Prostate Cancer Screening Part II: Treatment and Outcomes
Author: Marc B. Garnick, MD, Clinical Professor of Medicine, Harvard Medical School; Physician, Beth Israel Deaconess Medical Center, Boston, MA.
Peer Reviewer: Durado Brooks, MD, MPH, Director of Prostate and Colorectal Cancers, American Cancer Society, Atlanta, GA.
Prostate cancer is one of the leading causes of cancer in men, both in this country and in Europe. Part I of this two-part series provided an evaluation of the role of PSA-based screening for the early detection of prostate cancer in asymptomatic patient populations. Both the benefits and potential drawbacks of PSA screening were discussed, including a review of recommendations of major national public health policy organizations.
One of the most important emerging changes in practice now deals with redefining the concept of a "normal" PSA. While in the past a cut-point for determining a normal vs. abnormal value generally was agreed to be at a level of 4 ng/mL, more recent data from the Prostate Cancer Prevention Trial (PCPT) define a continuum of risk for prostate cancer based upon PSA values below 4 ng/mL.1 Newer thinking suggests that there is no absolute PSA value that should trigger further evaluations. The use of PSA isoforms may provide greater accuracy in the future.
Recognizing that the primary care physician often is the first health care professional who determines whether a PSA test is ordered and often is crucial in directing further follow-up relating to diagnosis and treatment selection, Part II will deal with important information regarding the choices for treating prostate cancer, and the side effects, efficacy, and quality-of-life issues that result from treatment. In addition to reviewing the important natural history studies of diagnosed but untreated prostate cancer, Part II reviews the effectiveness and harms of treatment of clinically localized prostate cancer and reviews future directions into helping understand the determinates of optimal patient selection. Part I also concluded with the fact that at the current time, there is no randomized clinical trial evidence that screening asymptomatic patients for prostate cancer leads to a reduction in overall mortality. Thus, a detailed review of the efficacy and harms of treatment for primary care physicians is mandatory for informed clinical decision-making.
The Editor
Introduction
In beginning this second part of a discussion of prostate cancer screening and treatment, it first is helpful to understand several terms, which are discussed in the following section. Table 1 explains the staging of prostate cancer, and Table 2 discusses the definition of Gleason score. (This review will also cite older data that use pathologic grade 1, 2, and 3 cancers; this roughly corresponds to Gleason 2-4, 5-7, and 8-10, respectively.)
| Table 1. Glossary of Terms |
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Several other terms important to this discussion include:
Active Surveillance. This is the practice in which prostate cancer patients do not receive active treatment interventions (e.g., surgery, radiation, hormonal therapy), also called watchful waiting or expectant management. Patients undergoing active surveillance can at any time during their evaluations be considered for active treatment based upon changes in PSA, physical examination, symptoms, or radiographic scans. An understanding of the behavior of prostate cancer is important for patients to consider when contemplating active surveillance.
Brachytherapy (also called seed implantation or interstitial seed implantation). This involves the placement (via ultrasound guidance) of radioactive seed pellets (usually composed of Iodine 125 or Palladium) into the prostate gland for the management of clinically localized prostate cancer. The seeds can be implanted either permanently or for a shorter period of time.
Capsular Penetration/Perforation. This pathologic term indicates the prostate cancer has either penetrated or perforated (gone through) the prostate capsule.
Nomogram. This is a set of statistical models that utilize readily available features of the individual patient's prostate cancer (e.g., Gleason score of the biopsy, PSA value, and clinical stage) to help determine a pre-defined outcome ( e.g., likelihood of having an undetectable PSA after prostatectomy) following a treatment.
Organ-Confined. This pathologic term generally describes the prostate specimen that is removed at the time of radical prostatectomy that indicates that prostate cancer is confined to the prostate gland and has not extended into the surrounding structures, such as seminal vesicles, prostatic capsule, or into the base of the bladder.
Positive Surgical Margin. This pathologic term indicates that the prostate cancer that has been removed at the time of radical prostatectomy was present at the surgically resected margin. In general, this finding implies that on the in situ portion of the resection margin (still in the patient) cancer may be present. The finding of positive surgical margins may prompt the consideration of additional therapy following radical prostatectomy.
Rising PSA/Biochemical Relapse. This situation exists when a patient has had clinically or pathologically organ-confined prostate cancer treated, and at some time after the treatment experiences a rise in the PSA. In the case of a prostatectomy patient, any value greater than 0.2 ng/mL (or above the lower limits of detection of the PSA assay) following prostatectomy or a value of greater than 1.5 ng/mL and continuously rising after radiation therapy may suggest the presence of "biochemical relapse" (i.e., PSA failure) if there is no other evidence of metastatic prostate cancer to account for the elevation in PSA value.
Part I of this series reviewed the critical issues surrounding the recommendations of national health organizations (such as the American Cancer Society, American Urological Association, American College of Physicians, and American Association of Family Practice) that guide a primary care physician in helping make a PSA-based screening decision. Part II will deal with the diagnosis, treatment counseling, and consequences of prostate cancers that are detected as a result of PSA based screening. Specifically, this part will focus predominantly on organ-confined/clinically localized cancerthe types of prostate cancers that are most likely to be detected by screening. Where appropriate, data from studies on the outcomes of prostate cancer treatments that are both screen-detected and clinically detected (e.g., by virtue of symptoms and/or an abnormal digital rectal examination [DRE]) will be reviewed.
The family physician, primary care physician, or internist plays a critical role in initiating the diagnostic and/or therapeutic cascade in prostate cancer management. While the diagnosis of prostate cancer can be suggested by an abnormal DRE, usually performed as part of an annual evaluation, more often the diagnosis follows an evaluation of an "abnormal" PSA test. While there no longer is the distinct demarcation between a normal and abnormal PSA level, the primary care physician or equivalent health care provider will initiate the discussion with a patient and, possibly, make the recommendation of obtaining a PSA. Regardless of what the PSA value is, data from the Prostate Cancer Prevention Trial demonstrated that for a subset of men older than 55 years, all of whom had a PSA value of less than 4 ng/mL and a negative DRE and underwent a prostate biopsy, the incidence of cancer, including significant cancers, could be found at all levels, including PSA values below 4 ng/mL and with a normal DRE.1
Determinations to Help Predict that Prostate Cancer is Clinically Localized or Organ-Confined
"Bedside" Predictors of Prognosis: Clinical Tumor (T) Stage, Gleason Score of the Prostate Biopsy, and Serum PSA Value. While substantial progress has been made in further understanding the molecular biology of prostate cancer that may be useful in future decision-making, for today's practicing physician the use of three readily available variablesclinical tumor (T) stage, Gleason score of the prostate biopsy, and serum PSA valueprovide a wealth of information to help arrive at treatment decisions and assess outcomes following treatment. This section will explore the utility of these three variables in helping determine rational treatment approaches and their incorporation into predictive nomograms and prognostic probability tables of outcome.
