eMedicine Specialties > Urology > Cancer, Prostate

Controversies in Prostate Cancer

Author: Isamettin Andrew Aral, MD, MSc, Medical Director, 21st Century Oncology; Clinical Assistant Professor of Radiation Oncology, State University of New York Downstate College of Medicine
Coauthor(s): Fazal Hussain, MD, MBBS, Director, Clinical Research, King Faisal Cancer Centre; Hassan Aziz, MD, Clinical Professor, Department of Radiation Oncology, Downstate Medical Center and Long Island College Hospital, State University of New York at Downstate; Michael Giasullo, MD, Clinical Assistant Professor, Department of Urology, State University of New York Downstate Medical Center; Chief, Department of Surgery, Divison of Urology, Lutheran Medical Center; Consulting Staff, Bay Ridge Urology Associates; Assistant Attending Physician, Department of Surgery, Urology Section, Methodist Hospital; Nicholas Karanikolas, MD, Associate Professor, Department of Urology, SUNY Downstate College of Medicine; Director, Urologic Oncology, Staten Island University Hospital; Attending Physician, Department of Urology, Brooklyn Veterans Administration Hospital
Contributor Information and Disclosures

Updated: Apr 24, 2009

Introduction

Prostate cancer remains the most commonly diagnosed solid tumor and the second-most-common cause of death due to malignancy among males in the United States. According to the American Cancer Society, approximately 186,320 new cases will be diagnosed in 2008, which makes prostate carcinoma the most frequently diagnosed solid tumor in adult males. Approximately 17,500 males will die of prostate cancer during the same period.

Mortality rate of prostate cancer

The mortality rate associated with prostate cancer has decreased over the last decade. This rate has consistently abated since the mortality-rate peak in 1997, when the American Cancer Society reported 41,800 associated deaths. The significance of this apparent decrease in mortality rate has been controversial. Those who support routine screening and early intervention suggest that the decreased mortality rate reflects the success of therapy. Those who refute the merits of routine screening suggest that survival improvements are due to lead-time bias. Continued patient follow-up from completed clinical trials (eg, the Prostate Intervention Versus Observation Trial [PIVOT]) should clarify this point of contention. Regardless, it is important to understand that more men die with prostate cancer than of prostate cancer.

Prostate cancer screening

Screening for prostate cancer, which commonly includes serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE), has been widely used in American men older than 50 years. The merit of screening for prostate cancer is the core of any comprehensive discussion of prostate cancer controversies. Arguments against screening are based on the limited understanding of the natural history of the disease. Without information about the natural history of untreated disease, the potential benefits of therapeutic intervention cannot be accurately addressed. In short, no conclusive body of medical literature has indicated that screening for prostate cancer alters its outcome. This simple statement appears to contradict a paradigm that holds true for most solid tumors: Early detection, followed by early intervention, translates to improved outcome.

Defining the natural history of prostate cancer has been difficult because no reproducible method is available to determine in whom the disease will rapidly progress in the absence of therapy. In fact, many researchers have argued that early intervention for prostate cancer does not offer a measurable survival advantage. National clinical trials, including the ongoing PIVOT, may help address some of the unresolved issues regarding the merits of therapeutic intervention. Data from clinical trials in Canada suggest that screening adult males for prostate cancer confers a potential benefit.

The absence of clarity regarding the benefit of screening for prostate cancer is the most pressing issue in the current controversy. Until the issue of screening is resolved, routine PSA testing or DRE (for prostate examination) should not be performed without a prior physician-patient discussion of the current controversies surrounding this process.

Despite the apparent survival advantage of early diagnosis conferred by PSA screening, a recent U.S. Preventive Services Task Force statement recommends against screening for prostate cancer in men aged 75 years or older. The statement also concludes that, currently, the balance of benefits versus drawbacks of prostate cancer screening in men younger than age 75 years cannot be assessed because of insufficient evidence.1

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center and Men's Health Center. Also, see eMedicine's patient education articles Prostate Cancer, Enlarged Prostate, and Cancer: What You Need to Know.

Staging

The most important prognostic variable for any tumor should be its stage. Staging (either clinical or pathologic) has therefore become the accepted method for tumor classification. If properly constructed, a staging system should correlate with commonly assessed disease parameters, including local control and survival.

The most widely accepted staging system for prostate cancer is the American Joint Committee on Cancer classification, which was last modified in 2002. The current system is a 4-tiered classification. Disease is assessed by tumor (T), nodal (N), and metastatic (M) classifications. Although this system addresses the extent of disease, current medical literature suggests that additional variables, including PSA level and Gleason score, may offer greater value in the prediction of non–organ-confined disease. The inadequacies of the current staging system complicate the comprehensive assessment of disease response to treatment.

