser-induced prostatectomy (TULIP). The TULIP system combines an endourethral real-time ultrasound probe and an Nd:YAG laser filter. The system creates a controlled coagulation necrosis of the prostate tissue without bleeding; therefore, no irrigation or urethral catheterization is required. Preliminary results show that treatment with TULIP is as effective as treatment with TURP after three months’ follow-up. Progress in the medical therapy of BPH Modern plant remedies A number of extracts derived from plants have been used in clinical trials involving patients with BPH. The sources of these extracts range from pumpkin seeds to dwarf palms. The mechanism of action of these extracts is unknown, although steroid-related compounds called sitosterols have been implicated as the active components. A considerable number of studies have described the effects of plant extracts in the management of BPH. Also subjective improvement has been reported in 60 to 80 percent of patients, similar improvements were seen in patients receiving placebo. Alpha-adrenergic-receptor blockers In addition to the passive component resulting from the enlarged prostatic mass, outflow obstruction in BPH is believed to contain a dynamic component resulting from increased urethral smooth-muscle tone. In the mid-19th century, the French urologist Jean Civiale emphasized the importance of this dynamic component. More recent research has established that urethral smooth- muscle tone, which is estimated to account for up to 40 percent of the total urethral pressure, is largely mediated by alpha1-adrenergic receptors in the prostatic capsule and stroma. Alpha-adrenergic-receptor blocking drugs relax the smooth-muscle component of the prostate and may thereby reduce the dynamic component (i.e., the symptoms) of obstructed urinary flow. These drugs do not affect the underlying basis of the disease, however. Following experimental evidence that the prostatic urethral tone could be decreased by alpha- adrenergic blockade, Caine et al demonstrated that phenoxibenzamine produced a fall in urethral resistance that was associated with an improvement in symptoms and in increase in urinary flow rate. Little or no reduction occurred in the quantity of residual volume, however. These and similar studies confirmed the utility of alpha blockers in BPH, but phenoxibenzamine, a nonselective agent that blocked both alpha1- and alpha2-receptors proved unsatisfactory because of the large number of side effects. Prazosin was the first selective alpha1-adrenoreceptor-blocking agent to be used in the treatment of prostatic outflow obstruction. Clinical studies, including those carried out by Kirby et al, have shown that prazosin increases flow rate and reduces voiding frequency. Like other alpha- adrenergic blockers, prazosin is associated with hypotensive side effects, particularly following the initial dose, but the incidence of side effects is substantially lower with prazosin than with phenoxibenzamine. To date, the side effects and relatively short duration of action of alpha-adrenergic blockers have limited their usefulnessin BPH, although new agents are being developed. The future for treatment of BPH What lies in store for treatment of BPH? can we improve on current therapies, both surgical and medical? In terms of surgical techniques for reducing the hyperplastic prostate, the introduction of TURP might be regarded as a major step toward minimal surgery for BPH. We have also seen how the principles of balloon dilatation in angioplastic surgery of coronary arteries have been applied to the prostate in an attempt to expand the prostatic urethra, relieve urinary retention, and improve urinary outflow. New specialized techniques have included the use of lasers in eye surgery (treatment of detached retinas) and gynaecological procedures (treatment of carcinoma of the cervix). Kidney stones that previously required major surgery for removal can be successfully treated in many cases by ultrasonic lithotripsy. The future may provide new, minimally invasive or noninvasive techniques for prostate surgery. In terms of medical therapy for BPH, growing evidence suggests that the prostate functions in a multihormonal environment and responds to variety of growth regulatory factors. Androgens play a key role in the development, differentiation, maintenance, and pathological changes of the prostate, although other regulatory components appear necessary. Oestrogens have been implicated in the pathogenesis of BPH, in both dogs and humans, and antioestrogens may be a plausible method for treating BPH. Further clinical research is required, however, to establich the true role of oestrogens in prostate pathology. Assuming that oestrogens do have an aetiological role in BPH, this does not imply that antioestrogen treatment will reverse the process and be effective in the medical treatment of BPH. Pushing back the frontiers Over the past century, our understanding of the prostate gland has expanded rapidly as new technology and research have allowed us to discover some of the innermost secrets of this mysterious gland. Studies have pushed back the limits of our knowledge on the prostate from the level of