Prostate Cancer

April 17, 2009

Prostate cancer is the most common non-skin cancer and the second leading cause of cancer mortality in American men. Despite the fact that this cancer will be diagnosed in an estimated 186,320 American men in the year 2008 and will lead to the death of approximately 28,660 men, there is no universally agreed-upon strategic plan for its diagnosis and management.

Prostate cancer is the most common non-skin cancer and the second leading cause of cancer mortality in American men. Despite the fact that this cancer will be diagnosed in an estimated 186,320 American men in the year 2008 and will lead to the death of approximately 28,660 men, there is no universally agreed-upon strategic plan for its diagnosis and management.

Epidemiology

Age The risk of developing prostate cancer begins to increase at age 50 years in white men who have no family history of the disease and at age 40 years in black men and those who have a first-degree relative (father, brother) with prostate cancer. Risk increases with age, but, unlike other cancers, prostate cancer has no “peak” age or modal distribution. There has been a downward “age migration” in the PSA (prostate-specific antigen) era such that the median age at diagnosis is now approximately 60 years old.

Race The highest incidence of prostate cancer in the world is found in American black men, who have approximately a 9.8% lifetime risk of developing this cancer. This rate is slightly higher than the 8% lifetime risk for American white men. Black men have an incidence of prostate cancer that is 1.6 times that of white men.

The Japanese and mainland Chinese populations have the lowest rates of prostate cancer. Interestingly, although Japanese immigrants to the United States have a higher incidence of prostate cancer than Japanese people living in Japan, their rate is still about half that of American whites.

Socioeconomic status appears to be unrelated to the risk of prostate cancer, and the explanation for racial variability is unknown. However, an interplay of diet, hormonal factors, and genetics likely accounts for the variability.

Geography The incidence of prostate cancer is highest in Scandinavian countries (22 cases per 100,000 population) and lowest in Asia (5 per 100,000). Risk may be inversely related to ultraviolet light exposure, as the incidence increases the farther one lives from the equator. However, recent studies show extremely high rates in populations of African heritage, such as Jamaicans.

Etiology and risk factors

Family history Men who have a first-degree relative with prostate cancer have approximately a twofold increased risk of developing prostate cancer during their lifetime. An individual who has two first-degree relatives with prostate cancer has a ninefold increase in lifetime risk.

True hereditary prostate cancer occurs in a small number of men and tends to develop at an early age (< 55 years old).

Dietary fat Studies have suggested that dietary fat may increase the risk of prostate cancer. However, no definitive proof of its role has yet been found.

These studies indicate that progression of prostate cancer, which is likely to be more clinically relevant, has different risk factors than those associated with its initiation/incidence and that some of these risk factors are likely modifiable. Recent findings from the Health Professionals Follow-up study have, however, demonstrated different dietary risk factors for the incidence compared with progression of prostate cancer. For example, African-American race, a positive family history, low consumption of tomato products, and high consumption of alpha-linolenic acid have been associated with higher risks of incident prostate cancer. However, height, body mass index, low physical activity, smoking, low consumption of tomato sauce, high calcium and alpha-linolenic acid intake, African-American race, and positive family history have all been associated with fatal cancer.

In addition, recent findings suggest that cruciferous or brassica family vegetables may reduce the risk of advanced prostate cancer. This family includes broccoli, cauliflower, cole slaw, and sauerkraut. Interestingly, the intake of brussels sprouts, spinach, and mustard greens did not appear to be protective, and the consumption of fruit was not associated with the incidence or progression of prostate cancer.

Vasectomy Several large epidemiologic studies suggest that vasectomy may increase the relative risk of prostate cancer by as much as 1.85. However, these same studies do not report an increased risk of dying from prostate cancer associated with vasectomy but do indicate a statistically increased risk of dying from lung cancer. These findings argue against an association between vasectomy and prostate cancer. Currently, this association is unproven and does not constitute grounds for fundamental changes in the use of vasectomy.

Sexual activity/sexually transmitted disease A large prospective study of more than 29,000 men demonstrated an association between high ejaculatory frequency (more than 21 ejaculations/month) and a decreased risk of prostate cancer, with a lifetime relative risk of 0.67. However, there may be several confounding factors associated with high sexual activity, such as differences in prostate cancer screening or lifestyle. There was no associated increased risk for men in the lowest ejaculatory frequency category.

Inflammation may underlie the findings associated with a relatively higher risk of prostate cancer in men seen in STD (sexually transmitted disease) clinics, but it may also be related to screening bias. Several cohort studies and one meta-analysis have demonstrated a protective role for the daily intake of aspirin and the risk of prostate cancer. In addition, the lipid-lowering and anti-inflammatory statin compounds have been associated with a reduction in the risk of high-grade tumors. These findings require prospective validation in randomized trials.

Prevention Active research on the chemoprevention of prostate cancer is ongoing. The only prospective randomized trial to demonstrate an effect was the Prostate Cancer Prevention Trial (PCPT), which showed a 24.8% reduction in the risk of prostate cancer among men randomized to receive finasteride (Proscar) daily versus those men on the placebo arm. Finasteride as a chemopreventive agent has not been universally accepted, however, because patients in the treatment arm were possibly more likely to exhibit higher-grade prostate cancer. Recent follow-up studies of the PCPT suggest that finasteride probably does not induce high-grade disease, and the observation may be a detection artifact. Other agents under study include vitamin E and selenium, both of which have been associated with a decreased risk of prostate cancer. A large prospective randomized trial to evaluate the effects of these agents in healthy men is currently under way.

Signs and symptoms

Early-stage disease Men with organ-confined prostate cancer often are completely asymptomatic. Men with a large component of benign prostatic hyperplasia often present with bladder outlet obstruction unrelated to prostate cancer.

Locally advanced disease Bladder outlet obstruction is the most common sign of locally advanced prostate cancer. A few men with locally advanced disease present with hematuria, urinary tract infections, and irritative voiding symptoms secondary to bladder outlet obstruction.

Advanced disease Rarely, men with bulky lymph node metastasis may present with bilateral lower-extremity edema. Men with bony metastasis often present with bone pain and, uncommonly, with lower-extremity weakness or paralysis from spinal cord compression.

Screening and diagnosis

Prostate cancer screening with PSA and digital rectal examination (DRE) has resulted in not only an increase in prostate cancer detection but also a stage shift. More cancers are now being detected at earlier stages, when they are potentially curable. Prior to screening efforts, most prostate cancers were detected when they produced local symptoms or distant metastases, at which point treatment for cure often was impossible.

Digital rectal examination Prostate biopsy prompted by abnormal findings on DRE, such as nodularity or induration of the prostate, leads to a diagnosis of prostate cancer in only 15% to 25% of cases. This rate compares with a prostate cancer prevalence of < 5% among men of similar age without an abnormal DRE. Although neither accurate nor sensitive for prostate cancer detection, abnormal DRE is associated with a fivefold increased risk of cancer present at the time of screening.

PSA is a serine protease produced by the prostatic epithelium and secreted in the seminal fluid in large quantities. The level of PSA in serum is increased by inflammation of the prostate, urinary retention, prostatic infection, benign prostatic hyperplasia, prostate cancer, and prostatic manipulation. The optimal threshold to recommend prostatic biopsy has come under increasing scrutiny. The overall sensitivity for PSA levels is approximately 50% to 70% depending on the threshold used, but it is not as specific and does not allow for differentiation between indolent and aggressive disease. For example, by using a threshold of 4.1 ng/mL, the majority of cancers in men < age 60 would potentially be missed. However, a PSA cutoff of 4.1 ng/mL only has a positive predictive value of approximately 30%, meaning two out of three men would undergo biopsy for benign disease.

A more worthwhile approach for PSA screening may be to use the rate of rise in PSA (PSA velocity) in combination with the absolute PSA value. This approach has been shown to be useful recently in the form of age-adjusted PSA velocity, but accepted guidelines are still controversial.