The current American Joint Committee on Cancer staging system can be used to stage patients either clinically or surgically. Surgical staging of a tumor (ie, T and N stages) is the criterion standard to which clinical staging is compared. As more patients elect to consider nonsurgical management for their prostate cancer, attempts to identify clinical tools that provide a high degree of specificity become increasingly important.

Standard components of clinical staging include information obtained through physical examination and radiographic studies. DRE has been used to assess the extent of local disease for many years, although it has been shown to have a poor capacity to predict the extent of extracapsular disease at the time of surgery. Imaging studies have been identified as a potential source through which one can gain information regarding both the local and regional extent of disease.

Imaging studies

The optimum study has not been identified; however, the detecting power of transrectal ultrasound-guided biopsy has made this the most widely performed study in all patients with prostate cancer. The ability of ultrasonography to reveal clinically occult disease (ie, disease not found with DRE) is user-dependent. Up-staging from PSA-detected, nonpalpable disease (ie, T1c) to more advanced disease (eg, T2a) can be based on the results of ultrasonography or other diagnostic imaging studies. (For additional information on staging, see the eMedicine article Prostate Cancer: Biology, Diagnosis, Pathology, Staging, and Natural History.)

Completing both a physical assessment (ie, DRE) of the gland and accurate imaging of the prostate ensures proper clinical staging of a patient. Recent data from the Memorial Sloan-Kettering Cancer Center challenge the significance of ultrasonographically identifiable disease, although the current staging system includes individuals with such disease in the T2 classification grouping.

Radiographic assessment of the extent of tumor progression is desirable for most cancers. Ideally, these studies should reproducibly assess the locoregional and distant extent of disease. Local extension of tumors has been assessed with ultrasonography, CT scanning, and MRI.

Comparisons of the accuracy of each imaging modality fail to provide a uniform consensus regarding the optimum study. Enhanced diagnostic tools (eg, MRI with endorectal coil) have been embraced in certain centers because they appear to more accurately predict extracapsular extension of disease. Recently, positron emission tomography (PET) scanning has been used in the diagnostic evaluation of prostate cancer. To date, these studies are not considered an essential test in the staging of newly diagnosed patients. The role of PET imaging in the management of prostate cancer will evolve as more clinical trials address its potential usefulness.

Defining the best candidates for radiographic assessment depends on both a clear understanding of the accuracy of the proposed study and the expected prevalence of the anticipated finding in the population at risk. Understanding the relative prevalence of the suspected abnormality (eg, non–organ-confined disease, regional nodal involvement) is important in the decision algorithm. Retrospective surgical data (eg, from Partin and colleagues) provide information regarding the frequency of these findings in operative candidates. Summary tables of Partin and colleagues' findings have been reported, and certain trends appear obvious. Patients who present with early-stage disease (£T2a), those with PSA values less than 10, and those with a Gleason score of 6 or less are at low risk for non–organ-confined disease.2

The merit of routine pelvic imaging to determine the presence of either extracapsular extension or regional nodal involvement is unclear; however, the current staging system suggests that these studies should be included to optimize clinical staging of disease. The value of imaging in the staging of patients with prostate cancer will likely remain controversial for several years. The currently accepted staging system allows for inclusion of these studies in the assessment of disease, although the medical literature suggests that no single study can be used to reproducibly detect non–organ-confined disease.

Surgical staging

A second staging controversy surrounds the merits of surgical staging of patients. In patients undergoing radical prostatectomy, pathological assessment of extracapsular disease extension and regional nodal involvement is readily available. (See the eMedicine articles Prostate Cancer: Radical Perineal Prostatectomy, Prostate Cancer: Radical Retropubic Prostatectomy, and Laparoscopic and Robotic Radical Prostatectomy.) In patients who have not undergone definitive surgical therapy, surgical evaluation of regional nodal disease has been considered. This tool is perhaps most valuable in patients who are considering treatment options that do not address regional nodal disease (eg, permanent prostate brachytherapy).

Regional lymph nodes can be assessed via laparoscopy or laparotomy. Proponents of laparoscopy argue that the lymph nodes most at risk can be effectively sampled with minimal intervention. Data from Solberg et al suggests that laparoscopic lymph node sampling is also associated with significantly fewer lymphoceles. In this retrospective review, patients undergoing open lymph node procedures were compared with those undergoing laparoscopic procedures. The frequency of lymphocele development in the open procedure group was approximately 60%. In contrast, 37% of patients who underwent laparoscopy developed lymphoceles.3

In contrast, laparotomy offers the potential advantage of allowing exploration of regional nodal basins not commonly accessible via laparoscopy (eg, presacral lymph nodes); however, recently published data do not suggest that more extensive dissections detect a statistically number of significant number tumors that extend beyond the hypogastric or obturator lymph nodes.

