Prostate Cancer

Overview 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 220,000 American men in 2015 and will lead to the death of approximately 27,540 men, there is no universally agreed-upon strategic plan for its detection, diagnosis, and management. The estimated number of cases increased from the previous year. However, the death rate per 100,000 people declined 3.2% per year from 2007 to 2011, and the denominator (the older population) grew, so the overall rate of death is lower. 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 prostate-specific antigen (PSA) era such that the median age at diagnosis is now approximately 60 years. 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, studies show extremely high rates of prostate cancer 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 and Lifestyle Although early studies suggested a link between dietary fat and prostate cancer risk, more recent studies have failed to confirm these observations. Thus, the relationship between dietary fat and prostate cancer risk remains unclear. Using animal models, one study pointed to high levels of simple carbohydrates being a culprit in promoting prostate cancer growth. Studies indicate that progression of prostate cancer, which is likely to be more clinically relevant, has different risk factors from those associated with its initiation/incidence and that some of these risk factors are likely modifiable. Findings from the Health Professionals Follow-up study have, however, demonstrated different dietary risk factors for the incidence of prostate cancer, compared with its progression. 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 (BMI), low physical activity, smoking, high consumption of red meat, low consumption of tomato sauce, high calcium and alpha-linolenic acid intake, African-American race, and positive family history have all been associated with more advanced cancer. In addition, findings suggest that cruciferous or Brassica family vegetables may reduce the risk of advanced prostate cancer. This family includes broccoli, cauliflower, and cabbage (eg, eaten as coleslaw 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 controversial and does not constitute grounds for fundamental changes in the use of vasectomy. Testosterone Replacement Therapy Testosterone replacement therapy (TRT) can alleviate symptoms in hypogonadism, either primary or secondary after androgen deprivation therapy. When given for hypogonadism, TRT has not been directly linked to the risk of developing prostate cancer. A systematic review by Shabsigh et al found 11 randomized controlled trials and 29 retrospective non-controlled studies of patients who had not had prostate cancer, as well as 4 studies in patients who had hypogonadism in the setting of prostate cancer. The risk for prostate cancer was not increased in patients who received TRT in any of these studies. TRT for hypogonadism after radiation therapy and radical prostatectomy for prostate cancer has also been studied, without evidence of disease progression of prostate cancer (Warburton D et al, Asian J Androl, 2015). However, these have been small retrospective observational studies, and larger prospective studies are needed to determine any actual risk that TRT might have on the development or progression of prostate cancer. In patients with active prostate cancer, most experts are reluctant to prescribe TRT. However, after successful treatment in men without recurrence, TRT is becoming more clinically acceptable. 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 sexually transmitted disease (STD) 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. Recent data related to a possible viral etiology of prostate cancer (ie, the XMRV virus) have now been formally withdrawn; they were likely due to a contamination artifact and are unlikely to be causally related to prostate cancer. Prevention Active research into the chemoprevention of prostate cancer is ongoing. Two prospective randomized trials have demonstrated a 20% to 25% reduction in the risk of prostate cancer among men randomized to receive either finasteride or dutasteride daily vs men on the placebo arm. Finasteride or dutasteride chemopreventive agents have not been universally accepted, however, because of concerns over the relative merits of prevention of low-grade disease, with little effect on high-grade tumors. In addition, concerns over side effects such as impotence, as well as reductions in PSA levels with these therapies that may make cancer detection more challenging, have limited the generalized use of these drugs and thus an individualized risk/benefit discussion about use of these agents as preventive measures is recommended. Finally, randomized trials using selenium and vitamin E have failed to demonstrate a benefit of these agents to reduce prostate cancer risk. Ongoing studies will examine vitamin D and omega-3 fatty acid supplementation as preventive strategies in cancer, including prostate cancer. Andriole and colleagues reported on a long-term prostate cancer prevention study with dutasteride (a dual 5-alpha reductase inhibitor) in men with an elevated PSA level and a negative initial biopsy. They demonstrated a 22.8% relative risk reduction overall in prostate cancer incidence (5.1% absolute risk), although the for-cause rate of biopsies (ie, not protocol-specified) was not different between the two arms. There was an apparent greater reduction in this trial of low-grade (Gleason score < 7) tumors, and no major effect in preventing higher-grade tumors, with a higher percentage of Gleason score 8-10 tumors detected in the dutasteride arm in years 3 and 4. Dutasteride is known to reduce PSA levels by more than twofold. Its use in conjunction with hormonal treatment for prostate cancer prevention should take into account consideration of risk and uncertainty weighed against the benefits, appropriate surveillance strategies for patients while they are being treated with a dihydrotestosterone inhibitor, and side effects including erectile/sexual dysfunction. The US Food and Drug Administration (FDA) has ruled that dutasteride is not approvable for prostate cancer chemoprevention. In a follow-up report of SELECT (Selenium and Vitamin E Cancer Prevention Trial), there was an increased risk of prostate cancer for men randomized to treatment with vitamin E. Compared with the placebo (referent) group, in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% confidence interval [CI], 1.004–1.36, P = .008), as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93–1.27; P = .18) and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89–1.22; P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1,000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination. Recent updated data from the Health Professionals Follow-up study of more than 4,400 men with localized prostate cancer found that selenium supplementation increased the risk of PC-specific mortality. This, combined with updated data from SELECT demonstrating that selenium supplementation may promote high-grade PC among men with high baseline selenium levels, raises the level of concern about this supplement. Patients should be informed about supplementation with vitamin E and selenium, given the increased risk of prostate cancer and clear lack of benefits with selenium supplementation. Smoking Studies of smoking in relation to prostate cancer mortality or recurrence in prostate cancer patients are limited, with few prostate cancer–specific outcomes. A large prospective observational study of 5,366 men diagnosed with prostate cancer between 1986 and 2006 in the Health Professionals Follow-Up Study was published in 2011 by Kenfield et al in JAMA. There were 1,630 deaths, 524 (32%) due to prostate cancer and 416 (26%) due