Natural Cures For Prostate Cancer

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The Molecular Biology of Prostate Cancer

Prostate cancer is the most frequently diagnosed malignancy among men in industrialized countries. In the United States, one in eight men will develop prostate cancer during their lifetime 1 , and in 1999 approximately 37,000 died from the disease 2 . In England and Wales, 17,000 cases are diagnosed and there are nearly 9000 deaths annually from prostate cancer 3 . Advances in our understanding of the molecular basis of cancer have led to the characterization of critical pathways regulating tumor growth, which should provide the potential for the development of more effective and less toxic targeted therapies. In 1941 Huggins and Hodges first demonstrated that malignant tumors arising from the prostate were responsive to androgen withdrawal. Since then, hormonal therapy has been established as the principal treatment modality for advanced disease. Over time,however,resistance to treatment occurs. As a result, there has been much interest not only in the molecular changes associated...

Epidemiology of Prostate Cancer

The epidemiology of prostate cancer has provided a number of clues to the etiology of the disease. The incidence of prostate cancer increases with age. However, there is a discrepancy between the clinical incidence of prostate cancer and prevalence of the disease at autopsy 4 . The frequency of autopsy-detected cancer has been reported to be 30 to 40 in men over the age of 50. The incidence also varies markedly throughout the world, with the United States, Canada, Sweden, Australia, and France having the highest rates and Asian populations the lowest 5 . These differences may be due to genetic factors, but environmental factors may also be at play. Japanese male immigrants in the United States have a higher mortality rate compared with those in Japan 6 dietary changes are thought to be a significant environmental factor 4,7 (Table 1.1). Prostate cancer risk, particularly that of early-onset disease, is affected by family history. The association, however, is not as marked as in breast...

Treatment of Early Localized Prostate Cancer

The optimum management of patients with localized prostate cancer remains controversial. Three major treatment options are available radical prostatectomy, radical radiotherapy (external beam radiotherapy EBRT or brachy therapy), and active surveillance (also known as active monitoring and watchful waiting). Each treatment involves its own risk. Radical treatments can cause harmful side effects including incontinence, erectile dysfunction, and even death, whereas watchful waiting causes anxiety relating to the presence of cancer and carries a risk of disease progression. However, outcomes in terms of overall survival appear similar with each of the three modalities. There is relatively little randomized evidence concerning the effectiveness of the different management options for early prostate cancer. In a Scandinavian study 1 , men with early prostate cancer (stages T1b-c or T2) were randomly assigned to radical prostatectomy or watchful waiting. After a median follow-up of 6.2...

Androgen Receptor and Prostate Cancer Etiology

The reason for the varying incidence of prostate cancer between racial groups is undoubtedly multifactorial, with the contribution of both genetic and environmental factors. African-American men have the highest risk of prostate cancer and Asian populations have the lowest 38 . 5a-Reductase, which converts testosterone into the more active androgen DHT activity, correlates with race, with low levels of activity in Japanese men and higher levels in African Americans and Caucasian 57 . Racial variations have also been found in the gene encoding 3b-hydrox-ysteroid dehydrogenase 2, which is involved in the breakdown of DHT, suggesting it may play a role in prostate cancer predisposition 58 .There has been much interest in possible racial differences in male testosterone levels however, studies have shown conflicting results 59,60 . Interestingly, although the incidence of clinical prostate cancer is high in the United States and low in Asian countries, the frequency of sub-clinical...

Retropubic Prostatectomy

The retropubic approach to radical prostatectomy did not develop until Terence Millin's description of his now classical operation for benign disease, the transcapsular prostatectomy. He adapted this operation to total (radical) prostatectomy, which had not been possible with the transvesical procedures with which surgeons had hitherto become familiar 3 . During the ensuing years, the perineal and retropubic approaches for radical prostatectomy each had its advocates. Radical prostatectomy nevertheless remained a formidable procedure, particularly the retropubic approach, with the risk of uncontrolled hemorrhage from San-torini's plexus. In spite of encouraging cancer-specific outcomes in patients undergoing radical prostatectomy for organ-confined cancer, the surgical difficulties persisted, and rudimentary understanding of surgical anatomy precluded any substantial progress. Complications related, first, to the undocumented course of the periprostatic veins and bleeding consequent...

Perineal Prostatectomy

Retropubic prostatectomy continues to be undertaken with excellent results, though some surgeons prefer the perineal approach. The perineal approach avoids the bleeding sometimes encountered from the dorsal venous complex, as the prostate is removed behind this plane. As a result, the anterior surgical margin can be compromised, and this may have some adverse therapeutic significance in some patients, particularly those with extensive or anterior tumors. Complications specific to this approach relate mostly to anal or rectal injury, with a risk of fecal incontinence, infection, and fistula, but such sequelae are uncommon. The perineal route does not allow for assessment or removal of pelvic lymph nodes however, when this is considered important, pelvic lymphadenectomy may need to be carried out as a prior open or laparoscopic procedure. Perineal prostatectomy, therefore, may not be ideal in patients at high risk of a non organ-confined pathological stage.

Familial Prostate Cancer

Prostate cancer (PCa) is the most common cancer diagnosed in North American men, excluding skin cancers. It is estimated that, in 2004, approximately 230,110 new cases and 29,900 prostate cancer-related deaths will occur in the United States 1 . In Australia, one in 11 men will develop the disease during their lifetime 2 . The annual number of new cases registered in England and Wales increased by over threefold between 1971 and 2004, from 6174 to over 21,000 3 (www.icr.ac.uk Everyman). Prostate cancer remains a major public health problem. Over the last 45 years, prostate cancer has been observed to run in families. Familial aggregation (at least two cases in the family) has been observed in around 20 of cases and a hereditary form of PCa in approximately 5 7 . Epi-demiological evidence shows familial clustering of PCa, and it is currently established that a positive family history is a strong risk factor. One of the major issues surrounding familial prostate cancer (FPC) includes...

Evidence for the Genetic Etiology of Prostate Cancer

Evidence for familial aggregation of prostate cancer dates as far back as 1956 8 . Significant linkage in familial prostate cancer was first published in 1996 by a group from Johns Hopkins University, Baltimore, Maryland 9 . This group reported linkage at a locus on chromosome 1q24-25, which was named hereditary prostate cancer 1 (HPC1). Several large linkage studies have since been conducted, and the results revealed new loci and challenged others summarized in refs. 10-13 .

Principles of Radical Prostatectomy

Radical prostatectomy is generally carried out with the intent of achieving long-term disease-free survival and thereby cure of early-stage prostate cancer 20 . Secondary, but nevertheless important, concerns are the maintenance of quality of life, in particular continence and erectile function. In some countries, interest is growing in a potentially palliative role in patients with more advanced and noncurable disease. Favorable long-term survival in patients with pathologically organ-confined tumors has been recognized since Young's early experience 21 . In spite of early concerns, nerve sparing does not compromise cure rate 22 . Today, alongside the shift of pathological stage toward organ-confined disease at diagnosis, neurovascular bundles are rou

Genome Searches in Prostate Cancer

Predisposing genes by looking for co-segregation of markers with the disease in families. The attempt to identify prostate cancer susceptibility loci has been undertaken across the genome by numerous groups. The Union Biomed (ACTANE) group has defined age at onset and number of cases and focused on the collection of clinically significant PCa, because the disease manifests 10 years later on average than prostate-specific antigen (PSA)-detected disease, and hence men with clinically detected early-onset PCa could have had a raised PSA level at an earlier age 36 . Thus far, several GWSs have been reported for prostate cancer 9,11,13,65-80 . The significant results are summarized as follows

Sporadic and Familial Prostate Cancer Biochemical Failure and Differences in Survival

Gronberg et al. 122 tried to estimate the survival of men with FPC and compare them with prostate cancer cases unselected for family history. No significant differences in either overall or prostate cancer-specific survival between familial and sporadic cases were found. Tumor grade at diagnosis in familial cases did not differ from that in a population with prostate cancer unselected for family history. The conclusion, based on the result from this study, was that no differences in treatment between men with and without a positive family history of prostate cancer are justified. However,Kupelian et al. 123 ,in an analysis of the outcome after radical prostatectomy of patients with familial versus sporadic prostate cancer, observed that the former group has a higher likelihood of biochemical failure after radical prostatectomy. They concluded that this effect was independent of pretreatment or pathological factors. Currently, it may be reasonable to recommend that treatment plans...

Screening for Prostate Cancer

Prostate cancer screening is one of the most controversial public health issues in urology. The natural aging of the population and the continued and widespread use of improved diagnostic tests, such as serum prostate-specific antigen (PSA), are resulting in an increase in the numbers of men diagnosed with localized prostate cancer. The issue of screening to identify organ-confined prostate cancer has provoked much public and scientific attention, and there is intense debate about its role in improving men's health. Despite constant pressure from strong advocates of screening, including the general public, special-interest groups, and certain aspects of the media, the findings from most reviews of the scientific evidence conclude that it is insufficient, at present, to recommend routine population screening because of the lack of evidence that this would improve either survival or the quality of men's lives. Particular concerns in these reviews relate to the lack of knowledge about...

Prostate Specific Antigen PSA

Prostate specific antigen (PSA) is a protein found in normal prostate cells of all males. Identifying variations in the serum levels of this antigen is the most effective way to diagnose prostate cancer, identify tumor recurrence, and monitor the response to therapy for prostate carcinoma. The prostate-specific antigen and the prostatic acid phosphatase tests are used to identify and monitor tumors of the prostate. Variations from Normal. Caution must be used when interpreting PSA results. While increases in PSA levels occur in 80 of patients exhibiting prostate cancer, the degree of increase may represent very different diagnoses. Prostate cancer, benign prostatic hypertrophy, and prostatitis can display increased prostate-specific antigen results. Based on the normal range cited above, an increase in serum PSA levels of 4.0-8.0 ng mL may indicate benign prostatic hypertrophy or possible cancer of the prostate. Elevations in excess of 8.0 ng mL are highly suggestive of malignancy. As...