Regional assessment of disease has been further complicated by recent attempts to reproduce commonly accepted dissection techniques used in the management of breast carcinoma (ie, sentinel lymph nodes). Unlike the widely accepted data that support the benefit of treating patients with histologically detected nodal metastatic breast cancer, similar data are not as clear in the management of prostate cancer.

Controversies addressing the significance of micrometastatic disease (ie, detected with immunostaining or molecular techniques such as reverse transcriptase-polymerase chain reaction) will not be answered until a consensus regarding macroscopic metastatic disease is reached. At present, data support the use of nodal sampling/dissection in patients undergoing radical surgery. These data support the use of regional lymph node sampling as both a diagnostic and therapeutic modality; however, the former conclusion is more dubious. To this end, routine pelvic lymph node sampling is considered appropriate during the process of radical prostatectomy.

The extent of regional nodal metastasis will likely become an important prognostic variable. Retrospective data from the University of Bern in Switzerland suggests that individuals with single nodal metastasis experience lengthy biochemical disease-free survival (median follow-up of 45 mo). In contrast, only 10% of patients with multiple lymph node metastasis (ie, >2) experience a similar interval of biochemical disease-free survival.4

Algorithms have been used in a continued attempt to determine which patients will benefit from lymph node exploration. In 1998, the Hamburg group detailed the importance of Gleason score at the time of biopsy in determining risk groups for metastatic nodal disease. In this study, a risk assessment was made that correlated the actual risk of nodal involvement (ie, pathologic data at the time of surgery) with predicted values based on surgical observations. Three distinct patient groups were derived from this analysis. In all cases, the major component of disease was at least Gleason 4 disease (ie, minimum Gleason score of 4+1 and maximum Gleason score of 4+5). Patients with no evidence of Gleason 4 disease (as their major component of disease) have a very low risk of regional lymph node involvement (2.2%).5

Investigators from Johns Hopkins University have validated this data. Their analysis of the Hamburg nomogram for surgically treated patients reveals a similar low risk for certain groups of patients (2.5% vs 2.2%). More importantly, their analysis further stratifies patients into low, intermediate, and high risk for nodal involvement. These categories correspond to the number of sextant biopsy specimens that are positive (+) with at least Gleason 4+3 disease. Patients with no evidence of Gleason 4+3 disease (or greater) have a very low risk for nodal involvement (2.5%). Patients with 1-3 biopsy specimens positive for Gleason 4+3 disease or greater are at intermediate risk (20% chance) of nodal involvement. Finally, patients with 4-6 cores positive for Gleason 4+3 or greater disease are at high risk (44.4%) for nodal involvement.6

Although the Hamburg nomogram and the clinical validation by the Hopkins group highlights patient cohorts who may benefit from surgical exploration of regional nodal disease, neither addresses the importance of this finding in relation to patient outcome. One might reasonably conclude that the risk of regional nodal disease is very low in patients with a Gleason score of 6 or less. This result is not unlike information summarized in the Partin tables.

Regional lymph node status has important diagnostic implications associated with changes in staging (ie, all node-positive patients have stage IV disease). The continued use of nodal dissection can only become universally embraced if data demonstrate that improved outcome (eg, biochemical disease-free survival, overall survival) is associated with the removal of affected nodal basins. To date, limited information is available to directly answer this question.

The merits of similar interventions in patients undergoing nonsurgical therapy will probably continue to evolve over the next several years.

To Treat or Not to Treat

Aggressive screening programs have increased the number of men diagnosed with prostate tumors. Earlier detection of disease has led to both stage migration and the diagnosis of disease in younger men. Both of these trends make comparisons to historical data difficult. Nevertheless, data from the American Cancer Society have demonstrated a continued decrease in prostate cancer mortality rates over the past 5 years. One presumed explanation for this observation is the success of early intervention. Treatment of prostate cancer is complex but follows accepted intervention rationales. Ideally, treatment of a malignant disease process should enhance local tumor control. Improved local control should enhance regional control of disease and, in turn, result in a diminution of distant disease.

This cascade of events is generally associated with improved overall survival rates. The ultimate goal of cancer treatment should be improved survival; however, the absence of detailed information regarding the natural history of prostate cancer complicates the demonstration of improved survival. As younger men continue to be diagnosed with prostate cancer, direct comparisons with older counterparts will further complicate treatment decision algorithms.

Albertsen et al reviewed survival in patients diagnosed with prostate cancer. This retrospective analysis of nearly 800 patients assessed the probability of dying of prostate cancer based on the Gleason score after prostate biopsy. Patients with higher Gleason scores were more likely to die from prostate cancer than those with lower Gleason scores. The calculated risk for patient mortality at 15 years was low for Gleason 2-4 disease (4-7%) and high in those with either Gleason 7 disease (42-70%) or Gleason 8-10 disease (60-87%).

