|NCI/PDQ® Health professionals: Prostate Cancer Treatment (PDQ®)|
|National Cancer Institute|
| Last Modified: September 21, 2012
Estimated new cases and deaths from prostate cancer in the United States in 2012: 1
Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone. Because the median age at diagnosis is 72 years, many patientsespecially those with localized tumorsmay die of other illnesses without ever having suffered significant disability from the cancer. The approach to treatment is influenced by age and coexisting medical problems. Side effects of various forms of treatment should be considered in selecting appropriate management. Controversy exists in regard to the value of screening, the most appropriate staging evaluation, and the optimal treatment of each stage of the disease. 2
A complicating feature of any analysis of survival after treatment of prostate cancer and comparison of the various treatment strategies is the evidence of increasing diagnosis of nonlethal tumors as diagnostic methods have changed over time. Nonrandomized comparisons of treatments may be confounded not only by patient-selection factors but also by time trends. For example, a population-based study in Sweden showed that from 1960 to the late 1980s, before the use of prostate-specific antigen (PSA) for screening purposes, long-term relative survival rates after the diagnosis of prostate cancer improved substantially as more sensitive methods of diagnosis were introduced. This occurred despite the use of watchful waiting or palliative hormonal treatment as the most common treatment strategies for localized prostate cancer during the entire era (<150 radical prostatectomies per year were performed in Sweden during the late 1980s). The investigators estimated that if all cancers diagnosed between 1960 and 1964 were of the lethal variety, then at least 33% of cancers diagnosed between 1980 and 1984 were of the nonlethal variety. 3[Level of evidence: 3iB] With the advent of PSA screening, the ability to diagnose nonlethal prostate cancers may increase further. Another issue complicating comparisons of outcomes among nonconcurrent series of patients is the possibility of changes in criteria for histologic diagnosis of prostate cancer. 4 This phenomenon creates a statistical artifact that can produce a false sense of therapeutic accomplishment and may also lead to more aggressive therapy. For example, prostate biopsies from a population-based cohort of 1,858 men diagnosed with prostate cancer from 1990 through 1992 were re-read in 2002 to 2004. 5 6 The contemporary Gleason score readings were an average of 0.85 points higher (95% confidence interval [CI], 0.790.91; P <.001) than the same slides read in 1990 to 1992. As a result, Gleason score-standardized prostate cancer mortality for these men was artifactually improved from 2.08 to 1.50 deaths per 100 person yearsa 28% decrease even though overall outcomes were unchanged.
The issue of screening asymptomatic men for prostate cancer with digital rectal examination (DRE), PSA, and/or ultrasound (US) is controversial. 7 8 Serum PSA and transrectal US are more sensitive and will increase the diagnostic yield of prostate cancer when used in combination with rectal examination; however, these screening methods are also associated with high false-positive rates and may identify some tumors that will not threaten the patient's health. 9 10 11 12 The issue is further complicated by the morbidity associated with work-up and treatment of such tumors and the considerable cost beyond a routine DRE. Furthermore, because a high percentage of tumors identified by PSA screening alone have spread outside the prostate, PSA screening may not improve life expectancy. In any case, the clinician who uses PSA for the detection of prostate cancer should be aware that no uniform standard exists; if a laboratory changes to a different assay kit, serial assays may yield nonequivalent PSA values. 13 In addition, the upper limit of the normal range of PSA, and therefore the threshold at which to biopsy, is not well defined. 14 A multicenter trial (PLCO-1) that was sponsored by the National Cancer Institute was conducted to test the value of early detection in reducing mortality. (Refer to the PDQ® summary on Prostate Cancer Screening for more information.)
Survival of the patient with prostatic carcinoma is related to the extent of the tumor. When the cancer is confined to the prostate gland, median survival in excess of 5 years can be anticipated. Patients with locally advanced cancer are not usually curable, and a substantial fraction will eventually die of the tumor, though median survival may be as long as 5 years. If prostate cancer has spread to distant organs, current therapy will not cure it. Median survival is usually 1 to 3 years, and most such patients will die of prostate cancer. Even in this group of patients, however, indolent clinical courses lasting for many years may be observed.
Other factors affecting the prognosis of patients with prostate cancer that may be useful in making therapeutic decisions include histologic grade of the tumor, patient's age, other medical illnesses, and level of PSA. 15 16 17 18 19 Poorly differentiated tumors are more likely to have already metastasized by the time of diagnosis and are associated with a poorer prognosis. For patients treated with radiation therapy, the combination of clinical tumor stage, Gleason score, and pretreatment PSA level can be used to more accurately estimate the risk of relapse. 20[Level of evidence: 3iDii] In most studies, flow cytometry has shown that nuclear DNA ploidy is an independent prognostic indicator for progression and for cause-specific survival in patients with pathologic stages III and IV prostate cancer without metastases (Jewett stages C and D1). Diploid tumors have a more favorable outcome than either tetraploid or aneuploid tumors. The use of flow cytometry techniques and histogram analysis to determine prognosis will require standardization. 21 22 23 24
Often, baseline rates of PSA changes are thought to be markers of tumor progression. Even though a tumor marker or characteristic may be consistently associated with a high risk of prostate cancer progression or death, it may be a very poor predictor and therefore of very limited utility in making therapeutic decisions. For example, baseline PSA and rate of PSA change were associated with subsequent metastasis or prostate cancer death in a cohort of 267 men with clinically localized prostate cancer who were managed by watchful waiting in the control arm of a randomized trial comparing radical prostatectomy to watchful waiting. 25 26 Nevertheless, the accuracy of classifying men into groups whose cancer remained indolent versus those whose cancer progressed was poor at all examined cut points of PSA or PSA rate of change.