Does Screening for Prostate Cancer Reduce Mortality from the Disease

Since the introduction of the PSA test, screening for early prostate cancer has become prevalent in the United States, with, as expected, a sharp rise in the incidence of the disease in the early 1990s. This was contrasted by a static incidence rate in countries where screening was not widely practiced, such as the United Kingdom. However, by 1996 the U.S. started to experience a slow but constant decrease in the prostate cancer mortality rate, which was advocated by some as resulting from early aggressive intervention with the intensive screening program. This conclusion is flawed by a number of problems. First, in view of the protracted natural history of the disease, it is unlikely that early treatment could have caused this reduction in mortality within such a short time period. Second, similar reductions in mortality rates were observed in countries where screening had not been adopted, such as England and Wales, and the Netherlands, suggesting that other factors, including diet...

What Do Men with Prostate Cancer Think of Screening for the Disease

Public perception of screening for the disease varies. There is widespread pressure for the establishment of national screening programs, with resistance to this pressure often misinterpreted as attempts to save money, deceive the public, or even as sex discrimination. A recent interesting and elegant qualitative research study by Chapple et al. 35 highlighted these feelings, interviewing 52 men with prostate cancer from various geographical areas of the U.K. Although some factual conceptions were revealed, there were also many misconceptions, such as early diagnosis brings better chances of cure, 5-year survival figures in the U.S. are higher than in Britain because of PSA screening programs, PSA testing is not taking place because of lack of resources in the NHS, men should be tested for prostate cancer as women are for breast cancer, men with urinary tract symptoms should all be tested for prostate cancer, and the government is not spending enough money on prostate cancer...

The Hormonal Treatment of Locally Advanced and Metastatic Prostate Cancer

The history of hormonal therapy for prostate cancer dates back to the 1890s, when patients with prostatic diseases, which included cancer, were treated by orchiectomy, and their condition improved. Scientific analyses of the results of treatment emerged nearly a century later, and, after enormous resistance from the urological surgical community, medical therapies for prostate cancer began to replace orchiectomy as a standard treatment for the condition. The urologists argued from the surgical viewpoint that orchiectomy was a simple procedure, and that patients treated in this way could forget about their condition. Medical oncologists argued that it seemed a pretty bad stroke of luck to get cancer, but to be castrated because you had this initial piece of bad luck seemed an unfair twist of fate. Some 20 years after the initial introduction of the concept of luteinizing hormone-releasing hormone (LHRH) agonist treatment for prostate cancer, treatment with these agents is now accepted...

Diet and Prostate Cancer

Prostate cancer is the most commonly diagnosed malignancy in men in industrialized countries and the second leading cause of male cancer-related death. Given the trebling of death rates in the last 30 years and the relative lack of a survival benefit from the treatment of advanced disease, it is critical that we look at preventative stratagems to reduce death rates. Although aging is the most significant risk factor for prostate cancer with a virtually exponential increase in age-related incidence and mortality, prostate cancer is also characterized by a marked variation in its worldwide incidence. Superficially, it would seem to be difficult to separate environmental factors from racial factors in explaining this difference in the incidence of this tumor, but studies of migrant populations suggest that environment is overwhelmingly more significant than genetics in the origins of this cancer. For example, when migrants from a low-risk country such as Japan move to the United States,...

Diet and Prostate Cancer Biology

Although prostate cancer is primarily a disease of older men, neoplastic changes may occur in the prostatic epithelium as early as in the third decade. The time required for some of these early neoplastic transformations is likely to be long. Some dietary compounds display antioxi-dant properties, thus preventing peroxidation and generation of free radicals with potential DNA-damaging effects. Others are inhibitors of cell proliferation, apoptosis inducers, or enhancers of cellular differentiation. Some may act at a hormonal level, as the prostate is an androgen-regulated organ. In many cases, though, the precise pathways modulated by these compounds and mechanisms of DNA damage induced by carcinogenic agents are still poorly understood.

The Treatment of Recurrent Prostate Cancer

There is clinical evidence of prostate-specific antigen (PSA) progression after a median period of 13 months' hormonal therapy. Some 2 years after this evidence emerges, clinical symptoms develop, to be followed a median of 7 months later by death, and this course of events is not what we want for our patients. The biological basis for relapse is of more than passing interest. If patients' biopsy specimens are compared at presentation and relapse, mutations are seen within the androgen receptor in 45 to 55 of patients. It is these mutations that facilitate tumor progression. The androgen receptor is a transcription factor that binds to coactivators and co-repressors together with heat shock proteins, and by this process initiates gene transcription. It may well be that in patients who do not have obvious mutations of the androgen receptor, mutations of coactivators or co- repressors of the androgen receptor are responsible for tumor progression (Fig. 3.1). Fig. 3.1. The androgen...

Prostate Cancer Risk Reduction by Dietary Modification

Preventive medicine is currently a topical issue. Cardiovascular disease is a well-known example. The identification of atherosclerosis as one of the causative mechanisms of cardiovascular disease has resulted in important lifestyle modifications in diet, tobacco use, and exercise. This has led to a significant decrease in the incidence of heart disease in many countries. Prostate cancer potentially represents an ideal target for chemoprevention because of its long latency. Although the use of new biological strategies is being examined in the context of primary prevention and progression of prostate cancer, it has been suggested that nutrition may also have a role. However, does the weight of Diet and Prostate Cancer current scientific and clinical data support a relation between diet and prostate cancer Is there enough evidence for us to be able to advise dietary modifications, such as reduced fat and increased soy protein consumption, and the use of nutritional supplements, for...

Radical Radiotherapy for Prostate Cancer

The incidence of prostate cancer is rising worldwide due to the ageing of the population and the increasing availability of prostate-specific antigen (PSA) screening. Prostate-specific antigen testing has led specifically to an increase in the proportion of patients diagnosed with early-stage (localized) prostate cancer. Radical radiotherapy is one of the curative treatment options for localized prostate cancer and it also has a role to play in locally advanced and even metastatic disease. This chapter reviews the relative merits of radiotherapy in comparison to the other management options for early prostate cancer and summarizes the staggering technological advances that have occurred in prostate radiotherapy over the last decade.

Prostate Brachytherapy

Prostate brachytherapy involves placement of radioactive sources directly into the parenchyma of the prostate. It is a highly conformal form of therapy, permitting dose escalation to the target volume far exceeding that of other radiation modalities. The surrounding normal tissues are spared because of the rapid dose falloff with distance from the source (inverse square law). The evolution of TRUS imaging, a closed transper-ineal approach, and the increasing sophistication of computerized planning have resulted in a worldwide resurgence of interest in this treatment technique. Its appeal lies in its speed and convenience (it can be done as an outpatient procedure) and the low long-term risk of proctitis impotence is also less likely than after radical prostatectomy. Brachytherapy to the prostate can be delivered either with permanent seed implants or with removable implants,which are often delivered at a high dose rate with iridium wire. Permanent implants may be used alone as...

Hormone Refractory Prostate Cancer

Hormone-refractory prostate cancer is defined as disease that progresses despite castrate testosterone levels, and is refractory to all hormonal manipulations including withdrawal of antian-drogen therapy. Until recently, there had been no standard chemotherapeutic approach for HRPC. Several agents had been evaluated in clinical trials, but many older studies suffered from methodological deficits such as small numbers of patients, heterogeneity of enrolled patients, and lack uniform response criteria 5 . Overall there have been very few recent phase III trials completed in HRPC (Table 4.1) making it difficult to draw firm conclusions about the efficacy of many regimens. However, it would appear that chemotherapy at a minimum does provide a palliative benefit. Table 4.1. Summary of recent (1996-2003) phase III trials in hormone refractory prostate cancer (HRPC) Table 4.1. Summary of recent (1996-2003) phase III trials in hormone refractory prostate cancer (HRPC) PSA, prostate-specific...

Soy Isoflavones and Breast or Prostate Cancer Risk

The observation that both breast and prostate cancers are common in the Western industrialized nations, while relatively rare in oriental countries such as China and Japan, suggests that some component of the oriental diet may include substances that protect against these cancers. In addition, studies of migrants from these low-risk countries to the U.S. revealed that risk of breast and prostate cancer increased to the level of Caucasians in the U.S. after only a few generations. Although the biologic evidence suggesting that soy may be important in the development of prostate cancer is quite strong, only a few epide-miologic studies have evaluated this relationship. Among men of Japanese ancestry living in Hawaii, risk of prostate cancer was reduced 65 in those men who ate tofu more than five times per week, in comparison with those who ate it less than once per week. However, the number of men in the study was small and the finding was of borderline statistical significance.45 Among...

Prostate Cancer Immediate vs Deferred Treatment

There continues to be controversy about the timing of treatment for localized, for locally advanced, and for metastatic prostate cancer. The decision for early radical treatments in localized disease has been based on the patient's age, general health, and preference. However, an increased understanding of the natural history of this cancer may allow us to select patients at risk for whom treatment might possibly improve survival while reducing the risk of treatment-related morbidity in those not at risk 1,2 . The survival benefits of radical treatments for localized prostate cancer still remain unclear. To date, no randomized controlled trial has demonstrated whether radical surgery or radiotherapy is more effective than watchful waiting in improving overall survival. There is evidence that radical prostatectomy may significantly reduce disease specific mortality when compared to watchful waiting, but watchful waiting may be a viable option for some men 2 . Results from hormonal...