Determining Whether Prostate Cancer Is Organ-ConfinedConsiderations to Help Determine both Anatomic and Systemic Extent of Disease. One of the greatest challenges facing generalists and specialists alike is the prediction or determination of whether prostate cancer diagnosed by a prostate biopsy is organ-confined or whether the cancer has indeed extended beyond the anatomic confines of the prostate gland. While in the past this determination was made by the expertise of the physician's examining finger at the time of DRE, many studies have shown this to be relatively inaccurate and insensitive in determining the true anatomic extent of cancer.2 Consequently, methodologies (e.g., endorectal MRI examination3) and data analyses have emerged to more accurately predict both the anatomic extent of the primary cancer as well as the potential systemic advancement at the time of diagnosis or the likelihood of relapse after treatment of the primary cancer. The most commonly used include the following:
Correlation of Clinical T Stage and Findings at Radical Prostatectomy. Utilizing data emanating from a randomized study of patients who received androgen deprivation therapy prior to radical prostatectomy compared to radical prostatectomy alone, all with an assigned clinical localized stage of T2B,4,5 patients who received surgery alone demonstrated, at the time of pathologic analysis of the radical prostatectomy specimen, a 78% rate of capsule penetration, a 48% positive surgical margin rate, and a 17% positive urethral margin. These features collectively identify prostate cancer that is unlikely to be organ-confined and emphasizes the likely understaging (predicting a lower stage) of prostate cancer as determined by the DRE.
Gleason Score. The Gleason score (see Table 2) of the prostate biopsy is one of the most important determinants of prostate cancer behavior and a predictor of the cancer being organ-confined or more disseminated. The majority of cancers that are detected by either PSA screening programs or by routine physical examination are Gleason 3+3 (Gleason 6 of 10); or 3+4 (Gleason 7 of 10); with fewer patients harboring Gleason 3+2 (Gleason 5 of 10); or Gleason 4+4, 4+5, or 5+5 (Gleason 8, 9, or 10 of 10, respectively). In general, most patients who are found to have a Gleason score of 8 at the time of radical prostatectomy are likely to have non-organ-confined disease and a high likelihood of progression shortly after the prostatectomy. However, as part of several PSA-based screening programs, some investigators have reported on longer-term outcomes of patients with organ-confined prostate cancer determined at the time of radical prostatectomy that contained Gleason score 8 to 10 prostate adenocarcinoma. In one study of 5100 radical prostatectomy specimens obtained between 1995 and 2000,6 222 prostates (4.2%) contained Gleason score 8 to 10 cancer. Of these, 27 men (27/222, 12.2%) had pathologically organ-confined cancer (T2N0M0) after examination of the radical prostatectomy specimen. Of these men, the 33-month actuarial risk of progression was 32%, with 10 of the 27 men developing progression during the study timeframe. Other characteristics would have predicted a much more favorable outcome. This extraordinarily high progression rate contrasts with substantially lower progression rates if the organ-confined prostate cancer contains Gleason scores of 7 or less. This indicates that prostate cancers of Gleason score of 8 to 10 are associated with unfavorable short-term outcomes that would not have been predicted based upon either preoperative clinical data or postoperative pathologic information of disease extent.
| Table 2. Gleason Score Definition |
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Nomogram Considerations. There are two nomograms that will be of invaluable help to the primary care physician in guiding treatment decisions for their patients diagnosed with prostate cancer. A nomogram is a statistical database, usually in tabular form or synthesized into a visual data display, that utilizes a set of characteristics and assigns a probability that a certain outcome will occur or is likely to happen if the patient undergoes a certain treatment procedure.
• Partin Tables.7 This nomogram or set of tables evaluates a large number of men who have undergone radical prostatectomy, and, based upon the clinical tumor stage (T stage), Gleason score of the prostate biopsy, and the pre-operative PSA values, assigns a likelihood that the patient will have, at the time of radical prostatectomy either extracapsular extension of the tumor, seminal vesicle involvement, or involvement of the lymph nodes, if a lymphadenectomy is performed. It essentially provides a likelihood of the cancer being pathologically organ-confined.
• Kattan Nomograms.8-11 (See Figure 1.) This nomogram, based upon the data from thousands of patients, comes in various forms. The most widely used is the likelihood of biochemical failure following radical prostatectomy. In this pictorial display of data, a patient's tumor (T) stage, PSA, and Gleason score of the prostate biopsy are assigned; each of these individual characteristics is placed upon a statistically generated line, which corresponds to a certain number of points. The total points, representing the summation of these three characteristics, is totaled; this summed value then is assigned a probability score, which represents the percentage likelihood that a patient with these characteristics, if treated with a radical prostatectomy, will be alive and biochemically (i.e., PSA) free of disease 60 months following a radical prostatectomy. While the Partin table provides pathological likelihood of cancer involvement at the time of the surgical removal of the prostate gland, the Kattan Nomogram provides outcomes data based upon these three characteristics.
| Figure 1. Preoperative Nomogram for Prostate Cancer Recurrence |
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The main utility of these nomograms is to help counsel the patient about appropriate treatment options. Clearly, if the probability of being biochemically disease free five years post radical prostatectomy is only 30%, both the patient and his physician should consider alternative options, since radical prostatectomy is perhaps not the best or only choice for treatment.
Risk Stratifications.12 A third manner in which prognostication can be obtained using T stage, Gleason biopsy score, and PSA is based again on being biochemically (i.e., PSA free) disease-free five years following definitive local therapy (e.g., radical prostatectomy, radiation therapy, interstitial seed implantation [brachytherapy]). In this risk stratification, the following classifications have emerged:
Low Risk: More than 85% five-year PSA failure-free survival rate. The 1992 American Joint Committee on Cancer (AJCC) clinical stage T1c or T2a and PSA less than or equal to 10 ng/mL and biopsy Gleason score of 6 or less.
Intermediate Risk: 50% five-year PSA failure-free survival rate. The 1992 AJCC clinical stage T2b or PSA between 10 and 20 ng/mL or biopsy Gleason score of 7.
High Risk: 33% five-year PSA failure-free survival rate. The 1992 AJCC clinical stage T2c disease or PSA greater than 20 ng/mL or biopsy Gleason score of 8 or higher.
Again, these risk stratifications predict outcomes. Patients in the intermediate- and high-risk categories could consider more intensive treatment options given the high likelihood that primary localized therapies are not likely to be curative, despite the cancer clinically being staged as localized.
PSA Velocity.13,14 Patients recently diagnosed with prostate cancer may be at a heightened risk of prostate cancer mortality and all-cause mortality if the PSA value in the year preceding the diagnosis rose by more than 2 ng/mL. While this reflects the concept of PSA velocity (as discussed in Part I), this rate of change, especially when accompanied with a high Gleason score (e.g., Gleason 8 or above) portended a very poor prognosis and prompts the need for considering additional alternatives to localized therapy.
Other Useful Nomograms.15 There are additional nomograms that are emerging to help predict the likelihood of extra-prostatic capsular extension of cancer detected at the time of radical prostatectomy based upon pre-operative prostate biopsy characteristics. While these nomograms may be used more routinely by specialists, the key characteristics that include percent of biopsies/total biopsies taken that contain cancer and the percent of the actual biopsy core that contains cancer (in addition to the previously mentioned PSA, Gleason Score, and T stage) all are powerful predictors of assessing the probability that the cancer was organ-confined.