Several nomograms have been developed to predict outcomes either prior to 27 28 29 30 or after 31 32 radical prostatectomy with intent to cure. Preoperative nomograms are based on clinical stage, PSA, Gleason score, and the number of positive and negative prostate biopsy cores. One independently validated nomogram demonstrated increased accuracy in predicting biochemical recurrence-free survival by including preoperative plasma levels of transforming growth factor B1 and interleukin-6 soluble receptor. 33 34 Postoperative nomograms add pathologic findings, such as capsular invasion, surgical margins, seminal vesicle invasion, and lymph node involvement. The nomograms, however, were developed at academic centers and may not be as accurate when generalized to nonacademic hospitals, where the majority of patients are treated. 35 36 In addition, the nomograms use nonhealth (intermediate) outcomes such as PSA rise or pathologic surgical findings and subjective endpoints such as the physician's perceived need for additional therapy. In addition, the nomograms may be affected by changing methods of diagnosis or neoadjuvant therapy. 28
Definitive treatment is usually considered for younger men with prostate cancer and no major comorbid medical illnesses because younger men are more likely to die of prostate cancer than older men or men with major comorbid medical illness. Elevations of serum acid phosphatase are associated with poor prognosis in both localized and disseminated disease. PSA, an organ-specific marker with greater sensitivity and high specificity for prostate tissue, is often used as a tumor marker. 17 18 37 38 39 40 41 42 After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease; 39 however, a substantial proportion of patients with elevated or rising PSA levels after surgery may remain clinically free of symptoms for extended periods of time. 43 Biochemical evidence of failure on the basis of elevated or slowly rising PSA alone therefore may not be sufficient to alter treatment. For example, in a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA of 0.2 ng/mL or higher, which is evidence of biochemical recurrence. Of these 315 men, 103 men (34%) developed clinical evidence of recurrence. The median time to development of clinical metastasis after biochemical recurrence was 8 years. After the men developed metastatic disease, the median time to death was an additional 5 years. 44
After radiation therapy with curative intent, persistently elevated or rising PSA may be a prognostic factor for clinical disease recurrence; however, reported case series have used a variety of definitions of PSA failure. Criteria have been developed by the American Society for Therapeutic Radiology and Oncology Consensus Panel. 45 46 It is difficult to base decisions about instituting additional therapy on biochemical failure. The implication of the various definitions of PSA failure for overall survival (OS) is not known, and as in the surgical series, many biochemical relapses (rising PSA alone) may not be clinically manifested in patients treated with radiation therapy. 47 48
Using surrogate endpoints for clinical decision making is controversial. Preliminary data from a retrospective cohort of 8,669 patients with clinically localized prostate cancer treated with either radical prostatectomy or radiation therapy suggested that short posttreatment PSA doubling time (<3 months in this study) fulfills some criteria as a surrogate endpoint for all-cause mortality and prostate cancer mortality after surgery or radiation therapy. 49 Likewise, a retrospective analysis has shown that PSA declines of 20% to 40% (but not 50%) at 3 months and 30% or more at 2 months after initiation of chemotherapy for hormone-independent prostate cancer, fulfilled several criteria of surrogacy for OS. 50 These observations should be independently confirmed in prospective study designs and may not apply to patients treated with hormonal therapy. In addition, there are no standardized criteria of surrogacy or standardized cutpoints for adequacy of surrogate endpoints, even in prospective trials. 51
After hormonal therapy, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status; 17 however, decreases in PSA of less than 80% may not be very predictive. 17 Yet, because PSA expression itself is under hormonal control, androgen-deprivation therapy can decrease the serum level of PSA independent of tumor response. Clinicians, therefore, cannot rely solely on the serum PSA level to monitor a patient's response to hormone therapy; they must also follow clinical criteria. 52
More than 95% of primary prostate cancers are adenocarcinomas, and this discussion is confined to patients with this diagnosis. In general, the degree of tumor differentiation and abnormality of histologic growth pattern directly correlate with the likelihood of metastases and with death. Because of marked variability in tumor differentiation from one microscopic field to another, many pathologists will report the range of differentiation among the malignant cells that are present in a biopsy (Gleason grade). 1 2
When the cytopathologist is experienced in the technique, and the specimen is adequate for analysis, fine-needle aspiration of the prostate (usually performed transrectally) has been shown to have an accuracy of diagnosis equal to that of traditional core-needle biopsy. 3 Fine-needle aspiration is less painful than core biopsy and, therefore, can be performed as an outpatient procedure and at periodic intervals for serial follow-up. Controversy exists as to whether it is as reliable for grading purposes, particularly with grade range apparent in different fields. 4 Many urologists now use a bioptic gun with ultrasound (US) guidance, which is relatively painless. The risk of complications with this technique is low. A transperineal, US-guided approach can be used in those patients who may be at increased risk of complications through a transrectal approach. 5 In a series of 670 men undergoing biopsy with an 18-gauge needle, the complication rate was 2% with only 4 patients requiring hospitalization. 6
