Definition
Content
Definition
Prostate cancer has evolved from a relatively common but infrequently discussed neoplasm to a major clinical entity with significant public health and economic ramifications. The widespread application of prostate-specific antigen (PSA) into clinical practice in the late 1980s has had a paradigm-shifting impact on the management of prostate cancer. Among the most visible consequences of PSA-based screening is the substantial increase in the percentage of patients who are believed to have clinically localized disease. This, in turn, has translated into a significant increase in the number of patients undergoing curative-intent surgery and radiotherapy. Additional prostate cancer subsets have been created, including patients with PSAonly evidence of disease following curative-intent therapy, termed biochemical failure, and patients with rising PSA levels following androgen-deprivation therapy, termed castrate progressive prostate cancer, biochemically defined.
Epidemiology
It is estimated that in 2009 approximately 192,280 men in the United States will be given a new diagnosis of prostate cancer. Although the vast majority present with early disease, more than 27,000 men are destined to die from advanced disease yearly. Prostate cancer is the most common malignancy in U.S. men (excluding nonmelanoma skin cancer), and it is the second most common cause of cancer death, after lung cancer, in American men. Worldwide, prostate cancer ranks third in cancer incidence and sixth in cancer mortality in men. There is, however, a significant disparity in incidence and mortality rates among world regions, with a very low incidence in China and Japan in contrast to the United States and parts of western Europe. This wide variability in incidence is likely multifactorial, with varying effects of genetic predisposition, diet, environmental factors, and the increased frequency of prostate biopsies performed in asymptomatic men undergoing screening with PSA. Prostate cancer is also a disease of the older adults, as has been demonstrated in various autopsy series showing 70% to 80% of men older than 80 years with some evidence of latent disease. It is this observation that has complicated the prostate cancer screening debate, with critics questioning the ability of screening to discriminate between clinically relevant disease and latent disease that is not destined to cause symptoms or affect survival.
Risk factors
The causes of prostate cancer remain poorly understood. The main predictors of prostate cancer risk are age, race or ethnicity, and family history. The incidence of prostate cancer in U.S. men increases significantly above age 50 years. African American men have a higher incidence of prostate cancer–related death than European American and Latin American men. Prostate cancer can be sporadic, hereditary, or familial; the familial type is defined by a clustering of prostate cancer cases within members of a family. Men with an affected first-degree relative (i.e., father or brother) have a two-fold increase in their risk of developing prostate cancer. Similarly, early age of onset in any family member also increases the risk. In families with two or three affected first-degree relatives, the risk of developing prostate cancer increases 5- to 11-fold.1
There are numerous purported molecular, genetic, environmental, and dietary factors, with varying degrees of supporting evidence. Studies have provided compelling data to support the role of elevated serum testosterone and insulin-like growth factor-1 levels as significant risk factors. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including animal fat, calories, fruits and vegetables, antioxidants, and various micronutrients, but the specific role of dietary agents in promoting or preventing prostate cancer remains controversial. Also controversial are the data from recent observational studies that have hypothesized statins and nonsteroidal anti-inflammatory drugs (NSAIDs) as agents capable of decreasing the risk of developing any malignancy, including prostate cancer.
Pathophysiology
The pathophysiology of prostate cancer is poorly understood and, for many years, was an underrepresented area of investigation, in contrast to work in other solid tumors. Over the past decade, there has been a significant increase in prostate cancer research, with a concomitant increase in funding for basic investigation. Among the challenges faced by investigators attempting to understand early steps in the carcinogenic pathway is the lack of a reliable animal model of prostate cancer. Although prostate cancer typically manifests in men older than 65 years, a growing body of evidence suggests that prostatic carcinogenesis is initiated much earlier. Prostatic intraepithelial neoplasia (PIN) is the histologic entity widely considered to be the most likely precursor of invasive prostate cancer. Although not all patients with high-grade PIN (HGPIN) progress to develop invasive disease, PIN is characterized by cellular proliferation within pre-existing ducts and glands, with cytologic changes that mimic those of cancer.1 PIN is associated with progressive abnormalities of phenotype and genotype that are intermediate between normal prostatic epithelium and cancer. The recognition of the strong association of HGPIN and cancer has led many investigators to propose its use as an intermediate marker in chemoprevention studies. Prostate cancer progression has also been related to a number of genetic abnormalities that affect the androgen receptor (AR) and other molecules that are involved in cell survival and apoptosis. In fact, over the past decade, recognition of a hereditary form of prostate cancer has prompted a vigorous research effort into the molecular genetics of prostate cancer, with various research teams performing linkage studies leading to the identification of several chromosomal loci that may be the source of prostate cancer susceptibility genes. At least six prostate cancer susceptibility loci have been identified to date, with increasing evidence that there is no single major gene accounting for a large portion of susceptibility to the disease. The fraction of prostate cancer cases caused by mutations in these genes is estimated to be 5% to 10%, and the hereditary form of the disease is diagnosed, on average, approximately 7 years earlier than the sporadic form of the disease. Despite of the heterogeneity of this tumor and the lack of appropriate model systems of prostate cancer progression, these studies are beginning to provide important insights into the pathogenesis of this neoplasm.