Critical Issues for the Primary Care Physician in Determining the Need for Treating Clinically Localized Prostate Cancer. The primary care physician should appreciate that the optimal treatment for clinically localized prostate cancer remains unknown. In guiding treatment options, it is important to realize that the prostate cancer specific survival rates overall are excellent, with five-year survival rates exceeding 95% for localized disease and 80% for more advanced stages. Therefore, men nearly always have time after a diagnosis of prostate cancer to learn all they can about various treatment options and make truly informed decisions before embarking on a specific course of treatment.
Perhaps one of the most important questions that requires evaluation following a newly detected prostate cancer relates to the issue of offering active treatment or having the patient undergo programs known as watchful waiting, expectant management, or active surveillance. This latter treatment option is possible since the natural history of untreated prostate cancer is variable, with certain subsets of patients living for extended periods of time without active treatment intervention.
The National Comprehensive Cancer Network provides guidelines for the management of prostate cancer based upon consensus recommendations and evidence based upon a variety of factors including life expectancy, PSA value, Gleason score, and symptoms. The guidelines suggest that factors that should be considered in recommending treatment options should take into account the expected biologic behavior of the cancer, the patient's expected longevity, and preference regarding potential side effects.16,17
What Evidence Is Available to Support Active Surveillance for Clinically Localized Prostate Cancer?
The Scandinavian Study.18,19 A long-term, population-based, cohort study with a mean observation period of 21 years that included a consecutive sample of 223 patients with early-stage initially untreated prostate cancer evaluated progression-free, cause-specific, and overall survival. Overall, 39 (17%) of all patients experienced generalized disease, and at 15 years of follow up, the outcomes of the untreated patients seemed not to differ from an age-matched control population who did not have prostate cancer. However, a follow-up at 15 to 20 years from diagnosis was associated with a substantial decrease in cumulative progression-free survival (from 45.0% to 36.0%), survival without metastases (from 76.9% to 51.2%), and prostate cancer-specific survival (from 78.7% to 54.4%). The prostate cancer mortality rate increased from 15 per 1000 person-years (95% confidence interval, 10-21) during the first 15 years to 44 per 1000 person-years (95% confidence interval, 22-88) beyond 15 years of follow-up (P =.01). This study suggested that an untreated population of men with prostate cancer who undergo watchful waiting may experience significant morbidity and mortality 15 years following their diagnosis. However, another study (see below), performed in the United States, comes to a different conclusion.
The Connecticut Tumor Registry Study.20,21 In a retrospective cohort study conducted utilizing data from the Connecticut Tumor Registry, 767 patients diagnosed with localized prostate cancer between 1971 and 1984 were either not treated or treated with immediate or delayed hormonal therapy. Patients whose Gleason scores were between 2 and 4 had a lower chance (4-7%) of dying from prostate cancer within 15 years of diagnosis than those patients with more aggressive Gleason scores. Further follow-up of this data set shows that the annual mortality rates from prostate cancer remain stable in those with localized and low-grade prostate cancer even after 15 years from diagnosis.
A third study22 of no active intervention again suggests that patients with low-grade Gleason tumors (e.g., Gleason combined score of 2-4 or equivalent), long-term survival is achievable without active intervention at least through 10 years of follow-up. A retrospective study of 828 men treated conservatively (with observation and delayed hormone therapy but no radical surgery or radiation) for clinically localized prostate cancer showed that 10 years after diagnosis, disease-specific survival was 87% for grade 1 or 2 tumors and 34% for grade 3 tumors, and metastasis-free survival was 81%, 58%, and 26% for grade 1, 2, and 3 disease, respectively.
Intensive Lifestyle Change Study.23 Alterations in lifestyle and diet for men with localized prostate cancer who elect not to receive any conventional therapy for their prostate cancer have yielded information about PSA progression during the period of no active treatment. This study randomized 93 men with recent diagnosis of early stage prostate cancer who chose not to receive any conventional therapy (i.e., radiation, surgery, hormonal therapy) to intensive lifestyle changes or a control group. The former included a vegan diet supplemented with soy, fish oil, vitamin E, selenium, vitamin C, exercise, stress management, and support group intervention. After one year of adhering to the intensive intervention program, serum levels of PSA decreased by 4%, compared to an increase of 6% in the control group. Other parameters that included preclinical evaluation of the cancer inhibitory activity of patient's serum on experimental prostate cancer cell lines demonstrated that a greater degree of growth inhibition accompanied the serum of those undergoing intensive lifestyle changes.
While the above four groups of studies certainly can provide a level of comfort for justifiably pursuing a course of active surveillance or expectant management, a recent analysis of a randomized study of radical prostatectomy vs. watchful waiting has been completed and suggests caution in advocating a no-treatment option. This important study24 suggests that radical prostatectomy may decrease disease-specific mortality and improve overall survival in men with clinically detected localized prostate cancer compared to those who are managed expectantly.
This study randomized 695 men with clinically localized prostate cancer (T1b, T1c, or T2) and compared radical prostatectomy to watchful waiting. There was a significant decrease in disease-specific mortality (8.6% compared to 14.4%, p = 0.01) in favor of radical prostatectomy. With longer follow-up and using 10-year actuarial estimates, there was a relative reduction of 26% in overall mortality favoring the radical prostatectomy group (p = 0.04). It should be appreciated that this population of men did not have their cancers detected through a screening program, and the extrapolation of these positive results to screen-detected populations is speculative, but likely to be answered as ongoing randomized screening studies mature. (See Part 1.)
In this study, various quality-of-life parameters including erectile dysfunction and urinary leakage were compared. Both erectile dysfunction (80% vs 45%) and urinary leakage (49% vs 21%) were more common following surgery, whereas urinary obstruction (e.g., 28% vs 44% for weak urinary stream) was less common. Other parameters of quality of life appeared similar.25 However, as this study matured and longer-term results were reported, the patients in the watchful waiting group developed a higher rate of metastatic disease with associated complications.24
What Are the Clinical and Pathologic Characteristics of Screen-Detected Cancers?
A basic premise underlying the endorsement of screening for the detection of early stages of prostate cancer assumes that the cancer so detected will possess more favorable characteristics. In general, prostate cancers that are detected from screening programs are less likely to be metastatic, more likely to have a more favorable Gleason pathology score, and are less likely to be treated with hormonal therapy compared to control patients who do not undergo screening.26,27 Most screen-detected cancers are classified as T1C cancers. Even within this group of screen-detected T1C cancers, there are further classifications that can help stratify treatment options and outcomes.
One important study26 reviewed 1149 T1C patients treated with radical prostatectomy (RP). Criteria were developed to quantify the likelihood of biochemical failure (PSA 0.2 ng/mL or greater) post-prostatectomy. Using several clinical criteria (PSA, biopsy Gleason score, percent cancer on any biopsy core), two groups were identified [T1CI (Gleason sum less than 7 and PSA 10 ng/mL or less) and T1CII (Gleason sum 7 or greater or PSA greater than 10 ng/mL)]. The analysis showed that for T1CI cancers, freedom from PSA recurrence at 3, 5, and 10 years after surgery was 98%, 96%, and 96%, respectively; for T1CII was 86%, 83%, and 73%, respectively (P < 0.001). Further risk stratification was observed when a cutoff of 50% of cancer in a single core biopsy was added.