The authors concluded that both expected longevity and Gleason score at diagnosis should be used to determine the necessity of treatment. Careful review of the data also suggests that the risk of prostate cancer mortality is as high as 30% in patients with Gleason 6 disease. Arguably, the risk of mortality in most patients diagnosed with prostate cancer would support treatment; however, the age of the patient must be an equally important variable in the decision-making process.7

Survival may not be the only variable that leads the clinician or patient toward treatment. Recent retrospective data from Laufer et al suggest that younger men (<50 y) have improved biochemical disease control at 15 years following surgery. Although the differences did not reach statistical significance, findings from this large cohort of patients support earlier detection and treatment of disease.8

The treatment for prostate cancer continues to evolve, although the identification of clinically significant disease remains difficult. Clinically significant disease has been defined as prostate cancer that is likely to become symptomatic during the patient's lifetime. Postmortem study findings suggest that up to 80% of men older than 80 years have occult prostate cancer. Identifying men who will become symptomatic from their disease or who will develop non–organ-confined disease should be the focus of studies addressing the natural history of prostate cancer. These studies have not been widely embraced in the United States because of a perceived benefit of intervention (ie, treatment). The PIVOT will likely answer many of the questions surrounding this debate, but meaningful conclusions cannot be reached for several years.

Further complicating the treatment controversy are the effects of age migration due to screening in younger men. As younger men are diagnosed, disease progression in the absence of intervention is more likely. Watchful waiting embraces this concept and acknowledges that tumor progression is typically linked to PSA progression; however, the degree of correlation is not clear. In the absence of a clear understanding of the natural history of the disease, demonstrating a survival advantage with therapy is problematic.

In 2002, the New England Journal of Medicine published data from a large clinical trial by Holmberg et al that showed an approximate doubling of death rates due to prostate cancer in subjects who underwent watchful waiting. The frequency of non–prostate cancer deaths was similar in the 2 groups studied.9 This trial highlighted the potential limitations of watchful waiting in an increasingly younger group of patients. Although arguments both for and against watchful waiting remain at the forefront of prostate cancer research, the issue regarding treatment is unresolved.

A 2008 research summary by the Agency for Healthcare Research and Quality (AHRQ) concluded that men with clinically localized prostate cancer detected by methods other than PSA testing who were treated with radical prostatectomy experienced fewer deaths from prostate cancer, marginally fewer deaths from any cause, and fewer distant metastases than men who underwent management with watchful waiting.10 The AHRQ notes that the advantage of radical prostatectomy with regard to lower cancer-specific and overall mortality rates appears to be limited to men younger than 65 years but is unrelated to baseline PSA level or histologic grade. Prostatectomy was associated with greater urinary and sexual dysfunction.

Patients who elect to pursue an observational course should review the intended goals of this treatment strategy with their clinicians. Objective assessment of any management (including nontreatment) must have reproducible guidelines by which outcome data can be reviewed. The endpoints of treatment are obvious and include improved locoregional disease control, disease-free survival rates, and overall survival rates. Watchful waiting does not provide the patient or clinician with a simple method to evaluate "treatment" (ie, nontreatment). Moreover, because different patients elect to pursue therapy (ie, opt out of the watchful-waiting mode) at different points in the disease course, comparisons with standard treatment arms are difficult.

Watchful waiting remains an excellent strategy in the treatment of patients with a limited life expectancy. The importance of the patient's age at diagnosis is detailed in the current National Comprehensive Cancer Network practice guidelines for prostate cancer management. Decisions regarding the appropriateness of treatment remain controversial; however, as younger men are diagnosed with prostate cancer, the impact of therapy on survival becomes increasingly important. Prospective data from completed national trials, including the PIVOT, will likely provide more direction regarding the suitability of therapeutic intervention for all patients.

Defining Optimum Treatment

Tremendous controversy surrounds the optimum treatment for prostate cancer. This is largely attributable to the absence of compelling clinical data to support the superiority of one treatment over another. According to Byar et al, older clinical trials, including those conducted by the Veterans Administration Cooperative Urological Research Group (VACURG), suggest a survival benefit to surgery over radiotherapy.11 The VACURG study has been criticized for poor design, but it is one of the last prospective multi-institutional studies to attempt to answer the question of treatment superiority.