Signs and symptoms
The clinical manifestations of prostate cancer result from the effects of local growth of the tumor, the spread to regional lymph nodes via the lymphatics, and the hematogenous dissemination to distant metastatic sites. Although most patients with early-stage prostate cancer are asymptomatic, locally advanced disease can lead to obstructive or irritative voiding symptoms that result from local tumor growth into the urethra or bladder neck, extension into the trigone of the bladder, or both. Prostate cancer most often spreads to bone, commonly leading to bone pain. A small but important subset of patients develop spinal cord impingement from the epidural spread of disease, resulting in pain and neurologic compromise that, depending on the location of the spinal lesion, could include the irreversible loss of bowel and bladder function and the ability to walk. Other common sites of metastatic spread include lymph nodes, with some patients presenting with progressive lymphedema, renal insufficiency, or both as a consequence of obstruction of pelvic lymphatics and ureteral outlet obstruction.
Diagnosis
With the introduction of PSA into clinical practice in the late 1980s and the subsequent influential recommendations of the American Urological Society and the American Cancer Society, prostate cancer screening (PSA plus digital rectal examination [DRE]) has become widely used in the United States. Prostate cancer screening remains controversial, as evidenced by the wide array of screening recommendations (Box 1), because there is no prospective evidence demonstrating a decrease in prostate cancer-specific mortality.2 Box 1: Summary of Current Prostate Cancer Guidelines From Selected Organizations American College of Physicians—American Society of Internal Medicine Physicians should describe potential benefits and known harms of screening, diagnosis, and treatment, listen to the patient's concerns, and then individualize the decision to screen. American Cancer Society and American Urological Association Physicians should offer annual DRE and PSA screening, beginning at age 50 years, to men who have at least a 10-year life expectancy and to younger men at high risk. Canadian Task Force on Preventive Health Care and U.S. Preventive Services Task Force DRE and PSA tests are not recommended for the general population. American Academy of Family Physicians No published standards or guidelines are available for low-risk patients. American Medical Association Physicians should provide information regarding the risks and potential benefits of prostate screening. DRE, digital rectal examination; PSA, prostate-specific antigen. Several prospective screening trials are ongoing in the United States and worldwide. Among the largest are the European Randomized Screening for Prostate Cancer (ERSPC) trial, with more than 160,000 men, and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), sponsored by the National Cancer Institute, which completed enrolment of more than
154,000 participants, including 75,000 men, in the summer of 2001. It is hoped that the results of these trials will provide more definitive guidance to patients and clinicians about the impact of screening. Until more definitive data are available, many major medical societies have recommended a careful discussion with individual patients, before screening, regarding the potential risks and benefits. Patients with significant comorbid conditions and those with life expectancies of less than 10 years are much less likely to benefit from therapeutic intervention and therefore should not be considered for screening. Alternatively, patients at potentially high risk, such as African Americans and those with one or more affected first-degree relatives, might be appropriate candidates for screening at an earlier age, 40 to 50 years. Over the last decade, the penetration of PSA-based screening has caused a stage migration, with an increasing percentage of patients with normal rectal examination findings receiving a diagnosis on the basis of an elevated PSA level (clinical stage T1c in the tumor, node, metastasis [TNM] staging classification). There has also been a concomitant dramatic decrease in the number of patients who present initially with evidence of metastatic disease. Following a biopsy-proven diagnosis of prostate cancer, patients are clinically staged using the TNM system (Table 1) based on the extent of local tumor on rectal examination and the presence or absence of metastatic disease. In the last several years, a series of outcomes-based nomograms have been developed to improve the clinician's ability to predict the patient's pathologic stage (http://urology.jhu.edu/prostate/partintables.php) and his response to therapy (http://www.mskcc.org/mskcc/html/10088.cfm). These nomograms use clinically available parameters such as PSA, Gleason scores obtained from prostate biopsies or surgery, and other known prognostic factors, such as prostate capsule penetration, margin status, involvement of the seminal vesicles, and node status.
Table 1: TNM Clinical Stages of Prostate Cancer
Stag e T1a T1b T1c T2a T2b T2c T3a
Features Nonpalpable, with %5% of tissue with cancer, low grade (diagnosed by transurethral resection of the prostate) Nonpalpable, with >5% of tissue with cancer, high grade (diagnosed by transurethral resection of the prostate), or both Nonpalpable, but prostate-specific antigen level elevated Palpable, one half of one lobe or less Palpable, more than one half of one lobe, not both lobes Palpable, involves both lobes Palpable, unilateral capsular penetration
TNM, tumor, node, metastasis.