to cardiovascular disease, and 878 biochemical recurrences. Absolute crude rates for prostate cancer–specific death for never vs current smokers were 9.6 vs 15.3 per 1,000 person-years; for all-cause mortality, the corresponding rates were 27.3 and 53 per 1,000 person-years. Smoking at the time of prostate cancer diagnosis is associated with increased overall and cardiovascular disease mortality and prostate cancer–specific mortality and recurrence. Men who have quit for at least 10 years have prostate cancer–specific mortality risks similar to those who have never smoked. Sidebar: In the Prostate Cancer Prevention Trial (PCPT), finasteride significantly reduced the risk of prostate cancer but was associated with an increased risk of high-grade disease. Now with up to 18 years of follow-up, prostate cancer has been diagnosed in 989 of 9,423 (10.5%) in the finasteride group and 1,412 of 9,457 (14.9%) in the placebo group (relative risk in the finasteride group, 0.70; 95% CI, 0.65–0.76; P < .001). Of the men who were evaluated, 333 (3.5%) in the finasteride group and 286 (3%) in the placebo group had high-grade cancer (Gleason score, 7 to 10) (relative risk, 1.17; 95% CI, 1–1.37; P = .05). Of the men who died, 2,538 were in the finasteride group and 2,496 were in the placebo group, for 15-year survival rates of 78% and 78.2%, respectively. The unadjusted HR for death in the finasteride group was 1.02 (95% CI, 0.97–1.08; P = .46). Ten-year survival rates were 83% in the finasteride group and 80.9% in the placebo group for men with low-grade prostate cancer and 73% and 73.6%, respectively, for those with high-grade prostate cancer. There was no significant between-group difference in the rates of overall survival or survival after the diagnosis of prostate cancer. These data suggest that finasteride is safe and effective for prostate cancer chemoprevention, although the drug remains not approved by the US Food and Drug Administration for this indication (Thompson IM Jr et al: N Engl J Med 369:603–610, 2013). Signs and Symptoms Early-Stage Disease Men with organ-confined prostate cancer often are completely asymptomatic, given the predominant posterior peripheral zone location of prostate adenocarcinomas. 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 levels and digital rectal examination (DRE) has resulted not only in 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. However, since 2011, when the United States Preventive Services Task Force (USPSTF) gave PSA screening a “D rating,” indicating that it is associated with more harm than benefit, the topic of screening for prostate cancer has been extremely controversial, with the question regarding its appropriateness in flux. 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. Currently, the National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) guidelines recommend a DRE as part of the screening process in men who are well informed about the pros and cons of screening, however the latest American Cancer Society (ACS) guidelines consider the DRE to be an optional test. PSA 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. Two large randomized multisite trials examined the role of PSA screening in US and European populations over time. In the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial, nearly 77,000 US men were randomized to annual PSA and DRE screening or to standard practice (which included PSA screening). After 7 years of follow-up, prostate cancer was more commonly detected in screened men, but fatal disease was not detectably different. In contrast, in the European study, named ERSPC, 182,000 men in various countries were assigned to PSA screening at various intervals or to no screening. Contamination seemed to be less common in the control group in this study, and at 9 years’ median follow-up, a 20% reduction in prostate cancer mortality was noted. In this study, nearly twice as many screened men were diagnosed with prostate cancer. The number needed to screen in this study to avoid 1 prostate cancer death was 1,410, and the number needed to treat with local therapy was 48. Data from the PCPT (Prostate Cancer Prevention Trial) illustrate that there is no “normal” level for PSA. Indeed, there is a continuum of risk that exists, even at low levels of PSA. For example, among men in the placebo arm of the study, 11% of men with a serum PSA level < 1 ng/mL had prostate cancer at the end-of-study biopsy. The proportion of men with prostate cancer rose to 30% among those with PSA levels between 3.1 and 4 ng/mL, which is still within the “normal” range. Furthermore, with a median follow-up of 9 years, the cancer-specific survival rate was improved by 20% in the screening group vs controls. However, the investigators report an overdetection of small, nonlethal cancers. Schroder et al from the ERSPC recently reported updated data on prostate-cancer mortality. After a median follow-up of 11 years, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio, 0.79; 95% CI, 0.68–0.91; P = .001), and it was 29% after adjustment for noncompliance. The absolute reduction in mortality in the screening group was 0.1 deaths per 1,000 person-years or 1.07 deaths per 1,000 men who underwent randomization. The rate ratio for death from prostate cancer during follow-up years 10 and 11 was 0.62 (95% CI, 0.45–0.85; P = .003). To prevent 1 death from prostate cancer at 11 years of follow-up, 1,055 men would need to be screened and 37 cancers would need to be detected. PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality. An additional potentially 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 in the form of age-adjusted PSA velocity, but accepted guidelines are still controversial, and the independent predictive utility of this measure remains to be demonstrated. Another commonly employed test for patients with a PSA level 4 ng/mL, a free PSA level 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 ng/mL, a free PSA level < 10% should prompt a repeat biopsy. Using a baseline PSA value to risk-stratify young men for their future risk of prostate cancer is increasingly recognized as clinically useful. Tang et al, in a study of more than 9,500 men aged 50 or younger, showed that a baseline PSA of 1.5 to 2.4 ng/mL increased the relative risk for prostate cancer by 9.3-fold for white men and sixfold to sevenfold for black men. Overall, an initial PSA > 1.5 was a powerful predictor of subsequent prostate cancer, confirming the Physicians Health Study and other published data. Despite these robust yet retrospective data on baseline PSA, the AUA did not recommend obtaining a baseline PSA for men younger than 55 years old in their updated 2013 PSA best practice guidelines. Obesity may be another factor that influences PSA values. Using data from the Shared Equal Access Regional Cancer Hospital, the Duke Prostate Center, and Johns Hopkins Hospital, investigators concluded that higher BMI was significantly associated with higher plasma volume and lower PSA concentrations in men undergoing radical prostatectomy. Hemodilution may therefore be responsible for the lower serum PSA concentrations among obese men with prostate cancer. While obesity might lower PSA, there are no specific accepted guidelines on obesity or BMI-adjusted PSA thresholds; however, clinicians may want to have a higher index of suspicion for borderline PSA in obese males and take this into consideration when considering prostate biopsy or referral to a urology specialist. Current Screening Recommendations There remains significant controversy as to the wisdom and effectiveness of PSA screening for the general male population. This is exemplified in the 2012 update by the USPSTF, in which PSA screening was given a “D” rating. This means that this committee believes that