The results from several large double-blind, randomized chemoprevention trials have established 5α-reductase inhibitors (5ARI) as the predominant therapy to reduce the future risk of a prostate cancer diagnosis. The Prostate Cancer Prevention Trial (PCPT), in which men older than age 55 years received the 5α-reductase inhibitor finasteride, which inhibits the type 1 isoform, or a placebo, showed a 25% (95% confidence interval 19–31%) reduction in the period prevalence of prostate cancer across all age groups in favor of finasteride (18.4%) over placebo (24.4%). In REDUCE (Reduction by Dutasteride of Prostate Cancer Events Trial), a similar 23% reduction in the 4-year period prevalence was observed in favor of dutasteride (p = 0.001). Dutasteride inhibits both the type 1 and type 2 5ARI isoforms. These results contrast with those of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) in which African American men aged ≥50 years and others aged ≥55 years were enrolled, which showed no difference in cancer incidence in patients receiving vitamin E (4.6%) or selenium (4.9%) alone or in combination (4.6%) relative to placebo (4.4%). A similar lack of benefit for vitamin E, vitamin C, and selenium was seen in the Physicians Health Study II.
The need to pursue a diagnosis of prostate cancer is based on symptoms, an abnormal DRE, or, more typically, a change in or an elevated serum PSA. The urologic history should focus on symptoms of outlet obstruction, continence, potency, or change in ejaculatory pattern.
The DRE focuses on prostate size and consistency and abnormalities within or beyond the gland. Many cancers occur in the peripheral zone and can be palpated on DRE. Carcinomas are characteristically hard, nodular, and irregular, while induration may also be due to benign prostatic hypertrophy (BPH) or calculi. Overall, 20–25% of men with an abnormal DRE have cancer.
PSA (kallikrein-related peptidase 3; KLK3) is a kallikrein-related serine protease that causes liquefaction of seminal coagulum. It is produced by both nonmalignant and malignantepithelial cells and, as such, is prostate-specific, not prostate cancer–specific, and serum levels may also increase from prostatitis and BPH. Serum levels are not affected by DRE but the performance of a prostate biopsy can increase PSA levels up to tenfold for 8–10 weeks. PSA circulating in the blood is inactive and mainly occurs as a complex with the protease inhibitor α1-antichymotrypsin SERPIN A3 and as free unbound PSA forms. The formation of complexes between PSA, α2-macroglobulin, or other protease inhibitors is less significant. Free PSA is rapidly eliminated from the blood by glomerular filtration with an estimated half-life of 12-18 hours. Elimination of PSA bound to α1-antichymotrypsin is slow (estimated half-life of 1-2 weeks) as it is too large to be cleared by the kidneys. Levels should be undetectable after about six weeks if the prostate has been removed. Immunohistochemical staining for PSA can be used to establish a prostate cancer diagnosis.
PSA testing was approved by the U.S. FDA in 1994 for early detection of prostate cancer, and the widespread use of the test has played a significant role in the proportion of men diagnosed with early-stage cancers: more than 70–80% of newly diagnosed cancers are organ confined. The level of PSA in blood is strongly associated with the risk and outcome of prostate cancer. A single PSA measured at age 60 is associated (AUC of 0.90) with lifetime risk of death from prostate cancer. Most (90%) prostate cancer deaths occur among men with PSA levels in top quartile (>2 ng/mL), although only a minority of men with PSA >2 ng/mL will develop lethal prostate cancer. Despite this and mortality rate reductions reported from large randomized prostate cancer screening trials, routine use of the test remains controversial. The American Cancer Society (ACS) recommends that physicians offer PSA testing and a DRE on an annual basis for men older than age 50 years with an anticipated survival of >10 years; this includes men up to age 76 years. For African Americans and men with a family history of prostate cancer, testing is advised to begin at age 45 years. The American Urologic Association recommendations are similar, with the proviso that the risks and benefits of the performance of these tests are not defined. The American College of Physicians recommends that physicians "describe the potential benefits and known harms of screening" and to "individualize the decision to screen." The National Comprehensive Cancer Network (NCCN) guidelines mirror those of the ACS, with the proviso that "physicians and potential participants must thoroughly discuss the pros and cons of screening." The NCCN also advises that men who opt to participate obtain a baseline PSA and DRE in their values and use the value to stratify future risk. As PSA values may fluctuate for no apparent reason, it is advised that isolated abnormal values should be confirmed before proceeding with further testing.
The PSA criteria used to recommend a diagnostic prostate biopsy have evolved over time. However, based on the commonly used outpoint for prostate biopsy CPSA4 mg/mL, most men with a PSA elevation do not have histologic widence of prostate cancer at biopsy, and commonly, many men with PSA levels below this cut point harbor cancer cells in their prostate. The goal is to increase the sensitivity of the test for younger men more likely to die of the disease and to reduce the frequency of detecting cancers of low malignant potential in elderly men more likely to die of other causes. Previously, the threshold for performance of a biopsy was 4.0 ng/mL, which has been reduced to 3 mg/mL or 2.6 ng/mL for men aged <60 years by many groups based on the finding that nearly half of the men with PSAs who reached this level increased to 4 ng/mL within a relatively short (4-year) time frame and that, once diagnosed, in nearly one-third it had spread beyond the confines of the gland.