Treatment and outcomes
Chemoprevention
Features such as a high prevalence rate, a long latency period, and identifiable risk factors have made prostate cancer a desirable tumor to test different chemopreventive strategies. Several studies have evaluated different agents thought to be capable of reducing the risk of prostate cancer. Although agents such as retinoids and toremifene have failed to show statistical benefits in this setting, finasteride, an inhibitor of 5α-reductase (5-AR) widely used to treat symptoms related to benign prostatic hyperplasia, appears to reduce the risk for developing prostate cancer. A large randomized trial with more than 18,000 participants comparing finasteride with placebo in men with a normal DRE and normal serum PSA values but with an elevated risk for prostate cancer (aged 55 or older, African American ethnicity, or a first-degree relative having prostate cancer) demonstrated a 25% decrease in the incidence of prostate cancer over a 7-year period for men taking finasteride. Despite this result, the controversy about a possible increase in the incidence of high-grade tumors (Gleason scores >7) initially dampened enthusiasm for the use of this agent as a chemopreventive strategy. Subsequent explanations for these findings suggest a diagnostic bias due to the effect of finasteride on prostate size. In fact, when prostate size was included in the analysis, the risk for high-grade tumors disappeared. Currently, an international multicenter double-blind, placebo-controlled chemoprevention trial is evaluating dutasteride, a more potent 5-AR dual inhibitor. Other, smaller studies also continue to evaluate minimally toxic compounds such as vitamins, minerals, and micronutrients as potential chemopreventive agents in prostate cancer. Localized Prostate Cancer For appropriately selected patients with clinically organ-confined prostate cancer, potential curative options include radical prostatectomy (RP) and radiation therapy (external-beam radiation therapy [EBRT], brachytherapy, or both). Other options include active surveillance, androgen-deprivation therapy (ADT), and cryotherapy. The optimal treatment for localized prostate cancer remains undefined, in part because of the absence of prospective randomized clinical trials comparing outcomes of surgery and radiotherapy. To date, only one randomized phase III trial has directly compared RP and watchful waiting in men with clinically localized disease. This study demonstrated a significant improvement in disease-specific survival as well as overall survival in men undergoing surgery. Other factors that complicate our understanding of the impact of these therapies include the stage migration resulting from screening and the long natural history of localized prostate cancer. Using biochemical relapse (BCR)—PSA recurrence following radical prostatectomy (PSA >0.2) or the nadir PSA value + 2ng/mL in patients receiving radiotherapy—as an intermediate end point and after adjustment for stage and grade of tumors, outcomes with EBRT and radical prostatectomy at 8 years' follow-up are equivalent.3 Among the challenges in identifying the most beneficial therapy for localized disease is the relatively rapid evolution of radiotherapy techniques over time. Over the last 5 to 10 years, there has been increasing evidence of a dose-response relationship for prostate cancer, leading to an increase in conventional radiotherapy dosages for localized disease from the upper 60-Gy range to current doses of 72 to 78 Gy. This increase in dosage has been
made possible by technologic improvements in radiotherapy delivery systems using threedimensional conformal radiation theray (3D-CRT) (computer-guided dosing techniques that attempt to minimize radiation dosage outside the target field), such as intensity-modulated radiotherapy. Evidence from contemporary prospective, randomized clinical trials has also demonstrated that for selected patients, such as those with locally advanced disease (large tumor size, high Gleason grade, and high PSA levels), a disease-free survival, time to the development of progressive disease, and overall survival benefit is gained when patients are treated with ADT. The addition of ADT has been prospectively studied in several settings, including neoadjuvant, concurrent, and adjuvant for periods often persisting for 6 to 36 months. Prostate brachytherapy with 125I or 103Pd, which involves placing radioactive, rice-sized pellets directly into the prostate gland, has increasingly been used in the management of appropriately selected patients opting for radiotherapy. Compared with external beam radiotherapy, it has some important patient advantages, including a single outpatient treatment versus the typical 7-week course of external beam treatment. Some patients undergo brachytherapy followed by supplemental external beam radiotherapy. Whether the addition of supplemental external beam therapy improves outcomes and can justify increases in patient toxicity and cost remains controversial. Given the lack of definitive evidence of the optimal therapy for localized prostate cancer, an important consideration for patients and the physicians helping guide their decision is the potential side effects of radiotherapy and surgery (Table 2). The major side effects of therapy for localized prostate cancer affect urinary, bowel, and sexual function. Recent evidence has suggested that for patients undergoing radical prostatectomy, urologists with high-volume prostatectomy practices may have better patient outcomes.4 Although, historically, reports of these side effects in the literature were typically those reported to the treating physicians in retrospective reviews, there has been a large effort by numerous investigators using “modern” quality-of-life assessment tools to quantitate more precisely the impact of local therapies on long-term quality of life.5 These assessments should be used by patients and physicians to help guide treatment decisions.