Another commonly employed test for patients with a PSA level < 10 ng/mL is the percent-free PSA level. There is an inverse relationship between the percent-free PSA level and the risk of a cancer diagnosis. Most urologists utilize a cutoff of 10% to prompt a recommendation for biopsy. In men who have never had a prostate biopsy but who have a total PSA level > 4.0 ng/mL, a percent-free PSA less than 25% may suggest a 50% to 60% probability of prostate cancer. In men who have had a prior negative biopsy but who have a persistently elevated PSA level > 4.0 ng/mL, a percent-free PSA < 10% should prompt a repeat biopsy.

Current screening recommendations The American Cancer Society and the American Urological Association (AUA) recommend that the PSA test and the DRE should be offered annually beginning at age 50 to men who have a life expectancy of at least 10 years. In high-risk men (African Americans and those with a first-degree relative diagnosed with prostate cancer), screening should be offered at an earlier age (40–45 years old). Prior to testing, physicians should discuss with their patients the potential benefits of early prostate cancer detection and its implications in the need for subsequent treatment so that patients can make an informed decision about undergoing screening.

There are currently two ongoing major prostate cancer screening trials: The Prostate, Lung, Colorectal, and Ovarian (PLCO) trial in the United States funded by the National Cancer Institute and the European Organisation for Research and Treatment of Cancer (EORTC) trial. The National Comprehensive Cancer Network (NCCN) has recently published aggressive screening guidelines on its website (www.nccn.org). These new controversial guidelines call for baseline PSA levels at a younger age (generally age 40) and suggest that any young man with a PSA level > 0.7 ng/mL (median in men aged 40–49) be tested annually.

Biopsy When indicated, prostate biopsy is usually performed as an office procedure by transrectal ultrasonographic guidance using an automated 18-gauge biopsy gun. The procedure is performed with, at most, local anesthesia and carries a risk of significant infection of only 1 in 200 cases. Additional side effects of hematuria and hematochezia are common for 2 to 3 days following the biopsy. Hematospermia may last for up to 4 to 6 weeks. Since about the year 2000, prostate biopsy includes laterally directed extended core protocols employing 8 to 12 biopsy cores per procedure. Multiple studies have demonstrated that the addition of the lateral cores improves the accuracy of biopsy.

If the biopsy result is negative, these men are typically followed conservatively with serial PSA levels and DRE repeated annually. Repeat biopsy is performed only when PSA levels rise at abnormal rates (> 0.8 ng/mL/yr) or if DRE findings show new nodularity or induration. Men in whom high-grade prostatic intraepithelial neoplasia is found on biopsy usually should undergo repeat biopsy, since one-third to one-half will be found to have prostate cancer.

Recently, a new test, the UPM-3 urine test, has become more widely available. This test, performed on voided urine after an “attentive” DRE, is based on reverse transcriptase–polymerase chain reaction assay for a PSA product (DD3). It is becoming useful not as a primary screening test, but to dictate the need for repeat prostate biopsy in men with persistently elevated PSA levels.

In addition, researchers at Johns Hopkins University have developed a blood-based test called EPCA-2, which detects a nuclear matrix protein linked to prostate cancer. Elevated levels of EPCA-2 were found to be more sensitive and specific for prostate cancer, even in men with normal PSA levels and benign prostatic hypertrophy, and predicted extracapsular disease as well. Currently, this test is being further optimized and validated in a large series of patients. Additional future studies will investigate the role of a novel fusion protein (TMPRSS2-ETS) commonly found in prostate tumors, both as a diagnostic and prognostic marker. This fusion gene is androgen regulated and directs oncogenic signals and has been found in over 50% of localized prostate cancer.

Pathology

Adenocarcinomas make up the vast majority of prostate carcinomas. A total of 70% of prostate adenocarcinomas occur in the peripheral zone, 20% in the transitional zone, and approximately 10% in the central zone.

Other tumor types are relatively rare and include ductal adenocarcinoma, which occurs in the major ducts and often projects into the urethra; and mucinous adenocarcinoma, which secretes abundant mucin and does not arise from the major ducts. Transitional carcinoma of the prostate occurs within the ducts and, to a lesser extent, in the prostatic acini. Typically, primary transitional carcinomas are aggressive cancers that have a poor prognosis. Similarly, neuroendocrine (small-cell) tumors are rare and aggressive, have a poor prognosis, and typically require aggressive surgical management. Other rare types include foamy carcinoma, mucinous adenocarcinoma, large cell neuroendocrine tumors, and signet ring tumors.

Histologic grade The grading system developed by Gleason from data accumulated by the Veterans Administration Cooperative Urologic Research Group appears to provide the best prognostic information in addition to clinical stage and is the predominant grading system in widespread use.

Metastatic spread Adenocarcinoma of the prostate may spread locally through direct extension into periprostatic fat or via the ejaculatory ducts into seminal vesicles; lymphatically to regional lymph nodes, including the hypogastric and obturator lymph nodes; and hematogenously to bone. The most common sites of bony metastases are the lumbosacral spine (probably related to venous drainage of the prostate through Baston’s plexus) and the axial skeleton, but any bone, including the skull and ribs, can be involved. Rare sites of metastatic spread include the liver and lungs.

Prevention

Until 2004, there was no intervention known to prevent prostate cancer. The primary objective of the PCPT was to describe the prevalence of histologically proven prostate cancer among men randomized to receive daily finasteride (a 5-alpha-reductase inhibitor that decreases prostate size and serum/prostate dihydrotestosterone levels) or placebo. The authors described a 24.8% reduction in the prevalence of prostate cancer among men taking finasteride, suggesting that it either prevents or delays the appearance of prostate cancer. The caveat of their findings, however, was that these cancers that developed in the treatment arm were of a higher grade.

Prognosis and natural history

Staging systems The most widely used and universally accepted staging system for prostate cancer is the TNM system (Table 1). In the TNM system, T1 and T2 tumors are confined to the gland, whereas T3 and T4 tumors have local extension.

Risk-adapted staging The development of the “Partin Tables” in 1993 ushered in a new era of combining clinical stage, Gleason score, and PSA level to predict pathologic stage after radical prostatectomy. More recently, this has led to the D’Amico et al risk groupings for newly diagnosed men with clinically localized disease (Table 2). Patients are divided into three risk groups (low, intermediate, or high) of occult micrometastases and relapse after initial local therapy. Although not perfect, this system is currently in widespread use and allows a framework for multimodal and multidisciplinary treatment strategies based on risk grouping. Finally, Kattan et al have developed preoperative and postoperative nomograms as clinical tools to predict the risk of recurrence after radical prostatectomy. Although these nomograms are imperfect, they may be useful for estimating risk and planning therapy as well as for stratifying and selecting patients for clinical trials.

Prognosis The optimal management of patients with prostate cancer varies widely and is highly dependent upon a patient’s age, overall health, and tumor risk assessment. The natural history of the disease process can be heterogeneous, ranging from an incidental finding unlikely to result in cancer-specific mortality, to very aggressive, resulting in early widespread metastatic disease and death. Therefore, treating physicians should carefully consider the value of curative therapy with potential toxicity in the context of a patient’s comorbidities and life expectancy.

Among patients with clinically localized prostate cancer treated conservatively (observation or hormonal therapy alone), those with a low Gleason score (2–4) have a small risk of dying of their cancer within 15 years (4%–7%). However, those with poorly differentiated tumors (Gleason score 8–10) have a greater risk of dying of prostate cancer than of any other cause, even when the cancer is diagnosed in the eighth decade of life. Indeed, a man diagnosed before the age of 60 with a clinically localized, Gleason score 8 to 10 prostate cancer has an 87% risk of dying of the disease within 15 years if untreated (Table 3).