the risk of population-based PSA screening outweighs the benefits and does not recommend routine testing. This announcement in May 2012 was immediately met with a firestorm of criticism and controversy, and even a US House of Representatives Bill to rebuke the guidelines and adjust the composition of the committee, requiring specialists in the field in question. Furthermore, both the AUA and ACS updated their 2010 guidelines. In 2012, the AUA took a more “proactive” stance by recommending that all men consider having a baseline PSA test at age 40. This guideline was useful to risk-stratify men to future testing frequency. If at age 40 a man’s PSA level is less than 1 ng/mL, the man can be reassured that he is at low risk and will be asked to return at age 45 for consideration of additional screening tests. However, in 2013, the AUA reversed this recommendation and did not recommend the baseline PSA concept (see sidebar). The ACS took a more cautious stance with its 2010 update. The ACS is now de-emphasizing mass screening programs, while emphasizing a discussion of the pros and cons of testing with PSA levels assessed based on individualized risk. The NCCN and American Society of Clinical Oncology (ASCO) have also adapted an individualized risk assessment and informed discussion with patients about the pros and cons of screening, to begin in the 40s for high-risk men, and at age 50 for men of average risk. Readers should refer to acs.org or nccn.org for updates of these guidelines. Sidebar: The American Urological Association (AUA) conducted a systematic review of more than 300 studies that addressed prostate cancer incidence/mortality, quality of life, diagnostic accuracy, and harms of PSA testing. In addition to the quality of the evidence, the panel considered values and preferences expressed in a clinical setting (patient-physician dyad) rather than having a public health perspective. Guideline statements were organized by age group (age < 40; 40–54; 55–69; and ≥ 70). With the exception of PSA-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest with respect to the other tests. The quality of evidence for the benefits of screening was moderate, and evidence for harm was high for men 55 to 69 years of age. For men outside this age range, evidence was lacking for benefit, but the harms of screening, including overdiagnosis and overtreatment, remained. Modeled data suggested that a screening interval of 2 years or more may be preferred, to reduce the harms of screening. The Panel recommended shared decision-making for men aged 55 to 69 years considering PSA-based screening, a target age group for whom benefits may outweigh harms. In summary, the AUA only recommends PSA testing after shared decision-making every other year for men 55 to 69 years of age; does not recommend population-based screening in any group; and does not recommend the baseline risk-assessment PSA that it had endorsed just 1 year earlier (Carter HB et al: J Urol 190:419–426, 2013). Sidebar: The American Urological Association (AUA) 2013 prostate cancer/PSA guidelines are very controversial among the majority of urologists. Moul et al criticized the AUA guidelines, citing the potential harm of waiting until age 55 to screen many men, particularly African-American men and men with a strong family history of prostate cancer. They were also critical of the elimination of the baseline “risk-assessment” PSA in the 2013 AUA guidelines. Furthermore, the current recommendations do not take into account the marked reduction in metastatic disease rates in the PSA era and the reverse stage-migration that will undoubtedly occur if PSA testing is abandoned. It is possible that the cost savings associated with less screening and early disease treatment will be erased by the costs associated with increased rates of metastatic disease and use of the newer expensive treatments for advanced prostate cancer (Moul JW et al: J Urol 190:1134–1137, 2013). 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 in only 1 of 200 cases, although the risk of post-biopsy urosepsis has been increasing recently due primarily to ciprofloxacin-resistant Escherichia coli. Some urologists are now performing a rectal swab culture screen for ciprofloxacin-resistant E coli before biopsy and adjusting prophylactic antibiotics accordingly, although this practice remains controversial. 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 20 biopsy cores per procedure. Multiple studies have demonstrated that 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 (> 0.8–2 ng/mL/year, depending on the patient) or if DRE findings show new nodularity or induration. Men in whom high-grade prostatic intraepithelial neoplasia (PIN) or atypical small acinar proliferation (ASAP) is found on biopsy usually should undergo repeat biopsy, since one-third to one-half will be found to have prostate cancer. Recently, the recommendation of repeat biopsy for PIN alone has been relaxed, such that repeat biopsy may not be recommended and a more personalized approach to follow-up is taken. Age and overall health status must also be considered, and rebiopsy decisions should be individualized. Prostate MRI Magnetic resonance imaging (MRI) traditionally has not been very useful for prostate cancer staging, particularly for assessing intra-gland anatomy. Over the last few years, later-generation 3 Tesla magnet machines combined with multiparametric (mp) imaging and the use of endorectal and surface coils have improved the quality and utility of this procedure. However, this mpMRI technique is not standardized, there is no universally accepted system for grading lesions seen within the prostate, and performing scans within a year’s time of a prostate biopsy may lead to intra-gland artifact. Nevertheless, and especially in Europe, the concept of obtaining an mpMRI initially for an elevated PSA is gaining popularity. Studies from top centers are reporting up to 86% sensitivity and 94% specificity for cancer detection with this approach. In men who have a negative mpMRI for lesions, the risk of high-grade cancer being present is very low. In one recent randomized clinical trial of standard transrectal ultrasound (TRUS)-guided prostate biopsy vs initial mpMRI, none (0%) of 130 men with a negative MRI had any Gleason pattern 4 identified on saturation biopsy. The new PI-RADS (Prostate Imaging Reporting and Data System) scoring system for mpMRI lesions is gaining support. In summary, if a patient has a normal (PIRADS 1-2) mpMRI that is of high quality and well reported, the chance of having nothing greater than Gleason pattern 3 disease in the prostate lies between 94% and 100%. On the other hand, this is predicated on an initial prebiopsy MRI and might be useful for initial biopsy or active surveillance decisions. The question of how to use mpMRI in the follow-up of patients under active surveillance is much more speculative. The impact of prior (possibly multiple) biopsies on the continued accuracy of lesion detection and characterization is unknown. In the US, a major challenge is insurance coverage for mpMRI, especially in the initial workup of a patient with an elevated PSA. It is even challenging to obtain insurance coverage for mpMRI for the workup of men who have persistently elevated PSA despite a prior negative (TRUS-guided) prostate biopsy. mpMRI-Directed Prostate Biopsy Using the newer mpMRI capability noted above, MRI-directed prostate biopsy can be performed in three ways: in-gantry MRI-directed biopsy in real time, visually directed MRI-assisted (TRUS) guided prostate biopsy, and computer software–guided TRUS prostate biopsy using information from MRI. The in-gantry method is not commonly followed due to the challenges of using MRI equipment for excessive periods of time. The visually directed