As treatment strategies have evolved to include multiple forms of radiotherapy (eg, conventional radiotherapy, 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy), direct comparisons to surgery have become increasingly difficult. (For more information on radiotherapy used to treat prostate cancer, see the eMedicine article Prostate Cancer: External Beam Radiation Therapy.) Similarly, surgical treatment of prostate cancer has significantly advanced over the past 2 decades to include nerve-sparing techniques, laparoscopic procedures, robotic-assisted procedures, and variations on the classic retropubic prostatectomy (eg, the perineal approach). (For more information, see the eMedicine articles Prostate Cancer: Radical Retropubic Prostatectomy, Prostate Cancer: Radical Perineal Prostatectomy, and Laparoscopic and Robotic Radical Prostatectomy.)

Despite the increasing number of patients diagnosed with prostate cancer each year, only one active trial is comparing surgical and minimally invasive interventions. The American College of Surgeons Oncology Group Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT) is comparing the outcomes of radical prostatectomy with brachytherapy in low-risk patients (see Study Synopsis).

Clinicians should formulate treatment decisions based on the desired goals of therapy. If the patient is at low risk for non–organ-confined disease, treatment may be selected to address intraprostatic disease alone. In contrast, if the patient's calculated risk of non–organ-confined disease is high, treatment will likely be designed to address both the intraprostatic and extraprostatic components of disease using a multimodality approach. Controversy remains regarding the optimum treatment strategy within each clinical cohort (ie, presumed organ-confined disease, presumed non–organ-confined disease). Several attempts to provide guidance in predicting patients at risk for non–organ-confined disease have been published.

Presumed Organ-Confined Disease

Methods of staging

Although tumor stage remains the most widely accepted prognostic variable for all cancers, additional information can be obtained from the review of specific disease-associated factors (eg, PSA value and Gleason score in prostate cancer). Both serum PSA level and Gleason score have been evaluated as independent prognostic tools in the management of prostate cancer. In the absence of surgery, the clinician seeks to reproducibly predict the probability of organ-confined disease. Tables published by the group from Johns Hopkins University aid in the prediction of disease extent (eg, nodal involvement, seminal vesicle involvement, metastatic disease).

Similar information can be obtained from mathematical models that attempt to predict the probability of non–organ-confined disease. Using the surgical tables generated by Partin et al (see Partin tables) or using the calculated probabilities of non–organ-confined disease described by Roach, treatments that address the patient's anticipated sites of disease can be selected.2,12 In patients at high risk for organ-confined disease, treatment should be designed to address intraprostatic tumor. Generally accepted treatments include surgery, external beam radiotherapy, and prostate brachytherapy. Newer forms of therapy, including cryosurgery, are now being explored as potential local therapies for prostate cancer. Controversy surrounds the superiority of each treatment option.

Theoretically, surgical extirpation of disease should facilitate more accurate staging of disease, although, as above, direct comparisons are not readily available. In turn, all pathologically staged prostate cancers would be expected to demonstrate improved outcomes compared with their clinically staged counterparts. This surgical bias can be minimized by considering disease parameters other than stage (eg, PSA value, biopsy Gleason score). Nevertheless, the ability to more accurately categorize disease through surgery should yield an outcome advantage. Prospective studies that directly compare surgery, external beam radiotherapy, and prostate brachytherapy would answer an important clinical question. Because such studies are not planned, more meaningful comparisons of treatment strategies may arise through the inclusion of quality-of-life analyses in future clinical trials.

Surgical intervention

No consensus has been reached regarding who will benefit from surgical intervention, but such procedures are generally reserved for younger patients (typically <70 y) with a good performance status. The obvious goal of surgical intervention is the removal of all gross disease. Data from D'Amico et al (2002) suggest a slight superiority of surgery over external beam radiotherapy in low- and intermediate-risk patients.13 Specifically detailed is the 8-year "PSA survival rate." Among patients undergoing surgery (low-risk group), the PSA survival rate was 88%. This contrasts with the 78% rate of patients undergoing conventional radiotherapy.

Radiotherapy versus surgery

The importance of dose escalation in disease control complicates extraction of meaningful conclusions from current radiotherapy treatments (ie, 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy). Researchers at The Cleveland Clinic analyzed a similar group of patients treated in their facility. Eight-year biochemical control of disease was virtually identical (72% vs 70%) in this report, suggesting that radiotherapy and surgery may be equally acceptable treatments in patients with organ-confined disease.

Brachytherapy

Brachytherapy has also been compared with surgery in the management of early-stage disease. Direct comparisons (ie, prospective randomized trials) are not readily available, but preliminary data from most centers suggest that permanent prostate implants yield comparable local control and biochemical disease-free rates.

Additional information on localized prostate cancer can be found in the eMedicine article Prostate Cancer: Management of Localized Disease.

Selection of treatment modality

The AHRQ review concluded that no single therapy can be considered the preferred treatment for presumed organ-confined prostate cancer.10 This is partly because of inadequate data regarding efficacy and partly because of the differences in adverse effects, convenience, and costs among the therapies, which may be important factors in the choice of treatment in an individual patient. Although all treatment options carry adverse effects, patient satisfaction with therapy is high.