D’Amico et al combined a number of national datasets to report 10-year cancer-specific mortality rates for men undergoing radical prostatectomy or external-beam radiotherapy (EBRT) by this risk grouping and age at diagnosis. These 10-year mortality graphs are useful to counsel contemporary-era men contemplating surgery or radiation therapy. Given recent advances in the treatment of metastatic disease, identifying men at high risk for metastatic disease following local therapy is important, as these agents are incorporated earlier in the disease course.

Treatment of localized prostate cancer

There are several treatment options for localized prostate cancer, including radical prostatectomy, EBRT, and brachytherapy (interstitial radiation/seeds). Multiple treatment series with each modality have documented the validity of the risk-stratification model based on clinical palpation stage, Gleason score, and serum PSA level. More recently, it has been suggested that biopsy quantification may also be an important factor. Specifically, counting the number of involved needle biopsy cores or the percentage of each core involved by cancer may be prognostic. Low-risk patients experience a favorable 85% to 90% freedom from recurrence, compared with approximately 75% and 35% to 50% for the intermediate- and high-risk patients, respectively. Although no randomized studies have been performed, contemporary series, which stratify patients by the risk model, demonstrate remarkably similar outcomes independent of the treatment modality. For this reason, treatment recommendations should be individualized based on patient preference, life expectancy, and discussion of potential toxicities.

TREATMENT OF CLINICALLY LOCALIZED DISEASE (T1, T2)

Radical prostatectomy

Radical prostatectomy can be performed retropubically through a lower midline incisionan approach that may include pelvic lymph node dissection. Alternatively, some urologists prefer the perineal approach. With the latter approach, a separate incision is required if lymph node removal is desired.

Although the morbidity of radical prostatectomy was a major concern in the past, improvements were made during the 1980s. Among the various treatment options for prostate cancer, only radical prostatectomy has been demonstrated to confer a survival advantage over no treatment. Bill-Axelson and colleagues found a 44%, 40%, and 67% decrease in the risk of prostate cancer mortality, distant metastases, and disease progression, respectively, among those undergoing radical prostatectomy compared with those treated expectantly. The hazards of anesthesia, risk of blood loss, and hospital stay have all been minimized. Nationwide, Medicare data suggest that surgical outcomes are significantly better at those centers performing > 40 prostatectomies per year than at other hospitals with a lower surgical volume.

Transfusion is usually unnecessary, and treatment-related mortality is < 0.05% at leading prostate cancer centers. The average hospital stay of a man undergoing radical prostatectomy is now approximately 1 to 3 days at leading referral centers in the United States; several institutions routinely discharge patients within 24 hours. Although urinary incontinence is common in the first few months after prostatectomy, most men recover urinary control; at some leading centers, 90% to 98% of men report few or no long-term urinary problems.

Nerve-sparing radical prostatectomy is appropriate for men with small-volume disease. It offers those men with good potency prior to surgery the probability of recovering that function following the operation. By permitting better visualization of Santorini’s dorsal venous plexus, the apical prostate, the urethra, and the striated urethral sphincter, the nerve-sparing technique also reduces blood loss and improves recovery of urinary continence. In appropriately selected individuals, a nerve-sparing procedure confers no greater risk of prostate cancer recurrence after considering other relevant clinical information (PSA level, Gleason score, margin status, seminal vesicle involvement, and the presence of extraprostatic spread).

Referral centers have reported that 50% to 90% of patients who are fully potent prior to surgery recover erections following a nerve-sparing procedure, but the quality (rigidity and duration) of these recovered erections may be compromised compared with preoperative erections. Erection recovery rates can be higher than 80% in patients < 60 years of age and lower in older men. Potency may return anywhere from 2 to 24 months following surgery. Regardless of potency, sensation of the penis is not changed after this procedure, and men still experience orgasm. Nerve-sparing radical prostatectomy has not compromised cancer control outcomes in well-selected men with early-stage disease. Also, a recent study has suggested that early postoperative use of sildenafil (Viagra) may facilitate the return of natural erections more quickly. Generally speaking, recovery of erectile function after radical prostatectomy is mediated by age (the younger, the better), pretreatment erectile function (the stronger, the better), and a nerve-sparing approach (bilateral is better than unilateral, which is better than none, which is better than wide dissection).

Robotic radical prostatectomy

Laparoscopic prostatectomy was initially described by Schuessler in 1997 but was abandoned because of its technical difficulty and long operative time with little apparent benefit over the conventional technique. A resurgence in the technique was prompted by improved instrumentation and refinements in the procedure itself, although the laparoscopically naive urologist must endure a substantial learning curve (with attendant perioperative morbidity) prior to meeting the outcome standards set by the open technique.

The robotic-assisted prostatectomy was developed to overcome some of the difficulties of the standard laparoscopic prostatectomy (eg, intracorporeal suturing). The robotic technique allows for three-dimensional (3D) visualization of the operative field and provides for a significantly wider range of movements intracorporeally than do standard laparoscopic instruments. This advance has prompted the assimilation of the technique into the armamentarium of many urologists.

Current evidence suggests that in experienced hands, the laparoscopic and robotic techniques have similar oncologic efficacy to that of the open procedure. However, the length of follow-up (usually < 12 months) in these studies is limited, suggesting that a measure of caution be taken when interpreting the results. Furthermore, recent studies suggest the learning curve is prolonged, with 200 to 250 cases necessary before results can be compared with those of experienced surgeons. Long-term effects of these modalities on sexual and urinary health (as measured by a psychometrically valid survey) have not been reported, and such data are critical in the context of the prostatectomy patient when evaluating technical results. Though it is a promising advance in the treatment of prostate cancer, published data suggest further research in this area is warranted.

Pelvic lymph node dissection Studies now indicate that regional pelvic lymph node dissection may not be necessary for patients with stage T1c disease if the total Gleason score is < 7 and the PSA level is < 10.0 ng/mL, ie, low-risk individuals. Selected intermediate-risk men may also not require this staging procedure, but in high-risk men, it is still considered imperative.

Neoadjuvant hormonal therapy

Approximately 15% to 35% of men who undergo radical prostatectomy for clinical stage T2 prostate cancer will be found to have pathologic T3 disease following surgery. This finding led some investigators to evaluate the efficacy of neoadjuvant androgen deprivation therapy in prospective clinical trials. Early data from these trials suggested that neoadjuvant hormonal therapy led to a reduction in positive surgical margins. However, these findings need to be considered in a technical context: Androgen deprivation therapy causes artifactual changes in prostate morphology that cause difficulties for the pathologic identification of prostate cancer foci.

Indeed, more recent data from prospective studies have shown no benefit of neoadjuvant therapy with regard to disease progression-free survival. At present, therefore, it appears that neoadjuvant hormonal therapy does not improve the curative potential of radical prostatectomy but instead is associated with morphologic alterations that complicate the prognostic utility of standard pathology. Consequently, neoadjuvant hormonal therapy should be reserved for evaluation as an experimental modality in the context of clinical trials.

Adjuvant therapy postprostatectomy

The potential indications for adjuvant therapy following radical prostatectomy in patients with clinical T1 or T2 malignancy include pathologic evidence of T3 disease, positive nodes, a rising PSA level, and positive surgical margins, among others. Possible adjuvant treatments include radiation therapy and androgen deprivation either alone or in combination. Best available evidence suggests that early salvage radiotherapy (eg, postprostatectomy PSA level < 1.0 ng/mL) affords the best results in terms of subsequent biochemical recurrence.

Radiation therapy Men with positive margins or pathologic T3 disease following radical prostatectomy are potential candidates for adjuvant EBRT. Some controversy exists as to the efficacy of early postoperative therapy versus intervention once a biochemical failure has been documented.

Valicenti et al demonstrated that the 5-year PSA control rate with immediate postoperative radiation therapy for patients with pathologic T3 disease was 89%, compared with 55% for a matched-pair analysis of surgery alone. Additionally, they demonstrated a favorable dose response in patients receiving EBRT doses above 64.8 Gy.