Most PSA is complexed to α1-antichymotrypsin (ACT); only a small percentage is "free," and lower in men with cancer. Free and complexed PSA measurements are used when levels are between 4 and 10 ng/mL to decide whether a biopsy is needed. The risk of cancer is under 10% if the free PSA is >25% but as high as 56% for those with a free PSA <10%. PSA density (PSAD) measurements were developed to correct for the contribution of BPH to the total PSA level. PSAD is calculated by dividing the serum PSA by the prostate weight estimated from transrectal ultrasound (TRUS). Values <0.10 ng/mL per cm3 are consistent with BPH, while those >0.15 ng/mL per cm3 suggest cancer. PSA dynamics is the rate of change in PSA levels over time and is expressed most commonly as the PSA velocity or PSA doubling time. It is particularly useful for men with seemingly normal values that are rising. For men with a PSA level higher than 4 ng/mL, rates of rise >0.75 ng/mL per year suggest cancer, while for those with lower PSA levels, rates >0.5 ng/mL per year should be used to advise a biopsy. As an example, an increase from 2.5 to 3.2 ng/mL in a 1-year period would warrant further testing.
PSA-based detection strategies have changed the clinical spectrum of the disease. Now, 95–99% of newly diagnosed cancers are clinically localized, 40% are not palpable, and of these, 70% are pathologically organ-confined. However, the benefits of PSA screening remain controversial due to the overdetection of cancers with low malignant potential that may lead to overtreatment and unnecessary morbidity. To this end, the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial found no mortality benefit from combined PSA screening and DRE in 76,693 randomized men (annual exam vs. standard care) with a median follow-up of 11 years. However, important caveats about the PLCO study include (1) many screening participants had already undergone PSA screening before the trial; (2) contamination from PSA testing among controls increased from 40% in year one to 52% in year six and; (3) and the biopsycompliance was low. These factors make interpretation difficult. A subgroup analysis of this trial showed a reduction in cancer mortality among screened men with little or no comorbidity. The European Randomized Study of Screening for Prostate Cancer (ERSPC) trial followed 182,000 men a median of 9 years randomized either to PSA screening every 4 years or to a group not receiving regular PSA screening. In this study, PSA screening without DRE corresponded to a 20% relative reduction of the rate of death from prostate cancer. A report from the Swedish subgroup of this study based on 14 years follow-up suggested that PSA screening may reduce cancer-specific mortality by nearly half with less overdiagnosis and treatment than was noted in the European Study as a whole. Men remain advised to make an informed decision on an individual basis about whether to undergo testing.
A diagnostic algorithm based on the DRE and PSA findings is illustrated in Fig. 95-2. In general, a biopsy is recommended if the DRE or PSA is abnormal. Twenty-five percent of men with a PSA >4 ng/mL and an abnormal DRE have cancer, as do 17% of men with a PSA of 2.5–4 ng/mL and normal DRE.
Algorithm for diagnostic evaluation of men based on digital rectal examination (DRE) and prostate-specific antigen (PSA) levels; TRUS, transrectal ultrasound.
A diagnosis of cancer is established by a TRUS-guided needle biopsy. Direct visualization by ultrasound or MRI assures that all areas of the gland are sampled. A minimum of six separate cores, three from the right and three from the left, is advised, as is a separate biopsy of the transition zone if clinically indicated. Contemporary schemas advise an extended-pattern 12- to 14-core biopsy that includes the sextant sampling above plus 6 cores from the lateral peripheral zones as well as a lesion-directed palpable nodule or suspicious image-guided sampling. Patients with prostatitis should have a course of antibiotics before biopsy. Men with an abnormal PSA and negative biopsy are advised to undergo a repeat biopsy.
Each core of the biopsy is examined for the presence of cancer, and the amount of cancer is quantified based on the length of the tumor within the core and the percentage of the core involved.
The noninvasive proliferation of epithelial cells within ducts is termed prostatic intraepithelial neoplasia. PIN is a precursor of cancer, but not all PIN lesions develop into invasive cancers. Of the cancers identified, >95% are adenocarcinomas; the rest are squamous or transitional cell tumors or, rarely, carcinosarcomas. Metastases to the prostate are rare, but in some cases colon cancers or transitional cell tumors of the bladder invade the gland by direct extension.
When prostate cancer is diagnosed, a measure of histologic aggressiveness is assigned using the Gleason grading system, in which the dominant and secondary glandular histologic patterns are scored from 1 (well-differentiated) to 5 (undifferentiated) and summed to give a total score of 2–10 for each tumor. The most poorly differentiated area of tumor (i.e., the area with the highest histologic grade) often determines biologic behavior. The presence or absence of perineural invasion and extracapsular spread are also recorded.
The TNM staging system includes categories for cancers that are palpable on DRE, those identified solely on the basis of an abnormal PSA (T1c), those that are palpable but clinically confined to the gland (T2), and those that have extended outside the gland (T3 and T4) (Table 95–1, Fig. 95-3). DRE alone is inaccurate in determining the extent of disease within the gland, the presence or absence of capsular invasion, involvement of seminal vesicles, and extension of disease to lymph nodes. Because of the inadequacy of DRE for staging, the TNM staging system was modified to include the results of imaging. Unfortunately, no single test has proven to accurately indicate the stage or the presence of organ-confined disease, seminal vesicle involvement, or lymph node spread.