Table 2: Common Side Effects of Standard Treatment Modalities for Localized Prostate Cancer
Treatment Modality Brachytherapy External beam radiotherapy Radical prostatectomy
Impotence Variable
Urinary Function
Rectal Injury
Acute bladder irritation, — common; incontinence, rare Acute diarrhea, common; rectal Acute cystitis, common; late Common bleeding, infrequent; rectal cystitis, infrequent perforation, rare Variable Incontinence (variable) —
Cryotherapy is another modality of local treatment for prostate cancer that initially had been abandoned because of its high rate of complications. Recently this modality of treatment has
regained momentum as new and improved instruments and techniques have allowed reductions in toxicities and and possibly greater efficacy. Currently, cryotherapy remains experimental in the United States. Metastatic Prostate Cancer Hormonal therapy—androgen ablation—has for more than 60 years been the primary initial treatment of patients with metastatic prostate cancer. Androgen ablation options for patients with advanced prostate cancer include bilateral orchiectomy, luteinizing hormone–releasing hormone (LHRH) analogues and antagonists, and combined androgen blockade, a combination of either an orchiectomy or LHRH analogue plus an antiandrogen. Although orchiectomy remains the historical gold standard, LHRH therapy is equivalent therapeutically, and patients are increasingly opting for medical therapy, in part because of the psychological implications of surgical castration. Orchiectomy remains an important option for patients presenting with spinal cord compression or diffuse, painful bone metastases, because it leads to the rapid achievement of castrate levels of testosterone (hours) compared with the 14 to 21 days required for LHRH analogues. In human males, 5% to 10% of circulating testosterone originates from the conversion of adrenal steroid precursors. Nonsteroidal antiandrogens act at the level of the androgen receptor to inhibit the stimulatory effects of testosterone. The use of an antiandrogen, in addition to LHRH or orchiectomy, is referred to as combined androgen blockade. The role of combined androgen blockade remains controversial, with meta-analysis evidence of only a modest improvement in survival, with some added toxicity and significant expense.6 Approximately 10% of patients started on LHRH therapy have an initial testosterone flare, so patients at risk—such as those with known bone or nodal metastases or at risk for urinary outlet problems—should be started concomitantly on an antiandrogen (e.g., bicalutamide, flutamide) for 2 to 3 weeks to minimize this possibility. Unfortunately, the vast majority of patients with metastatic prostate cancer have evidence of disease progression on hormonal therapy (median response duration to hormonal therapy, 24-36 months). Patients with advanced prostate cancer typically have progressive bone pain, cancer cachexia, and fatigue. Significant anemia is common, although transfusion dependency is rare. Some patients with primarily nodal involvement develop significant lymphedema or ureteral obstruction. Spinal cord compression is relatively common, and a high index of suspicion must be maintained for patients presenting with back pain, even in the absence of neurologic findings. In prostate cancer patients with suspected spinal cord compression (without cervical spine symptoms, clinical findings, or plain film evidence of bone destruction), magnetic resonance imaging (MRI) of the thoracic and lumbosacral spine, with and without gadolinium, should be performed. Given the high incidence of involvement of both the lumbar and thoracic spines, failure to image both areas can compromise radiotherapy if untreated lesions become symptomatic and are detected later. Historically, management of advanced disease consisted of second-line hormonal therapies and palliative radiotherapy. Palliative radiotherapy remains an important component of patient management. There has been evidence, similar to findings for breast cancer and multiple
myeloma, that bisphosphonate therapy with zoledronic acid can decrease skeletal progression rates and complications in patients with androgen-independent metastatic bone disease.7 Chemotherapy has the potential to provide meaningful palliation for select patients, with improvement in pain and other disease-related symptoms. Two important phase III studies have evaluated docetaxel-based therapies in patients with advanced prostate cancer and demonstrated, for the first time, the ability to improve the survival of patients with advanced disease, albeit modestly.8 New drugs in development are targeting the androgen receptor directly with androgen-receptor antagonists and by inhibition of androgenic steroid synthesis. Although recent progress has been made and new agents are on the horizon, advanced prostate cancer remains an incurable disease. Vigorous efforts to manage pain and other disease-related symptoms through the appropriate use of opiods and palliative radiotherapy are essential for the optimal management of patients with progressive disease.
Summary
•
• •
Prostate cancer is the most commonly diagnosed neoplasm (excluding nonmelanoma skin cancer) and is the second most common cause of cancer death, after lung cancer, in American men. Prostate cancer screening with PSA testing and a digital rectal examination is widely performed, but data supporting an impact on survival are not yet available. Chemotherapy for advanced prostate cancer can palliate the disease and modestly improve survival.
References
1. Bostwick DG. High-grade prostatic intraepithelial neoplasia: The most likely precursor of prostate cancer. Cancer. 1995, 75: 1823-1836. 2. American College of Physicians. Screening for prostate cancer. Ann Intern Med. 1997, 126: 480-484. 3. Kupelian PA, Elshaikh M, Reddy CA, et al: Comparison of the efficacy of local therapies for localized prostate cancer in the PSA era: A large single-institution experience with radical prostatectomy and external beam radiotherapy. J Clin Oncol. 2002, 20: 33763385. 4. Bianco FJ Jr, Riedel ER, Begg CB, et al: Variations among high-volume surgeons in the rate of complications after radical prostatectomy: Further evidence that technique matters. J Urol. 2005, 173: 2099-2103. 5. Harlan LC, Potosky A, Gilliland FD, et al: Factors associated with initial therapy for clinically localized prostate cancer: Prostate Cancer Outcomes Study. J Natl Cancer Inst. 2001, 93: 1864-1871. 6. Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: An overview of the randomised trials. Lancet. 2000, 355: 1491-1498. 7. Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002, 94: 1458-1468.
8. Tannock I, de Wit R, Berry W, et al: Docetaxel plus prednisone or mitoxantrone plus
prednisone for advanced prostate cancer. N Engl J Med. 2004, 351: 1502-1512.