Surgical Treatment of Prostate Cancer

Surgery for prostate cancer has evolved, with the main purpose of curing one of the most common male malignancies at an early stage in its natural history, and preventing the morbidity otherwise associated with unchecked disease progression to more advanced, incurable stages. The operation by which this may be achieved, radical prostatectomy, advanced considerably during the 20th century through developments in anatomical knowledge and surgical experience. It is now a routine surgical procedure in urological oncology carried out through a range of surgical approaches, each with its own advantages and disadvantages. The first radical prostatectomy operations were done through a perineal approach, adapted from contemporaneous techniques for stone surgery. Theodore Bilroth is credited with the first radical prostatectomy, carried out in 1866 however, the use of this operation was slow to develop owing to its considerable morbidity and mortality. In 1905, Hugh Hampton Young 1 at the Johns...

Laparoscopic Prostatectomy

Laparoscopic radical prostatectomy has developed within the past 10 years, recognizing the many potential benefits of laparoscopic surgery. It was first described by Schuessler et al. 10 in 1992, and at that time presented significant challenges 11 . Reduction in the extent of surgical incisions, postoperative pain, and analgesic requirement, and shorter convalescence including reduced hospital stay contribute to its potential advantages. Disadvantages relate to the considerable specific skills and experience that need to be acquired and maintained. Procedure-specific advantages and disadvantages must also be considered in relation to open surgery 12 . Operative blood loss in laparoscopic prostatectomy may be minimal by comparison with the open procedure. In experienced hands blood transfusion is rarely required, though this may also apply for the open procedure. For the surgeon, laparoscopy provides an excellent magnified visual field via a monitor, although two-dimensional, and a...

Hormone Therapy for Prostate Cancer

Prostate cancer is now the most prevalent of all male malignancies and the second most common cause of male cancer deaths. Death rates have trebled over the last 30 years, and changes in mortality during this period are shown in Table 8.1 1 . Prostate cancer is initially an androgen-dependent tumor, and treatment aims to reduce androgen supply to it. It is over a century since the first treatment for prostate cancer was introduced by an English surgeon, who castrated patients with benign and malignant prostatic conditions and observed the responses. Since that time there have been refinements of treatment so that we are now able to deal more humanely with this condition. We understand more about the toxicities of treatment and the value of second-line therapies. This has led to an improvement in survival. Our hope for the future is that new developments and therapeutic options will result from our increased understanding of the molecular basis of prostate cancer. This chapter surveys...

Chemotherapy in Prostate Cancer

Prostate cancer is now most frequently diagnosed malignancy and the second leading cause of cancer-related death 1 . Death rates have increased over the past 20 years and mortality may approach that of lung cancer within 15 years 2 . For patients with advanced disease, the response rate to hormonal therapy is about 80 , but this is not durable, and all patients will eventually develop hormone-refractory prostate cancer (HRPC) 3 . Chemotherapy has been shown to have palliative benefit in symptomatic HRPC, but has not yet been demonstrated to prolong survival. Median life expectancy for patients with HRPC is only 12 to 18 months, underscoring the urgent need for new therapeutic approaches 4 . Historically, the role of aggressive systemic chemotherapy in HRPC had been questioned because elderly patients with poor marrow reserve, concomitant illnesses, and poor performance status tolerated it poorly. Coupled with this, chemotherapy trials before 1991 reported response rates of only 5 . In...

Early Proteomic Studies into the Prostate and Prostate Cancer

Until very recently the number of prostate-related proteomics or 2DGE-based publications was decidedly small, due to the inherent problems in carrying out such studies. In 1989 a study was carried out by Sherwood et al. 1 , comparing the profiles of proteins obtained from stromal and epithelial cells from patients undergoing prostatectomy for benign prostatic hyperplasia (BPH). Differences were noted for cytokeratin levels and also vimentin, which was shown to be present in stromal cells via immunoblotting, as were three potential markers of stromal cell types named SM1, SM2, and SM3. As the existing technology did not yet allow identification of these markers, no identities were obtained for them. In 1992 2DGE was carried out on isolated androgen receptor, revealing two isoforms of the receptor at the isoelectric point, pI 5.3 and 7.2 and molecular weight 90 to 95kd in both prostate and foreskin 2 . A further study by Xia et al. 3 discovered three isoforms of the androgen receptor...

Proteins Differing Between Normal and Cancerous Prostate

One of the most appealing studies that one can carry out with proteomics technology is the investigation of proteins with differing expression levels between normal and cancerous prostate. The first directly prostate-cancer related proteomics paper appeared in 1997, in which Partin et al. 4 identified a protein, PC-1, that was present in prostate cancer but not in normal or hyperplastic prostate. The protein, to which an antibody was subsequently raised, was then used in experiments to investigate its potential use in prostate cancer screening via immunohistochemistry. Despite encouraging results, this study does not appear to have been developed further. A study of prostate cancer can be further broken down into the investigation of different stages of cancer, from prostatic intraepithelial neoplasia (PIN) to hormone therapy-resistant cancer, and all stages in between. Although the technology now exists to make this task possible, the problems that dog any other similar study on...

Serum Markers for Prostate Cancer

The discovery and development of PSA in the 1980s revolutionized the diagnosis of prostate cancer. The marker, which is simple to detect, easy to access, and relatively noninvasive for the patient, is an ideal find. It is now firmly established that PSA is one of the most reliable cancer markers currently in use. It is also true, however, that there are a very high number of false-positive and false-negative diagnoses obtained via PSA testing, and for this reason the use of PSA as a screening test in the United Kingdom has always been avoided. It is worthy of note, however, that its application in the United States has led to an increased number of diagnoses and arguably a drop in mortality. This demonstrates the value of such screening regimes in saving lives. It therefore follows that an accurate and informative blood test for prostate cancer would be invaluable in the clinics, allowing early diagnosis and possibly even informing the type of treatment required for each patient. In...

Gene Therapy for Prostate Cancer

Prostate cancer has recently become the most commonly diagnosed male malignancy in industrialized countries and the second leading cause of cancer-related mortality in men. Over the last 30 years death rates from prostate cancer have more than doubled in England and Wales 1 . It is argued that disease confined to the prostate can be successfully treated by radiation or surgery, with adjuvant hormonal therapy. However, up to half of men with clinically localized disease are not cured by these approaches 2 . In the United Kingdom over 60 of men with prostate cancer have either locally advanced or metastatic disease at presentation and are incurable. These patients are treated by androgen ablation, but the efficacy of this approach is limited by the development of hormone-refractory disease. Although chemotherapy can have a role to play in patients with advanced prostate cancer, response rates are modest and the survival benefit marginal. There is thus clearly a need for novel therapies...

Incidence Of Incontinence After Prostatectomy

The incidence of urinary incontinence is approximately 1-3 in patients undergoing transurethral resection of the prostate or open prostatectomy for benign disease (3,4). The incidence of incontinence following radical prostatectomy has been reported to range from 2.5 (5) to 87 (6). This wide discrepancy is a result of several factors. The definition of incontinence varies widely among series, ranging from any degree of wetting or restricted to total incontinence. In addition, the method of data acquisition has a significant effect on reported rates of incontinence. Studies that involve patient questionnaires and or direct patient input generally have higher rates of incontinence than data obtained by chart review or physician interview. In a sample of Medicare patients undergoing radical prostatectomy, 47 had leakage of urine daily, and 6 needed surgical intervention (7). Incontinence after prostatectomy has a significant negative impact on a patient's quality of life. Herr discovered...

Enlarged Prostate Gland

This condition is most common in men over 40 years old. It is caused by a swelling of the prostate gland, which is between the bladder and the urinary tube (urethra). Treatment for an enlarged prostate Note Both prostate trouble and gonorrhea (or chlamydia) can also make it hard to pass urine. In older men it is more likely to be an enlarged prostate. However, a younger man especially one who has recently had sex with an infected person probably has gonorrhea or chlamydia.

Etiology Of Incontinence Following Prostatectomy

When considering the etiology of urinary incontinence, it is essential to identify that leakage may occur as a result of an abnormality of bladder and or sphincteric function. Urodynamic studies provide information concerning the relative contributions of bladder and or sphincteric dysfunction in patients with incontinence after prostatectomy. The presence of isolated bladder dysfunction as the predominant cause of incontinence following prostatectomy has been identified in reports utilizing urodynamic studies (42,43). These reports concluded that sphincteric weakness is not the major factor contributing to incontinence following prostatectomy. In contrast, sphincteric weakness alone has been implicated as the predominant cause of postprostatectomy incontinence (44,45) (see Table 1). Several factors have been proposed to explain for this discrepancy (45). Many studies documenting a high incidence of bladder dysfunction alone contain a large percentage of patients following...

T XJuALXvIOSi Of Postprostatectomy Incontinence

Present prior to surgery The events occurring during leakage (activity, urgency or no sensation) as well as associated urinary symptoms (force of stream, complete emptying) are important factors. Day and nighttime pad usage should be documented to measure the severity of leakage. A pad-weight test may also more accurately quantify urine leakage. Any associated neurologic symptoms or history of previous incontinence therapy should be obtained. The physical examination should include focus on the neurologic status of the perineum and lower extremities. Rectal examination should be performed to rule out recurrence in cancer cases, and to assess the size of the prostate in patients following TURP. A urinalysis and residual urine should be obtained in all patients, and PSA testing should be considered in all patients with a history of prostate cancer to rale out recurrence. Urodynamic evaluation is essential to determine the etiology of incontinence following prostatectomy, and should be...