Table 95-1 TNM Classification |Favorite Table|Download (.pdf)
Table 95-1 TNM Classification
|TNM Staging System for Prostate Cancera|
|Tx||Primary tumor cannot be assessed|
|T0||No evidence of primary tumor|
|T1||Clinically inapparent tumor, neither palpable nor visible by imaging|
|T1a||Tumor incidental histologic finding in ≤5% of resected tissue; not palpable|
|T1b||Tumor incidental histologic finding in >5% of resected tissue|
|T1c||Tumor identified by needle biopsy (e.g., because of elevated PSA)|
|T2||Tumor confined within prostateb|
|T2a||Tumor involves half of one lobe or less|
|T2b||Tumor involves more than one half of one lobe, not both lobes|
|T2c||Tumor involves both lobes|
|T3||Tumor extends through the prostate capsulec|
|T3a||Extracapsular extension (unilateral or bilateral)|
|T3b||Tumor invades seminal vesicles(s)|
|T4||Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall.|
|N1||Positive regional lymph nodes|
T stages of prostate cancer. (A) T1—Clinically inapparent tumor, neither palpable nor visible by imaging; (B) T2—Tumor confined within prostate; (C) T3—Tumor extends through prostate capsule and may invade the seminal vesicles; (D) T4—Tumor is fixed or invades adjacent structures. Eighty percent of patients present with local disease (T1 and T2), which is associated with a 5-year survival rate of 100%. An additional 12% of patients present with regional disease (T3 and T4 without metastases), which is also associated with a 100% survival rate after 5 years. Four percent of patients present with distant disease (T4 with metastases), which is associated with a 30% 5-year survival rate. (Three percent of patients are ungraded.) (Data from AJCC, http://seer.cancer.gov/statfacts/html/prost.html. Figure © Memorial Sloan-Kettering Cancer Center Medical Graphics; used with permission.)
TRUS is the imaging technique most frequently used to assess the primary tumor, but its chief use is directing prostate biopsies, not staging. No TRUS finding consistently indicates cancer with certainty. CT lacks sensitivity and specificity to detect extraprostatic extension and is inferior to MRI in visualization of lymph nodes. In general, MRI performed with an endorectal coil is superior to CT to detect cancer in the prostate and to assess local disease extent. T1-weighted images produce a high signal in the periprostatic fat, periprostatic venous plexus, perivesicular tissues, lymph nodes, and bone marrow. T2-weighted images demonstrate the internal architecture of the prostate and seminal vesicles. Most cancers have a low signal, while the normal peripheral zone has a high signal, although the technique lacks sensitivity and specificity. MRI is also useful for the planning of surgery and radiation therapy.
Radionuclide bone scans (bone scintigraphy) are used to evaluate spread to osseous sites. This test is sensitive but relatively nonspecific because areas of increased uptake are not always related to metastatic disease. Healing fractures, arthritis, Paget's disease, and other conditions will also cause abnormal uptake. True-positive bone scans are rare if the PSA is <8 ng/mL and uncommon when the PSA is <10 ng/mL unless the tumor is high-grade.
Treatment: Prostate Cancer
Clinically Localized Disease
Localized prostate cancers are those that appear to be nonmetastatic after staging studies are performed. Patients with localized disease are managed by radical prostatectomy, radiation therapy, or active surveillance. Choice of therapy requires the consideration of several factors: the presence of symptoms, the probability that the untreated tumor will adversely affect the quality or duration of survival and thus require treatment, and the probability that the tumor can be cured by single-modality therapy directed at the prostate or requires both local and systemic therapy to achieve cure. As most of the tumors detected are deemed clinically significant, most men undergo treatment.
Data from the literature do not provide clear evidence for the superiority of any one treatment relative to another. Comparison of outcomes of various forms of therapy is limited by the lack of prospective trials, referral bias, the experience of the treating teams and differences in endpoints and cancer control definitions. Often, PSA relapse–free survival is used because an effect on metastatic progression or survival may not be apparent for years. After radical surgery to remove all prostate tissue, PSA should become undetectable in the blood within 4 weeks, based on the PSA half-life in the blood of 3 days. If PSA remains detectable, the patient is considered to have persistent disease. After radiation therapy, in contrast, PSA does not become undetectable because the remaining nonmalignant elements of the gland continue to produce PSA even if all cancer cells have been eliminated. Similarly, cancer control is not well defined for a patient managed by active surveillance because PSA levels will continue to rise in the absence of therapy. Other outcomes are time to objective progression (local or systemic) and cancer-specific and overall survival; however, these outcomes may take years to assess.
The more advanced the disease, the lower the probability of local control and the higher the probability of systemic relapse. More important is that within the categories of T1, T2, and T3 disease are tumors with a range of prognoses. Some T3 tumors are curable with therapy directed solely at the prostate, and some T1 lesions have a high probability of systemic relapse that requires the integration of local and systemic therapy to achieve cure. For T1c tumors in particular, stage alone is inadequate to predict outcome and select treatment; other factors must be considered.