Prostate cancer has evolved from a relatively common but infrequently discussed neoplasm to a major clinical entity with significant public health and economic ramifications. The widespread application of prostate-specific antigen (PSA) into clinical practice in the late 1980s has had a paradigm-shifting impact on the management of prostate cancer. Among the most visible consequences of PSA-based screening is the substantial increase in the percentage of patients who are believed to have clinically localized disease. This, in turn, has translated into a significant increase in the number of patients undergoing curative-intent surgery and radiotherapy. Additional prostate cancer subsets have been created, including patients with PSAonly evidence of disease following curative-intent therapy, termed biochemical failure, and patients with rising PSA levels following androgen-deprivation therapy, termed castrate progressive prostate cancer, biochemically defined.
Epidemiology
It is estimated that in 2009 approximately 192,280 men in the United States will be given a new diagnosis of prostate cancer. Although the vast majority present with early disease, more than 27,000 men are destined to die from advanced disease yearly. Prostate cancer is the most common malignancy in U.S. men (excluding nonmelanoma skin cancer), and it is the second most common cause of cancer death, after lung cancer, in American men. Worldwide, prostate cancer ranks third in cancer incidence and sixth in cancer mortality in men. There is, however, a significant disparity in incidence and mortality rates among world regions, with a very low incidence in China and Japan in contrast to the United States and parts of western Europe. This wide variability in incidence is likely multifactorial, with varying effects of genetic predisposition, diet, environmental factors, and the increased frequency of prostate biopsies performed in asymptomatic men undergoing screening with PSA. Prostate cancer is also a disease of the older adults, as has been demonstrated in various autopsy series showing 70% to 80% of men older than 80 years with some evidence of latent disease. It is this observation that has complicated the prostate cancer screening debate, with critics questioning the ability of screening to discriminate between clinically relevant disease and latent disease that is not destined to cause symptoms or affect survival.
Risk factors
The causes of prostate cancer remain poorly understood. The main predictors of prostate cancer risk are age, race or ethnicity, and family history. The incidence of prostate cancer in U.S. men increases significantly above age 50 years. African American men have a higher incidence of prostate cancer–related death than European American and Latin American men. Prostate cancer can be sporadic, hereditary, or familial; the familial type is defined by a clustering of prostate cancer cases within members of a family. Men with an affected first-degree relative (i.e., father or brother) have a two-fold increase in their risk of developing prostate cancer. Similarly, early age of onset in any family member also increases the risk. In families with two or three affected first-degree relatives, the risk of developing prostate cancer increases 5- to 11-fold.1
There are numerous purported molecular, genetic, environmental, and dietary factors, with varying degrees of supporting evidence. Studies have provided compelling data to support the role of elevated serum testosterone and insulin-like growth factor-1 levels as significant risk factors. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including animal fat, calories, fruits and vegetables, antioxidants, and various micronutrients, but the specific role of dietary agents in promoting or preventing prostate cancer remains controversial. Also controversial are the data from recent observational studies that have hypothesized statins and nonsteroidal anti-inflammatory drugs (NSAIDs) as agents capable of decreasing the risk of developing any malignancy, including prostate cancer.
Pathophysiology
The pathophysiology of prostate cancer is poorly understood and, for many years, was an underrepresented area of investigation, in contrast to work in other solid tumors. Over the past decade, there has been a significant increase in prostate cancer research, with a concomitant increase in funding for basic investigation. Among the challenges faced by investigators attempting to understand early steps in the carcinogenic pathway is the lack of a reliable animal model of prostate cancer. Although prostate cancer typically manifests in men older than 65 years, a growing body of evidence suggests that prostatic carcinogenesis is initiated much earlier. Prostatic intraepithelial neoplasia (PIN) is the histologic entity widely considered to be the most likely precursor of invasive prostate cancer. Although not all patients with high-grade PIN (HGPIN) progress to develop invasive disease, PIN is characterized by cellular proliferation within pre-existing ducts and glands, with cytologic changes that mimic those of cancer.1 PIN is associated with progressive abnormalities of phenotype and genotype that are intermediate between normal prostatic epithelium and cancer. The recognition of the strong association of HGPIN and cancer has led many investigators to propose its use as an intermediate marker in chemoprevention studies. Prostate cancer progression has also been related to a number of genetic abnormalities that affect the androgen receptor (AR) and other molecules that are involved in cell survival and apoptosis. In fact, over the past decade, recognition of a hereditary form of prostate cancer has prompted a vigorous research effort into the molecular genetics of prostate cancer, with various research teams performing linkage studies leading to the identification of several chromosomal loci that may be the source of prostate cancer susceptibility genes. At least six prostate cancer susceptibility loci have been identified to date, with increasing evidence that there is no single major gene accounting for a large portion of susceptibility to the disease. The fraction of prostate cancer cases caused by mutations in these genes is estimated to be 5% to 10%, and the hereditary form of the disease is diagnosed, on average, approximately 7 years earlier than the sporadic form of the disease. Despite of the heterogeneity of this tumor and the lack of appropriate model systems of prostate cancer progression, these studies are beginning to provide important insights into the pathogenesis of this neoplasm.