Lymphoma of the Prostate

Primary lymphoma of the prostate is very rare, representing only approximately 0.2 to 0.8 of extranodal lymphomas and 0.1 of all prostate neoplasms 1,64,65 . Secondary involvement of the prostate by lymphoma or leukemia is more frequent,being found at postmortem in up to 8 of non-Hodgkin lymphomas and up to 20 of cases of CLL 66 . However, in most cases this involvement is not clinically apparent. In a series of 62 prostatic lymphomas, Bostwick et al. 67 found 35 to be primary (defined by presenting symptoms of prostatic enlargement, predominant involvement of the prostate, and no involvement of lymph nodes, blood, liver, or spleen within 1 month of diagnosis), 48 to be second

Small Cell Tumors of the Bladder and Prostate

The vast majority of small round blue-cell tumors of the bladder and prostate prove to be either lymphomas or systemic infiltrates in patients with a known history of leukemia. These entities have been covered in detail in the preceding section. information provided, and in particular on the age of the patient. In children and adolescents, the most common small round blue-cell tumor of the bladder and prostate, other than leukemia and lymphoma, is embryonal rhabdomyosar-coma. Although there are reports of other rare primary or metastatic tumors occurring in the bladder and prostate, including primitive neu-roectodermal tumor (PNET), neuroblastoma, Wilms' tumor, and desmoplastic small round cell tumor 73-78 , these should be considered only after exclusion of the more common entities outlined above. In adults, the main differential diagnosis of nonlymphoid small round blue-cell tumors includes poorly differentiated carcinoma and neuroendocrine tumors such as car-cinoid and small cell...

Human Prostate Cancer

The reproductive organs are not required for an individual's survival but are required for survival of the species. As the individual approaches adulthood, the prostate undergoes developmental changes, resulting in maturation of this gland at puberty. At this stage, the prostate becomes a differentiated gland that produces proteins and other substances fundamental for reproduction and survival of the species. By the age of 50, as many as 30 of all men will harbor microscopic foci of prostate adenocarcinoma (CaP), and the incidence increases with age. In the United States, CaP is clinically diagnosed in approx 10 of men during their lifetime (189,000 yr), where it will claim 31,900 lives each year (13 of male cancer deaths) (1). The recent rising incidence of CaP (2) has plateaued (3), but the high prevalence of this disease and the aging of the US population still makes this a cancer that demands prompt attention. The proliferation and differentiation of prostatic tissue is influenced...

Rodent Prostate Cell Determination

The rodent prostate gland consists of four different lobes defined as ventral, dorsal, lateral, and anterior (coagulating gland), where the epithelial cells are specialized and express specific protein products. Each lobe is anatomically distinct, but the dorsal and lateral lobes, because of their size and proximity, are often examined collectively as the dorsolateral prostate. The rodent dorsolateral prostate is considered to be homologous to the human prostate peripheral zone (57), the most common site of prostate cancer in humans. In the rodent, the urogenital sinus (UGS) begins to develop in the embryo day (E) 10-11 of gestation, and testicular androgen production in the mouse begins E 12.5-13, peaking at E 17-18 gestation, thereafter declining until birth (58,59). 5a-reductase activity is detected in the UGS at E 14.5 (60), and coincides with Wolffian-duct differentiation into the epididymis, seminal vesicles, and ductus deferens as the Mullerian duct degenerates. Normal rodent...

Rodent Prostate Cell Differentiation

Biochemical analysis exists on the rat prostate, but limited information is published on the secretory proteins of the mouse prostate. Also, no rodent analog for human PSA has been identified. The rat ventral lobe differs most significantly from the other lobes because its protein products are quite distinct (101-103). The rat anterior lobe produces many of the androgen-regulated proteins seen in the dorsolateral prostate (104). The seminal-vesicle secretion II (SVSII) is a major secretory product of both the seminal vesicle and the dorsolateral prostate (103,105), and Dorsal Prostate I and II are found in the dorsal prostate (104,106). Probasin (PB) is detected in all lobes of the prostate and the seminal vesicles, with lateral lobe expression the highest (100 ) followed by dorsal (33 ), anterior (14 ), ventral (4 ), and seminal vesicles (2 ) (103,107,108). Some of these secretory proteins are detected in the prostate between 2-3 wk of animal age (102 103) but the major increase in...

Anatomy Of The Prostate Gland And Urinary Sphincter

Verumontanum

The prostate gland is comprised of three glandular zones and one nonglandular region, the anterior fibromuscular stroma. The three glandular regions arise from different segments of the prostatic urethra (13). The transition zone constitutes about 5 of prostatic glandular tissue and is located on both sides of the prostatic urethra. It is in this zone that benign prostatic hyperplasia develops (14). The transition zone is separated from the central and peripheral zones of the prostate by the surgical capsule, which marks adequate depth of resection of adenomatous prostatic tissue when performing transurethral prostatectomy. The peripheral zone comprises about 70 of the mass of the glandular prostate, and it is in this zone that most prostate cancers arise (15). It is located at the posterior and lateral aspects of the prostate gland with its ducts exiting from the base of the verumontanum to the prostatic apex. The central zone constitutes about 25 of the glandular tissue around the...

Transurethral Resection of the Prostate and Open Prostatectomy

Prostatectomy

In many cases, prostatic hypertrophy extends beyond the verumonta-num (25,26) (Fig. 2). Thus, the verumontanum remains a critical landmark when performing a transurethral prostatectomy. If the resection is carried past the vera, violation of the distal urethral sphincter will occur, resulting in postoperative incontinence. The distal limit of resection should be at the verumontanum, even if a small rim of adenoma is left behind. This small amount of adenoma may provide some protection against stress urinary incontinence (27). Care should be taken to minimize bleeding to insure adequate visualization, and cautery should be employed judiciously in this area to avoid thermal muscle damage. Most frequently damage to the distal urethral sphincter occurs anteriorly between the 10 and 2 o'clock positions (16). When performing open prostatectomy for benign disease, great care must be taken to preserve the distal sphincteric mechanism. Most of these glands are quite large with adenomatous...

Prostate Ultrasonography

Prostate ultrasonography, also called transrectal or rectal ultrasound, is an ultrasound study of the prostate gland. This procedure is used to examine the size, shape, texture, and position of the prostate gland and its tissue, and to diagnose abnormal conditions. Prostate ultrasonography is also used to guide the physician in performing prostate biopsy, and placing radioactive seeds into the prostate gland for cancer treatment. Prior to prostate ultrasonography, the patient may be placed on antibiotics and given an enema to empty the rectum of stool. The patient is prepared for the procedure by being placed on the left side with the rectal area exposed. Following a rectal exam, a rectal probe equipped with a transducer and covered with a condom sheath is lubricated and inserted into the rectum. The condom sheath is filled with water in order to facilitate the transmission of sound waves between the prostate and the transducer. As the transducer is rotated along the prostate, images...

Prostate

Apoptosis occurs in a hormone-sensitive manner in the prostate. Either androgen withdrawal or castration results in increased apoptotic death in the prostate glandular epithelium (173). Little is currently known about the roles of the Bcl2 family in the regulation of prostate apoptosis. While Bcl2 is not detected in normal prostate epithelial cells in humans, Bcl2 expression is detectable, and increases as prostate cancers become androgen-independent, raising the possibility that Bcl2 may have a role in neoplastic growth in this tissue (174). In support of this hypothesis, mice that overexpress a Bcl2 transgene in prostate epithelial cells have morphologically abnormal prostates, with an accumulation of cells in stromal and epithelial compartments (175). Understanding Bcl2 family function in the prostate may ultimately have useful value for treatment of prostatic cancer.

Prostate biopsy

Prostate biopsy remains a controversial issue with no standardized consensus with regard to technique, number of biopsy cores and region of prostate to be biopsied. The larger the gland, the lesser the likelihood of CAP detection and the greater the false-negative rate. The rate of CAP detection increases from 23 to 31 in glands > 50 cc to 38-50 in glands measuring < 30 cc. Generally, more biopsy cores must be taken in prostates which are larger on TRUS volume estimation. Directed biopsies biopsies directed toward a palpable nodule or from an abnormal-looking area on TRUS generally results in a poorer yield (cancer detection rate of just over 50 ) due to the varied appearance of prostate cancer on TRUS. Sextant technique the sextant biopsy technique has been the traditional gold standard method till recent years, with a sensitivity rate of approximately 70 . Three core biopsies are taken from both lobes of the prostate in the midlobe parasagittal plane at the base, middle, and...

Acute Prostatitis

PE rectal exam reveals enlarged, nodular prostate biopsy obtained to rule out carcinoma. Enlarged prostate with nodularity and calculi. Discussion Bacterial prostatitis is usually caused by the same gram- negative bacilli that cause UTIs in females 80 or more of such infections are caused by E. coli. Chronic bactcrial prostatitis is common in elderly males with prostatic hyperplasia and is a frequent cause of recurrent UTIs in males (most antibiotics poorly penetrate the prostate hence the bacteria are not totally eradicated and continuously seed the urinary tract).

Inherited Genetic Changes

Unlike in breast and colon cancer, no major predisposition genes for prostate cancer have been detected. However, a number of susceptibility loci have been identified. As yet the susceptibility genes for most of these regions remain unknown 10 . This suggests that the predisposition to prostate cancer is heterogeneous and may involve multiple genes. Seven prostate cancer susceptibility loci have thus far been described and tested on independent data sets 5,11 HPC1 (hereditary prostate cancer) at 1q24, PCaP (predisposing for prostate cancer) at 1q42, HPCX at Xq27, CAPB (cancer, prostate, and brain) at 1q36, HPC20 at 20q13, HPC2 ELAC2 at 17p11, and a new locus at 8p22-23 and at 16q23.2 10 . Candidate genes, which have been identified from a small number of families, include HPC2 ELAC2, RNASEL, and MSR1 9 .As well as being involved in the pathogenesis of prostate cancer, MSR1 and RNASEL are also involved in the host response to infectious agents 9 . It therefore has been hypothesized...