Known or Probable Non–Organ-Confined Disease

Current recommendations regarding the imaging workup in patients diagnosed with prostate cancer remain unclear. Many patients undergo either CT scanning or MRI of the pelvis. The capacity of either study to accurately reveal non–organ-confined disease varies, but most clinical trials require either study as an initial assessment of patients' clinical stage (local and regional staging).When clear evidence of non–organ-confined disease is demonstrated, as in persons with seminal vesicle or periprostatic involvement, the treatments offered may vary. Surgical cure rates for either group of patients remain low compared with those of patients with T1 or T2 disease. Neoadjuvant hormonal therapy has been used to clinically down-stage patients before surgery; however, the merits of this intervention are unclear. (For more information, see the eMedicine article Prostate Cancer: Neoadjuvant Androgen Deprivation.)

Many patients are not considered surgical candidates if seminal vesicle and/or regional nodal disease is detected. However, information from Messing et al suggests that immediate hormonal blockade (ie, surgical castration with luteinizing hormone–releasing hormone [LHRH] agonist therapy) decreases the risk of mortality.14 In this study , Messing et al reported on the results of 98 patients who underwent radical prostatectomy and pelvic lymph node dissection (ie, positive results for metastatic disease).

Patients were randomized to receive immediate hormonal blockade or to undergo observation. At a median follow-up of 7 years, the survival rate in the hormonal blockade group was superior to that in the observation group (85% vs 65%). This result becomes more impressive when only deaths due to prostate cancer are considered (94% vs 68%). Not unexpectedly, the use of early hormonal blockade was associated with a higher rate of grade I/II hematological, genitourinary, and constitutional (eg, weight gain) toxicities. The study by Messing et al supports the use of early hormonal blockade in the setting of regionally advanced disease (ie, node-positive); however, quality of life may be compromised unless patients are carefully selected to balance risks and benefits of therapy.

Unfortunately, the study by Messing et al does not address the potential benefit of postoperative locoregional therapy (ie, postoperative radiotherapy). The benefit of adjuvant postoperative therapy following radical prostatectomy has been demonstrated in certain high-risk patients (eg, positive surgical margins). In the former case, this is due to poor locoregional disease control rates. In the latter situation, concern remains regarding whether survival may be negatively affected by the presence of nodal disease.

Reports from the Memorial Sloan-Kettering Cancer Center suggest that long-term survival rates (ie, >15 y) are essentially zero in the setting of synchronous nodal involvement at diagnosis. In this group of patients, hormonal blockade with or without external beam radiation treatment is used. Patients in whom non–organ-confined disease is suspected or confirmed typically receive radiotherapy with either hormonal manipulation (ie, peripheral antiandrogen therapy, LHRH agonist treatment) or chemotherapy (eg, taxane-based therapy).

Several phase 3 randomized clinical trials have assessed the value of total androgen blockade in the treatment of patients with non–organ-confined disease. In each of these reports, patients exhibit longer disease-free intervals and PSA control of disease when using total androgen suppression (TAS) either during or after radiotherapy treatment. Few data suggest that the improved biochemical control of disease translates to improved survival.

A study by Bolla et al has demonstrated increased survival following the use of hormonal blockade when given in conjunction with external beam radiotherapy.15 The authors reported that hormonal blockade markedly improved 5-year disease-free survival rates (74% for combination therapy vs 40% for external beam radiotherapy alone). Moreover, overall 5-year survival rates improved, favoring patients who received 3 years of LHRH agonist treatment (78% vs 62%). These data suggest the importance of prolonged antiandrogen therapy in combination with external beam radiotherapy. This remains one of the only studies to demonstrate a survival advantage from hormonal manipulation in the management of prostate cancer.

Summary data reported in 2001 by Lawton et al from a series of Radiation Therapy Oncology Group subjects help define the individuals most likely to benefit from TAS in conjunction with radiotherapy.16 The role of TAS therapy in combination with permanent prostate brachytherapy is not as clear, but the synergy observed with external beam radiotherapy is not unexpected in this form of therapy. The optimum sequencing of androgen blockade and radiotherapy remains unclear. Current clinical trials should clarify this issue.

Metastatic Disease

Hormone therapy

The management of metastatic prostate carcinoma typically involves therapy directed at relief of particular symptoms (eg, palliation of pain) or attempts to slow further progression of disease. In both instances, hormone manipulation has become increasingly important. The historical dependence of prostate cancer on testosterone has been known for many decades. Initial attempts to capitalize on this relationship involved orchiectomy, which has a direct and profound effect on circulating testosterone levels. Although clearly cost-effective, this form of therapy was used less frequently as the benefits of estrogen therapy became apparent. (For more information, see the eMedicine article Prostate Cancer: Metastatic and Advanced Disease.)