In the largest study27 to date from the European Randomized Screening Study for Prostate Cancer, researchers evaluated the clinical and pathologic characteristics of screen-detected and clinically diagnosed prostate cancer in men aged 55-74. Out of 35,149 men, 17,636 were randomized to be screened; 17,513 out of 35,149 served in the control arm. Cancers detected by screening were less likely to be metastatic (0.6% vs 6.7%); more likely to have a more favorable Gleason pathology score (84.1% with a Gleason of 5-7 vs 69.8%); and less likely to be treated with hormonal therapy (2% vs 17.4%).
Who Are the Optimal Candidates for Active Surveillance?
Based upon these considerations and additional studies that have attempted to correlate prostate biopsy specimens with clinical behavior, a recent review28 proposed a possible algorithm for suggesting active surveillance for a subset of men with recently diagnosed prostate cancer. The eligibility factors include:
- PSA less than or equal to 10 ng/mL;
- Gleason score less than or equal to 6;
- T1c to T2a disease;
- greater than 15-year life expectancy;
- less than 3 cores positive on prostate biopsy and less than 50% of any core involved.
The suggested follow-up is:
- PSA, DRE every 3 months for 2 years; then every 6 months, assuming a stable PSA value;
- 10-12 core prostate biopsy at 1 year, then every 3 years until age 80.
Interventions from active surveillance to treatment would be triggered by:
- PSA doubling time of less than 3 years, based upon 8 PSA determinations;
- Gleason score progression to 7 (4+3) or greater.
It is anticipated that 20% of patients would require intervention based upon the PSA doubling parameter, and 5% based upon the Gleason progression parameter. This schematic may be a potentially attractive option for selected patients who do not desire any active interventions and can be justified by the lack of definitive data that active surgical or radiation treatments (with or without hormonal therapies) prolong survival. If such an algorithm is selected, the primary care physician will assume a greater responsibility in the management and monitoring of these patients.
What Are the Outcomes of Curative Therapy (Radical Prostatectomy, External Beam Radiotherapy, and Interstitial Seed Implantation, with or without Hormonal Therapy) for Organ-Confined Prostate Cancer?
The majority of data to answer this question come from observational studies that have pooled patient data across institutions. Thus, the patient selection criteria, pre-treatment workup, staging evaluations, and methods to measure outcomes were not rigorously and prospectively defined. Nevertheless, these survival statistics represent the most current information available on large numbers of patients treated across academic and community practices both in the United States and select centers in Europe.
It is important to appreciate that any non-randomized comparisons between surgery and radiation therapy for localized prostate cancer must take into account the concept of clinical vs. pathologic staging. In general, surgical series include a staging pelvic lymph node dissection as well as the specific and final pathologic stage of the resected cancer-containing prostate gland. Radiation therapy series, on the other hand, are based upon clinical staging generally without the aid of knowing the pathologic status of the pelvic lymph nodes or the actual pathologic stage of the primary prostate cancer. Thus results from radiation series are likely to reflect patients who have been understaged (i.e., have a lower stage of cancer than actually exists) leading to potential biases in favor of surgical results. Likewise, patients selected for radiation therapy may have co-morbid medical conditions that precluded them from undergoing surgeryanother potential confounding factor favoring surgical results when comparisons between the two treatments are made for all-cause mortality.
Radical Prostatectomy Series. General Comments. There are several methods of performing a radical prostatectomy. Most commonly, a retropubic approach is used. A midline incision inferior to the umbilicus is made, allowing access to one or several chains of lymph nodes that drain the prostate gland and periprostatic tissue. While in the past most patients underwent a staging pelvic lymphadenectomy as part of the radical prostatectomy, given the rarity of finding nodes today, this may or may not be performed routinely. The operation allows the lymph node sampling and prostatectomy to be accomplished with one surgical incision.
The perineal approach requires an incision to be made in the perineum to gain access to the prostate gland. Though not used routinely today, lymph node sampling would require a second abdominal incision. The surgeon attempts to perform a so-called anatomic (also known as nerve-sparing) radical prostatectomy when using either the retropubic or perineal approach. By identifying the nerves and blood vessels that course along the lateral border of the prostate gland and provide innervation and blood supply to the prostate gland, in some circumstances potency may be preserved by sparing this so-called neurovascular bundle. The decision to spare the nerves generally is made intraoperatively. If both neurovascular bundles can be preserved, the likelihood of maintaining potency is greater than if only one neurovascular bundle is preserved. Palpable disease on one side of the prostate gland generally will require sacrifice of the neurovascular bundle on that side.
More recently, the use of laparoscopic surgery has gained popularity. This procedure may be performed with or without the assistance of a robotso-called robotic-assisted laparoscopic radical prostatectomy. While the follow-up data are not extensive, proponents of the procedure cite less post-operative pain and less blood loss compared to traditional open radical prostatectomy. The incidence of incontinence and impotence, at this time seem to be comparable to more commonly performed open procedures. During robotic surgery, the surgeon sits at a site near the operating table and is able to view the operative field with magnification, in three dimensions, and with multiple degrees of freedom embedded within the operating robotic arm. This type of surgery is likely to increase in future years as more surgeons become trained in its use.
Results of Studies. A retrospective, nonrandomized, multi-institutional pooled analysis of 2758 men with stage T1 and T2 prostate cancer treated with radical prostatectomy reported disease-specific survival (and associated 95% confidence intervals) 10 years following surgery to be 94% (87%-98%), 80% (74%-85%), and 77% (65%-86%) for grade 1, 2, and 3 tumors, respectively. Metastasis-free survival at 10 years was 87% (78%-92%), 68% (62%-73%), and 52% (38%-64%) for grade 1, 2, and 3 cancers, respectively.
A retrospective review30 of 2091 men with stage T1 and T2 prostate cancer treated with radical retropubic prostatectomy reported overall actuarial 5-, 10-, and 15-year biochemical recurrence-free survival rates of 84%, 72%, and 61%, respectively. The pre-operative characteristics that included Gleason score, TNM stage, and PSA were predictive of probability of biochemical relapse.
A review31 of 1916 patients treated with radical prostatectomy and followed for 14 years after radical prostatectomy (10,540 patient-years) demonstrated that none who were followed for an average of greater than five years who also had an undetectable PSA developed either a local recurrence or metastatic disease. None of the patients who had a local recurrence or distant metastases did so with an undetectable PSA.
In general, it is reasonable to counsel patients who have undergone a radical prostatectomy at an average of five years earlier and who have an undetectable PSA that they are less likely to experience a local recurrence or develop metastatic disease. The tumor grade of the prostate cancer is an important determinant of disease-specific survival. A summary of the above data indicates that the disease-specific survival and metastases-free survival 10 years following radical prostatectomy for early prostate cancer range between 77% and 94%, and 52% to 87%, respectively, depending upon tumor grade. However, as more studies mature that include patients who were diagnosed and treated in the PSA screening era, late relapses (greater than 8 years following radical prostatectomy) do occur.