To better assess risk and guide treatment selection, many groups have developed prognostic models or nomograms that use a combination of the initial T stage, Gleason score, and baseline PSA. Some use discrete cut points (PSA <10 or ≥10 ng/mL; Gleason score of ≤6, 7, or ≥8); others employ nomograms that use PSA and Gleason score as continuous variables. More than 100 nomograms have been reported to predict the probability that a clinically significant cancer is present, disease extent (organ-confined vs. non–organ-confined, node-negative or -positive), or the probability of success of treatment for specific local therapies using pretreatment variables. Considerable controversy exists over what constitutes "high risk" based on a predicted probability of success or failure. In these situations, nomograms and predictive models can only go so far. Exactly what probability of success or failure would lead a physician to recommend and a patient to seek alternative approaches is controversial. As an example, it may be appropriate to recommend radical surgery for a younger patient with a low probability of cure. Nomograms are being refined continually to incorporate additional clinical parameters, biologic determinants, and year of treatment, which can also affect outcomes, making treatment decisions a dynamic process.
The frequency of adverse events varies by treatment modality and the experience of the treating team. For example, following radical prostatectomy, incontinence rates range from 2 to 47% and impotence rates range from 25 to 89%. Part of the variability relates to how the complication is defined and whether the patient or physician is reporting the event. The time of the assessment is also important. After surgery, impotence is immediate but may reverse over time, while with radiation therapy impotence is not immediate but may develop over time. Of greatest concern to patients are the effects on continence, sexual potency, and bowel function.
The goal of radical prostatectomy is to excise the cancer completely with a clear margin, to maintain continence by preserving the external sphincter, and to preserve potency by sparing the autonomic nerves in the neurovascular bundle. The procedure is advised for patients with a life expectancy of 10 years or more and is performed via a retropubic or perineal approach, or via a minimally invasive robotic-assisted or hand-held laparoscopic approach. Outcomes can be predicted using postoperative nomograms that consider pretreatment factors and the pathologic findings at surgery, with PSA failure defined generally as a value greater than 0.2 or 0.4 ng/mL. Specific criteria to guide the choice of one approach over another are lacking. Minimally invasive approaches offer the advantage of a shorter hospital stay and a more rapid recovery with the trade-off of higher rates of incontinence and erectile dysfunction. Cancer control rates are comparable.
Neoadjuvant hormonal therapy has also been explored in an attempt to improve the outcomes of surgery for high-risk patients using a variety of definitions. The results of several large trials testing 3 or 8 months of androgen depletion before surgery showed that serum PSA levels decreased by 96%, prostate volumes decreased by 34%, and margin positivity rates decreased from 41 to 17%. Unfortunately, hormones did not produce an improvement in PSA relapse–free survival. Thus, neoadjuvant hormonal therapy is not recommended.
Factors associated with incontinence include older age and urethral length, which impacts the ability to preserve the urethra beyond the apex and the distal sphincter. The specific surgical technique, open vs. laparoscopic vs. robotic, as well as the skill and experience of the surgeon are also factors. In a series treated at an academic center, 6% of patients had mild stress urinary incontinence (SUI) (requiring 1 pad/day), 2% moderate SUI (>1 pad/day), and 0.3% severe SUI (requiring an artificial urinary sphincter). At 1 year, 92% were completely continent. In contrast, the results in a Medicare population treated at multiple centers showed that at 3, 12, and 24 months following surgery, 58, 35, and 42%, respectively, wore pads in their underwear, and 24, 11, and 15% reported "a lot" of urine leakage.
Recovery of erectile function is associated with younger age, quality of erections before surgery, and the absence of damage to the neurovascular bundles. In general, erectile function begins to return in a median of 4–6 months if both bundles are preserved. Potency is reduced by half if at least one nerve bundle is sacrificed. In cases where cancer control requires the removal of both bundles, sural nerve grafts have shown no utility. Overall, with the availability of drugs such as sildenafil, intraurethral inserts of alprostadil, and intracavernosal injections of vasodilators, many patients recover satisfactory sexual function.
Radiation therapy is given by external beam, by radioactive sources implanted into the gland, or by a combination of the two techniques.
External Beam Radiation Therapy
Contemporary external beam radiation therapy requires three-dimensional conformal treatment plans intensity-modulated radiation therapy (IMRT) to maximize the dose to the prostate and to minimize the exposure of the surrounding normal tissue. IMRT permits shaping of the dose, and allows the delivery of higher doses to the prostate and a further reduction in normal tissue exposure than 3D-conformal treatment alone. These advances have enabled the safe administration of doses >80 Gy, higher local control rates, and fewer side effects.
Cancer control after radiation therapy has been defined by various criteria, including a decline in PSA to <0.5 or 1 ng/mL, "nonrising" PSA values, and a negative biopsy of the prostate 2 years after completion of treatment. The current standard definition of biochemical failure (the Phoenix definition) is a rise in PSA by ≥2 ng/mL higher than the lowest PSA achieved. The date of failure is "at call" and not backdated.