More recently, Bolla et al reported the results of a randomized, controlled study of observation versus EBRT in 500 patients with pathologic T3 disease following radical prostatectomy. Although to date there are no data demonstrating an overall survival difference, with a median follow-up of 5 years, the progression-free survival was significantly improved with treatment (74% vs 53%). A subsequent update suggested the benefit might be limited to patients with positive margins.

Less controversy exists regarding the role of salvage radiation therapy for PSA recurrence. Approximately 60% to 70% of patients with favorable disease after surgical failure (PSA level < 2.0 ng/mL, a slow PSA doubling time, and a long interval to failure after surgery) will experience durable disease-free survival after adjuvant radiotherapy, presumably due to a smaller tumor burden and a lower likelihood of occult metastatic disease.

Stephenson et al evaluated a large number of patients with persistent or increasing PSA levels after surgery from five American academic institutions. Forty-five percent of patients were free of disease at 4 years. Patients with no adverse risk features achieved a 4-year progression-free probability of 77%. The authors subsequently developed a nomogram based on established risk factors to more accurately identify patient-specific risks to assist in clinical decision-making. Patients who experience PSA failure after radical prostatectomy should be restaged with pelvic CT, bone scan, and DRE. Patients with no evidence of metastatic disease should be evaluated for adjuvant radiotherapy.

Hormonal therapy Significant controversy exists within the academic community as to the timing of initiating androgen deprivation following radical prostatectomy. Clinical trials have documented a benefit only for those patients with nodal involvement.

Treatment recommendations for postprostatectomy recurrence

Following radical prostatectomy, it is expected that serial PSA levels will become undetectable. Any detectable PSA level (> 0.2 ng/mL) following surgery indicates possible recurrent disease and the need for restaging and possible salvage therapies, including radiation or hormonal therapy, experimental protocols, or observation. However, some patients can develop low levels of detectable PSA after prostatectomy without cancer recurrence, presumably due to small foci of benign prostate tissue in situ. Although there is concern for recurrence when the PSA level is > 0.2 ng/mL, most clinicians will wait until a PSA threshold > 0.4 ng/mL is reached to assume that the rise in PSA level represents real recurrence.

Recent findings have suggested that tumor grade, time to PSA recurrence after surgery, and PSA doubling time predict the 5-, 10-, and 15-year risks of prostate cancer mortality and can help to guide the timing and need for androgen ablation. Although these findings do not prove that early androgen ablation is more beneficial than delayed androgen ablation based on a PSA threshold or development of metastatic disease, it does help to risk-stratify patients into those most likely to derive benefit from androgen ablation early. Moreover, men with a PSA doubling time of less than 15 months may be more likely to die of prostate cancer than of other competing causes, suggesting that these men should be evaluated in controlled trials of hormonal or novel therapeutic agents.

Definitive radiation therapy

EBRT EBRT utilizes high-energy photons to destroy cancer cells by damaging cellular DNA. Traditional EBRT utilized bony landmarks and standard beam arrangements to deliver dose to the pelvic region. Technologic advances in treatment planning, driven by improved computing power and the incorporation of individualized patient anatomy, have led to dramatic improvements in treatment delivery. (For a more complete discussion of radiation therapy techniques, see chapter 1.)

3D conformal EBRT creates 3D representations of target structures (ie, the prostate) and designs highly tailored treatment portals utilizing various angles to create a volume of high radiation dose that conforms to the target shape. The anatomic information used to define the target is generally derived from CT images obtained while the patient is placed in an immobilization device in the precise treatment position. With the selective delivery of dose to the target and avoidance of the surrounding normal tissue, the therapeutic ratio is improved. This approach has permitted the use of doses far higher than tolerable with traditional therapy, with fewer bowel and bladder complications.

Treatment volumes in patients with low-risk disease are designed to encompass the prostate plus a margin for daily variations. Patients with a high risk for periprostatic extension and/or regional lymph node metastasis receive initial pelvic treatment of 45 to 50 Gy, followed by a coned-down boost to the prostate.

RTOG (Radiation Therapy Oncology Group) 9413 was designed to test the addition of whole pelvic radiation and the timing of androgen deprivation in the treatment of high-risk patients (lymph node–positive potential > 15% or locally advanced [Gleason score ≥ 6 and > cT2c] cancers). At a median follow-up of 59.5 months, Roach et al noted an improved 4-year disease progression-free survival (60%) among those receiving whole pelvic radiotherapy in conjunction with neoadjuvant androgen deprivation, compared with other treatment arms (44%–50%). An update at 7 years confirmed improved progression- free survival for larger fields in this group.

EBRT dose The previous standard radiation dose with conventional therapy was 70 Gy given over 7 weeks; however, much recent work has suggested a positive dose response, particularly in the intermediate- and high-risk patient populations. Multiple single-institution experiences have demonstrated that 3D conformal EBRT techniques with doses of 75 Gy and higher can be delivered with minimal toxicities.

A randomized trial from the M. D. Anderson Cancer Center compared 70 Gy given conventionally with 78 Gy delivered with a conformal boost. With a median follow-up of 8.7 years, it showed an advantage in freedom from failure for the higher-dose arm in patients with a PSA level > 10 ng/mL (78% vs 39%). Kupelian et al presented pooled data for nearly 5,000 patients from 9 institutions over a narrow time range (1994–1995) to remove treatment technique, stage migration, and lead-time bias. They demonstrated favorable biochemical control outcomes for doses higher than 72 Gy in all risk groups.

The RTOG has completed a dose-escalation trial to assess toxicity with 3D conformal EBRT. In this multi-institutional trial, 78 Gy (prescribed as a minimum to the tumor volume in 2-Gy fractions) was well tolerated, with only 3% of patients experiencing significant (grade 3+) acute gastrointestinal/genitourinary (GI/GU) morbidity and a 6% rate of significant late toxicity. A comparison trial is being conducted by the RTOG (P0126); it will accrue 1,520 cases and provide information regarding any beneficial effect on mortality with higher radiation doses. Although no standard exists, doses ≥ 75 Gy with 3D conformal EBRT techniques appear to be well tolerated and improve biochemical response rates.

Intensity-modulated radiation therapy (IMRT) is becoming a widely used treatment for prostate cancer. This refinement of conformal therapy employs high nonuniform beam intensity profiles and dynamic multileaf collimation to create even more conformal dose distributions. Further improving the therapeutic index compared with 3D conformal EBRT, IMRT is associated with reduced toxicity, permitting further dose escalations previously unattainable.

IMRT was pioneered in several major centers, and Memorial Sloan-Kettering Cancer Center has reported a series of 772 patients treated with doses between 81 and 86.4 Gy. With a median follow-up of 24 months, the side-effect profile was improved, despite these higher doses, with less than 1% of patients experiencing late grade 3+ GI/GU toxicity. The early PSA relapse-free survival rates for favorable, intermediate, and unfavorable risk groups were 92%, 86%, and 81%, respectively. Although IMRT is quickly becoming the standard of care at most institutions, some caution should be exercised. The precision of dose delivery and the complexity of treatment planning demand a strong commitment by both physicians and physics personnel to ensure high-quality IMRT.

Proton therapy Technically a form of EBRT, proton therapy has been utilized in clinical practice for more than 10 years. It offers a potential advantage over photon-based IMRT by exploiting superior dose distributions of the Bragg peak effect. The routine implementation of this technology has been hampered by the staggering costs of building and maintaining a facility. The largest experience involving 1,277 patients at the Loma Linda proton facility was reported in 2004 and demonstrated “comparable control rates with minimal toxicity” compared with other local therapies. Although there are theoretical benefits and ongoing trials evaluating the possibility of further safe dose escalation with protons, to date there is little clinical evidence to support a significant benefit over IMRT. With several new centers now under construction, and a published economic evaluation questioning its cost-effectiveness, the future of eventual widespread application of proton therapy remains unclear.