anatomy to the levels of biochemistry and, more recently, of molecular biology. The fact that diffusable growth factors may be prominently involved in the growth regulation of the prostate could offer exciting possibilities for novel therapeutic agents. If one or more of these trophic factors become implicated in the pathological changes leading to abnormal growth of the prostate, another route for the management of BPH may be opened. The prostate, however, presents a complex web of cellular regulation involving steroids, peptide hormones, and peptide growth factors, and further research is needed to unravel its strands. Putting the patient first The quest to unravel the mysteries of the prostate gland has been a phenomenal story, and we have yet to reach the final chapter. The prostate was unrecognized in ancient times, but over the centuries physicians have gradually become more aware of the problems associated with urinary retention, the role of the prostate in this disorder, and the nature of prostatic enlargement. In recent times, we have focused attention both on the normal and pathological prostate. Despite the advances in our understanding of the prostate, one element has remained unchanged: the caring relationship achieved between doctor and patient. When one reflects on the treatment of urinary retention throughout history, the methods employed by some of our ancestors now seem crude and barbaric in comparison with modern patient care. Nevertheless, although they did not share the same depth of knowledge that we enjoy today, ancient physicians made valiant efforts to relieve the suffering of their patients. While our predecessors lacked proper clinical knowledge and technology, many physicians today face a bewildering array of techniques for the diagnosis and treatment of patients presenting with symptoms of BPH. As clinicians become more enamoured of technological improvements, it is often too easy to forget the basic principles of treatment. Despite the rapid developments in the treatment of BPH, the care of the patient, the relief of his suffering, and the promotion of recovery must remain the ultimate objectives of every practicing physician. B. Prostate cancer: Introduction: the cancer of the prostate is considered as one of the most frequently meeting malignancies in men of average and elderly age. Prostate cancer advances on the second place in structure of oncologic diseases at man’s group of the population is now observed. According to the data of epidemiological researches conducted in USA and Europe, the cancer of the prostate most frequently meets among common malignant tumors after a lung cancer. More often cancer of the prostate is observed at men who is more than 50 years old. About 50% of the prostate cancer patients, in connection with the features of the clinical current, to the moment of establishment of the diagnosis had already metastases. Etiology and pathogenesis of prostate cancer At the present stage, etiology of prostate cancer remains one of the most urgent questions. Series of researches prove the connection of occurrence of prostate cancer with infringements of endocrine regulation of sexual hormones balance at a hypothalamopituitary level, adrenal gland and sexual glands. The cancer of prostatic gland is classified according to International System ofd classification TNM. At stages T1 and T2 tumor does not overstep the bounds of the prostatic gland. At T3 the tumor occupies prostatic gland, extends outside the prostate capsule. Occur expressed metastases in regional lymphatic nodes. At T4 the tumor invades surrounding tissues and organs, gives numerous metastases. Hystomorphology characteristic of prostate cancer according to classification made by International Anticancer Association includes three types of histologic gradation: 1 – high degree of differentiation, 2 – moderate degree of differentiation, 3 – low degree or absence of differentiation. In most cases adenocarcinoma originally develops in prostatic acinuses or canalicunus. Its frequency makes about 90 % of all histological forms. The sarcoma of prostatic gland meets in 0,5 – 1 % of cases and more often in young age. Diagnostics of prostate cancer Diagnostics is based on complex inspection of the patients. The digital rectal examination and definition of serum prostate-specific antigen level are the primary diagnostics tools. Then follows the roentgenurologic examination – survey and excretory urography, transrectal ultrasonography, computed tomography, bones scanning with the help of radiosfumacevtic agents and also magnetic resonance examination, which allows alongside with roentgenodiagnostics and a computed tomography to reveal metastases in pelvic bones. PSA serum level testing (at norm is not higher than 4,0 ng/ml) has a high sensitivity and specificity, low frequency of false-positive or false-negative results and both high positive and negative prognostic importance. The American Urological Association (AUA) recommends realization of this test annually for all healthy men elder than 50 years, at which the expected duration of life is not less than 10 years. In case of the presumable diagnosis of prostate cancer on the data