Somatic Genetic Changes

Although the molecular genetic changes responsible for prostate cancer development and progression is poorly understood, as with other solid tumors the number of changes increases with the stage of disease 9 , suggesting that the disease progresses as the result of an accumulation of genetic changes (Fig. 1.1). This may involve activation of dominant oncogenes-by amplification, translocations or point mutations, or inactivation of recessive tumor suppressor genes-loss of an allele (known as loss of het-erozygosity, LOH), allele inactivation by mutation, promoter hypermethylation, and haploinsufficiency.

Chromosomal Alterations

Up to 54 of primary cancers and 100 of metastatic tumors have LOH occurring in at least one chromosome. The technique of comparative genomic hybridization (CGH) has helped to identify the most commonly altered chromosomal regions in prostate cancer. Chromosomal losses are far more common that gains in primary tumors however, they are found at equal frequencies in hormone-refractory tumors 10 . This suggests that tumor suppressor inacti-vation may be an early event in prostate cancer The Molecular Biology of Prostate Cancer Normal prostate gland Prostate carcinoma 20 . In metastatic or treatment-resistant disease, however, the incidence reaches 50 to 75 17 . This suggests that mutations of the p53 gene are a late development in prostate cancer progression.

The PTENPI3KAkt Pathway

PTEN is located on 10q23 and is mutated in up to a third of hormone refractory prostate cancer 9 . Homozygous deletions and mutations have also been identified in a subset of primary prostate cancers 18 . The loss of PTEN expression in primary prostate cancer has been found to correlate with a high Gleason score and an advanced stage 19 .

CpG Island Promoter Methylation

The most common genomic change in prostate cancer is silencing of the gene encoding the pi class of glutathione-S transferase (GSTP1) by hypermethylation of the promoter region. This change has been found in 90 to 95 of prostate cancers and 70 of high-grade prostatic intraepithelial neoplasia lesions 9 . The GSTP1 enzyme has a cell-detoxifying function, and therefore may protect cells from environmental carcinogens and DNA damage. Detection of the methylated GSTP1 promoter in urine and semen is being investigated as a possible biomarker for prostate cancer diagnosis 9 . Other genes that have been found to have selective promoter methylation in prostate cancer include CD44-, a cell adhesion molecule that may have a role in metastasis EDNRB, which encodes the endothelin B receptor and ER-ab, which encodes the estrogen receptors a and p.

Other Amplified Genes with Clinical Potential

A-Methylacyl-coenzyme A (CoA) racemase (AMACR) is an enzyme involved in the b oxidation of dietary branched-chain fatty acids. It is overexpressed in prostate cancer at both the RNA and protein level 9 . Recent work has identified AMACR as a new diagnostic marker for prostate cancer needle biopsies 9 . It is also an androgen-independent growth modifier and so has the potential to be a complementary target with androgen ablation in prostate cancer treatment 31 . Another gene product that is overexpressed in prostate cancer is fatty acid synthetase (FAS). Inhibitors to FAS are therefore also being investigated as a therapeutic target in the disease 9 .

The Androgen Receptor

The action of androgens in prostate cancer, as in the normal prostate, is mediated through the androgen receptor. Androgen deprivation is the accepted treatment for advanced prostate cancer and results in responses in 50 to 80 of patients. Unfortunately, despite initial responses to such treatment, prostate cancer inevitably progresses to an androgen-independent state within 13 months from starting treatment. As a result, much research has focused on androgen signaling in prostate cancers.

The Androgen Receptor and Androgen Synthesis

Testosterone is the main circulating androgen and is primarily produced by the Leydig cells in the testes. Its release is influenced by the pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (Fig. 1.2). Once reaching the prostate, 90 of the testosterone is converted intracellularly by the enzyme 5a-reductase to dihydrotestosterone (DHT). Both DHT and testosterone bind to the androgen receptor (AR) and DHT has 100 times more relative androgenicity than testosterone. There are a number of target genes that are regulated in this way including those encoding prostate-specific antigen (PSA), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and keratinocyte growth factor (KGF). These have been found to have an important role in prostate cancer angiogenesis, metastases, and differentiation.

Trinucleotide Repeats

The first exon of the AR gene contains several regions of repetitive DNA sequences. Of interest is a CAG triplet repeat, the length of which is highly polymorphic, ranging from 14 to 35 repeats, and its length may affect AR activity and prostate cancer risk. The number of X- chromosome-associated CAG and GGC trinucleotide repeats has been shown to correlate with the severity of a number of neuromuscular degenerative disorders, such as Kennedy's disease. Of interest, this condition is also accompanied by androgen insensitivity caused by attenuated activity of the AR 51 . A shorter glutamide repeat coded by the CAG sequence has also been shown to increase AR activity. This has subsequently been found to predict for a higher grade and more advanced disease at diagnosis 52 . Racial differences have also been noted, with a significantly reduced number of CAG repeats in African-American men and elevated number in Asian-American men compared with Caucasian men 53 . This may be associated...

Tumor Environment Interactions

The prostate gland is composed of epithelial cells, which form two cell layers, and stromal cells. The basal epithelial cells are androgen independent,lack AR, and are thought to be stem cells for secretory epithelial cells. The stroma of the prostate is composed of fibroblasts, smooth muscle cells, lymphocytes, and neuromuscular tissue embedded in an extracellular matrix. During early prostate cancer development, the AR is initially expressed in mesenchymal tissue 62 . Later it is found in both mesenchymal and epithelial cells. This epithelial-stromal interaction plays an important role in normal prostatic morphogenesis and remains significant in the adult prostate. Growth factors are thought to maintain homeostasis between these cell types in a paracrine fashion. It may be that imbalances of these factors lead to benign prostatic hypertrophy and prostate cancer development, and in andro-gen-independent prostate tumors replace androgen as the primary-stimulatory growth signal. The...

Other Cellular Matrix Interactions

The cadherins are a class of cell-adhesion molecules that are involved with cell-to-cell recognition, and thus help maintain epithelial tissue differentiation and structural integrity. Reduced expression of E-cadherin is associated with advanced stage and grade 54 of prostate Epitheliale ell Normal prostate tissue Prostate cancer tissue The Molecular Biology of Prostate Cancer cancers and also poor clinical outcome 9 . In a cellular model, inhibition of E-cadherin leads to disruption of normal contact inhibition of growth and an invasive phenotype 86 . a-Catenin associates with E-cadherin and can also be altered in prostate cancer 9 . CD44 is part of the CD family of transmembrane glycoproteins principally involved in cell-extracellular matrix interactions and is encoded on chromosome 11. In a rat model of prostate cancer CD44 behaves as a metastases suppressor gene 87 . Downregulation of CD44 expression also occurs in high-grade prostate cancer 9 . A proposed mechanism for CD44...

Dietary factors that may decrease risk

A deficiency of folate is associated with cancer of the colon, rectum, and breast. In the USA, many grain products are now fortified with folate. A diet that includes fruits, vegetables, and enriched grains should provide sufficient intake. Animal studies and one human study have shown that selenium deficiency is associated with lung, colon, and prostate cancer. If selenium supplements are taken, then the maximum dose should be 200 g day.5

Q2324 HPC and the Rnasel Data

A group from Johns Hopkins University, Baltimore, Maryland, conducted a study in 91 North American and Swedish families, and its report suggested that 34 of families might be linked to this locus 9 . This GWS identified a locus named HPC1 (hereditary prostate cancer 1) at 1q24-25. Various groups have since either confirmed 81-84 , or challenged 65,66, 68,72,85,86 the Hopkins' observation. Goode et al. 72 , and Goddard et al. 87 identified evidence of linkage in families with more aggressive PCa. Xu 88 , in a meta-analysis, found that approximately 6 of all PCa families were linked to 1q24-25. A further analysis concluded that HPC1 might play a role in a subset of families with several young-onset cases especially in African-American men. Carpten et al. 89 subsequently found mutations in the cell proliferation and apoptosis regulating gene RNASEL. Some reports have shown RNASEL mutations to be associated with PCa, but with a much lower RR than would be extrapolated by the linkage...

Other Significant Loci

PCaP (1q42.2-43 65 ) was a locus identified in the German French population, but not confirmed by other groups. CAPB (1p36 67 ) is a locus associated with primary brain tumor and PCa, which on further analysis was probably more associated with young-onset PCa rather than brain tumor 95 . Suarez et al. 66 described a locus on chromosome 16q in sibling pairs. Berry et al. 71 described another one on 20q (HPC20). These are still to be confirmed. It is likely that the HPC20 locus is not real, as recent analyses from multiple groups in the International Consortium for Prostate Cancer Genetics (ICPCG) have failed to confirm linkage to this locus in a meta-analysis (Schaid and the ICPCG, in press, 2004). A further locus has been described on the long arm of chromosome X (HPCX Xq27-28) by Xu et al. 96 . Some loci, for example, 7q, 19q 97-99 , have been found to be associated with more aggressive PCa. Eight GWSs have been published recently in one issue of The Prostate (ACTANE Consortium 80...