Detection of asymptomatic metastatic disease in prostate cancer is greatly affected by the staging tests performed. Radionuclide bone scans are currently the most widely used tests for metastases to the bone, which is the most common site of distant tumor spread. Magnetic resonance imaging (MRI) is more sensitive than radionuclide bone scans but is impractical for evaluating the entire skeletal system. Some evidence suggests that serum prostate-specific antigen (PSA) levels can predict the results of radionuclide bone scan in newly diagnosed patients. In one series, only 2 of 852 patients (0.23%) with a PSA of less than 20 g/L had a positive bone scan in the absence of bone pain. 1 In another series of 265 prostate cancer patients, 0 of 23 patients with a PSA of less than 4 ¼g/L had a positive bone scan, and 2 of 114 patients with a PSA of less than 10 AMBERSANDCHAR188;g/L had a positive bone scan. 2 Prognosis is worse in patients with pelvic lymph node involvement.
Whether to subject all patients to a pelvic lymph node dissection (PLND) is debatable, but in patients undergoing a radical retropubic prostatectomy, the nodal status is ascertained as a matter of course. In patients who are undergoing a radical perineal prostatectomy in whom the PSA value is less than 20 and the Gleason sum is low, however, evidence is mounting that a PLND is probably unnecessary, especially in patients whose malignancy was not palpable but detected on ultrasound (US). 3 4 A PLND remains the most accurate method to assess metastases to pelvic nodes, and laparoscopic PLND has been shown to accurately assess pelvic nodes as effectively as an open procedure. 5 The exact role of PLND in diagnosis and subsequent treatment is being evaluated, though it has already been determined that the length of hospital stay following laparoscopic PLND is shorter than that following an open procedure. The determining factor when deciding if any type of PLND is indicated is whether definitive therapy may be altered. Likewise, preoperative seminal vesicle biopsy may be useful in patients with palpable nodules who are being considered for radical prostatectomy (unless they have a low Gleason score) because seminal vesicle involvement could affect choice of primary therapy and predicts for pelvic lymph node metastasis. 6
In patients with clinically localized (stage I or stage II) prostate cancer, Gleason pathologic grade and enzymatic serum prostatic acid phosphatase values (even within normal range) predict the likelihood of capsular penetration, seminal vesicle invasion, or regional lymph node involvement. 3 Analysis of a series of 166 patients with clinical stage I and stage II prostate cancer undergoing radical prostatectomy revealed an association between Gleason biopsy score and the risk of lymph node metastasis found at surgery. The risks of node metastasis for patients grouped according to their Gleason biopsy score was 2%, 13%, and 23% for Gleason scores of 5, 6, and 8, respectively. 7
Transrectal US (TRUS) may facilitate diagnosis by directing needle biopsy; however, US is operator dependent and does not assess lymph node size. Moreover, a prospective, multi-institutional study of preoperative TRUS in men with clinically localized prostate cancer felt to be eligible for radical prostatectomy showed that TRUS was no better than digital rectal examination in predicting extracapsular tumor extension or seminal vesicle involvement. 8 Computed tomography (CT) can detect grossly enlarged nodes but poorly defines intraprostatic features; 9 therefore, it is not reliable for the staging of pelvic node disease when compared to surgical staging. 10 Although MRI has been used to detect extracapsular extension of prostate cancer, a positive-predictive value of about 70% and considerable interobserver variation are problems that make its routine use in staging uncertain. 11 US and MRI, however, can reduce clinical understaging and improve patient selection for local therapy. Preliminary data with the endorectal MRI coil for prostate imaging report the highest sensitivity and specificity for identification of organ-confined and extracapsular disease. 3 12 13 MRI is a poor tool for evaluating nodal disease.
Two systems are in common use for the staging of prostate cancer. The Jewett system (stages A through D) was described in 1975 and has since been modified. 14 In 1997, the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer adopted a revised tumor, nodes, metastasis (TNM) system that employs the same broad T stage categories as the Jewett system but includes subcategories of T stage, such as a stage to describe patients diagnosed through PSA screening. This revised TNM system is clinically useful and more precisely stratifies newly diagnosed patients. The AJCC further revised the TNM classification system in 2002 and, most recently, in 2010. 15 Both staging systems are shown below, and both are used in this summary to discuss treatment options. A thorough review of the controversies of staging in prostate cancer has been published. 16
The AJCC has designated staging by TNM classification to define prostate cancer. 15