Androgen ablation with EBRT Two potential benefits of the use of transient androgen ablation prior to EBRT have been identified. First, there may be some synergy between the apoptotic response induced by androgen deprivation and radiotherapy that may increase local control.

Second, androgen deprivation results in an average 20% decrease in prostate volume. This volume reduction not only may reduce the number of target cells, and thereby improve tumor control, but also may shrink the prostate and, thus, diminish the volume of rectum and bladder irradiated during conformal therapy. Complete androgen blockade can be achieved with luteinizing hormone-releasing hormone (LHRH) agonists plus an oral antiandrogen.

The survival benefits of androgen suppression therapy (AST) for patients with intermediate-risk disease have been uncertain. A recent single-institution prospective trial by D’Amico et al randomized patients with a PSA level > 10 ng/mL, a Gleason score ≥ 7, or radiographic evidence of extraprostatic disease to receive EBRT (70 Gy) alone or the same EBRT with 6 months of AST. After a median follow-up of 4.5 years, patients treated with combined EBRT and AST were found to have improved disease progression-free, prostate cancer–specific, and overall survival (P = .04). Although hormone therapy for 3 years has been shown to be beneficial in locally advanced cases, this trial in men with more localized disease showed a benefit to shorter duration of hormone therapy. However, it is not known whether high-dose radiotherapy will obviate the need for AST in this group of patients. The survival benefit in this study was largely confined to those men with few cardiovascular comorbidities, illustrating the importance of patient selection for AST.

Recent secondary findings from a large randomized study (RTOG 9202) suggest that men with high-grade tumors (Gleason score 8–10) and high-risk (T2c–T4) localized disease benefit from long-term androgen ablation (2 years) compared with short-term androgen ablation (4 months), based on improved prostate cancer–specific and overall survival. A caveat to these findings has been the increased incidence or acceleration of incident cardiovascular death in men older than 65 years of age starting androgen ablation compared with those men who did not receive androgen ablation. These findings suggest that cardiac evaluation should be considered in those men older than age 65 with cardiovascular risk factors prior to undergoing androgen ablation.

Interstitial radiotherapy In the 1970s, the use of permanently placed radioactive iodine implants produced initial results as good as those obtained with other available radiotherapy techniques and posed a small risk of impotence and other morbidity when compared with conventional EBRT and radical prostatectomy. However, ultimate control rates were unacceptable. The technique used (freehand placement of seeds during laparotomy) was found to distribute the radioactive seeds unevenly throughout the gland; cold regions may have contributed to the relatively poor outcome.

The advent of improved imaging and seed placement techniques coupled with better patient selection has resulted in vast improvements in cancer control. The perception of fewer side effects in a single outpatient treatment has also contributed to a recent surge in this treatment modality. Transrectal ultrasonography is now utilized to guide seed placement from a transperineal approach, which has corrected the problem of poor seed placement in experienced hands. Two radioactive seed isotopes have been used: iodine (I-125), with a half-life of 60 days, and palladium (Pd-103), with a shorter half-life (17 days) and subsequent higher dose rate. The advantage of the brachytherapy technique is that substantial dose can be delivered to the prostate with minimal effect on the surrounding tissue.

Although concentrating dose with brachytherapy represents a potential advantage over EBRT, it also highlights the need for appropriate patient selection. Significant dose falloff 2 to 3 mm beyond placement of the seeds within the gland limits the application of seed monotherapy in patients with potential periprostatic or regional disease extension. Large studies from several leading institutions have now matured and confirm the long-term effectiveness and safety of this approach in low-risk populations. Favorable results have also been reported in selected intermediate-risk patients. Typical monotherapy doses of 145 Gy for I-131 and 125 Gy for Pd-103 are utilized. To date, the data do not support the use of either isotope over the other.

In addition to disease risk factors, certain patient selection factors are important in considering implants. A large prostate size (> 60 cc) may make the procedure more challenging, both from the perspective of increased prostate gland swelling due to the increased number of needles and the difficulty of the pubic bone obstructing needle placement. Patients with outlet obstruction symptoms (American Urological Society score > 15) have an increased risk of requiring catheterization following implantation. Patients who have undergone prior trans-urethral resection of prostate (TURP) have been reported to have an increased risk of incontinence; recognizing this risk and placing seeds farther from the defect may help to minimize this risk. Therefore, with proper counseling, patients with small TURP defects may still be considered implant candidates.

For patients with intermediate- or high-risk disease, implants may be combined with EBRT. There is sound logic in combining high-dose therapy to the prostate with an implant and moderate doses of EBRT to the regional tissues to sterilize micrometastatic disease. In this situation, an implant (110 Gy of I-131 or 100 Gy of Pd-104) usually either precedes or follows 20 to 45 Gy delivered to the pelvis. Some reports have suggested an increase in rectal toxicity with this approach; however, this is likely due to the poor quality of the implant. At least one study from a leading implant center suggested no significant increase in severe early or late GI/GU morbidity with combination therapy. The value of supplemental EBRT needs to be evaluated in comparison to full-dose EBRT in terms of long-term morbidity and cancer control.

High-dose–rate (HDR) devices Besides permanent implants, which deliver low-dose-rate (LDR) radiotherapy, brachytherapy for prostate cancer has been delivered using temporary high-dose-rate devices, usually in patients with locally advanced disease. In this technique, a high dose (minimum, approximately 5 Gy) is delivered to the prostate over ≤ 1 hour by remotely inserting a highly radioactive source into catheters placed into the prostate under ultrasonographic guidance while the patient is under anesthesia. Several treatments are given on separate occasions, and EBRT is used for approximately 5 weeks as well.

More reports are accumulating on the application of HDR brachytherapy to prostate cancer. Various dose-fractionation combinations of HDR with or without combined pelvic EBRT have been employed, with a dose-response relationship apparent in biochemical control. Although the follow-up is short and no prospective randomized trials evaluating this approach have yet been published, it appears that HDR prostate brachytherapy in combination with pelvic EBRT may be effective. The long-term consequences for normal tissue of delivering large doses per fraction using this technique are unclear.

Medications and devices to manage impotence after prostatectomy, EBRT, or brachytherapy

Treatment for postprostatectomy impotence includes the phosphodiesterase inhibitors sildenafil, vardenafil (Levitra), and tadalafil (Cialis); prostaglandin E1, administered as a urethral suppository (Muse); intercavernosal injection (Caverject, Edex); or vacuum-pump erection aids that are useful for improving erections in men who have poor erectile function after prostatectomy, radiation therapy, or brachytherapy. These therapies are effective in 15% to 40% of men with postprostatectomy impotence and in 50% to 75% of men with postradiotherapy erectile dysfunction. Insertion of a penile prosthesis is typically offered to patients only after unsuccessful trials with the previously mentioned less invasive interventions.

DETECTION AND TREATMENT OF RECURRENCE

Significance and definition of a rising PSA level postirradiation

The use of PSA levels following definitive therapy (either radiotherapy or radical prostatectomy) can detect early recurrences that may be amenable to salvage treatment. A rising PSA profile following radiotherapy is unequivocal evidence of the presence of a residual prostatic neoplasm. However, the definition of a rising PSA level after radiation therapy varies in the literature. A 1996 consensus conference recommended that PSA failure be considered to have occurred after three consecutive PSA level rises, with the rate of failure defined as halfway between the first rise and the previous PSA level.

Moreover, patients with a rising PSA level after irradiation may be a heterogeneous group, including patients with truly localized failure as well as those with metastatic disease. Also, certain patients will have a slowly rising PSA level after irradiation and may not require additional treatment. In patients who do not receive androgen ablation, the 5-year actuarial risk of distant metastasis from the time that the PSA level begins to rise is ~50%. A rapidly emerging key concept in rising PSA levels is PSA velocity, or more specifically PSA doubling time. Multiple recent studies have found that a PSA doubling time
< 10 to 12 months predicts early clinical relapse if biochemical recurrence is untreated.