Radiation Therapy Series. General Comments. There are several forms of radiation therapy that are utilized in the management of clinically localized prostate cancer, and there currently is no consensus regarding the best treatment option.32 The historical use of conventional x-rays has given way to more complicated and sophisticated methodologies that include three-dimensional conformal radiation therapy; more recent advances include so-called intensity modulated radiation therapy, conformal proton beam radiation therapy, and conformal neutron beam radiation therapy. These sources of external beam radiation therapy (EBRT) are external to the body and derive differences by using techniques that more precisely outline the three-dimensional volume of the prostate gland and periprostatic tissues. By more accurately delineating these volumetric structures, more radiation dose can be delivered to the target tissue (the tissue that contains the cancer or is likely to contain cancer) and less to surrounding normal tissues, thereby theoretically improving efficacy and diminishing adverse events.
In addition to external sources of radiation, the source can be internal by placing the radiation source directly into the prostate gland (i.e., brachytherapy, seed implantation, or interstitial radiation therapy).33 This therapy may be used as monotherapy or in combination with EBRT. The seeds that are implanted may be done so permanently (permanent prostate implants, delivering a low-dose rate to get to the high cumulative dose) or as temporary seeds, providing a high-dose rate.
The effectiveness of all forms of radiation therapy may be improved by the addition of hormonal therapy or androgen deprivation therapy.
Results of Studies. A retrospective, nonrandomized, multi-institutional pooled analysis34 of 1765 patients with stage T1 and T2 prostate cancer treated with external beam radiation therapy alone reported five-year estimates of overall survival, disease-specific survival, and the freedom from biochemical failure to be 85.0% (95% confidence interval [CI], 82.5%-87.6%), 95.1% (95% CI, 94.0%-96.2%), and 65.8% (95% CI, 62.8%-68.0%), respectively. In this study, there were four separate prognostic groups: group 1 included patients with a PSA level of less than 9.2 ng/mL; group 2 had a PSA level of at least 9.2 but less than 19.7 ng/mL; group 3 had a PSA level at least 19.7 ng/mL and a Gleason score of 2 to 6; and group 4 had a PSA level of at least 19.7 ng/mL and a Gleason score of 7 to 10. The estimated rates of biochemical relapse-free survival at five years are 81% for group 1; 69% for group 2; 47% for group 3; and 29% for group 4. Of the 302 patients followed beyond five years who were free of biochemical disease, 5.0% relapsed from the fifth to the eighth year.
Effect of Radiation Dose. A recent randomized study35 of 393 men with recent diagnosis of stage T1b through T2b prostate cancer and serum PSA levels of less than 15 ng/mL were randomized to receive external beam radiation to a total dose of either 70.2 Gy (conventional dosing) or 79.2 Gy (high dose), using a combination of conformal photon and proton beam radiation sources. The percentage of men who were free from experiencing a biochemical failure, defined as an increasing PSA value five years after treatment, was 61.4% (95% CI 54.6%-68.3%) for conventional dose and 80.4% (95% CI 74.7%-86.1%) (p < 0.001) for high-dose therapy, indicating a substantial reduction in biochemical failure rate. Overall survival was similar, as were urinary and rectal side effects.
A study36 of 125 consecutive patients treated with iodine-125 brachytherapy for T1 and T2 prostate cancer demonstrated a biochemical (e.g., PSA) progression-free survival rate of 87% after 10 years of follow-up. These patients had pre-treatment PSA values of less than 10 ng/mL, Gleason scores of 2-6, and T1 or T2b cancers.
A more recent37 study of 232 patients with clinically localized prostate cancer who were treated with either iodine(125) (I(125)) or palladium (103) (Pd (103)) brachytherapy and neoadjuvant external beam radiation therapy were evaluated for 10-year biochemical relapse-free survival (BRFS). Overall, the 10-year BRFS for the entire treatment group was 70%. Using the risk stratifications discussed earlier in this review, biochemical control according to risk was: low-risk, 86%; intermediate-risk, 90%; and high-risk, 48%. These two forms of brachytherapy, combined with EBRT, resulted in high rates of biochemical control at 10 years.
Two additional larger series38,39 of prostate brachytherapy treatment just recently published have reported 10- to 12-year disease-specific survivals of 93% to 96%, and overall survivals of 74% to 81%.
Novel Methods for Treating Clinically Localized Prostate Cancer
Cryotherapy. Cryoablation refers to the use of freezing and then thawing tissue, which results in cellular destruction of the tissue so treated. In practice, the prostate cancer patient is treated with several cryoprobes that are implanted temporarily into the prostate under ultrasound guidance. The probes are cooled, allowing an ice mass to develop in the gland, and then thawed. In general, the patient receives several cycles of freezing followed by thawing. The procedure still is in its infancy and no long-term 10- and 15-year cause-specific survival data are available. However, one study of 975 patients40 from five institutions reported a five-year actuarial BRFS rate was 51% for patients with PSA values of less than 0.5 ng/mL and 63% for values less than 1 ng/mL. In practice today, cryoablation often is used as a salvage therapy for patients who have residual prostate cancer following radiation therapy. As technical factors are solved, cryotherpay may become more of a standard option for the management of clinically localized prostate cancer in the future. However, given the substantial morbidities that have been reported that include fistula formation, high rates of impotence, and incontinence, more technical work on understanding the optimal way to utilize cryoablation needs to occur.
| Table 3. Complications of Local Therapies for Organ-Confined Prostate Cancer |
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Role of Hormonal Therapy Used in Conjunction with either Radical Prostatectomy or Radiation Therapy
General Comments. The use of hormonal therapy (also called endocrine therapy or androgen deprivation therapy) has traditionally been the mainstay of treatment for patients with metastatic prostate cancer.41 The history of hormonal therapy dates back to nearly 70 years ago following the important observations of Dr. Charles Huggins who noted that prostate cancer was under the influence of the male hormone testosterone. Cancer remission could be induced with androgen ablation (then, using diethtylstilbestrol or surgical castration) and prostate cancer disease worsening occurred during androgen administration with exogenous testosterone. Thus, decreasing the circulating levels of testosterone (either medically or surgically) has been a mainstay of palliative therapies for advanced or metastatic prostate cancer.
Over the years, the use of hormonal therapy has been studied in patients with clinically localized or regionally advanced prostate cancer, both in conjunction with radical prostatectomy and radiation therapy. Most studies have not shown consistent benefit when hormonal therapy is added to radical prostatectomy in the absence of lymph node metastases. However, in many studies, the addition of androgen ablation has become the standard of care for a large number of patients receiving radiation therapy. In general, the advantages of combination hormonal therapy and radiation include improvement in biochemical disease free survival, progression free survival, and overall survival. Today, most practitioners use medical methods to achieve castrate levels (usually defined as less than 50 ng/dL of testosterone) by administering an LHRH (luteinizing hormone releasing hormone) agonist (which blocks the pituitary release of luteinizing hormone and subsequent testosterone release by the testis) alone or in combination with a non-steroidal antiandrogen (which blocks the interaction of androgens, specifically, dihydrotestosterone, with the cytoplasmic androgen receptor.) In practice, the hormonal therapy generally is administered for 2-4 months before radiation therapy, continued throughout radiation therapy, and then for several months thereafter.