Biological Aggressiveness

The biologic aggressiveness of FPC has been the focus of interest of several investigators. Walsh 111 first noted that there was no significant difference between phenotypes of hereditary, familial, and sporadic prostate cancer among those who underwent radical prostatectomy with respect to preoperative PSA, PSA density, Gleason score, tumor histology, pathological stage, or clinical stage. Kupelian et al. 112 later observed that men with localized PCa with a positive family history may have a worse outcome at 3 and 5 years following either radiation therapy or surgery than those with sporadic cases. Three further studies found no difference in the aggressiveness of the disease in familial compared with sporadic cases 113-115 . Familial Prostate Cancer

Treatment Versus Observation in Screen Detected Patients

Tions in BRCA2, were replicated, there would be a rationale for offering genetic counseling and testing for this disease. At present, these results should be replicated on a further sample set of blood samples from PCa cases diagnosed at young age prior to offering clinical diagnostic BRCA2 genetic counseling and testing, and this is in progress in the U.K. Familial Prostate Cancer Study 10 . The American Urological Association currently recommends that men at high risk of developing PCa, that is, those with a family history of the disease or men of African-American descent, begin receiving routine prostate cancer screening at age 40 124 . Its recommendation is that such men receive PSA testing and digital rectal examination (DRE) annually starting at age 50. This is recommended earlier if there is a family history of the disease or if one is of African-American descent, as above 125 . The main recent area of controversy is the utility of the PSA value, particularly at low levels (see...

Role of Chemoprevention

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a phase III clinical trial designed to test the efficacy of selenium and vitamin E alone and in combination in the prevention of prostate cancer 130 . Refinements in new powerful tools such as proteomic analysis of tissue-based and secreted proteins 131 and gene chip complementary DNA (cDNA) microarrays for multiplex gene expression profiling could help optimize the identification of new molecular targets, cohorts at risk, and the design of suitable combination trials. Familial Prostate Cancer

Modifications of PSA testing

Larger prostate glands will produce more PSA. Therefore, in an attempt to resolve the considerable overlap in serum PSA between patients with BPH and early CAP, the notion of PSA density (PSAD) was introduced Presumed greatest utility in the 4-20 ng mL PSA range, in terms of determining the need for prostate biopsies For these above reasons, currently, PSAD is not routinely indicated in prostate cancer screening programmes or in the assessment of patients with suspected CAP. yet unable to detect PSA-AMG. It has been proposed that there is a lower concentration of free PSA in patients with CAP compared to those with BPH, such that there is a lower free total (f t) PSA ratio and a higher complexed total (c t) PSA ratio in prostate cancer patients.

Genetic Counseling and Testing Research

Currently, genetic analysis (e.g., BRCA2 mutation analysis) should be performed only within the context of a research study that will determine penetrance and genotype-phenotype correlation of specific mutations. The criteria for the Cancer Research U.K. British Prostate Group British Association of Urological Surgeons' Section of Oncology Familial Prostate Cancer Study (principal investigator Dr. Eeles) are as follows Even in the absence of genetic testing, African-American men and men with a strong family history of prostate cancer (as defined in the TAPS study, see above), may opt to initiate screening by PSA and DRE from as early as 40 years.

The Disease Should Be an Important Health Problem

As the most common male cancer in Europe and the United States, and second only to lung cancer in terms of male cancer deaths, there is little doubt that prostate cancer represents a significant public health burden in Western countries 2 . In the U.S. alone, an estimated 220,900 new prostate cancer cases were diagnosed in 2003, with 28,900 deaths attributable to the disease 3 .Although a dramatic increase has been observed in the number of men diagnosed with localized disease as a consequence of PSA testing, those with advanced prostate cancer continue to present a significant burden to the community, developing metastatic disease at a rate of 8 per year, and reaching 40 at 5 years. These metastases predominately affect the skeleton, causing high levels of morbidity and hospitalization, and necessitating expensive palliation. In addition, the use of hormone manipulation in the form of androgen suppression to treat advanced disease causes iatrogenic morbidity by reducing bone density...

There Should Be a Preclinical State More Amenable to Successful Treatment than Clinical Disease

This criterion remains unclear in prostate cancer, largely because of the rather loose definition of clinically significant disease. Despite the fact that with increasing age most men will develop microscopic foci of prostate cancer, only a small percentage of these slow-growing tumors will develop into invasive prostate cancer, and an even smaller proportion will cause premature death. It is hoped that the epidemiological investigation of prostate cancer will identify factors ideally amenable to intervention that cause the common microscopic form of the disease to progress to invasive disease. However, to date, the etiology of prostate cancer remains virtually unknown and continues to pose a major challenge to epidemiologists. Although both genetics and environment are likely to play a role in the evolution of the disease, the role of genetic factors in prostate cancer susceptibility has stimulated significant interest following a number of genetic linkage analyses based on families...

Acid Phosphatase Prostatic Acid Phosphatase PAP

The enzyme acid phosphatase is present in various tissues, including bone, liver, kidneys, spleen, and red blood cells. Since the highest concentration of acid phosphatase, also known as prostatic acid phosphatase (PAP), is in the prostate gland, the diagnostic significance of acid phosphatase levels relates to that gland. Acid phosphatase levels are used to diagnose and stage cancer of the prostate, especially when the disease has metastasized to the bone. Acid phosphatase levels are used to monitor the effectiveness of prostate cancer treatments. Successful surgical intervention or treatment by estrogen therapy results in decreased acid phosphatase levels. Elevated acid phosphatase levels after treatment can indicate metastasis and a poor prognosis. Variations from Normal. A significant elevation of acid phosphatase usually indicates metastatic cancer of the prostate. Moderate increases of acid phosphatase levels are associated with carcinoma in situ of the prostate, Paget's...

The Natural History of the Disease Should Be Known

The natural history of prostate cancer in the PSA era is uncertain, because men are far more likely to die with, rather than from, the disease. The lifetime risk of having microscopic prostate cancer for a man aged 50 years is 42 , although his risk of dying from the disease is about 3 10 . There is little published long-term outcome data for prostate cancer in the PSA era, which makes any previous data difficult to translate in contemporary terms. In clinical practice, it has become customary to state that unless a man has a minimum of 10-year life expectancy, conservative therapy is indicated. This appears to stem from the work by Barnes 11 in the late 1960s, who investigated the long-term survival of patients with clinically localized prostate cancer who were treated conservatively. Barnes noted that over two thirds of these patients died from competing medical hazards rather than from their prostate cancer. Between 1989 and 1997, Johansson et al. 12 carried out a prospective study...

There Should Be an Accepted and Effective Treatment

Until recently, there was a significant lack of first-degree evidence through large randomized controlled trials that aggressive treatment of localized prostate cancer improves survival or quality of life. Outcomes for different treatment options in men with localized prostate cancer are difficult to interpret, because many of the published studies are observational, contain too small numbers, and are otherwise insufficiently robust. For example, men treated by watchful waiting may have been selected because they are older, with lower grade tumors, whereas those treated by radiotherapy may have been more likely to have more advanced tumors. Therefore, only data from well-conducted large randomized controlled trials can confidently be used to compare treatment options. Such a trial has been performed in Scandinavia, the results of which were published recently 25,26 . The trial randomized 695 men with early prostate cancer to either watchful waiting or radical prostatectomy, with a...

Screening CT Colonography

Such as inflammatory bowel disease, familial adeno-matous polyposis, hereditary nonpolyposis colorec-tal cancer, or a first degree relative with a history of colorectal adenoma or colorectal cancer (Winawer et al. 1991 Ahsan et al. 1998). The age range for development of colon cancer is late 40s to 70s in average-risk patients. The high-risk patient population accounts for approximately 25 of the colorectal cancer incidence in the United States. Deaths from colorectal cancer rank third after lung and prostate cancer in men and third after lung and breast cancer in women.

How Can We Study Screening

As mentioned above, screening for prostate cancer can be studied by randomized controlled trials such as the ones currently underway in Europe and the U.S. These involve randomizing a population of men at risk of harboring the disease, with good life expectancy, to either an intensive screening program or to no screening. The outcome is measured by analyzing differences in mortality between the two groups, on the assumption that the screened group would have received early aggressive intervention, compared with the nonscreened group. The ERSPC trial, and the Prostate, Lung, Colon, and Ovary (PLCO) cancer trial in the U.S. represent such examples 34 . The ERSPC trial is a large international cooperative study that was initiated in 1994 involving the Netherlands, Belgium, Finland, Italy, Sweden, Spain, and Switzerland, and was planned with a total sample of 190,000 men aged 55 to 74 years. However, over time, targets have changed, and it is now estimated that 120,000 and 140,000 men...

Screening Policies Worldwide

Because of the uncertainties described above, it is not surprising to find that screening policies for prostate cancer differ considerably among countries where prevalence is high. A recent survey of large numbers of countries requested three specific pieces of information 37 (1) Does the country have a mass screening program (2) Does the country encourage and allow early detection and (3) Is the PSA test reimbursable Interestingly, the only country that appears to have a mass screening program for prostate cancer is one of the smallest, Luxembourg. A large proportion of countries allow early detection, and a few reimburse the cost of PSA tests, but opinions and practices are divided. For instance in the U.S., the American Cancer Society and American Urological Association recommend prostate screening for all men aged 50 years and older, whereas the U.S. Preventative Services Task Force, American Academy of Family Physicians, and American College of Physicians recommend not screening...

Combined Antiandrogen Treatment

Labrie, a French Canadian, has made a great contribution to prostate cancer treatment, and suggested that in a disease that is androgen sensitive it is important to eliminate all sources of androgen. Labrie advocated the use of a combination of an antiandrogen with an LHRH agonist in the treatment of prostate cancer. The sources of androgen supplied to the prostate are dietary, adrenal, and testicular. The use of an antiandrogen, such as flutamide, potentially has the benefit of acting synergis-tically with GnRH agonist. Labrie's early work was not based on any randomized study, and so was not greeted with universal acceptance, but rather the opposite However, his opinion has been vindicated by randomized controlled trials and meta-analyses of these studies. The randomized trials show a 7-month survival advantage to combination antiandrogen treatment. The meta-analyses, however, do not look at survival advantage, but at overall 5-year survival, and these report a 3 benefit to...