method is followed when the urologist views/reviews the mpMRI to help better direct the TRUS prostate biopsy needles. The most elegant method is software transfer of mpMRI data to specialized TRUS equipment, allowing the urologist to more precisely direct the TRUS biopsy needles into the specified lesions identified by mpMRI. However, this technology is in its infancy; the methods are more time-consuming and require more patient visits; and reimbursements are generally suboptimal, considering the added time and skill needed compared with standard TRUS prostate biopsy. Novel Markers Below are brief summaries of the commercially available blood, urine, and tissue novel molecular biomarkers now coming into clinical use as of early 2015. The clinical utility of these tests to improve health outcomes in men being screened for, or diagnosed with, prostate cancer has not yet been established in prospective randomized controlled trials. This is one of the reasons that none yet have level 1 evidence in NCCN guidelines or other guidelines. Novel Blood Tests In addition to serum PSA and free PSA, there are now two commercially available novel serum markers being touted to improve management of men with elevated PSA and/or newly diagnosed prostate cancer. 4Kscore. The Opko 4Kscore test involves measuring four protein kallikrein levels: total PSA, free PSA, intact PSA, and hexokinase 2 (HK2) along with age, DRE, and prior biopsy status in a proprietary algorithm. The result provides a percent risk of having Gleason 7 or higher prostate cancer for an individual patient. The test was recently validated in 1,012 patients enrolled in 26 centers, showing an area-under-the-curve (AUC) of 0.82 for Gleason 7 or higher, thus approximating the rate for prostate biopsy. Prostate Health Index (phi). This blood test received FDA clearance by the manufacturer, Beckman-Coulter, in 2012. The phi = ([−2]pro PSA / free PSA) × √ PSA. The blood test measures an isoform of PSA called [−2]pro PSA, in addition to free and total PSA. The FDA registration study for phi was a prospective multi-institutional trial that evaluated the ability of phi to enhance specificity for overall and high-grade prostate cancer detection in 892 men with normal DRE results and PSA in the 2–10 ng/mL range who were undergoing a greater than six-core prostate biopsy. At 80% to 95% sensitivity, phi had greater specificity and AUC (0.703) than PSA and % free PSA. An increasing phi was associated with a 4.7-fold increased risk of prostate cancer and a 1.61-fold increased risk of Gleason > 4 + 3 = 7. Both the 4Kscore and phi appear to add clinical value beyond total and free PSA, but reimbursement remains an obstacle to widespread use. Novel Urine-Based Tests PCA-3. The FDA has approved the PROGENSA PCA3 (prostate cancer gene 3) assay to help determine the need for repeat prostate biopsies in men who have had a previous negative biopsy. PCA3 is a prostate-specific non-coding RNA that is overexpressed 60- to 100-fold more in prostate tumors. PCA3 can be detected in the urine, and the overexpression of PCA3 mRNA can be quantified and expressed relative to the PSA gene. PCA3 is commercially available, but it is not universally reimbursed by commercial insurance and Medicare. TMPRSS2-ERG. T2-ERG (T2E) is the most common genomic abnormality in clinically localized prostate cancer. It is a genetic rearrangement that occurs in about 50% of prostate cancers in PSA-screened populations. Considered on a per-patient basis, because of the multifocal nature of prostate cancer, about 75% to 80% of men will have at least one ERG-positive cancer in their prostate. The gene rearrangement results in a fusion transcript which fuses the androgen-regulated TMPRSS-2 gene to the oncogenic transcription factor, ERG. The principle behind testing is the detection of prostate cancer cells in the urine that contain this genetic abnormality. There have been multiple prospective studies of this biomarker, particularly detection of the combined presence of both T2E and PCA3 in the urine. T2E is not yet commercially available. Novel Tissue/Pathology-Based Tests Oncotype DX Prostate Cancer Test. This is a 17-gene genomic messenger RNA expression multipathway signature involving stromal response, androgen signaling, cell organization, and proliferation cellular genetic pathways. The test uses biopsy tissue (formalin-fixed) and the endpoint is adverse pathology (upgrading, upstaging). It is employed to assist with pretherapy decision-making and may play a role in monitoring patients on active surveillance. The result is provided as a Genomic Prostate Score (GPS). For the Oncotype DX test, there has been a clinical validation/clinical utility study showing that the test did alter care providers’ decision-making more than 50% of the time. Furthermore, there are newer studies showing that it helps clinicians to predict biochemical recurrence after surgery. Prolaris. This test involves analysis of formalin-fixed prostate tumor biopsies or radical-prostatectomy tissue for cancer-specific mortality risk. The RNA expression signature is derived from 31 cell cycle proliferation genes, normalized to 15 housekeeping genes, which provides a Prolaris score that ranges from −1.3 to +4.7. Each 1-unit change in the Prolaris score causes a doubling or halving of the risk. Prolaris has been validated in multiple tissue types, including biopsy and radical prostatectomy specimens. Overall, it remains unclear whether the use of Prolaris or the Oncotype GPS is superior. Furthermore, the tests are expensive (costing more than $3,000 USD), and they are not universally reimbursed. In 2015, both Oncotype GPS and Prolaris were listed as options in NCCN guidelines. PCMT Test. This test, performed on prostate biopsy tissue from a negative biopsy, identifies a large-scale deletion in mitochondrial DNA that indicates cellular change associated with undiagnosed prostate cancer. It suggests the presence of malignant cells in normal-appearing tissue across an extended prostate volume. The test is FDA-approved for patients who have had a negative biopsy. If the deletion is present, then the patient is at a high risk of having undiagnosed prostate cancer. If the test is negative, the risk of prostate cancer is very low, and repeat biopsy can be deferred; however, this recommendation is based on the results of only two peer-reviewed publications. The test has a high sensitivity of 85% and a negative predictive value of 91%; however, it is not universally reimbursed and not in wide clinical use. Confirm MDx. This test is performed on biopsy tissue from men who have a negative prostate biopsy. Confirm MDx measures methylation of the GSTP1 gene which occurs in and around almost all prostate cancers. It is meant to be done after a negative biopsy to ascertain whether cancer was missed by sampling error. This tissue test is commercially available but has yet to gain widespread use. Pathology Adenocarcinomas 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 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 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. The Gleason system was developed using radical prostatectomy surgical specimens and not modern era needle biopsies. While the original system graded cases from a sum of 2 (best/lowest grade) to 10 (worst/highest grade), the international pathology community held a consensus panel in the last few years and adjusted the reading criteria, given that modern small-core needle biopsy samples are not able to reflect traditional Gleason 2–4 scores. As a result, the vast majority of contemporary Gleason grading is 6 (low/good); Gleason 3 + 4 = 7 (intermediate/low); Gleason 4 + 3 = 7 (intermediate/high); and Gleason 8–10 (high/bad). From a clinical standpoint, this renders the older literature on Gleason grading less useful for current-era patients. 