The use of hormonal therapy as an adjunct to radiation therapy for localized prostate cancer or post-operatively in patients with confirmed extraprostatic nodal disease at the time of radical prostatectomy may confer an overall survival advantage. (The role of hormonal therapy as an adjunct for patients undergoing radical prostatectomy for clinically localized disease has been studied but not effective.5)
Results of Studies. A randomized trial42,43 of 415 patients with locally advanced prostate cancer (T1-2 tumors of WHO grade 3 or T3-4 N0-1 M0 tumors) found that XRT combined with an analogue of luteinizing-hormone releasing hormone for three years (XRT+HT) conferred an improved five-year disease-free survival over XRT alone of 74% vs. 40% (p = 0.0001), as well as improved five-year overall survival of 78% vs. 62% (p = 0.0002); and a five-year disease-specific survival of 94% vs. 79%.
In one randomized study44 of 98 men treated with radical prostatectomy and pelvic lymphadenectomy and nodal metastases were randomly assigned to receive immediate androgen deprivation therapy (ADT) (goserelin or bilateral orchiectomy) or no ADT, and both groups were followed until disease progression. After a median follow-up of 7.1 years, 7 of 47 in the ADT group had died, as compared with 18 of 51 men in the control (no ADT) group (P = 0.02). The cause of death was prostate cancer in 3 ADT patients compared to 16 controls (P < 0.01).
These two studies serve as the basis for combining hormonal therapy with either radiation therapy for men with both localized and regionally advanced prostate cancer or radical prostatectomy for men with nodal metastases.
What Are the Harms of Treatment of Special Interest to the Primary Care Physician?
In counseling patients to undergo treatment (or no treatment) for prostate cancer, the primary care physician is in the best position to advise patients about the potential morbidities of treatment approaches. Because the population with prostate cancer is generally elderly and has both mild and serious co-morbidities, the decision to undergo localized treatments must take these issues into account. For example, the existence of inflammatory bowel disease would factor into a decision about radiation therapy. Often the oncology specialist (either radiation or urologic) will confer with the primary care physician about the status of these co-morbidities. Diabetes, obesity, cardiac arrhythmias, many of which require anticoagulation, pulmonary illnesses such as emphysema, and peripheral vascular disease all factor into decision-making and communication between primary care physician and prostate cancer specialist. Moreover, complications of systemic hormonal therapy, which may include alterations of lipid metabolism, development of osteopenia, and several cardiac abnormalities, are all factors in decision-making and all may add to the morbidity of both surgical and radiation procedures.
Radical Prostatectomy. The complications of patients undergoing radical prostatectomy for screen-detected and clinically detected prostate cancers and clinically localized prostate cancer in general are similar and include:
- impotence;
- erectile dysfunction;
- urinary incontinence;
- bowel complications;
- cardiovascular complications; and
- death.
Bowel, Urinary, and Erectile Complications. A prospective study45 of 279 men using self-reported patient symptoms and quality-of-life measures following treatment for prostate cancer reported irritative bowel and bladder symptoms after radiotherapy and urinary incontinence and wearing of absorptive pads after radical prostatectomy. Sexual dysfunction occurred universally in men treated with surgery at three months, but some improved at 12 months in men younger than 65 years treated with radical prostatectomy.
A case-control study46 of California managed care patients with localized prostate cancer treated with radical prostatectomy, radiation therapy, or observation was compared to an age-matched and zip-code-matched cohort to assess health-related quality of life (HRQOL). Although no differences among treatment groups were seen in general HRQOL, significant differences among treatment groups were observed in function and bother in measures of sexual, urinary, and bowel domains. Patients who received radical prostatectomy or radiation therapy reported significantly worse sexual, urinary, and bowel function than men without cancer.
A two-part telephone survey study47 was conducted in 227 prostate cancer patients (initial study group) and then 1200 patients (second group) from the Department of Defense health system who had undergone radical prostatectomy. All patients had undergone treatment at least 12 months before being contacted for the telephone survey. In the 227 patient cohort, fecal incontinence occurred in 5% undergoing radical retropubic and 18% undergoing perineal prostatectomy; fewer than 50% of those with fecal incontinence told their physician. In the larger series, frequency of fecal incontinence was significantly higher among radical perineal compared to retropubic prostatectomy patients (p = 0.002). Patients undergoing perineal prostatectomy had lower rates of urinary incontinence compared to those undergoing retropubic prostatectomy.
A randomized prospective study25 comparing radical prostatectomy vs. watchful waiting (conducted in Sweden) evaluated 326 men and found that urinary leakage (49% vs 21%) was more common following radical prostatectomy; urinary obstruction, as measured by a weak urinary stream, was less common (28% vs 44%).
A postal survey48 of standardized questionnaires was sent to 2636 men who either were treated with definitive radiotherapy or underwent prostatectomy for localized prostate carcinoma. Forty-nine percent returned the questionnaire. At diagnosis, 36% had erectile dysfunction (ED). Within the past six months, 85% of men reported having ED. Only 13% of men were having reliable, firm erections spontaneously, and another 8% of men were having erections with the aid of a medical treatment. Men were as distressed about loss of desire and trouble having satisfying orgasms as they were about ED.
A questionnaire study49 of 431 men with prostate cancer and 435 randomly selected men with a similar age distribution reported a greater incidence of sexual dysfunction and sexually related disease-specific distress in the patients with prostate cancer.
The common finding of urinary and sexual function after radical prostatectomy was assessed in a study50 of 1288 men with localized prostate cancer who were treated with radical prostatectomy. These men were asked to complete a baseline survey within 6-12 months of diagnosis to assess temporal changes in urinary and sexual function up to five years after treatment. At 60 months, 14% reported frequent urinary leakage or no urinary control; 28% of the men had erections firm enough for intercourse.
A study51 of 1977 men from the Surveillance, Epidemiology, and End Results Prostate Cancer Outcomes Study with localized prostate cancer who received external beam radiation therapy or radical prostatectomy in 1994-1995 were surveyed for five outcome measures of erectile dysfunction that included treatment, perceived helpfulness, erectile sufficiency, sexual activity frequency, and erection maintenance. Overall, approximately half of the patients in this group of men used ED treatment during the five years following prostate cancer diagnosis.
Overall Complications Including Death. A study52 of 1000 men undergoing radical prostatectomy by a single surgeon evaluated intraoperative and post-operative complications using inpatient and outpatient medical record reviews and patient surveys. Intraoperative complications (0.8%) included five rectal injuries and one ureteral injury. Fourteen men (1.4%) experienced other complications during hospitalization. Until postoperative day 30, four pulmonary emboli (0.4%) with or without deep vein thrombosis and five myocardial infarctions (0.5%) developed. There were no intraoperative or in-hospital postoperative deaths. Mean hospitalization was 2.3 days, 9.7% of patients required allogenic blood transfusion, and 15 (1.5%) were rehospitalized. Ninety-eight percent had no intraoperative or postoperative complications.