Epidemiologic and Clinical Studies

Most of the available clinical evidence regarding the effect of dietary fat intake on prostate cancer comes from observational rather than interven-tional studies. A close correlation exists between average per capita fat intake and prostate cancer mortality in numerous countries round the world 9 . Japanese and Chinese men who migrate to the United States experience dramatic increases in prostate cancer risk within one generation compared to their Caucasian neighbors 10 . Numerous case-control studies over the past 25 years have demonstrated a positive correlation between prostate cancer and increased fat or fat-type food consumption. Such studies include an analysis of 384 men diagnosed with prostate cancer between 1990 and 1992 in Quebec, Canada 11 . On average, after controlling for age, grade, clinical stage, initial treatment, and total energy intake, saturated fat consumption was significantly associated with disease-specific survival. Compared with men in the lower tercile of...

Intermittent Hormonal Therapy

Among the most important quality of life issues for patients with prostate cancer is the loss of sexual function with treatment. For this reason many men delay treatment or take treatment intermittently. There is no evidence whatsoever that intermittent treatment is less successful than continuous therapy. Indeed, if one examines the effects of hormonal treatment on prostate cancer cells growing in culture, then a single exposure to antiandrogen therapy is seen to cause devastating destruction of cell cultures rather akin to the effects of chemotherapy. cate on one of the trust boards of the Prostate Cancer Charity. He presented with metastatic disease and took hormonal treatment for a period of 6 weeks. He responded well and discontinued treatment until he suddenly presented 4 years later with cord compression, a course of events that might have occurred if he had taken continuous therapy. This anecdote, though hardly hard science, if taken in context and considered in the light of...

Studies in Seventh Day Adventists

These studies are reviewed below. However, as early as 1958, Wynder and Lemon examined cancer and heart disease in SDA hospital patients compared with non-SDA patients.18 In this early study, based on 564 SDA and 8128 non-SDA patients admitted to eight SDA hospitals throughout the U.S., lower risk of epidermoid lung, mouth, esophagus, larynx, and bladder cancer were found in the SDAs than in the non-SDAs. Colon and rectum cancer, however, were not found less frequently in the SDA than the non-SDA comparison group, while prostate and breast cancer were found somewhat more frequently in the SDA patient series. Interviews with study subjects indicated that only 41 of the SDA patients consumed any meat, whereas 95 of the general population consumed meat. Between the years 1958 and 1965, an updated analysis that examined mortality in the SDA population was conducted wherein various adjustments were made to make the SDA non-SDA comparison more valid. In...

Vascular Risk Factor Modification in Peripheral Arterial Disease

Mortality of peripheral arterial disease (PAD).The 5-year mortality of PAD is relatively equivalent to numerous cancers (prostate, breast, colorectal, and lung). Figure 6.1. Mortality of peripheral arterial disease (PAD).The 5-year mortality of PAD is relatively equivalent to numerous cancers (prostate, breast, colorectal, and lung).

The Side Effects of Hormonal Therapy

In the treatment of any group of patients, there is a historical paradigm to clinical reportage. The initial publication describes an effect of a new treatment. The follow-up publications confirm this effect. A third group of publications then emerge comparing the effect of the new treatment to a standard therapy option, and then finally the side effects of the new treatment are reported. This has been the case with the hormonal treatment of prostate cancer. The initial reports of estrogen activity have been followed by overwhelming evidence of toxicity. This includes a 40 incidence of gastrointestinal toxicity, gynecomastia that is not prevented by the irradiation of breast buds, and cardiovascular toxicity that is not prevented by low-dose anticoagulation 10 . Nevertheless, estrogens are still prescribed in the United Kingdom, although their prescription is proscribed in many other countries in the European Union. As time has progressed, the GnRH agonists have also been shown to...

New Adventist Health Study

Prostate Using an external reference population (i.e., Connecticut Tumor Registry) to generate expected numbers of cancer cases (adjusting for age, sex, and calendar year), the California SDA population was found to experience decreased cancer risk, although the reduction was more apparent in males than females. For all cancer sites combined, the standardized incidence ratio in males was 0.73, and for females it was 0.92 the result in females was of borderline statistical significance.28 (See Figure 4.10.) For most of the major cancer sites, the SDAs experienced low cancer risk (e.g., colon, lung) although for other cancer sites, risk was not substantially different in the SDAs (e.g., breast) or even somewhat elevated (e.g., prostate, corpus uteri). Relationships between several foods and food groups have been examined in relation to cancer within the Adventist cohort for the years 1976 and 1982. Currently, results have been presented for breast, prostate, lung, colon, bladder, and...

The Role of Radical Radiotherapy

The optimum management of patients with localized prostate cancer remains controversial. Three major treatment options are available radical prostatectomy, radical radiotherapy (external beam radiotherapy EBRT or brachytherapy), and active surveillance (also known as active monitoring and watchful waiting). Each treatment involves its own risk. Radical treatments can cause harmful side effects including incontinence, erectile dysfunc There is relatively little randomized evidence concerning the effectiveness of the different management options for early prostate cancer. In a Scandinavian study 1 , men with early prostate cancer (stages T1b-c or T2) were randomly assigned to radical prostatectomy or watchful waiting. After a median follow-up of 6.2 years, there was a significant reduction in disease-specific mortality in the radical prostatectomy group compared with the watchful waiting group (4.6 vs. 8.9 , P .02), but there was no significant difference in overall survival between the...

Analysis Interpretation

Of the 145 SMRs or relative risks that were less than 100, 39 were deemed to be statistically significant (i.e., not due to chance). These figures varied when evaluating specific cancer sites, however. For colon cancer, out of a total of 20 studies, 19 (95 ) reported an SMR RR less than 100 (or 1.0). Six of these were statistically significant. For the other cancer sites evaluated, this figure was lower. For prostate cancer, only 55 of the SMRs reviewed were < 100 (none significantly so) while for breast cancer 67 were < 100, of which one was significantly less than 100 and two were significantly greater than 100. Table 4.3 summarizes the percent of SMRs and or RRs less than the null value for all cancer sites combined as well as for colon, prostate, breast, lung, stomach, pancreas and ovarian cancer as well as for the lymphatic hematopoietic cancers. Prostate When within-group comparisons are evaluated where dietary variation exists (e.g., within the SDA populations), several...

Intensity Modulated Radiotherapy

Early toxicity and biochemical outcomes have been reported for 772 patients with localized prostate cancer treated with high-dose IMRT (81 to 86.4 Gy, 1.8Gy fraction) at the Memorial Sloan-Kettering Cancer Center 16 . Intensity-modulated radiotherapy was associated with decreased rectal toxicity, and the actuarial rate of grade > 2 proctitis at 3 years was only 4 compared to the rate of 14 previously reported at the same center for patients receiving 81 Gy with 3D-CRT 11 . The 3-year actuarial PSA relapse-free survival rates were comparable to published results using 3D-CRT however, median follow-up was only 24 months and longer follow-up is required to substantiate these results. Preliminary results using hypofractionated IMRT (70 Gy at 2.5Gy fraction) show similar rates of late toxicity and biochemical outcome to high-dose 3D-CRT 17 , although again,longer follow-up is required.

Combined Radiotherapy and Hormone Therapy

The use of combined modality treatment, with hormone therapy and radiotherapy, for the treatment of prostate cancer may be beneficial for two reasons. First, by combining two effective modalities, there is hope that the anticancer effects will be additive. Second, the use of hormone therapy to shrink a large prostate before irradiation may improve efficacy by reducing the tumor burden and also may reduce rectal toxicity by reducing the volume irradiated to high dose 24 . The LHRH agonists (e.g., goserelin) are usually used, but antiandrogens (e.g., bicalutamide) may be useful in men who wish to retain their potency, although they result in less prostate shrinkage 25 . which hormone therapy was administered (Table 5.1). Based on these findings, there do appear to be several subsets of prostate cancer patients who benefit from hormone therapy plus radiotherapy over radiotherapy alone The potential benefits of androgen deprivation have to be balanced against toxicity. Most patients...

Adjuvant or Salvage Radiotherapy After Surgery

Following radical prostatectomy, patients with positive resection margins, extraprostatic exten sion (pT3 disease), or seminal vesicle invasion are at increased risk of disease recurrence. There is increasing interest in the role of postoperative radiotherapy in these patients. Radiotherapy (RT) can be administered immediately following prostatectomy (adjuvant RT) or may be postponed until the PSA has risen to a level that is indicative of residual or recurrent prostate cancer (salvage RT). There are no published randomized clinical trials of postprostatectomy radiotherapy, and it is not known whether the results of immediate adjuvant radiotherapy and early salvage radiotherapy are equivalent. Most retrospective studies, however, show that both are generally well tolerated. Adjuvant radiotherapy is given postopera-tively to eradicate possible microscopic residual disease in the periprostatic tissues or adjacent pelvic lymph nodes. It may be considered in men with positive resection...

Incidence and Indication

In order to underline the importance of the differential indication, the location of the meatus was investigated in 500 adult patients admitted for transurethral resection of the prostate 7 and was found in only 55 (O Fig. 6.2) on the tip of the glans. A hypospadia was found in 65 (13 ) of the otherwise undisturbed patients. It was also never mentioned by their wives - in the majority already multiple grandmothers - and the question concerning the psychological impact of this frequent anomaly became even more debatable (O Fig. 6.3).