Radiation dose is important and a minimum of 75.6 to 79 or 80 Gy advised. In a representative study, a PSA nadir of <1.0 ng/mL in 90% of patients receiving 75.6 or 81.0 Gy vs. 76% and 56% of those receiving 70.2 and 64.8 Gy, and positive biopsy rates at 2.5 years were 4% for those treated with 81 Gy vs. 27 and 36% for those receiving 75.6 or 70.2 Gy.
Overall, radiation therapy is associated with a higher frequency of bowel complications (mainly diarrhea and proctitis) than surgery. The frequency relates directly to the volume of the anterior rectal wall receiving full-dose treatment. In one series, Grade 3 rectal or urinary toxicities were seen in 2.1% of patients who received a median dose of 75.6 Gy, while Grade 3 urethral strictures requiring dilatation developed in 1% of cases, all of whom had undergone a transurethral resection of the prostate (TURP). Pooled data show that the frequency of Grade 3 and 4 toxicities is 6.9 and 3.5%, respectively, for patients who received >70 Gy. The frequency of erectile dysfunction is related to the quality of erections pretreatment, the dose administered, and the time of assessment. Postradiation erectile dysfunction is related to a disruption of the vascular supply and not the nerve fibers.
Neoadjuvant hormone therapy before radiation therapy has been studied. The aim is to decrease the size of the prostate and, consequently, to reduce the exposure of normal tissues to full-dose radiation, to increase local control rates, and to decrease the rate of systemic failure. Short-term hormone therapy can reduce toxicities and improve local control rates, but long-term treatment (2–3 years) is needed to prolong the time to PSA failure and lower the risk of metastatic disease. The impact on survival has been less clear. The decision to treat the pelvic lymph nodes is based on the nomogram-predicted risk of nodal spread.
Brachytherapy is the direct implantation of radioactive sources (seeds) into the prostate. It is based on the principle that the deposition of radiation energy in tissues decreases as a function of the square of the distance from the source (Chap. 85). The goal is to deliver intensive irradiation to the prostate, minimizing the exposure of the surrounding tissues. The current standard technique achieves a more homogeneous dose distribution by placing seeds according to a customized template based on CT and ultrasonographic assessment of the tumor and computer-optimized dosimetry. The implantation is performed transperineally as a one-day procedure with real-time imaging.
Improvements in brachytherapy techniques have resulted in fewer complications and a marked reduction in local failure rates. In a series of 197 patients followed for a median of 3 years, 5-year actuarial PSA relapse–free survival for patients with pretherapy PSA levels of 0–4, 4–10, and >10 ng/mL were 98, 90, and 89%, respectively. In a separate report of 201 patients who underwent posttreatment biopsies, 80% were negative, 17% were indeterminate, and 3% were positive. The results did not change with longer follow-up. Nevertheless, many physicians feel that implantation is best reserved for patients with good or intermediate prognostic features.
Brachytherapy is well tolerated, although most patients experience urinary frequency and urgency that can persist for several months. Incontinence has been seen in 2–4% of cases. Higher complication rates are observed in patients who have undergone a prior TURP, while those with obstructive symptoms at baseline are at a higher risk for retention and persistent voiding symptoms. Proctitis has been reported in <2% of patients.
While prostate cancer is the most common form of cancer affecting men in the United States, patients are being diagnosed earlier and more frequently present with early-stage disease. Active surveillance, described previously as watchful waiting or deferred therapy, is the policy of monitoring the illness at fixed intervals with DREs, PSA measurements, and repeat prostate biopsies as indicated until histopathologic or serologic changes correlative of progression warrant treatment with curative intent. It evolved from studies that evaluated predominantly elderly men with well-differentiated tumors who demonstrated no clinically significant progression for protracted periods, recognition of the contrast between incidence and disease-specific mortality, the high prevalence of autopsy cancers and an effort to reduce overtreatment. A recent screening study estimated that between 50 and 100 men with low-risk disease would need to be treated to prevent one prostate cancer–specific death.
Arguing against active surveillance are the results of a Swedish randomized trial of radical prostatectomy vs. active surveillance. With a median follow-up of 6.2 years, men treated by radical surgery had a lower risk of prostate cancer death relative to active surveillance patients (4.6 vs. 8.9%) and a lower risk of metastatic progression (hazard ratio 0.63). Case selection is critical, and determining clinical parameters predictive of cancer aggressiveness that can be used to reliably select men most likely to benefit from active surveillance is an area of intense study. In one prostatectomy series, it was estimated that 10–15% of those treated had "insignificant" disease. One set of criteria includes men with T1c tumors that are Gleason grade 6 or less involving 3 or fewer cores, each of them having less than 50% involvement by tumor and a PSAD of 0.15.
Concerns include the limited ability to predict pathologic findings by needle biopsy even when multiple cores are obtained, the recognized multifocality of the disease, and the possibility of a missed opportunity to cure the disease. Nomograms to help predict which patients can safely be managed by active surveillance continue to be refined, and as their predictive accuracy improves, it can be anticipated that more patients will be candidates.