of clinical symptoms, DRE and data PSA serum level, a biopsy of the prostate gland is made. At a positive result of a biopsy, the further step of diagnostic algorithm is the definition of prevalence of malignant process. At stages T3 and T4 the tumor is distributed in tissues which surround the prostatic gland. In the process of a tumor growth there are signs of diseases poorly distinguished from clinical symptoms of BPH (under condition of absence of metastases). To them concern: dysuria, impairment of urinary stream force to complete urinary retention, pain in an anus, sacrum, loin, legs, feeling of gravity in a perineum. Late manifestations of cancer are the symptoms of defeat of the upper urinary ways, which is connected with an extending tumor growth in area of ostium ureteris exposed to a mechanical squeeze. The treatment of prostate cancer till now remains a difficult and inconsistent problem that is explained by features of clinical current of disease and various character of a tumor reaction on a certain medical influence. In case of early diagnostics of a prostate cancer when the tumor is circumscribed of the prostate gland the recovery can be achieved in overwhelming majority of cases. The parameter of a 5-years survival rate in similar cases makes 90 %. At a metastatic defeat of separate organs or bones even at use of the best modern ways of treatment the survival does not exceed three years. At stages T1 – T2 – localized cancer of the prostate – the basic ways of treatment are the surgical method and radiotherapy (Tab. No.5). The surgical treatment – radical prostatectomy – consists in a complete ablation of the prostatic gland, seminal vesicles and, frequently, pelvic lymphatic nodes. The radiotherapy is made by outside irradiation with the focus on the prostatic gland or implantation of radioactive capsules in the prostate (brachytherapy). A prevailing method of palliative treatment of an advanced prostate cancer is the hormonal therapy the purpose of which is achievement of a disease remission by suppression of androgen- dependent tumors. The standard position of modern hormonal therapy of prostate cancer is the concept of the maximum androgen blocade. According to this conception it is necessary to completely remove an influence of male sexual hormones (Fig. No.No.6,7). An androgen deprivation can be attained by three pharmaceutical approaches as well as by surgical castration (orchidectomy): - Administration of exogenous estrogens such as diethylstilbestrol; - Use of analogues of luteinizing hormone releasing hormone (LHRH) which inhibit the release of pituitary gonadotropins (zolodex or decapeptyl); - Elimination of androgen influences on target tissues with antiandrogens (cazodex, androcur) or combined androgen blockade with the use of LHRH agonists plus antiandrogens. The hormonal therapy is applied to treatment both localized and metastatic cancer of the prostate. Also can be applied the combination of various medical methods: surgical, radio or hormonal treatment. Pharmacological castration: LHRH agonists Bilateral orchidectomy removes the primary source of circulating androgen, and the castrate range of testosterone in serum is reached within 24 h. While orchidectomy is still considered the ‘gold standard’ treatment, the primary draw-back is the psychological impact; also the need for, and waiting time for, surgical intervention contributed to the enthusiasm when a pharmacological alternative was introduced. Many studies have found treatment with luteinizing hormone releasing hormone (LHRH) agonists to be comparable to surgical castration with regard to efficacy. Like the endogenous LHRH, synthetic agonists stimulate the pituitary to release luteinizing hormone (LH). However, continuous stimulation by potent synthetic agonists with longer half-life than the endogenous LHRH results in down-regulation of pituitary LHRH receptors and a paradoxical suppression of circulating levels of LH and sex steroids. The castrate range of testosterone is generally reached within two weeks and maintained for the duration of therapy. The initial stimulatory effect of LHRH agonists occurring during the first week of treatment is associated with objective and subjective signs, referred to as the ‘flare phenomenon’. Anti-androgens or estrogens given during this initial period of LHRH agonist therapy counteract the flare. Recently, synthetic and potent LHRH antagonists have been introduced. These agents cause an immediate inhibition of the release of LH, follicle stimulating hormone (FSH) and sex steroids. Whether LHRH antagonists have clinical potential either alone or in combination with LHRH agonists awaits further research. LHRH agonists are polypeptides and cannot be administered orally. Depot preparations for monthly injections are most commonly used: 2- or even 3-monthly depots are currently being introduced. Estrogens revisited The antigonadotropic effect of estrogens has been used in the treatment of prostate cancer since Huggins’ discoveries. Both experimental and clinical evidence suggest that estrogen therapy may be superior to castration in terms of efficacy, perhaps because of a direct effect on the tumor. However, apart