A review53 of 472 patients treated with radical retropubic prostatectomy between 1990 and 1994 by one surgeon at a high-volume institution assessed complications within 30 days postoperatively. To study co-morbidity, all patients had an assessment of the American Society of Anesthesiologists (ASA) physical status classification. Forty-six patients (9.8%) experienced major complications; 101 (21.4%) had minor complications; 341 (72.2%) no complications. Two deaths (0.42%) and a disproportionate portion of major complications occurred from the ASA class 3 population.
An administrative database study54 of 13,398 patients undergoing radical prostatectomy (RP) was undertaken to evaluate 30-day mortality and complication rates using the Department of Veterans Affairs Patient Treatment File and Outpatient Clinic File. Major cardiopulmonary complications, vascular complications, and colorectal injuries occurred in 1.7%, 0.2%, and 1.8% of men, respectively. Thirty-day mortality was 0.73% and was associated with a history of diabetes and congestive heart failure.
A recent study55 of 11,010 men who underwent radical prostatectomy between 1990 and 1999 was evaluated for 30-day mortality and complications, and was adjusted for competing co-morbidities using well-known comorbidity indicies. Overall, 53 men (0.5%) died, and 2246 (20.4%) had one or more complications within 30 days of the operation; an important factor that predicted for mortality and morbidity was age. This association was especially strong for older men with comorbidities who developed higher rates of cardiac, pulmonary, and other medical complications. Increasing comorbidity indicies were associated with the development of complications shortly after radical prostatectomy.
A review56,57 of the Surveillance, Epidemiology, and End Results-Medicare linked database claims records of 11,522 patients who underwent prostatectomy between 1992 and 1996 and were reviewed to determine rates of postoperative and late urinary complications (strictures or fistulas 31 to 365 days after the procedure) and long-term incontinence (more than 1 year after the procedure). Analyses related complications to hospital volume and surgeon volume. Very-high-volume hospitals and high-volume surgeons had lower post-operative morbidity rates than low-volume hospitals (27% vs 32%, P = 0.03) and (26% vs 32%, P < 0.001), respectively. Late urinary complications followed these volume-related trends. Preservation of continence did not follow these trends.
External Beam Radiation Therapy. The complications of patients undergoing external beam radiation therapy for screen-detected prostate cancers and clinically localized prostate cancer in general include:
- impotence;
- erectile dysfunction;
- urinary incontinence;
- cystitis;
- radiation proctitis;
- fatigue;
- bowel movement disorders; and
- increased incidence of rectal cancer.
A case control study58 of 200 patients who received pelvic external beam radiation therapy and an age-matched control utilized a questionnaire to assess urinary and intestinal problems 24-56 months post-treatment. Although most of the reported problems were considered minor, the following urinary complications were noted: control vs. treated: urgency (19 and 42%); starting problems (22 and 33%); leakage (11 and 32%). The following intestinal problems were noted: mucus (4 and 38%); cramps (5 and 14%); leakage (2 and 27%); and blood (2 and 36%).
A questionnaire59 administered to patients treated with either conventional dose or conformal radiation therapy for prostate cancer reported an overall rate of persistent incontinence of 29%; 36% reported urge incontinence, and 8% reported stress-related incontinence. Fewer than 2% required incontinent pads. Urgency of bowel movements that was concerning was reported in 27% of patients. Complications of incontinence and bowel function appeared higher in the conventional radiation treated group.
A meta-analysis of 40 articles60 to determine the rates of erectile dysfunction (using a simple logistic regression model) associated with RP and external beam radiotherapy demonstrated that the probability of maintaining erectile function after RP was 0.42, and 0.69 after radiation therapy. It should be noted that most of the studies included in this meta-analysis did not include more recent studies that included anatomic radical prostatectomies and conformal radiation therapy techniques.
A randomized study35 of 393 men with recent diagnosis of stage T1b through T2b prostate cancer and serum PSA levels of less than 15 ng/mL were randomized to receive external beam radiation to a total dose of either 70.2 Gy (conventional dosing) or 79.2 Gy (high dose), using a combination of conformal photon and proton beam radiation sources. The percentage of men who were free from experiencing a biochemical failure, defined as an increasing PSA value five years after treatment, was 61.4% (95% CI 54.6%-68.3% ) for conventional dose and 80.4% (95% CI 74.7%-86.1% ) (p < 0.001) for high-dose therapy, indicating a substantial reduction in biochemical failure rate. Overall survival was similar as were urinary and rectal side effects. (This study also is included in the treatment outcomes section.)
A retrospective cohort study61 using Surveillance, Epidemiology, and End Results (SEER) registry data from 1973 through 1994 evaluated a total of 30,552 men who received radiation, and 55,263 who underwent surgery only for prostate cancer, with an aim to determine whether the incidence of rectal cancer was increased following radiation. All patients survived at least five years. Three sites of the colorectum were evaluated: sites that were definitely irradiated sites (rectum); those potentially irradiated sites (rectosigmoid, sigmoid, and cecum); and non-irradiated sites (the rest of the colon). Colorectal cancers developed in 1437 patients: 267 in irradiated sites, 686 in potentially irradiated sites, and 484 in nonirradiated sites. Compared to the cohort who received surgery, the adjusted hazards ratio for development of rectal cancer was 1.7 for the radiation group (95% CI: 1.4-2.2). Radiation was independently associated with development of cancer over time in irradiated sites but not in the remainder of the colon.
Brachytherapy. The complications of patients undergoing brachytherapy for screen-detected prostate cancers and clinically localized prostate cancer in general include:
- irritative and obstructive urinary symptoms, occasionally causing acute urinary retention;
- proctitis;
- transient hematuria and hematospermia;
- radiation cystitis;
- incontinence;
- urethral stricture; and
- impotence.
A population study62 of 2124 men who underwent brachytherapy in 1991 in whom Medicare complication claims were submitted indicate the following complications: bladder outlet obstruction, 8.3%; colostomy, 0.3%; artificial urinary sphincter replacement, 0.2%; urinary incontinence, 6.6%; erectile dysfunction, 8.4%; rectal injury secondary to radiation, 5.5%. However, one should emphasize that this type of study, which relies on claims data submitted to Medicare, has limitations in determining patient outcomes.
A case-controlled comparative study63 of general and disease-specific health-related quality-of-life measures for early stage prostate cancer treated with brachytherapy (with and without pretreatment external beam radiation) or radical prostatectomy and age-matched healthy controls demonstrated urinary leakage was worse in the brachytherapy group than in controls but better than in the prostatectomy group; those treated with brachytherapy had more irritative urinary symptoms and worse bowel function than controls; sexual function and bother scores were worse in the groups treated with radical prostatectomy and brachytherapy groups compared to controls.
A study64 of 248 patients with T1 and T2 who underwent (125)I seed implantation and were followed for a minimum of 18 months were evaluated for urinary symptomatology by comparing post-treatment urinary symptomatology scores with post-treatment scores (range, 18 to 108 months; median, 31 months). With this longer-term follow-up, there were no significant differences between pretreatment and last mean scores for any of the categories except for a significant increase in urgency and weak stream. Those patients who initially presented with marked urinary symptom score demonstrated improvement after treatment.