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 Batson’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. This physiology forms the basis for staging studies to traditionally include nuclear medicine Tc-99 whole-body bone scans and CT scans of the abdomen and pelvis primarily looking for adenopathy. Most recently, sodium fluoride (F-18) positron emission tomography (PET) bone scanning is starting to replace traditional bone scans at major centers. The US Medicare program is funding a PET registry to further assess the value of F-18 PET in prostate cancer but results were not available as of mid 2015. Also, some, but not all, experts favor pelvic and prostate MRI over CT. In particular, prostate MRI with an endorectal coil and/or a 3 Tesla magnet machine is becoming popular for intra-gland and peri-gland imaging but is not universally accepted nor reimbursed. Some experts are using prostate MRI to better select candidates for active surveillance, although the validity of this practice is not yet confirmed by level 1 evidence. Prognosis and Natural History TABLE 1: 2010 TNM staging system of prostate cancer TABLE 2: 2010 TNM staging system of prostate cancer (anatomic stage/ prognostic group) TABLE 3: D’Amico et al risk stratification for clinically localized prostate cancer TABLE 4: Risk of dying of clinically localized prostate cancer without definitive locoregional therapy 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. In 2010, the American Joint Committee on Cancer (AJCC) updated prostate cancer staging recommendations in its 7th edition of the AJCC Cancer Staging Manual. These guidelines incorporate a more risk-based approach that utilizes the Gleason grading system and current PSA value in the staging system, which brings this system more in line with the risk-adapted approaches described in this chapter. Additionally, microscopic bladder neck invasion as a form of extracapsular extension was incorporated into the T3 stage designation rather than T4, given the more favorable outcomes of this subgroup of men. This scoring system is shown in Table 2. Use of either this staging system or the NCCN/D’Amico approach, or a nomogram-based risk assessment, will provide a more accurate prognostic classification system for prostate cancer at initial diagnosis. 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 3). Patients are divided into three risk groups (low, intermediate, or high) based on presence/absence 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. 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. In addition, Stephenson et al have developed a fairly robust postsurgical nomogram of over 12,000 men that is able to predict with > 80% accuracy 15-year prostate cancer–specific mortality. In this model, Gleason sum, PSA level, and clinical stage were the most important factors in predicting long-term outcome, whereas body mass index and PSA velocity were not able to add to the predictive accuracy of the model. According to the 2010 Guidelines, the NCCN defines as a “very low” risk group men with prostate cancer who have low volume using the Epstein criteria (T1c stage, Gleason < 7, PSA level < 10 ng/mL, fewer than three positive biopsy cores, < 50% cancer in each core, and PSA density < 0.15 ng/mL/g). These patients have a very low risk of prostate cancer death within 10 to 20 years and could be considered good candidates for active surveillance. These criteria are imperfect, and current efforts to improve upon them using nomograms may better help to select men who can safely defer initial aggressive therapy. New tissue- and serum-based molecular markers are increasingly being used to improve risk-adapted staging. 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 disease, 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 (6) have a small risk of dying of their cancer within 15 years (4% to 7%). However, those with poorly differentiated tumors (Gleason score 8 to 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 4). 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 There are several treatment options for localized prostate cancer, including radical prostatectomy, EBRT, brachytherapy (interstitial radiation/seeds), and cryotherapy. 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 very few 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. The multidisciplinary approach is becoming increasingly encouraged, but little is known about the multidisciplinary experience compared with routine care. A study by Stewart et al compared utilization determinants between a multidisciplinary clinic vs a urology prostate cancer clinic at Duke University Medical Center between 2005 and 2009, comparing 701 multidisciplinary clinic patients and 1,318 urology prostate cancer clinic patients. Patients seen at the multidisciplinary clinic were more likely to be younger and white, have a higher income, and travel a longer distance for evaluation. Of multidisciplinary clinic patients, 58% pursued primary treatment at the university medical center: these patients were more likely to be younger, black, and physician-referred; have a lower income; and reside closer to the medical center. Factors predictive of pursuing treatment at the medical center included high-risk disease and physician referral. Factors predictive of not receiving care at the university medical center were income greater than $40,000 and farther distance traveled (greater than 100 miles). Younger and wealthier patients seem to be utilizing the multidisciplinary approach. However, when treatment is pursued at the institution providing multidisciplinary services, the patient demographic resembles that of the treating institution. Clinically Localized Disease: T1, T2 Active surveillance Active surveillance in very low–risk to low-risk patients who have a limited life expectancy (< 10 to 15 years and even in men with normal life expectancy) also is emerging as an important initial treatment modality. Ongoing studies (Cancer and Leukemia Group B [CALGB]/National Cancer Institute of Canada [NCIC] START study) are examining the necessity of immediate vs deferred active definitive therapy. At this time, however, the majority of men in the United States receive initial radical surgery or radiation as treatment of localized prostate cancer. The NCCN recommends active surveillance as the first choice in treatment for all men with very low–risk disease, regardless of age. This is fast becoming an initial treatment selection of low and very low–risk men (Gleason score of 6 or less, low volume disease, PSA level 3 years). In these men, non-prostate cancer–specific mortality far outweighs prostate cancer–specific mortality, illustrating the need to assess age, comorbidities, and life expectancy in the initial treatment decisions of a man with prostate cancer. Approximately 25% to 30% of men will progress during this period and require definitive therapy, and this time, it is not known whether deferred active therapy results in inferior outcomes for these men compared with immediate therapy. Because level 1 multicenter prospective studies of active surveillance are lacking, there is still quite a bit of uncertainty in a defined protocol on follow-up of men on active surveillance. Recent studies have suggested that following PSA alone is inaccurate for assessing progression, and periodic repeat prostate biopsies are needed. The exact interval for repeat biopsy; however, remains uncertain. Younger and otherwise healthy men may warrant repeat biopsy as often as annually, while older and unhealthy men may never warrant rebiopsy. The biopsy pathologic criteria for progression are still somewhat uncertain as well. Patients who have clear-cut Gleason grade progression