from adverse feminizing effects, an unacceptable cardiovascular toxicity has brought the use of oral estrogens into disrepute. The dose-dependent cardiovascular side effects seem to be caused by an altered production of coagulation factors: increased factors VII and X and decreased antithrombin III as a result of a ‘first-pass’ effect of portal blood with high estrogen concentration following oral intake. However, recent studies have shown that parenterally administered estrogens do not entail an increased risk of thrombosis or cardiovascular disease. There is therefore a renewed interest in the use of estrogens. A multicenter study (SPCG 5) conducted by the Scandinavian Prostatic Cancer Group, comparing polyestradiol phosphate (Estradurin) 240 mg intramuscularly every 4 weeks (every 2 weeks for the first 2 months) with total androgen blockade has recently completed recruitment of more than 900 planned patients. No comparative data on major endpoints are yet available. Antiandrogens Antiandrogens are defined as substances that compete with testosterone and dehydrotestosterone (DHT) for the androgen receptor and thereby inhibit the action of androgens on their target site. Antiandrogens are administered orally and can be divided into two groups: steroid and non-steroid antiandrogens. Steroid antiandrogens. Steroid antiandrogens e.g. cyproterone acetate (CPA), have dual mechanism of action: they compete for the androgen receptors but also possess progesterone-like antigonadotropic activity, leading to a decreased secretion of LH and FSH with consequent decline in testosterone production and loss of sexual function. CPA is effective in preventing flare in conjunction with LHRH agonist treatment and can be used to suppress hot flushes following orchidectomy or LHRH agonist therapy. Non-steroid or pure antiandrogens. These interact with the androgen receptor and block the intracellular effects of testosterone and DHT. Flutamide, nilutamide and bicalutamide belong to this group of antiandrogens. The negative feedback of androgens at the hypothalamic level is also blocked, resulting in reflex increments of LH, testosterone and DHT levels. Treatment with non-steroid antiandrogens does not lead to bligatory loss of sexual function. This has obvious implications for quality of life, especially in younger patients with a strong desire to preserve potency. However, the marked rise in serum testosterone level is disturbing, because it may ‘overcome’ the blockade of androgen receptors by the antiandrogen. Clinically, non-steroid antiandrogens have been used in long-term combination with either surgical or medical castration as well as anti-flare therapy when treatment is initiated with LHRH agonists. Bicalutamide (Casadex) in monotherapy has been compared with castration in large international trials. A daily dose of 50 mg was found to be inferior to castration in terms of progression-free and overall survival, thus nourishing the fear that the androgen blockade with antiandrogen monotherapy may be insufficient. Higher doses of bicalutamide in monotherapy have been investigated. In two European studies more than 1400 patients with locally advanced or metastatic prostate cancer were randomized between surgical/pharmacological castration and bicalutamide 150 mg daily. Although bicalutamide at this dosage is inferior to castration in patients with metastatic disease, it seems to be at least as effective in patients with only locally advanced prostate cancer. However, the data in the latter group of patients are preliminary and further follow-up is necessary before valid conclusions can be drawn. What could be the explanation for this possible interaction between treatment and tumor burden? The same interaction is believed to exist when antiandrogens are used in combination with castration, and is dealt with further below. Although antiandrogens are often used in combination with castration in combined androgen blockade, another combination has lately attracted attention. 5a-Reductase inhibitors do not seem to have a role as monotherapy in prostate cancer; however, they may be of value in combination with non-steroidal antiandrogens. In principle, the combination is rational. While the former inhibits the formation of the most active androgen, DHT, the latter blocks the androgen receptors. Further, the combination holds the possibility of maintained sexual function and low toxicity. Preliminary studies are encouraging and larger comparative studies are under way. Antiandrogen withdrawal response First described as a flutamide withdrawal response, the phenomenon has currently been extended to an antiandrogen withdrawal response. Most probably caused by an androgen receptor mutation, the withdrawal response may be observed in 30-60 % of prostate cancer patients after discontinuation of the antiandrogen at the time of progression. The phenomenon has predominantly been reported in patients to whom the antiandrogen is administered as a component of combined androgen blockade. Not only has a decline in prostate specific antigen (PSA) been observed, but other objective signs of tumor regression and symptomatic responses have also been reported. What