Early studies using diethylstilbestrol (DES) in patients with metastatic prostate carcinoma found that DES conferred a survival rate that was comparable to that provided by surgery (ie, orchiectomy). The optimal dosage for this therapy has been published and has been largely established based on tolerance and morbidity data. As the importance of the pituitary-gonadal axis became more apparent, attempts to block production of testosterone became the goal of clinical intervention. As with the DES trials, most early studies of LHRH agonists found comparable control of metastatic disease compared with that of the historical criterion standard (ie, surgical castration). Despite the apparent benefit of this intervention, the importance of TAS remains unclear.

The presumed advantage of adding a peripheral antiandrogen treatment to either castration or LHRH agonist therapy is conceptually easy to understand. Regrettably, no consensus has been reached regarding the importance of total androgen blockade over monotherapy. Meta-analysis data from several authors led to different conclusions. In 1999, Bennett and colleagues from Northwestern University reviewed 9 prospective studies involving total androgen blockade.17 These studies included more than 4000 subjects undergoing either surgical or chemical castration (LHRH agonist treatment) in conjunction with peripheral antiandrogen therapy. The authors concluded that TAS offers a small but measurable survival advantage (approximately 10%).

This finding is similar to the conclusion from the Southwest Oncology Group (National Cancer Institute Intergroup Trial [NCI INT] 0105). In this study, subjects with metastatic prostate carcinoma were randomized to undergo either orchiectomy alone or orchiectomy plus flutamide therapy. This small difference is important; however, quality-of-life analyses of the same data show consistently poor results among patients receiving flutamide. A similar review was performed by Laufer and colleagues from Johns Hopkins University. Following a review of 27 clinical trials, the authors concluded that the current body of clinical information does not support the routine use of antiandrogen therapy in combination with medical or surgical castration.8

A review conducted by the Blue Cross and Blue Shield Association and reported by Seidenfeld et al (2000) detailed the information gathered from 21 clinical trials comparing surgical and chemical castration with and without peripheral antiandrogen therapy.18 At 2 years from initiation of therapy, no appreciable difference in survival was noted between the 2 groups; however, at 5 years, a statistically significant improvement in survival was noted among the TAS groups.

This observation may directly affect the selection of patients for TAS therapy (ie, those anticipated to have a shortened life expectancy). The authors further clarified their observations by noting that the benefit was not seen in patients with good prognoses, a designation including those with limited metastatic burden. They also noted that subjects in the combined-therapy arms routinely experienced higher rates of morbidity, which can potentially affect quality of life. The role of total androgen blockade in persons with metastatic disease remains controversial. Although most summaries of available literature support the role of total androgen blockade, this may not be important in patients with a relatively short life expectancy.

Chemotherapy

The use of chemotherapy in the management of metastatic prostate cancer continues to evolve. Response rates of taxanes and hybrid medications (eg, estramustine [Emcyt]) are high and may indicate a new standard of care in patients who no longer respond to conventional hormonal manipulation. Chemotherapy remains an important tool in the management of metastatic disease. Information from ongoing clinical trials should define the optimum use of systemic therapy in both hormone-naive and hormone-refractory patients.

With the increasing use of hormonal manipulation early in the course of prostate cancer therapy, refractoriness to this treatment has prompted renewed interest in chemotherapy. Recently published phase 2 clinical trials have attempted to address the importance of chemotherapy in the management of hormone-refractory prostate cancer. In 2003, the Cancer and Leukemia Group B reported the results of their clinical trial (99813) .19 This study assessed the merit of 3-agent therapy (ie, estramustine, docetaxel, and carboplatin) in conjunction with granulocyte colony-stimulating factor in the treatment of patients with hormone-refractory disease. A marked diminution in PSA levels was reported (approximately 60% of patients, with a 75% decline in serum PSA levels). One complete response and 10 partial responses were reported. Regrettably, the median time to progression was short-lived (8.1 mo). Importantly, the authors reported an overall survival period of 19 months.

This report offers more promise to the use of systemic therapy than a similar trial conducted at the M.D. Anderson Cancer Center. In a phase 2 trial reported by Daliani et al, oral cyclophosphamide, vincristine, and dexamethasone were used to treat hormone-refractory prostate cancer.20 Again, an impressive diminution in serum PSA levels was seen; however, the duration of response (10 wk) and median overall survival (10.6 mo) were both significantly less than reported by the Cancer and Leukemia Group B. Clearly, hormonal therapy offers some hope for patient's who have exhausted conventional hormonal manipulations. Continued efforts that optimize the proper agents and their sequencing in the management of this disease are necessary.