are relatively easy to define as having “failed” active surveillance, but sometimes more subtle changes on repeat biopsy are difficult to reconcile as constituting progression on active surveillance, or stability. As noted earlier, multiparametric 3T MRI is gaining popularity, as are molecular tissue biomarkers (such as Prolaris or Oncotype DX GPS), to better select men for active surveillance. However, prospective trials and level 1 evidence with these new tools are lacking. A critical question is related to active surveillance vs active treatment with radical prostatectomy. A 2011 study by Scandinavian Prostate Cancer Group Study 4 (SPCG-4) investigators reported on radical prostatectomy vs watchful waiting in early prostate cancer. In 2008, this group reported that radical prostatectomy, as compared with watchful waiting, reduced the rate of death from prostate cancer. After an additional 3 years of follow-up, they now reported estimated 15-year results. From October 1989 through February 1999, a total of 695 men with early prostate cancer were randomized to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009. During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P = .007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (95% CI, 0.44–0.87; P = .01). The number needed to treat to avert 1 death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was seven times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6–18.4). These results showed a continuing benefit with radical prostatectomy after 9 years of follow-up. Radical prostatectomy Radical prostatectomy can be performed retropubically (RRP) through a lower midline incision-an approach that may include pelvic lymph node dissection. Robotic-assisted laparoscopic prostatectomy (RALP) is now the most popular form of radical prostatectomy in the United States. Radical perineal prostatectomy is uncommon but remains a viable option. While RALP was originally touted to offer broad advantages over the open technique and its popularity soared, newer data from longer follow-up series suggest minimal differences when the experience of the surgeon is factored in. In other words, the skill and experience of the surgeon, whether by open prostatectomy or RALP, is much more important than the robotic device itself. That is, the robotic device does not necessarily improve outcomes, such as urinary or sexual recovery. The RALP is not cost-effective compared with open RRP. Among the various treatment options for prostate cancer, only radical prostatectomy has been demonstrated to confer a survival advantage over no treatment. The effectiveness of surgery vs observation for men with localized prostate cancer detected by PSA remains controversial. Investigators from the Prostate Cancer Intervention Versus Observation Trial (PIVOT) Study Group reported on radical prostatectomy vs observation for localized prostate cancer. From November 1994 through January 2002, a total of 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng/mL) were randomized to radical prostatectomy or observation and followed through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate cancer–specific mortality. During the median follow-up of 10 years, 171 of 364 men (47%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (HR, 0.88; 95% CI, 0.71–1.08; P = .22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (HR, 0.63; 95% CI, 0.36–1.09; P = .09; absolute risk reduction, 2.6 percentage points). Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng/mL (P = .04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P = .07 for interaction). Critics of the study cite limitations including short follow-up and the fact that most patients were enrolled from VA (US Department of Veterans Affairs) healthcare centers, which may not reflect characteristics of patients in other health settings. Although the morbidity of radical prostatectomy was a major concern in the past, improvements were made during the 1980s. 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 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 2 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. This approach is appropriate for men with small-volume disease. It offers 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 may improve 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 sufficient for intercourse 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, recent studies have suggested that early postoperative use of sildenafil, tadalafil, a vacuum entrapment device, and/or intracavernosal injection of vasoactive medications, such as papaverine, 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 patient morbidity) prior to meeting the outcome standards set by the open technique. RALP 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 oncologic efficacy similar to that of the open procedure. However, the length of follow-up (usually < 24 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 (and even the suggestion of more than 750 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. Although vision with robotic prostatectomy is excellent, the current-generation robotic device does not allow tactile sensation for the operating surgeon. Furthermore, the vast majority of robotic prostatectomies are performed via a transabdominal approach, whereas the open retropubic approach avoids the peritoneal cavity. A 2010 systematic review by Murphy et al showed the learning curve to be steep, and few published reports have reported outcomes in a standardized manner. The cost of the technology is substantial and RALP is generally not cost-effective compared with the open technique. 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 ng/mL, that is, low-risk individuals. Selected intermediate-risk men may also not require this staging procedure, but in high-risk men, it is still considered imperative. In addition, for high-risk and very high–risk men, there is growing use of extended pelvic lymphadenectomy, which includes more nodal regions (such as the internal iliac chain) than the standard obturator fossa. Unlike other malignancies, there is no minimum number of nodes recovered at pathology to determine the adequacy of the lymphadenectomy. 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 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. Neoadjuvant hormonal therapy is sometimes used for technical downsizing to facilitate surgical resectability. However, it is not routinely recommended to improve cancer control. With the approval of more effective hormonal agents, such as enzalutamide or abiraterone acetate, the role of neoadjuvant hormonal therapy prior to surgery may be revisited. Adjuvant therapy post prostatectomy Sidebar: The American Society of Therapeutic Radiation Oncology (ASTRO) and the American Urologic Association (AUA) recently released a joint guideline statement on the use of adjuvant and salvage radiotherapy after prostatectomy. While the statements largely mimic what has been trending as standard of care, this document formalizes the position of these two large societies. The key points reiterate the clinical benefit of adjuvant radiotherapy in reducing clinical progression in high-risk patients (seminal vesicle involvement, positive surgical margins, extraprostatic extension), while the impact on future development of metastasis and survival remains less clear. It also emphasizes the value of early intervention in men with a threshold PSA ≥ 0.2 ng/mL, as well as a second confirmatory PSA test after surgery to confirm relapse (Thompson IM et al: J Urol 190:441–419, 2013). These guidelines were subsequently endorsed by the American Society of Clinical Oncology (Freedland SJ et al: J Clin Oncol 32:3892–3898, 2014). 