is not clear at present is whether the withdrawal response reflects a serious drawback per se in the use of antiandrogens or whether the phenomenon, when exploited correctly, represents an extra possibility for improving progression-free and overall survival. The withdrawal response has served to emphasize the fact that we are far from fully understanding the mechanisms involved in the development of ‘hormone-refractory’ cancer of the prostate. Combined androgen blockade Whether the combination of castration (surgical or pharmacological) and an antiandrogen is superior to castration alone has been the issue of many debates since Labrie and colleagues advocated the clinical importance of adrenal androgens and introduced the principle of total or combined androgen blockade based on theoretical considerations and experimental observations. The first clinical series of Labrie and colleagues was essentially uncontrolled, and several trials, randomizing thousands of patients, were initiated to test the hypothesis. The designs of the studies have varied: three different antiamdrogens have been used, two non-steroidal and one steroidal: flutamide, nilutamide and CPA. Various LHRH agonists or bilateral orchidectomy have been used for castration in one or both arms. Few studies were double-blinded, and most studies have various methodological flaws or shortcomings, the most common of which is lack of statistical power to detect a meaningful difference in survival. Both the flare phenomenon associated with LHRH agonist monotherapy and the antiandrogen withdrawal response add to the controversy surrounding combined androgen blockade. None of the concepts were sufficiently well known when most of the trials were protocolled, and it is not clear to what extent these phenomena have contributed to observed differences between treatment arms and individual studies. No consensus about the value of combined androgen blockade in the treatment of prostate cancer appears from the published reports. However, when the results of the individual studies are reviewed, the following cautious conclusions may be drawn: the remarkable difference in favor of combined androgen blockade first reported by Labrie and co-workers has not been confirmed. Only two studies have shown a clear statistically significant survival advantage for combined androgen blockade. Some studies have demonstrated a significantly improved progression-free survival in treated patients. More studies have found some evidence of improved objective or subjective response (fall in PSA/prostatic acid phosphatase; relief of symptoms). Whenever a difference in parameters of anti-cancer efficacy has been reported, it has always been to the advantage of combined androgen blockade. Where benefits from combined androgen blockade have been demonstrated or suggested, the antiandrogen used has been a non-steroidal antiandrogen (flutamide or nilutamide). Finally, in all studies addressing the issue, a clear tendency towards more adverse effects, although generally not severe, has been observed among patients treated with combined androgen blockade. An overview, or meta-analysis, of 25 trials initiated before December 1989 has recently been published. In the analysis, where only overall survival was analyzed, individual patient data were obtained from 22 of the trials, totalling 5710 patients with advanced prostate cancer (87 % M1) of whom 3283 had died (57 %). The median follow-up was 40 months. Overall, mortality was 56,3 % in the combined androgen blockade group compared with 58,4 % among patients treated with castration alone. The 5-year survival estimates were 26,2 % and 22,8 %, respectively. These differences, although in favor of combined androgen blockade and corresponding to a 6,4 % reduction in the annual odds of death, are not statistically significant. Although differences in favor of combined androgen blockade were only found in studies using non-steroidal antiandrogens, exclusion of the studies employing CPA did not make the gain in survival statistically significant. Therefore, the meta-analysis did not demonstrate combined androgen blockade to be superior to castration in terms of survival, and one can conclude that if combined androgen blockade entails a gain in survival, it is unlikely to be large. However, the meta-analysis has been criticized. First of all, potential benefitssuch a symptom relief and length of symptom-free survival were not evaluated. Also, a lack of knowledge about prognostic factors makes a comparison between treatments, as well as analysis of subgroups, impossible. Trial maturity heterogeneity, and how this affects the statistical power of the meta- analysis for reaching a negative (‘no difference’) conclusion, has also been questioned. The Southwest Oncology Group embarked on a new study in 1989, INT 0105, investigating the addition of flutamide vs. placebo to surgical castration. Inclusion of almost 1400 patients is complete, and the first results are eagerly expected in 1996. Hopefully, this large study will provide us with a more precise understanding of the value and indications for combined androgen blockade.
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