Summary

The controversies surrounding proper diagnosis, staging, and treatment of patients with prostate cancer make clinical management of this disease challenging, and the absence of a thorough understanding of the natural history of this disease makes the establishment of treatment guidelines difficult. Diagnostic and treatment algorithms are available but should serve only as templates for clinical practice. As additional information is made available from ongoing clinical trials, controversies should diminish.

Keywords

prostate cancer, prostate-specific antigen, PSA, PSA testing, prostate carcinoma, prostatic carcinoma, carcinoma of the prostate, digital rectal examination, DRE, Gleason score, transrectal ultrasound biopsy, prostate cancer screening, Prostate Intervention Versus Observation Trial, PIVOT, extracapsular extension, prostatectomy, permanent prostate brachytherapy, total androgen suppression, TAS, orchiectomy, estrogen therapy, diethylstilbestrol, DES, chemical castration, LHRH agonist treatment, prostate cancer controversies, prostate cancer controversy

 


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References
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References

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Further Reading

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Keywords

prostate cancer, prostate-specific antigen, PSA, PSA testing, prostate carcinoma, prostatic carcinoma, carcinoma of the prostate, digital rectal examination, DRE, Gleason score, transrectal ultrasound biopsy, prostate cancer screening, Prostate Intervention Versus Observation Trial, PIVOT, extracapsular extension, prostatectomy, permanent prostate brachytherapy, total androgen suppression, TAS, orchiectomy, estrogen therapy, diethylstilbestrol, DES, chemical castration, LHRH agonist treatment, prostate cancer controversies, prostate cancer controversy

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Contributor Information and Disclosures

Author

Isamettin Andrew Aral, MD, MSc, Medical Director, 21st Century Oncology; Clinical Assistant Professor of Radiation Oncology, State University of New York Downstate College of Medicine
Isamettin Andrew Aral, MD, MSc is a member of the following medical societies: American College of Radiology, American Medical Association, and American Society for Therapeutic Radiology and Oncology
Disclosure: Nothing to disclose.

Coauthor(s)

Fazal Hussain, MD, MBBS, Director, Clinical Research, King Faisal Cancer Centre
Fazal Hussain, MD, MBBS is a member of the following medical societies: American College of Radiology
Disclosure: Nothing to disclose.

Hassan Aziz, MD, Clinical Professor, Department of Radiation Oncology, Downstate Medical Center and Long Island College Hospital, State University of New York at Downstate
Hassan Aziz, MD is a member of the following medical societies: American College of Radiology and American Society for Therapeutic Radiology and Oncology
Disclosure: Nothing to disclose.

Michael Giasullo, MD, Clinical Assistant Professor, Department of Urology, State University of New York Downstate Medical Center; Chief, Department of Surgery, Divison of Urology, Lutheran Medical Center; Consulting Staff, Bay Ridge Urology Associates; Assistant Attending Physician, Department of Surgery, Urology Section, Methodist Hospital
Michael Giasullo, MD is a member of the following medical societies: American Medical Association and American Urological Association
Disclosure: Nothing to disclose.

Nicholas Karanikolas, MD, Associate Professor, Department of Urology, SUNY Downstate College of Medicine; Director, Urologic Oncology, Staten Island University Hospital; Attending Physician, Department of Urology, Brooklyn Veterans Administration Hospital
Nicholas Karanikolas, MD is a member of the following medical societies: American Urological Association
Disclosure: Nothing to disclose.

Medical Editor

Leonard Gabriel Gomella, MD, FACS, The Bernard W Godwin Professor of Prostate Cancer Chairman, Department of Urology, Associate Director of Clinical Affairs, Kimmel Cancer Center, Thomas Jefferson University
Leonard Gabriel Gomella, MD, FACS is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Laser Medicine and Surgery, American Urological Association, Sigma Xi, Society for Basic Urologic Research, Society of University Urologists, and Society of Urologic Oncology
Disclosure: GSK Consulting fee Consulting; Astra Zeneca Honoraria Speaking and teaching; Watson Pharmaceuticals Consulting fee Consulting

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Dan Theodorescu, MD, PhD, Paul Mellon Professor of Urologic Oncology, Department of Urology, University of Virginia Health Sciences Center
Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology
Disclosure: Nothing to disclose.

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Director of Division of Minimally Invasive Urology, Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Terumo Corporation Consulting fee Consulting; Omeros Corporation Consulting fee Consulting

Chief Editor

Edward David Kim, MD, FACS, Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center
Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, and Tennessee Medical Association
Disclosure: Lilly Consulting fee Consulting; Astellas Consulting fee Speaking and teaching; Indevus Consulting fee Speaking and teaching

 
 
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