Treatment recommendations for recurrence postirradiation

In general, men who have clear evidence of a rising PSA level 2 years after definitive radiotherapy for localized prostate cancer should be advised about the options of hormonal therapy (see section on “Treatment of locally advanced disease [T3, T4]”), salvage surgery, salvage cryotherapy, observation, or experimental therapy.

If patients have minimal comorbidity, good life expectancy, and only local evidence of disease recurrence, salvage surgery is an option but should be preceded by a bone scan, CT scan, cystoscopy, and extensive counseling because urinary difficulties after salvage prostatectomy are substantial and highly prevalent. Factors that determine success of salvage surgery after radiation therapy include low (< 4–10 ng/mL) preoperative PSA level, low pathologic stage (T3a or less), and prior type of radiation therapy (brachytherapy, IMRT being favorable). However, no randomized trials have been conducted in this setting to provide level I evidence favoring surgery over other modes of treatment.

TREATMENT OF LOCALLY ADVANCED DISEASE (T3, T4)

The treatment of patients with locally advanced prostate cancer is centered on a multimodality and multidisciplinary approach, including radiation therapy (EBRT with or without HDR interstitial therapy), androgen ablation plus EBRT, or radical prostatectomy with or without androgen deprivation.

EBRT with and without HDR interstitial therapy

For patients with locally extensive prostate cancer, local failure remains a potential problem after EBRT. This problem has prompted investigations into alternative means to intensify therapy.

One strategy has been to deliver large fractions of radiotherapy using HDR interstitial techniques in combination with EBRT. The large interstitial fractions, which may be on the order of 5 Gy, deliver a high dose to the prostate but spare normal tissues, due to the rapid dose falloff outside the implanted volume. Early experience with this strategy is encouraging, but long-term data on outcome, particularly in patients with locally extensive disease, and on morbidity are awaited.

Patients with locally advanced prostate cancer probably are not good candidates for permanent prostate implants. Patients with stage T3/T4 tumors are at high risk of gross extraprostatic involvement, and this localized therapy may not offer adequate dosimetric coverage of extraprostatic disease.

As mentioned in the previous section, there may be a synergistic effect between hormonal therapy given in conjunction with radiation therapy. In addition to enhancing apoptosis and producing local cytoreduction, the use of early androgen deprivation may possibly delay or even prevent the development of metastatic disease.

The current body of evidence from two large randomized trials (RTOG 85-10 and EORTC 22863) suggests that immediate long-term androgen deprivation in conjunction with EBRT improves outcomes among men with locally advanced or high-risk (Gleason score ≥ 8) prostate cancer compared with radiation therapy alone. An analysis of RTOG 85-31 by Horwitz et al, which employed early indefinite androgen deprivation, demonstrated that patients with locally advanced disease (T3N0) had improved cause-specific failure and distant metastatic failure compared with EBRT alone. Furthermore, a comparison to RTOG 86-10, which studied similar patients treated with only 4 months of hormonal therapy, favored the long-term approach. The EORTC trial randomized 415 patients and demonstrated a 15% overall survival benefit to 3 years of combined therapy versus radiation therapy alone.

Radical prostatectomy with or without adjuvant therapy

Surgical monotherapy can be considered a reasonable option for patients with locally advanced prostate cancer. Stage T3 disease can be successfully treated with low morbidity and significant reductions in risk of local recurrence, with clinical overstaging (up to 26%) reported by Yamada et al. Well- and moderately differentiated cancers have cancer-specific survival rates of 76% at 10 years, comparable to those of other treatment modalities.

The Mayo Clinic has one of the largest radical prostatectomy series for T3 disease, consisting of more than 1,000 patients. In this population, of whom 34% received adjuvant therapy, 15-year cancer-specific survival and local recurrence rates were 77% and 21%, respectively. Ninety-eight men who were found to have nodal metastases following radical prostatectomy and pelvic lymphadenectomy were randomized to receive immediate androgen deprivation or be followed until clinical disease progression. At a median follow-up of 7 years, 18 of 51 men in the observation group had died, compared with only 4 of 47 in the treatment group (P = .02).

Treatment of node-positive disease

Whether any local treatment adds to the overall survival duration in patients with known nodal involvement is debatable. Until recently, the standard of care had been to perform frozen-section pathologic analysis on pelvic lymph nodes at the time of radical prostatectomy, prior to removal of the prostate. If this analysis revealed micrometastases, radical prostatectomy was thought to be contraindicated. Although retrospective in nature, recent data from several American centers, including one large study from the Mayo Clinic, have reported a survival benefit in men who undergo radical prostatectomy despite the presence of micrometastases to regional pelvic lymph nodes. These men tend to do better and survive longer when started on early hormonal therapy, either with orchiectomy or an LHRH agonist.

Radiation therapy There are also compelling data that long-term survival is achievable in these patients with combination radiation and hormonal therapy. Data from the M. D. Anderson Cancer Center indicate a benefit to pelvic/prostate radiation therapy plus immediate hormonal manipulation compared with hormones alone. A subset analysis of patients with node-positive disease from RTOG 85-31 revealed immediate hormonal therapy plus radiation therapy resulted in 5- and 9-year cause-specific survival rates of 84% and 76%, respectively. Therefore, aggressive locoregional therapy appears to be effective in this cohort of unfavorable patients.

TREATMENT OF ADVANCED SYSTEMIC DISEASE

Defining advanced disease

Metastatic prostate cancer This is a heterogeneous group of patients that ranges from those with pathologically detected locoregional nodal metastases at the time of radical prostatectomy to those with widespread systemic disease. The most common sites of metastatic disease are the bone and pelvic and abdominal lymph nodes. Other, less common sites include the liver and lungs. Complications of metastatic prostate cancer include pain, fatigue, skeletal fractures, spinal cord compression, urinary outlet obstruction, and failure to thrive. First-line hormonal therapy for men with metastatic prostate cancer delays these complications.

Rising PSA level A large series of more than 2,000 patients treated with radical prostatectomy at Johns Hopkins University demonstrated that approximately 17% of cases recurred, with only 5.8% being local disease. In the remaining patients, disease recurred initially with either a rise in PSA level alone (9.7%) or evidence of clinical metastases (1.7%).

Outcomes for men with only a rising PSA level can vary greatly. Time to PSA recurrence (< vs > 2 years), PSA doubling time (< vs > 9 months), and Gleason score (8–10 vs 5–7) are among the important factors for predicting the development of metastatic disease and survival. The major developments for hormonal therapy in advanced prostate cancer were achieved prior to routine PSA testing and were often complicated by problematic study design. There are no prospective data that confirm a benefit to early hormonal therapy for men with a rising PSA alone. However, for patients with a rising PSA level who are at high risk for the development of metastases, some physicians agree that early hormonal therapy is likely to benefit this group of patients as well as those with radiologic evidence of metastatic disease.

First-line therapies for advanced disease

The standard first-line treatment of advanced prostate cancer, regardless of whether local treatment has been applied, is to ablate the action of androgens by medical or surgical means. For the majority of patients, androgen ablation can result in a decline in PSA level, palliation of disease-related symptoms, and regression of metastatic disease on imaging.

Bilateral orchiectomy The advantages of orchiectomy over other means of castration include an immediate decline in testosterone levels and ease of compliance for patients. Given these advantages, however, many men still opt for medical castration, with the potential advantage of intermittent hormonal therapy. In addition, the psychological impact of orchiectomy can be significant. Nonetheless, bilateral orchiectomy may be appropriate and cost-effective for a select group of patients.