This state consists of patients in whom the sole manifestation of disease is a rising PSA after surgery and/or radiation therapy. By definition, there is no evidence of disease on scan. For these patients, the central issue is whether the rise in PSA results from persistent disease in the primary site, systemic disease, or both. In theory, disease in the primary site may still be curable by additional local treatment: external beam radiation for patients who had undergone surgery and prostatectomy for patients who had undergone radiation therapy.
The decision to recommend radiation therapy after prostatectomy is guided by the pathologic findings at surgery, as imaging studies such as CT and bone scan are typically uninformative. Some recommend a Prostascint scan—imaging with a radiolabeled antibody to prostate-specific membrane antigen (PSMA), which is highly expressed on prostate epithelial cells—to help with this distinction. Antibody localization to the prostatic fossa suggests local recurrence; localization to extrapelvic sites predicts failure of radiation therapy. Others recommend that a biopsy of the urethrovesical anastomosis be obtained before considering radiation. Factors that predict for response to salvage radiation therapy are a positive surgical margin, lower Gleason grade, long interval from surgery to PSA failure, slow PSA doubling time, and low (<0.5–1 ng/mL) PSA value at the time of radiation treatment. Radiation therapy is generally not recommended if the PSA was persistently elevated after surgery, which usually indicates that the disease had spread outside of the area of the prostate bed and is unlikely to be controlled with radiation therapy. As is the case for other disease states, nomograms to predict the likelihood of success are also available.
For patients with a rising PSA after radiation therapy, salvage prostatectomy can be considered if the disease was "curable" at the outset, if persistent disease has been documented by a biopsy of the prostate, and if no metastatic disease is seen on imaging studies. Unfortunately, case selection is poorly defined in most series, and morbidities are significant. As currently performed, virtually all patients are impotent after salvage radical prostatectomy, and approximately 45% have either total urinary incontinence or stress incontinence. Major bleeding, bladder neck contractures, and rectal injury are not uncommon.
More frequently, the rise in PSA after surgery or radiation therapy indicates subclinical or micrometastatic disease. In these cases, the need for treatment depends, in part, on the estimated probability that the patient will show evidence of metastatic disease on a scan and in what time frame. That immediate therapy is not always required was shown in a series where patients received no systemic therapy until metastatic disease was documented. Overall, the median time to metastatic progression was 8 years, and 63% of the patients with rising PSA values remained free of metastases at 5 years. Factors associated with progression included the primary tumor's Gleason grade, time to recurrence, and PSA doubling time. For those with Gleason grade ≥8 tumors, the probability of metastatic progression was 37, 51, and 71% at 3, 5, and 7 years, respectively. If the time to recurrence was <2 years and PSA doubling time was long (>10 months), the proportion with metastatic disease at the same time intervals was 23, 32, and 53%, vs. 47, 69, and 79% if the doubling time was short (<10 months). PSA doubling times are also prognostic for survival. In one series, all patients who succumbed to disease had PSA doubling times of 3 months or less. Most physicians advise treatment when PSA doubling times are 12 months or less. A difficulty with predicting the risk of metastatic spread, symptoms, or death from disease in the rising PSA state is that most patients receive some form of therapy before the development of metastases. Nevertheless, predictive models continue to be refined.
Metastatic Disease: Noncastrate
The state of noncastrate metastatic disease includes men with metastases visible on an imaging study and noncastrate levels of testosterone (>150 ng/dL). The patient may be newly diagnosed or have a recurrence after treatment for localized disease. Symptoms of metastatic disease include pain from osseous spread, although many patients are asymptomatic despite extensive spread. Less common are symptoms related to marrow compromise (myelophthisis), coagulopathy, or spinal cord compression.
Standard treatment is to deplete/lower androgens by medical or surgical means and/or to block androgen binding to the AR with antiandrogens. More than 90% of male hormones originate in the testes; <10% are synthesized in the adrenal gland. Surgical orchiectomy is the "gold standard" but is least acceptable to patients (Fig. 95-4).
Sites of action of different hormone therapies.
Medical therapies that lower testosterone levels include the gonadotropin-releasing hormone (GnRH) agonists/antagonists, 17,20-lyase inhibitors, cyp-17 inhibitors, estrogens, and progestational agents. Estrogens such as diethylstilbestrol (DES) have fallen out of favor due to the risk of vascular complications such as fluid retention, phlebitis, emboli, and stroke. GnRH analogues (leuprolide acetate and goserelin acetate) initially produce a rise in luteinizing hormone and follicle-stimulating hormone followed by a downregulation of receptors in the pituitary gland, which effects a chemical castration. They were approved on the basis of randomized comparisons showing an improved safety profile (specifically, reduced cardiovascular toxicities) relative to DES, with equivalent potency. The initial rise in testosterone may result in a clinical flare of the disease. These agents are therefore contraindicated in men with significant obstructive symptoms, cancer-related pain, or spinal cord compromise. GnRH antagonists such as degarelix achieve castrate levels of testosterone within 48 hours without the initial rise in serum testosterone.