Immediate or Deferred Treatment The Swinging Pendulum

The paradigm in oncology is that early diagnosis and treatment should enhance survival. This is the basis for the policy of screening for breast and cervical cancer, and similar benefits are proposed by those who advocate screening for prostate cancer. Indeed, the arguments concerning screening and those about deferred treatment are inextricably entwined. Just as the timing of hormonal treatment for advanced disease is controversial and definitions of immediate and deferred treatments still remain unclear, so do the arguments about which patients should undergo radical treatment for localized disease. Certainly in the United Kingdom, this is a new dimension, as radical prostatectomy was rarely considered an option before the mid-1980s, partly because of failure to diagnose the disease at an early stage, and radiotherapy was largely used for locally advanced disease. As more and more men are diagnosed with confined disease, radical prostatectomy initially confined to a few specialist...

Whole Grains and Cancer

There is a wide range of protective substances found in whole grains that exert their effect through various mechanisms including antioxidant activity, hormonal effects, binding of carcinogens, and otherwise influencing the environment of the gut in a beneficial fashion.60 A recent review of some 40 case-control studies (involving 20 different types of cancer) found a pooled odds ratio of 0.66 (99 confidence interval 0.60-0.72) for high vs. low whole grain intake.61 Most odds ratios in this review were < 1 for studies of colorectal cancers (or polyps), other gastrointestinal cancers, all hormone-related cancers, and all studies of pancreas cancer. Most of the odds ratios for the various cancer sites that were reviewed were of the order of 0.5 to 0.8, although for both breast and prostate cancer the relationship was not as pronounced. The odds ratios for breast cancer studies was 0.86 and was even higher for the prostate cancer studies reviewed (odds ratio 0.90). Overall, there...

Locally Advanced Disease

The results of the VACURG studies were considered inconclusive, but more recent studies have not fully answered these questions. The study sponsored by the British Medical Research Council (MRC) 17 ,which finished recruitment in 1993,provided evidence in favor of early treatment, as has the outcome of studies of adjuvant hormone treatment in patients receiving radiotherapy, reported from the European Organization for Research and Treatment of Cancer (EORTC) 18 and Radiation Therapy Oncology Group (RTOG) 19 . The MRC trial PR03 demonstrated not only an improvement in survival, but also a reduction in complications resulting from progression 20 . The increased risk seemed to continue even after treatment had been started in those in whom treatment was deferred, suggested as being due to disease progression during the period of deferred treatment and only being partly reversed when treatment is finally started. Further studies by the EORTC on somewhat different groups of patients are...

Fruits and Vegetables

The term vegetarian implies a lifestyle characterized by a diet rich in vegetable intake. A recent review based on 206 human epidemiologic studies and 22 animal studies concluded that fruits and vegetables were effective in the prevention of several forms of cancer including stomach, esophagus, lung, oral cavity, pharynx, endometrium, pancreas, and colon.62 Twenty cohort studies (perhaps offering the strongest type of evidence) were reviewed and indicated that fruit and vegetable consumption afforded protection against lung cancer across all studies reviewed. The 174 case-control studies that were reviewed indicated that there was convincing evidence for a protective role for fruits and vegetables for cancer of the lung, stomach, and esophagus and probable evidence for protection against cancer of the oral cavity and pharynx, colon, breast, pancreas, and bladder. In this review, prostate cancer was the one form of cancer not found to be associated with fruit and vegetable consumption....

Estramustine TaxaneBased Therapy

Summary of phase II clinical trials of estramustine plus a taxane in patients with hormone-refractory prostate cancer Table 4.2. Summary of phase II clinical trials of estramustine plus a taxane in patients with hormone-refractory prostate cancer Table 4.3. Summary of phase II trials using a single-agent taxane in patients with hormone-refractory prostate cancer Table 4.3. Summary of phase II trials using a single-agent taxane in patients with hormone-refractory prostate cancer prednisone (a weekly regimen or every 3 weeks) or the current standard, mitoxantrone and prednisone. End points included overall survival, PSA response, and palliative response. Docetaxel every three weeks led to superior survival (18.9 mo vx. 16.5 mo) and improved rates of response in terms of pain, serum PSA, and quality of life as compared with mitoxantrone plus prednisne 32a . The Southwest Oncology Group (SWOG) 9916 phase III study randomized 674 patients to receive estramustine and docetaxel or...

Neoadjuvant Chemotherapy

The use of systemic chemotherapy earlier in the course of treatment, an effective strategy in some malignancies, has been explored to a small degree in prostate cancer. The objectives of Several pilot neoadjuvant chemotherapy trials have now been reported, and suggest that from a surgical standpoint this is a feasible approach (Table 4.4). Pettaway et al. 38 treated patients with high-risk localized disease with 12 weeks of ketoconazole and doxorubicin alternating with vinblastine and estramustine (KAVE) and androgen ablation followed by radical prostatectomy (RP). The primary end point, a 20 pathological complete response (pCR), was not achieved, but there were fewer positive margins. Clark et al. 39 reported similar results, but increased thromboembolic events, using a neoadjuvant regimen of etopo-side and estramustine. The taxanes have also been evaluated in the neoadjuvant setting. Single-agent docetaxel administered prior to RP was well tolerated, with final efficacy results...

Is the Case for Immediate Treatment Proved

The difference between disease-specific and overall survival has been noted, and discussed earlier. If the reduction or delay in prostate cancer deaths was counteracted by treatment-induced mortality, it should be apparent from an increased death rate from other causes, as was noted in the VACURG studies for patients receiving oestrogens 9 . No such excess of noncancer deaths was noted in MRC trial PR03 20,28 . Unpublished data from the Prostate Cancer Trialists' Collaborative Group's meta-analysis confirms an excess death rate from estrogen treatment but not for patients treated with LHRH analogues or orchiectomy. To the body of evidence on hormonal treatment in advanced disease, we can now add one randomized study of radical prostatectomy versus watchful waiting.

Alternative Explanations for Low Cancer Risk in Vegetarians

Data have suggested that colon cancer may be associated with cigarette smoking (but only after a long latency period).64-65 The more relevant question today may be which cancer sites are not associated with tobacco the list appears to be quite short and currently includes prostate, endometrium, and breast cancer. Screening Bias For some forms of cancer, screening is effective in early detection. Specifically, some of the female cancers such as cervix and breast, as well as prostate cancer in men may be detected more frequently in populations that have a greater than normal degree of access to screening programs. For example, in the Adventist Health Study in which cancer incidence was monitored among SDA between 1976 and 1982, elevated incidence of skin cancer, prostate, and cervix cancers was observed.28 These findings may not be a reflection of an actual increased biologic risk of these forms of cancer in SDAs, but an artifact of more intense screening for cancers among SDAs than in...

Immediate or Deferred Treatment in 2005

Studies in rat prostate cancer models support the use of immediate hormone therapy, which is most effective in terms of survival when initiated at the time of, or early after, tumour implantation 29,30 . For patients with locally advanced prostate cancer who receive radiotherapy, several prospective randomized controlled multicenter trials have indicated that adjuvant hormone therapy (goserelin or orchiectomy) extends progression-free survival and may also improve overall survival in some patients 30,31 . Although data on the use of adjuvant hormone therapy after radical prostatectomy are currently more limited, results from two studies support this approach in patients with an unfavorable prognosis 32 . Meanwhile, practitioners who manage men with prostate cancer have to use the tools available at the moment. Imperfect though they are, current methods of hormone treatment are effective to an extent that is not available for many other types of cancer. We must recognize that this is a...

Recent Recommendations on Vitamins and Chronic Disease Prevention

Fletcher and Fairfield (172, 173) reviewed the use of vitamin supplements for chronic disease prevention and stated that suboptimal intake of some vitamins, at levels above those leading to classic vitamin deficiencies, can be risk factors for chronic diseases. They recommended that all adults take vitamin supplements tailored to their life situation and based on their doctor's advice. Specific responsibility was placed on the doctor to learn about their patients' use of vitamins to ensure proper supplement usage. Specific to vitamin E, recommendations for its use for reduction of prostate cancer were considered premature. For use as a preventative against cardiovascular problems, the authors believed that the literature suggested that it might be useful in primary prevention when taken throughout long periods and that some subgroups of the population might benefit more that the general population.

Epidermal Growth Factor Receptor Inhibitors

The epidermal growth factor receptor (EGFR) superfamily of receptors, which comprises four distinct receptors known as EGFR, Human Epidermal growth Factor Receptor, HER2, HER3, and HER4, is a potential therapeutic target in prostate cancer where overexpression is seen in up to 80 of metastasis, and is generally associated with a poorer overall prognosis. Several EGFR targeting agents are now available, including tyrosine kinase inhibitors and monoclonal antibodies. To date, the tyrosine kinase inhibitor gefitinib has undergone the most investigation in prostate cancer. Three phase II trials, with gefitinib alone, and in combination with either docetaxel and estramustine, or mitox-antrone and prednisone, have completed accrual, with final results pending at this time. Two studies, reported in abstract form only, suggest that single-agent gefitinib does not have significant activity 50,51 .

Angiogenesis Inhibitors

Targeting angiogenesis is another novel approach. Angiogenesis is a physiological process that is fundamental to cell growth and division. It is initiated by the release of proteases from activated endothelial cells, leading to degradation of the basement membrane, migration of endothelial cells into the interstitial space, and subsequent endothelial proliferation and differentiation into mature blood vessels 52 . Several agents targeting angiogenesis have been tested in prostate cancer, including suramin, thalidomide, matrix metalloproteinase inhibitors, endostatin, angio-statin, vascular endothelial growth factor (VEGF) inhibitors, and cell adhesion inhibitors, to name a few. These are all currently in early stages of development.

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