Use of Hormonal Therapy. The addition of hormonal therapy to either brachytherapy or external beam radiation for clinically localized prostate cancer increases side effects related to loss of libido, erectile dysfunction, and vasomotor hot flashes, whether it is used prior to, during, or after definitive primary therapies. Other well-known side effects of hormonal therapy include gynecomastia and breast tenderness, usually resulting from the use of non-steroidal anti-androgen therapy; thinning of bodily hair, weight gain, minor disturbances in glucose and lipid metabolism; changes in memory; and arthralgias. More recent information has shown that androgen deprivation therapy may be associated with increases in the QT and corrected QT interval on the electrocardiogram. With more prolonged usage, the development of osteopenia, osteoporosis, and increased risk of fracture may occur. However, when androgen deprivation therapy is used as part of radiation programs for cancers detected through screening or clinically localized disease, the duration of hormonal therapy generally is short-lived, thus minimizing many of these complications.
Side Effects Requiring Special Considerations
Erectile Dysfunction. A study65 of 199 prostate cancer patients who had received pelvic XRT with curative intent (with or without castration) and 200 age-matched controls used a self-administered questionnaire to assess sexual function. The percentages of failure to achieve erection were 12%, control subjects; 56%, XRT only; and 87%, XRT plus castration. The incidence of sexual dysfunction was greater in XRT-treated men compared to age-matched controls.
A prospective study66 of 482 men with prostate cancer who were able to maintain an erection prior to receiving permanent prostate brachytherapy (with or without androgen deprivation therapy [ADT] and external beam radiation therapy [EBRT]) revealed that 311 preserved potency with a five-year actuarial potency rate of 52.7%. For those treated with brachytherapy alone, potency rates were 76%; for EBRT plus brachytherapy, 56%; for ADT plus brachytherapy, 52%; for brachytherapy plus EBRT plus ADT, 29%. Eighty-four patients were treated with sildenafil; 62% (52 patients) reported success.
The use of sildenafil and other erectile dysfunction agents may restore sexual function when used after radiation therapy or prostatectomy. A randomized double-blind, placebo-controlled cross over study67 of 60 patients who had undergone external beam radiation therapy received sildenafil (50-100 mg) vs. placebo. Those receiving sildenafil had substantially higher scores of erectile satisfaction using the International Index of Erectile Function (IIEF) questionnaire. Overall, 45% of those on sildenafil compared to 8% on placebo (p < 0.001) responded favorably to an assessment of erectile improvement. Similar improvement in erectile dysfunction has been seen in patients receiving sildenafil following radioactive seed implantation.68
A double-blind, controlled study69 of 440 men who underwent nerve-sparing radical prostatectomy that compared 10 mg of vardenafil and 20 mg of vardenafil to placebo found response rates (as measured by improvement of quality of erections) in 59%, 65%, and 12.5%, respectively.
Other methods for managing erectile dysfunction and sexual satisfaction post radical prostatectomy include the use of penile prostheses implanted either after RP or simultaneously with RP. A study70 compared 51 men who had undergone simultaneous implantation of a penile prosthesis at the time of RP (PP+) to a group of 47 men who undergone RP alone (PP-) matched by age and year of surgery and a subgroup consisting of 15 patients who had undergone nerve-sparing RP. Though the sample size is small, the PP+ group had superior erectile dysfunction parameters and sexual satisfaction compared to the PP- patients, and comparable to the nerve-sparing group. The simultaneous implantation of a penile prosthesis may be appropriate in those men in whom an anatomic RP is not possible.
Other methods of improving sexual function and satisfaction post RP and radiation therapy include the use of vacuum devices and intracavernous injection or intraurethral insertions of prostaglandin preparations.
Urinary Incontinence. Post Radical Prostatectomy. The issue of urinary incontinence generally is more common in the first year post radical prostatectomy. In general, a small percentage of men (20%) will be continent immediately post-operatively; with 66% by six months, and 70-90% by one year. Thus any consideration for intervention (surgical or otherwise) for continence generally should wait for 12 months post-operatively. Non-operative approaches may include behavioral therapy, especially in those with an overactive bladder. Pharmacologic therapy in the form of anticholinergic therapies with or without alpha receptor blocker therapy may be useful.
The implantation of bulking agents, such as collagen (usually from a bovine source) injected to the area of the intrinsic sphincter, may be useful in selected patients. The use of artificial urinary sphincters, especially with better devices that deliver controlled pressures to the urethra, have gained popularity for the correctly selected patient. Detailed urodynamic testing and bladder evaluation are mandatory in optimizing patient selection and should be undertaken by specialists in continence restoration post prostatectomy. Less commonly used procedures utilize bulbourethral slings, employed in a fashion commonly used for females (vesicovaginal slings) with incontinence. Data are preliminary and worthy of further study. Penile clamps also may be used selectively.
Post Radiation Therapy. Incontinence in the post-irradiated patient (either EBRT or brachytherapy) or in the irradiated patient post RP poses challenging therapeutic situations. While the options are similar to those discussed in the post RP patient, reduced bladder capacity and urethral strictures may occur and complicate the selection of operative interventions. On occasion, bladder outlet surgery, which itself can exacerbate stress incontinence, may be required. The primary care physician should appreciate that the development of post-operative or post-radiation incontinence is one of the most distressing outcomes for patients, and there presently do not exist uniformly effective therapies.
What Are the Take-Home Points for the Primary Care Physician Dealing with the Effects of Treating Clinically Organ-Confined and Screen-Detected Prostate Cancers?
There are many important factors that the primary care physician should consider before ordering a screening PSA test. First, as emphasized both in Part I and Part II, there is no definitive evidence that screening, diagnosing, and treating an asymptomatic patient population for the presumed diagnosis of early prostate cancer leads to favorable survival outcomes compared to populations who do not undergo screening.
Part II has provided information, largely based upon the Gleason score, PSA, and clinical T stage, that can help predict outcomes of treatments and a rational approach to assessing risk of newly diagnosed patients. The listing of complications of treatment for clinically localized prostate cancer were extensively detailed, again to emphasize that issues of impotence, incontinence, proctitis, fecal dysfunction, and death are real possibilities that patients and their families may have to cope with following prostate cancer therapy. Helping the patient and his family assess this balanceof prostate cancer treatment and its efficacy with the real risks of treatmentis perhaps one of the most important functions a physician can provide for patients. It is hoped that this two-part series offers information that is useful in providing such advice and counseling to the patients served by primary care physicians. Additional resources are available through the American College of Physicians Physician Information and Educational Resource (PIER) site on Prostate Cancer Screening or publications of the American Foundation for Urologic Disease or the Prostate Cancer Foundation.
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Prostate cancer is one of the leading causes of cancer in men, both in this country and in Europe. Recognizing that the primary care physician often is the first health care professional who determines whether a PSA test is ordered and often is crucial in directing further follow-up relating to diagnosis and treatment selection, Part II will deal with important information regarding the choices for treating prostate cancer, and the side effects, efficacy, and quality-of-life issues that result from treatment.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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