Agents that lower testosterone are associated with an androgen-depletion syndrome that includes hot flushes, weakness, fatigue, impotence, sarcopenia, anemia, change in personality, and depression. Changes in lipids, obesity, insulin resistance, along with an increased risk of diabetes and cardiovascular disease can also occur. A decrease in bone density can also occur that worsens over time and results in an increase risk of clinical fractures. This is a particular concern in men with preexisting osteopenia that results from hypogonadism, steroid or alcohol use, and which is significantly underappreciated. Baseline fracture risk can be assessed using the FRAX scale, and to minimize fracture risk patients are advised calcium and vitamin D supplementation, along with a bisphosphonate or the recently approved RANK-ligand inhibitor, denosumab.
Nonsteroidal antiandrogens such as flutamide, bicalutamide, and nilutamide block the ligand binding to the AR and were initially approved to block the flare associated with the rise in serum testosterone associated with GnRH agonist/antagonist therapy. Given alone, testosterone levels remain the same or increase while relative to testosterone-lowering therapies, cause fewer hot flushes, less of an effect on libido, less muscle wasting, fewer personality changes, and less bone loss. Gynecomastia remains a significant problem but can be alleviated in part by tamoxifen.
Most reported randomized trials suggest that the cancer-specific outcomes are inferior when antiandrogens are used alone. Bicalutamide, even at 150 mg (three times the recommended dose), was associated with a shorter time to progression and inferior survival compared to surgical castration for patients with established metastatic disease. Nevertheless, some men may accept the trade-off of a potentially inferior cancer outcome for an improved quality of life.
Combined androgen blockade, the administration of an antiandrogen plus a GnRH analogue or surgical orchiectomy, or triple androgen blockade, which includes the addition of a 5ARI, have not been shown to be superior to androgen depletion monotherapies, and are no longer recommended. In practice, most patients who are treated with a GnRH analogue receive an antiandrogen for the first 2–4 weeks of treatment to protect against the flare.
Intermittent Androgen Deprivation Therapy (IADT)
Another way to reduce the side effects of androgen depletion is to administer antiandrogens on an intermittent basis. This was proposed as a way to prevent the selection of cells that are resistant to androgen depletion. The hypothesis is that by allowing endogenous testosterone levels to rise, the cells that survive androgen depletion will induce a normal differentiation pathway. In this way, the surviving cells that are allowed to proliferate in the presence of androgen will retain sensitivity to subsequent androgen depletion. Applied in the clinic, androgen depletion is continued for 2–6 months beyond the point of maximal response. Once treatment is stopped, endogenous testosterone levels increase, and the symptoms associated with hormone treatment abate. PSA levels also begin to rise, and at some level treatment is restarted. With this approach, multiple cycles of regression and proliferation have been documented in individual patients. It is unknown whether the intermittent approach increases, decreases, or does not change the overall duration of sensitivity to androgen depletion. The approach is safe, but long-term data are needed to assess the course in men with low PSA levels. A trial to address this question is ongoing.
Outcomes of Androgen Depletion
The antiprostate cancer effects of the various androgen depletion strategies are similar, and the clinical course is predictable: an initial response, then a period of stability in which tumor cells are dormant and nonproliferative, followed after a variable period of time by a rise in PSA and regrowth that is visible on a scan as a castration-resistant lesion. Androgen depletion is not curative because cells that survive castration are present when the disease is first diagnosed. Considered by disease manifestation, PSA levels return to normal in 60–70% of patients, and measurable disease regression occurs in 50%; improvements in bone scan occur in 25% of cases, but the majority remains stable. Duration of survival is inversely proportional to disease extent at the time androgen depletion is first started, while the degree of PSA decline at 6 months has been shown to be prognostic. In a large-scale trial, PSA nadir proved prognostic.
An active question is whether hormones should be given in the adjuvant setting after surgery or radiation treatment of the primary tumor, or at the time that a PSA recurrence is documented, or to wait until metastatic disease or symptoms of disease are manifest. Trials in support of early therapy have often been underpowered relative to the reported benefit or have been criticized for methodologic grounds. One trial, although it showed a survival benefit for patients treated with radiation therapy and 3 years of androgen depletion relative to radiation alone, was criticized for the poor outcomes of the control group. Another showing a survival benefit for patients with positive lymph nodes who were randomized to immediate medical or surgical castration compared to observation (p = .02) was criticized because the confidence intervals around the 5- and 8-year survival distributions for the two groups overlapped. A large randomized study comparing early to late hormone treatment (orchiectomy or GnRH analogue) in patients with locally advanced or asymptomatic metastatic disease showed that patients treated early were less likely to progress from M0 to M1 disease, to develop pain, and to die of prostate cancer. This trial was criticized because therapy was delayed "too long" in the late-treatment group. When patients treated by radical surgery, radiation therapy, or active surveillance were randomly assigned to receive bicalutamide 150 mg or placebo, hormone treatment produced a significant reduction in the proportion of patients who developed osseous metastases at 2 years (9% for bicalutamide; 13.8% for placebo). This result has not gained acceptance in part because too many "good-risk" patients were treated and because no effect on survival was demonstrated. These criticisms are valid; however, the net influence on survival from early hormone intervention is similar to that observed in patients with breast cancer, for which adjuvant hormonal therapy is routinely given. It is of note that the American Society of Clinical Oncology Guidelines do not support immediate therapy.