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. Radiation therapy. Men with positive margins or pathologic T3 disease following radical prostatectomy are potential candidates for early adjuvant EBRT. Previously there was some controversy as to the efficacy of early postoperative therapy vs intervention once a biochemical failure has been documented in patients who achieve an undetectable PSA level following surgery. However, more recent evidence would suggest that early intervention in these high-risk patients should be considered (see sidebar). Three randomized trials have been completed demonstrating a benefit to early adjuvant radiation therapy for men with positive margins, seminal vesicle invasion, or extracapsular extension. Typically, this treatment is offered after continence is restored, to allow healing to take place after surgery. With a median follow-up of 12 years, the most mature study (Southwest Oncology Group [SWOG] 8794), by Thompson et al, confirmed a significant improvement in the risk of metastasis (43% vs 54%) and in overall survival (41% vs 52%) among patients randomized to adjuvant radiation. The largest trial, by Bolla et al, included 1,000 patients with T3 disease randomly assigned to 60 Gy of radiation vs observation. At 5 years, progression-free survival was significantly improved (74% vs 53%), with no demonstration of an overall survival benefit. A subsequent update suggested that the benefit might be limited to patients with positive surgical margins. A German trial of 395 patients also demonstrated a biochemical progression–free survival benefit (72% vs 54%) to early radiation therapy in this pT3 group. The benefit of therapy was observed with or without positive margins (Wiegel et al, J Clin Oncol 2009). An alternate approach to early adjuvant radiation therapy is salvage radiation therapy for PSA recurrence. It remains unclear whether early salvage radiation based on PSA thresholds is inferior to the adjuvant approach, but it has the benefit of not treating all men with T3 disease with radiation. Of note, in the SWOG trial approximately one-third of patients initially assigned to observation ultimately received salvage radiation largely for PSA recurrence. In a retrospective analysis, there was a 5-year bNED (biochemical no evidence of disease, or undetectable PSA levels) advantage (77% vs 38%) to early vs salvage therapy. Based on this emerging evidence and the relatively low toxicity of the radiation levels employed, the use of early adjuvant radiation in this high-risk group should be considered. The use of salvage radiation after a PSA recurrence in the other patient groups should be based on the risk of having an isolated local/regional failure. Approximately 60% to 70% of patients with favorable disease after surgical failure (PSA level < 2 ng/mL, a slow PSA doubling time, and a long interval to failure after surgery) will experience durable disease-free survival after salvage 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 salvage EBRT and persistent or increasing PSA levels after surgery from five American academic institutions. Forty-five percent of patients were free of disease at 4 years after salvage EBRT. 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 generally should be restaged with pelvic CT, bone scan, and DRE. Patients with no evidence of metastatic disease should be evaluated for 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 survival benefit only for 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 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 the consensus definition of recurrence when the PSA level is > 0.2 ng/mL, most clinicians will also take into account other risk factors to try to ensure that they are observing a true cancer recurrence as opposed to a benign PSA detectability due to benign residual tissue. For example, in high-risk disease, a PSA above 0.2 ng/mL is likely to represent cancer recurrence and the need for early salvage radiation. On the other hand, a patient with lower-risk surgical pathologic features may be followed until the PSA is a bit higher (≥ 0.5 ng/mL), to better ensure that the PSA rise is truly due to cancer and not benign/BPH (benign prostatic hyperplasia) residual tissue. 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 of 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, they do 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. This approach 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. 3D conformal EBRT. This technique 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 are 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 have historically received initial pelvic treatment of 45 to 50 Gy, followed by a coned-down boost to the prostate. Radiation Therapy Oncology Group (RTOG) 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 > stage cT2c disease] cancers). At a median follow-up of 59.5 months, Roach et al (reporting in J Clin Oncol, 2003) noted an improved 4-year progression-free survival (60%) among those receiving whole pelvic radiotherapy in conjunction with neoadjuvant androgen deprivation, compared with other treatment arms (44% to 50%). In a subsequent update, the value of whole pelvic fields was limited to only patients receiving hormonal therapy, and the benefit became nonsignificant with a trend toward improved outcomes. Furthermore, a European randomized trial (GETUG-01) did not show a benefit to larger pelvic fields. Therefore, at this time, there is no consensus as to the use of whole pelvic or more limited prostate-only fields in the intermediate-/high-risk patient groups. EBRT dose. The previous standard radiation dose with conventional therapy was 70 Gy given over 7 weeks; however, more 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 MD Anderson Cancer Center compared 70 Gy given conventionally vs 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 (in Int J Radiat Oncol Physiol, 2005) 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 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). 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 that were previously unattainable. IMRT was pioneered in several major centers, and Zelefsky et al from Memorial Sloan-Kettering Cancer Center reported a series of 772 patients treated with doses between 81 and 86.4 Gy (Int J Radiat Oncol Biol Phys, 2002). 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+ gastrointestinal/genitourinary toxicity. The early PSA relapse−free survival rates for favorable-, intermediate-, and unfavorable-risk groups were 92%, 86%, and 81%, respectively. While IMRT should be considered the standard of care, continued caution is warranted with respect to quality assurance and accurate target localization. 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 are 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 or online, and a published economic evaluation questioning its cost-effectiveness, the future of eventual widespread application of proton therapy remains unclear. Stereotactic body radiotherapy (SBRT). Stereotactic body radiotherapy (SBRT) is being investigated as a method to treat early-stage prostate cancers. Utilizing several highly focused fractions, this method exploits the alpha/beta ratio typical of slowly growing malignancies. The technique, which employs high-dose radiotherapy (approximately 700 cGy) for several fractions (typically 5), can be delivered by several specialized methods, including linear accelerator-based models, tomotherapy, and CyberKnife. A pooled cohort of 41 patients with a median follow-up of 5 years demonstrated both the efficacy and safety of this approach utilizing the CyberKnife. This methodology represents a major paradigmatic shift over the typical 8-week course of IMRT. This approach is gaining favor with patients intrigued by the convenience of a short course of therapy. It is important to recognize that while results from several ongoing studies appear promising, further data maturation in a large patient population will likely be necessary to promote this as a standard technique. Additionally, several investigators are employing a hybrid of these approaches with hypofractionated (higher dose/fraction) IMRT to reduce treatment times by approximately 2 weeks. The extent to which the inverse relationship of smaller treatment fields to higher doses per fraction can be delivered with morbidity comparable to that of conventional therapy requires further study. 