LHRH analogs LHRH agonists, such as leuprolide (Lupron, Eligard) and goserelin (Zoladex), interfere with the normal pulsatile secretion of LH from the pituitary gland, resulting in an eventual decline in serum testosterone levels. The effect is reversible with cessation of therapy. Because LH is initially increased with LHRH agonists, testosterone levels may actually increase initially as well. This finding can result in a transient rise in PSA levels and potential growth of metastatic sites. Because of this initial “flare response” with LHRH agonists, consideration should be given to the administration of an antiandrogen prior to the LHRH, especially in patients who are at risk for complications from the disease (such as spinal cord compression, worsening pain, or urinary outlet obstruction; Table 4).

A pure LHRH antagonist (abarelix [Plenaxis]) has been approved by the US Food and Drug Administration (FDA). Its main advantage is the lack of an LHRH surge or flare, and it is indicated in men with impending spinal cord compression or other now uncommon clinical scenarios where a flare could be harmful. However, this drug must be administered every 2 weeks in the first month and monthly thereafter. Also, it can rarely be associated with an anaphylactic reaction.

Antiandrogens Antiandrogens function to block the binding of dihydro-testosterone (DHT) to the androgen receptor, blocking the translocation of the DHT-androgen receptor complex into the nuclei of cells. There are two general classes: steroidal and nonsteroidal. Steroidal antiandrogens include cyproterone and megestrol. The most commonly used antiandrogens include the nonsteroidal agents flutamide, bicalutamide (Casodex), and nilutamide (Nilandron). These agents differ slightly in their affinity for the androgen receptor and their side-effect profiles.

Typically, antiandrogens are used in combination with surgical or medical castration. Some trials comparing antiandrogens alone with LHRH analogs have shown similar efficacy, but more recent trials suggest that monotherapy with antiandrogens may be inferior in terms of time to disease progression and possibly survival. For example, a randomized trial of monotherapy with high-dose bicalutamide (150 mg daily) compared with flutamide plus goserelin demonstrated that patients treated with bicalutamide monotherapy had fewer side effects, such as loss of libido or erectile dysfunction, and trended toward improved quality of life. However, in patients with radiographic evidence of metastases, bicalutamide monotherapy was associated with a small 6-week decrease in survival (hazard ratio, 1.3). Despite this finding, for men who are intolerant to the side effects of LHRH analogs, monotherapy with antiandrogens can be considered after careful discussion with patients.

Antiandrogen monotherapy with flutamide or bicalutamide is also sometimes used to treat PSA recurrence. Used alone or in combination with a 5-alpha reductase inhibitor (finasteride or dutasteride), this approach is associated with fewer side effects than traditional androgen suppression therapy, but the approches have not been approved by the FDA. A significant downside is nipple tenderness or gynecomastia, but this “peripheral blockade” approach may preserve potency and libido. Prophylactic breast irradiation may prevent this complication.

Combined androgen blockade Combined androgen blockade (CAB) refers to the elimination of testicular androgens in combination with blockade of adrenal androgens, generally with an LHRH analog and an antiandrogen agent. The use of CAB is somewhat controversial. Several randomized trials comparing LHRH antagonists alone versus CAB have demonstrated a survival benefit with CAB. However, in one of the largest trials conducted by the United States Intergroup, more than 1,300 men were randomized to undergo orchiectomy versus orchiectomy plus flutamide. There was no significant advantage to CAB in terms of time to disease progression or overall survival. Some investigators believe that bicalutamide, a more potent agent, may be associated with greater survival when used as part of CAB.

Many investigators believe that the advantages observed in trials that include an LHRH antagonist exist because of the “flare phenomenon,” which occurs with LHRH antagonists alone and may be lost with a short period of treatment with antiandrogens during the expected flare period.

Diethylstilbestrol (DES) Estrogen administration, in the form of DES, also produces chemical castration. DES inhibits prostate growth, primarily through the inhibition of the hypothalamic-pituitary-gonadal axis, which blocks testicular synthesis of testosterone and thus lowers plasma testosterone levels. Since doses higher than 3 mg/d cause significant cardiovascular mortality, DES has fallen out of favor as a first-line therapy to induce castration.

Ketoconazole (Nizoral) Ketoconazole is an antifungal agent that can inhibit adrenal and testicular steroid synthesis at higher doses, leading to a decline in adrenal and testicular androgens. It has the benefit of a rapid decline in testosterone, which can be useful for patients who present emergently with a complication of newly diagnosed advanced disease. Ketoconazole is started at a dose of 200 mg three times daily and is increased to a total dose of 400 mg three times daily. Ketoconazole is associated with significant side effects (such as fatigue, nausea, and vomiting) and drug interactions, however, and must be given with supplemental hydrocortisone to avoid symptoms of adrenal insufficiency. Because of the side effects, its use is more common in the second-line setting, where responses can be expected in 20% to 40% of patients following disease progression with CAB.

Early versus late treatment Whether to treat patients early with hormonal therapy or wait until patients become symptomatic has been tested in a large European trial conducted by the Medical Research Council. Men were randomized to receive immediate hormonal therapy (orchiectomy or an LHRH analog) versus delayed therapy, which was initiated with symptomatic disease progression. Men who were treated with early therapy were less likely to experience urinary obstructive symptoms requiring intervention, pathologic fractures, and spinal cord compression than those treated in the delayed arm (Table 5). The survival benefit was less clear, however, because many of the men in the delayed arm died before they received any hormonal therapy. This study was also complicated by the initiation of PSA monitoring during the study period. Many patients and physicians currently are not comfortable delaying therapy until the onset of symptoms while the PSA level is rising; this fact limits the applicability of its findings in the modern era.

Other smaller trials have examined this issue as well. A Cochrane Database review was conducted in 2002; it demonstrated an increase in progression-free survival and a small, but significant, improvement in survival with early hormonal therapy.

One setting in which early adjuvant hormonal therapy has been associated with a survival benefit is in the postprostatectomy setting in men found to have pathologic lymph node–positive disease. Messing and colleagues published an adjuvant study that evaluated immediate hormonal therapy versus delayed treatment upon detection of distant metastases or symptomatic recurrence in men who had undergone radical prostatectomy and lymph node dissection and were found to have nodal metastases. At a median follow-up of 11.9 years (range, 9.7–14.5 for surviving patients), men assigned immediate androgen deprivation therapy had a significant improvement in overall survival, prostate cancer–specific survival, and progression-free survival.

Intermittent androgen deprivation Androgen deprivation is associated with several short-term and long-term adverse effects. These side effects make treatment breaks provided by intermittent androgen deprivation an attractive option. Additionally, results from preclinical studies suggest that hormonal resistance may be delayed with intermittent androgen deprivation. These potential advantages have led to significant interest among patients and caregivers in intermittent androgen deprivation.

Over the past decade, several phase II studies of intermittent androgen deprivation have demonstrated feasibility and safety with suggestion of improved quality of life without negative effects on time to disease progression or survival. More recently, a phase III trial was reported at the 2006 ASCO meeting. In this trial, patients randomized to the intermittent therapy arm were off therapy for a median of 52 weeks with no significant difference in time to disease progression or overall survival. The results of several ongoing phase III trials in metastatic disease and PSA-only relapse will better define the role of intermittent androgen deprivation. With the currently available information, intermittent androgen deprivation may be considered in select patient settings.

Treatment recommendations Just as for localized disease, initial treatment for advanced prostate cancer must be individualized. A patient who presents with a rising PSA level only after local treatment and a slow PSA doubling time, a prolonged time to PSA recurrence, and a low initial Gleason score may not require immediate therapy, especially if there are other more significant comorbidities. However, a patient with multiple metastatic sites will need immediate treatment, generally with orchiectomy or CAB initially followed by monotherapy with an LHRH analog, to prevent the sequelae of metastatic disease, such as fracture, spinal cord compression, and ureteral obstruction. Ketoconazole may be considered as the initial systemic therapy for patients presenting with spinal cord compression as the first presentation of prostate cancer. Given the overall limitations of hormone therapy, all appropriate patients should be offered access to clinical trials.