Signs and symptoms
The clinical manifestations of prostate cancer result from the effects of local growth of the tumor, the spread to regional lymph nodes via the lymphatics, and the hematogenous dissemination to distant metastatic sites. Although most patients with early-stage prostate cancer are asymptomatic, locally advanced disease can lead to obstructive or irritative voiding symptoms that result from local tumor growth into the urethra or bladder neck, extension into the trigone of the bladder, or both. Prostate cancer most often spreads to bone, commonly leading to bone pain. A small but important subset of patients develop spinal cord impingement from the epidural spread of disease, resulting in pain and neurologic compromise that, depending on the location of the spinal lesion, could include the irreversible loss of bowel and bladder function and the ability to walk. Other common sites of metastatic spread include lymph nodes, with some patients presenting with progressive lymphedema, renal insufficiency, or both as a consequence of obstruction of pelvic lymphatics and ureteral outlet obstruction.
Diagnosis
With the introduction of PSA into clinical practice in the late 1980s and the subsequent influential recommendations of the American Urological Society and the American Cancer Society, prostate cancer screening (PSA plus digital rectal examination [DRE]) has become widely used in the United States. Prostate cancer screening remains controversial, as evidenced by the wide array of screening recommendations (Box 1), because there is no prospective evidence demonstrating a decrease in prostate cancer-specific mortality.2 Box 1: Summary of Current Prostate Cancer Guidelines From Selected Organizations American College of Physicians—American Society of Internal Medicine Physicians should describe potential benefits and known harms of screening, diagnosis, and treatment, listen to the patient's concerns, and then individualize the decision to screen. American Cancer Society and American Urological Association Physicians should offer annual DRE and PSA screening, beginning at age 50 years, to men who have at least a 10-year life expectancy and to younger men at high risk. Canadian Task Force on Preventive Health Care and U.S. Preventive Services Task Force DRE and PSA tests are not recommended for the general population. American Academy of Family Physicians No published standards or guidelines are available for low-risk patients. American Medical Association Physicians should provide information regarding the risks and potential benefits of prostate screening. DRE, digital rectal examination; PSA, prostate-specific antigen. Several prospective screening trials are ongoing in the United States and worldwide. Among the largest are the European Randomized Screening for Prostate Cancer (ERSPC) trial, with more than 160,000 men, and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), sponsored by the National Cancer Institute, which completed enrolment of more than
154,000 participants, including 75,000 men, in the summer of 2001. It is hoped that the results of these trials will provide more definitive guidance to patients and clinicians about the impact of screening. Until more definitive data are available, many major medical societies have recommended a careful discussion with individual patients, before screening, regarding the potential risks and benefits. Patients with significant comorbid conditions and those with life expectancies of less than 10 years are much less likely to benefit from therapeutic intervention and therefore should not be considered for screening. Alternatively, patients at potentially high risk, such as African Americans and those with one or more affected first-degree relatives, might be appropriate candidates for screening at an earlier age, 40 to 50 years. Over the last decade, the penetration of PSA-based screening has caused a stage migration, with an increasing percentage of patients with normal rectal examination findings receiving a diagnosis on the basis of an elevated PSA level (clinical stage T1c in the tumor, node, metastasis [TNM] staging classification). There has also been a concomitant dramatic decrease in the number of patients who present initially with evidence of metastatic disease. Following a biopsy-proven diagnosis of prostate cancer, patients are clinically staged using the TNM system (Table 1) based on the extent of local tumor on rectal examination and the presence or absence of metastatic disease. In the last several years, a series of outcomes-based nomograms have been developed to improve the clinician's ability to predict the patient's pathologic stage (http://urology.jhu.edu/prostate/partintables.php) and his response to therapy (http://www.mskcc.org/mskcc/html/10088.cfm). These nomograms use clinically available parameters such as PSA, Gleason scores obtained from prostate biopsies or surgery, and other known prognostic factors, such as prostate capsule penetration, margin status, involvement of the seminal vesicles, and node status.
Table 1: TNM Clinical Stages of Prostate Cancer
Stag e T1a T1b T1c T2a T2b T2c T3a
Features Nonpalpable, with %5% of tissue with cancer, low grade (diagnosed by transurethral resection of the prostate) Nonpalpable, with >5% of tissue with cancer, high grade (diagnosed by transurethral resection of the prostate), or both Nonpalpable, but prostate-specific antigen level elevated Palpable, one half of one lobe or less Palpable, more than one half of one lobe, not both lobes Palpable, involves both lobes Palpable, unilateral capsular penetration
TNM, tumor, node, metastasis.