Metastatic Disease: Castrate
Castration-resistant prostate cancer (CRPC), a disease that progresses despite androgen suppression by medical or surgical therapies where the measured levels of testosterone are 50 ng/mL or lower, continues to express the androgen receptor (AR) and is dependent on signaling through the receptor for growth. CRPC can manifest in many ways. For some it is a rise in PSA with no change in radiographs and no new symptoms. In others it is a rising PSA and progression in bone with or without symptoms of disease. Still others will show soft tissue disease with or without osseous metastases, and others have visceral spread. The prognosis, which is highly variable, can be predicted using nomograms designed for CRPC. The important point is that despite the failure of first-line hormone treatment, these tumors remain androgen driven and are not "hormone-refractory": the majority of these tumors remain sensitive to second- and third-line hormonal treatments. The rising PSA is an indication of continued signaling through the AR axis.
The manifestations of disease in this patient group limit the ability to reliably assess treatment effects because the traditional measures of outcome such as tumor regression do not apply. Bone scans can be inaccurate for assessing changes in osseous disease, and no PSA-based outcome is a true surrogate for survival benefit. It is essential to define therapeutic objectives before initiating treatment, as there are defined standards of care for different disease manifestations. Therapeutic objectives need not be defined by survival only as useful endpoints also include relief of symptoms and delay of metastases or new symptoms of disease.
Management of pain secondary to osseous metastatic disease is a critical part of therapy. Optimal palliation requires assessing whether the symptoms and metastases are focal or diffuse and whether disease threatens the spinal cord, the cauda equina, or the base of the skull. Neurologic symptoms require emergency evaluation because loss of function may be permanent if not addressed quickly. Single sites of pain and areas of neurologic involvement are best treated with external beam radiation. As the disease is often diffuse, palliation at one site often is followed by the emergence of symptoms in a separate site that had not received radiation.
It is also essential to ensure that a castrate status be documented. Patients receiving an antiandrogen alone, whose serum testosterone levels are elevated, should be treated first with a GnRH analogue or orchiectomy and observed for response. Patients on an antiandrogen in combination with a GnRH analogue should have the antiandrogen discontinued, as approximately 20% will respond to the selective discontinuation of the antiandrogen. Any withdrawal response occurs within weeks of stopping flutamide but may take 8–12 weeks with nilutamide and bicalutamide because of their long terminal half-lives. Ketoconazole, 600 to 1200 mg daily in combination with hydrocortisone, which inhibits adrenal androgen production, also has activity in this setting, but has not been formally evaluated in definitive phase III trials.
Hormonal agents in late phase III development that target specific pathogenetic mechanisms of AR function reactivation include abiraterone acetate, a novel CYP17 inhibitor that blocks androgen synthesis in the adrenal gland, testis, and tumor; and MDV3100, a next-generation antiandrogen screened for activity in prostate cancer model systems with overexpressed AR. A phase III trial showed a 4-month survival benefit for abiraterone acetate plus prednisone over a placebo plus prednisone. These agents have also shown significant antitumor effects in patients who have progressed on chemotherapy.
Mitoxantrone was the first cytotoxic agent shown to provide palliation of pain secondary to castrate metastatic disease, and was approved for this indication without the demonstration of a clear survival benefit. In 2004, docetaxel was established as the first-line standard cytotoxic drug for patients in this state, based on a trial showing that q3w docetaxel was superior to weekly therapy and to mitoxantrone, results confirmed in a second trial of estramustine/docetaxel vs. mitoxantrone. The addition of estramustine produced significant toxicity with no apparent improvement in survival and has been dropped from these regimens. Docetaxel and other microtubule-targeted agents produce PSA declines in 50% of patients, measurable disease regression in 25%, and both an improvement in preexisting and prevention of future cancer-related pain. Dasatinib is an oral tyrosine kinase inhibitor which targets Src and other Src family kinases that contribute to ligand-independent AR activation, and which reduces bone turnover, is under study in combination with docetaxel. Two products approved based on a survival benefit in randomized trials include cabazitaxel, a second-generation taxane FDA-approved for patients who have progressed on docetaxel relative to mitoxantrone, and sipuleucel-t, a biologic approach in which antigen-presenting cells are activated ex vivo, pulsed with antigen, and reinfused.
Given the bone-dominant pattern of prostate cancer spread, two bone-seeking radioisotopes, 89Sr (Metastron) and 153Sm-EDTMP (Quadramet), are approved for palliation of pain, although they have no effect on PSA or survival. Fewer patients treated with one of these isotopes developed new areas of pain or required additional radiation therapy compared to patients receiving external beam radiation therapy alone. Additionally, patients randomly assigned to a combination of 89Sr and doxorubicin after induction chemotherapy had fewer skeletal events and longer survival than patients treated with doxorubicin alone. Confirmatory studies are ongoing.
An additional bone-targeting therapy, bisphosphonates inhibit osteoclasts and, in effect, protect against bone loss associated with androgen depletion and prevent skeletal events. Addition of the bisphosphonate zoledronate to "standard therapy" in patients with CRPC resulted in fewer skeletal events relative to placebo. Skeletal events included microfractures, new pain, and need for radiation therapy.