For patients with a rising PSA level who are at high risk for the development of metastases, a discussion regarding the potential advantages to early treatment and an explanation of the lack of randomized prospective data are warranted. Some investigators favor early treatment for these patients based on the data from the Medical Research Council trial and the Cochrane Database review, understanding that this information is extrapolated from data obtained prior to PSA testing and from patients with clinical and radiographic metastases.

Second-line hormonal therapies

Outcomes with initial androgen ablation can vary from responses that last from months to years; they also vary as a function of the Gleason grade, pretreatment PSA velocity, and extent of disease at the time of initiating treatment. Once PSA levels begin to rise with androgen ablation, the disease is often referred to as “hormone refractory.” This term is actually a misnomer, because preclinical data suggest that tumors may become hypersensitive to androgens, resulting in worsened disease if androgen ablation is removed entirely. Moreover, many patients have disease that remains sensitive to further hormonal manipulations, such as second-line antiandrogens, steroids, or ketoconazole.

An example of this sensitivity to hormonal manipulation is exemplified in the antiandrogen withdrawal response. Up to one-third of patients with a rising PSA level while receiving treatment with an antiandrogen will have a decline in PSA level and or clinical regression with antiandrogen withdrawal. The mechanism of this response has not been fully elucidated but supports the hypothesis that the androgen receptor remains important in progressive disease.

Although second-line hormonal therapy has demonstrated benefit in terms of PSA levels and response, there are no data to demonstrate a survival advantage with second-line hormonal therapy. Its role has further come into question with data that support the use of docetaxel (Taxotere) chemotherapy for men with metastatic androgen-independent prostate cancer to improve survival. The survival advantage of docetaxel is not limited by number of prior hormonal therapies.

For patients with a rising PSA level only, timing of chemotherapy is even less clear. The Eastern Cooperative Oncology Group attempted a trial comparing ketoconazole/hydrocortisone with docetaxel in patients with a rising PSA level but no evidence of metastatic disease after hormonal therapy, but the trial was closed early due to lack of accrual. Until prospective data are available, physicians will need to counsel patients carefully on the different options and timing of those options available at the time of disease progression, including second-line hormonal manipulation, chemotherapy, and especially clinical trials.

Chemotherapy for castration-resistant disease

Docetaxel The role of chemotherapy has changed significantly over the past several years, with the results of two large randomized trials demonstrating a survival benefit for men with castration-resistant metastatic prostate cancer treated with docetaxel-based chemotherapy (Table 6). Investigators from the Southwest Oncology Group randomized patients to receive mitoxantrone (Novantrone) plus prednisone versus docetaxel (60 mg/m2) plus estramustine (Emcyt) and dexamethasone every 3 weeks. Patients in the docetaxel arm had a significant improvement in survival by 2 to 3 months. Currently, estramustine is no longer being utilized in the front-line setting due to the 7% to 10% risk of arterial and venous thromboembolic events and the equivalent survival benefits seen with docetaxel alone compared with mitoxantrone.

A second trial by Tannock et al showed a similar survival benefit of 3 months with docetaxel (75 mg/m2) plus prednisone given every 3 weeks compared with mitoxantrone and prednisone. These trials were the first to demonstrate a survival benefit with chemotherapy in advanced prostate cancer and have sparked numerous studies involving docetaxel in combination with newer agents. Toxicities of docetaxel include myelosuppression and neuropathy, both of which can be dose-limiting.

A recent 5-year update of this study has confirmed a 3-month survival advantage to every-3-week docetaxel in the overall study population. In addition, nearly 18% of men experienced normalized PSA levels with every-3-week docetaxel, as opposed to 8% of men treated with mitoxantrone. Men with normalized PSA levels lived on average 33 months, compared with 16 months among men without normalized PSA levels, nearly a two-fold difference. Current studies indicate that a 30% or greater decline in the serum PSA level within 3 months of treatment initiation is the best predictor of disease outcome of all current surrogate markers in this disease and may be used to assist in prognostication after treatment initiation.

Mitoxantrone plus prednisone Mitoxantrone (12 mg/m2) plus prednisone has been approved for use in advanced prostate cancer based on improvement in palliation of pain and quality of life over prednisone alone despite no improvement in overall survival.

Bisphosphonates Bone metastases from prostate cancer are associated with increased bone formation around tumor deposits, resulting in characteristic osteoblastic metastases. However, concomitant with the osteoblastic activity is a marked increase in bone resorption and osteolysis, which can be inhibited by bisphosphonates.

Studies of bisphosphonates in prostate cancer have demonstrated mixed results. A combined analysis of two multicentered randomized controlled trials comparing pamidronate with placebo in men with androgen-independent progressive prostate cancer demonstrated no benefit in terms of skeleton-related events or palliation of symptoms. A phase III trial with an oral bisphosphonate, clodronate, demonstrated no difference in either symptomatic bone metastases or prostate cancer-related deaths when compared with placebo.

A phase III trial demonstrated a reduction in skeleton-related events for men with castration-resistant metastatic prostate cancer with a more potent bisphosphonate, zoledronic acid (Zometa). However, it is important to note that this trial did not show an improvement in quality of life with zoledronic acid, nor did it demonstrate a reduction in the development of new
metastases.

At this time, the recommendation for zoledronic acid in prostate cancer is limited to men with androgen-independent prostate cancer. It is important to recognize the limitations of this therapy and to understand that there is no defined role for its use in men with androgen-dependent prostate cancer. Although these men are at higher risk for osteoporosis, less potent oral bisphosphonates may be a more reasonable approach, given the long-term side effects associated with zoledronic acid (renal insufficiency and osteonecrosis of the mandible).

Newer therapies

Several new therapies for men with prostate cancer (some as single agents and some with chemotherapy) are under investigation, with promising early results. They include the endothelin receptor antagonist atrasentan, vitamin D3 (calcitriol), immunotherapies (Provenge and GVAX as autologous and allogeneic vaccination strategies), the vascular epidermal growth factor inhibitors bevacizumab (Avastin) and sunitinib (Sutent), a new class of antimicrotubule agents (the epothilones), and novel agents targeting the androgen receptor. There are ample preclinical and early clinical data to suggest that all of these agents may have activity against prostate cancer, but no definitive trials to establish their role have yet been completed. These agents are still considered investigational. Several trials are evaluating the combinations of docetaxel and bevacizumab, docetaxel and atrasentan, and docetaxel and a vaccine.

In addition, current trials are investigating the use of these systemic agents, including chemotherapeutic regimens such as docetaxel, in locally advanced disease, either prior to or adjuvant following surgery or radiation therapy (Table 7). Accrual to these trials (TAX3501, RTOG 0521, VA 553, and CALGB 90203) is a priority, as they are investigating the role of systemic therapy to prevent disease recurrence, similar to the widely accepted use of systemic therapy for other tumor types such as breast and colorectal cancers.

Radiation therapy for palliating bone metastasis

Radiotherapy is effective in controlling local pain associated with skeletal prostate metastasis. In general, a treatment regimen of 30 Gy over 10 treatments results in rapid and durable local symptom control and a reduced dependence on analgesics. Single-dose palliative XRT may provide equal palliation as well.

For patients with more extensive bone involvement causing pain that may be difficult to address with localized EBRT, alternatives include wide-field irradiation (ie, hemibody irradiation) or systemic administration of radioactive bone-seeking isotopes that can deliver therapeutic doses to skeletal metastatic disease. Radioactive isotopes used in this fashion include strontium-89 chloride (Metastron) and samarium SM 153 lexidronam (Quadramet). A more detailed discussion of these approaches can be found in chapter 37.

SUGGESTED READING

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