Treatment and outcomes
Chemoprevention
Features such as a high prevalence rate, a long latency period, and identifiable risk factors have made prostate cancer a desirable tumor to test different chemopreventive strategies. Several studies have evaluated different agents thought to be capable of reducing the risk of prostate cancer. Although agents such as retinoids and toremifene have failed to show statistical benefits in this setting, finasteride, an inhibitor of 5α-reductase (5-AR) widely used to treat symptoms related to benign prostatic hyperplasia, appears to reduce the risk for developing prostate cancer. A large randomized trial with more than 18,000 participants comparing finasteride with placebo in men with a normal DRE and normal serum PSA values but with an elevated risk for prostate cancer (aged 55 or older, African American ethnicity, or a first-degree relative having prostate cancer) demonstrated a 25% decrease in the incidence of prostate cancer over a 7-year period for men taking finasteride. Despite this result, the controversy about a possible increase in the incidence of high-grade tumors (Gleason scores >7) initially dampened enthusiasm for the use of this agent as a chemopreventive strategy. Subsequent explanations for these findings suggest a diagnostic bias due to the effect of finasteride on prostate size. In fact, when prostate size was included in the analysis, the risk for high-grade tumors disappeared. Currently, an international multicenter double-blind, placebo-controlled chemoprevention trial is evaluating dutasteride, a more potent 5-AR dual inhibitor. Other, smaller studies also continue to evaluate minimally toxic compounds such as vitamins, minerals, and micronutrients as potential chemopreventive agents in prostate cancer. Localized Prostate Cancer For appropriately selected patients with clinically organ-confined prostate cancer, potential curative options include radical prostatectomy (RP) and radiation therapy (external-beam radiation therapy [EBRT], brachytherapy, or both). Other options include active surveillance, androgen-deprivation therapy (ADT), and cryotherapy. The optimal treatment for localized prostate cancer remains undefined, in part because of the absence of prospective randomized clinical trials comparing outcomes of surgery and radiotherapy. To date, only one randomized phase III trial has directly compared RP and watchful waiting in men with clinically localized disease. This study demonstrated a significant improvement in disease-specific survival as well as overall survival in men undergoing surgery. Other factors that complicate our understanding of the impact of these therapies include the stage migration resulting from screening and the long natural history of localized prostate cancer. Using biochemical relapse (BCR)—PSA recurrence following radical prostatectomy (PSA >0.2) or the nadir PSA value + 2ng/mL in patients receiving radiotherapy—as an intermediate end point and after adjustment for stage and grade of tumors, outcomes with EBRT and radical prostatectomy at 8 years' follow-up are equivalent.3 Among the challenges in identifying the most beneficial therapy for localized disease is the relatively rapid evolution of radiotherapy techniques over time. Over the last 5 to 10 years, there has been increasing evidence of a dose-response relationship for prostate cancer, leading to an increase in conventional radiotherapy dosages for localized disease from the upper 60-Gy range to current doses of 72 to 78 Gy. This increase in dosage has been
made possible by technologic improvements in radiotherapy delivery systems using threedimensional conformal radiation theray (3D-CRT) (computer-guided dosing techniques that attempt to minimize radiation dosage outside the target field), such as intensity-modulated radiotherapy. Evidence from contemporary prospective, randomized clinical trials has also demonstrated that for selected patients, such as those with locally advanced disease (large tumor size, high Gleason grade, and high PSA levels), a disease-free survival, time to the development of progressive disease, and overall survival benefit is gained when patients are treated with ADT. The addition of ADT has been prospectively studied in several settings, including neoadjuvant, concurrent, and adjuvant for periods often persisting for 6 to 36 months. Prostate brachytherapy with 125I or 103Pd, which involves placing radioactive, rice-sized pellets directly into the prostate gland, has increasingly been used in the management of appropriately selected patients opting for radiotherapy. Compared with external beam radiotherapy, it has some important patient advantages, including a single outpatient treatment versus the typical 7-week course of external beam treatment. Some patients undergo brachytherapy followed by supplemental external beam radiotherapy. Whether the addition of supplemental external beam therapy improves outcomes and can justify increases in patient toxicity and cost remains controversial. Given the lack of definitive evidence of the optimal therapy for localized prostate cancer, an important consideration for patients and the physicians helping guide their decision is the potential side effects of radiotherapy and surgery (Table 2). The major side effects of therapy for localized prostate cancer affect urinary, bowel, and sexual function. Recent evidence has suggested that for patients undergoing radical prostatectomy, urologists with high-volume prostatectomy practices may have better patient outcomes.4 Although, historically, reports of these side effects in the literature were typically those reported to the treating physicians in retrospective reviews, there has been a large effort by numerous investigators using “modern” quality-of-life assessment tools to quantitate more precisely the impact of local therapies on long-term quality of life.5 These assessments should be used by patients and physicians to help guide treatment decisions.
Table 2: Common Side Effects of Standard Treatment Modalities for Localized Prostate Cancer
Treatment Modality Brachytherapy External beam radiotherapy Radical prostatectomy
Impotence Variable
Urinary Function
Rectal Injury
Acute bladder irritation, — common; incontinence, rare Acute diarrhea, common; rectal Acute cystitis, common; late Common bleeding, infrequent; rectal cystitis, infrequent perforation, rare Variable Incontinence (variable) —
Cryotherapy is another modality of local treatment for prostate cancer that initially had been abandoned because of its high rate of complications. Recently this modality of treatment has
regained momentum as new and improved instruments and techniques have allowed reductions in toxicities and and possibly greater efficacy. Currently, cryotherapy remains experimental in the United States. Metastatic Prostate Cancer Hormonal therapy—androgen ablation—has for more than 60 years been the primary initial treatment of patients with metastatic prostate cancer. Androgen ablation options for patients with advanced prostate cancer include bilateral orchiectomy, luteinizing hormone–releasing hormone (LHRH) analogues and antagonists, and combined androgen blockade, a combination of either an orchiectomy or LHRH analogue plus an antiandrogen. Although orchiectomy remains the historical gold standard, LHRH therapy is equivalent therapeutically, and patients are increasingly opting for medical therapy, in part because of the psychological implications of surgical castration. Orchiectomy remains an important option for patients presenting with spinal cord compression or diffuse, painful bone metastases, because it leads to the rapid achievement of castrate levels of testosterone (hours) compared with the 14 to 21 days required for LHRH analogues. In human males, 5% to 10% of circulating testosterone originates from the conversion of adrenal steroid precursors. Nonsteroidal antiandrogens act at the level of the androgen receptor to inhibit the stimulatory effects of testosterone. The use of an antiandrogen, in addition to LHRH or orchiectomy, is referred to as combined androgen blockade. The role of combined androgen blockade remains controversial, with meta-analysis evidence of only a modest improvement in survival, with some added toxicity and significant expense.6 Approximately 10% of patients started on LHRH therapy have an initial testosterone flare, so patients at risk—such as those with known bone or nodal metastases or at risk for urinary outlet problems—should be started concomitantly on an antiandrogen (e.g., bicalutamide, flutamide) for 2 to 3 weeks to minimize this possibility. Unfortunately, the vast majority of patients with metastatic prostate cancer have evidence of disease progression on hormonal therapy (median response duration to hormonal therapy, 24-36 months). Patients with advanced prostate cancer typically have progressive bone pain, cancer cachexia, and fatigue. Significant anemia is common, although transfusion dependency is rare. Some patients with primarily nodal involvement develop significant lymphedema or ureteral obstruction. Spinal cord compression is relatively common, and a high index of suspicion must be maintained for patients presenting with back pain, even in the absence of neurologic findings. In prostate cancer patients with suspected spinal cord compression (without cervical spine symptoms, clinical findings, or plain film evidence of bone destruction), magnetic resonance imaging (MRI) of the thoracic and lumbosacral spine, with and without gadolinium, should be performed. Given the high incidence of involvement of both the lumbar and thoracic spines, failure to image both areas can compromise radiotherapy if untreated lesions become symptomatic and are detected later. Historically, management of advanced disease consisted of second-line hormonal therapies and palliative radiotherapy. Palliative radiotherapy remains an important component of patient management. There has been evidence, similar to findings for breast cancer and multiple
myeloma, that bisphosphonate therapy with zoledronic acid can decrease skeletal progression rates and complications in patients with androgen-independent metastatic bone disease.7 Chemotherapy has the potential to provide meaningful palliation for select patients, with improvement in pain and other disease-related symptoms. Two important phase III studies have evaluated docetaxel-based therapies in patients with advanced prostate cancer and demonstrated, for the first time, the ability to improve the survival of patients with advanced disease, albeit modestly.8 New drugs in development are targeting the androgen receptor directly with androgen-receptor antagonists and by inhibition of androgenic steroid synthesis. Although recent progress has been made and new agents are on the horizon, advanced prostate cancer remains an incurable disease. Vigorous efforts to manage pain and other disease-related symptoms through the appropriate use of opiods and palliative radiotherapy are essential for the optimal management of patients with progressive disease.
Summary
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Prostate cancer is the most commonly diagnosed neoplasm (excluding nonmelanoma skin cancer) and is the second most common cause of cancer death, after lung cancer, in American men. Prostate cancer screening with PSA testing and a digital rectal examination is widely performed, but data supporting an impact on survival are not yet available. Chemotherapy for advanced prostate cancer can palliate the disease and modestly improve survival.
References
1. Bostwick DG. High-grade prostatic intraepithelial neoplasia: The most likely precursor of prostate cancer. Cancer. 1995, 75: 1823-1836. 2. American College of Physicians. Screening for prostate cancer. Ann Intern Med. 1997, 126: 480-484. 3. Kupelian PA, Elshaikh M, Reddy CA, et al: Comparison of the efficacy of local therapies for localized prostate cancer in the PSA era: A large single-institution experience with radical prostatectomy and external beam radiotherapy. J Clin Oncol. 2002, 20: 33763385. 4. Bianco FJ Jr, Riedel ER, Begg CB, et al: Variations among high-volume surgeons in the rate of complications after radical prostatectomy: Further evidence that technique matters. J Urol. 2005, 173: 2099-2103. 5. Harlan LC, Potosky A, Gilliland FD, et al: Factors associated with initial therapy for clinically localized prostate cancer: Prostate Cancer Outcomes Study. J Natl Cancer Inst. 2001, 93: 1864-1871. 6. Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: An overview of the randomised trials. Lancet. 2000, 355: 1491-1498. 7. Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002, 94: 1458-1468.
8. Tannock I, de Wit R, Berry W, et al: Docetaxel plus prednisone or mitoxantrone plus
prednisone for advanced prostate cancer. N Engl J Med. 2004, 351: 1502-1512.