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 tumor 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 or LHRH antagonist therapy. The survival benefits of androgen suppression therapy (AST) for patients with intermediate-risk disease have been uncertain. A 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 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 a 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 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 men who did not receive androgen ablation. These findings suggest that cardiac evaluation should be considered in men older than age 65 with cardiovascular risk factors prior to undergoing androgen ablation. RTOG 94-08 was presented at the American Society for Therapeutic Radiology and Oncology (ASTRO) meeting in April 2010. This study examined a short course (4 months) of androgen deprivation (flutamide plus either goserelin or leuprolide) with EBRT (66.6 or 68.4 Gy) in 1,979 men. For intermediate-risk men, the 8-year survival rate was 66% in men who received radiation therapy alone and 72% in men who also received hormones. There was no benefit observed to hormonal therapy in low-risk men. Finally, Pisansky et al reported recent data from RTOG 9910, which randomized 1,005 men with intermediate-risk prostate cancer to 8 weeks of neoadjuvant ADT followed by radiation with a further 8 weeks of ADT vs 28 weeks of ADT followed by radiation plus 8 further weeks of ADT found that the short course of ADT (4 months total) provided excellent and equivalent long-term disease control; the 10-year disease-specific survival rate was 95% and the risk of biochemical recurrence was low (27%), with lower treatment-related toxicity, illustrating that for most men with intermediate-risk prostate cancer, 4 months of ADT is sufficient with radiation. 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 some popularity of 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 2–3 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-125 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 and an International Prostate Symptom Score (IPSS) > 15 have an increased risk of requiring catheterization following implantation. Patients who have undergone prior transurethral 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-risk or high-risk disease, implants may be combined with EBRT. There is sound logic in combining high-dose radiotherapy 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 gastrointestinal/genitourinary 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 HDR devices, usually in patients with locally advanced disease. In this technique, a high dose (minimum, approximately 5 Gy) is delivered to the prostate over a period of 1 hour or less by remotely inserting a highly radioactive source into catheters placed into the prostate using 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 to 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, and tadalafil, and prostaglandin E1, administered as a urethral suppository (MUSE [Medicated Urethral System for Erections; alprostadil]); intercavernosal injection; or vacuum entrapment devices 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 post irradiation 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. More recently, this definition has been replaced by an absolute PSA rise of 2 ng/mL above the posttreatment nadir 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 are not treated with androgen ablation, the 5-year actuarial risk of distant metastasis from the time that the PSA level begins to rise is about 50%. A key concept in rising PSA levels is PSA velocity, or more specifically PSA doubling time. Multiple studies have found that a PSA doubling time < 10 to 12 months predicts early clinical relapse if biochemical recurrence is untreated. In addition, studies have documented the real phenomenon of postradiotherapy PSA bounce, which is defined as a rise above the baseline PSA following the initiation of radiotherapy. This may occur in 20% to 40% of men depending on the threshold of PSA rise and is not known to have prognostic significance. Thus, PSA rises should be confirmed over time to ensure that they are durable rather than transient prior to initiating salvage systemic therapy. Treatment recommendations for recurrence post irradiation 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 next section, “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 to 10 ng/mL) preoperative PSA level, low pathologic stage (T3a or less), and prior type of radiation therapy (with brachytherapy and IMRT being favorable). However, no randomized trials have been conducted in this setting to provide level 1 evidence favoring surgery over other modes of treatment. 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 for 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 three large randomized trials (RTOG 92-02, RTOG 85-10, and European Organisation for Research and Treatment of Cancer [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 (Int J Radiat Oncol Biol Phys 2001), 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 those treated using 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 vs radiation therapy alone. This result was confirmed by Warde et al in a large randomized trial of 1,205 locally advanced patients reported in 2011. The addition of radiation therapy to lifelong hormonal deprivation improved overall survival by 7% at 7 years with minimal additional toxicity. These studies have confirmed that EBRT with long-term hormonal therapy is necessary for management of locally advanced or high-risk prostate cancer as compared to hormonal therapy alone, due to improvements in local control as well as systemic control, and this combination should be considered a standard initial therapy for high-risk men. 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% (Yamada et al, J Clin Oncol 1994). Well-differentiated 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, comprising more than 1,000 patients. In this population, 34% of whom received adjuvant therapy, 15-year cancer-specific survival and local recurrence rates were 77% and 21%, respectively. In an Eastern Cooperative Oncology Group (ECOG) clinical trial, 98 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 4 of 47 in the treatment group (P = .02). In one interesting series, Briganti et al found that adjuvant radiation therapy with androgen deprivation therapy was associated with a survival benefit (biochemical and prostate cancer–specific) in node-positive men treated with radical prostatectomy initially, even after adjustment for known confounders. This finding suggests that local tumor control may prevent distant failure in this disease. 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 shown 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 analog. 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 MD 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 patients with nodal involvement. 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 pelvis 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 levels 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 ( 2 years), PSA doubling time ( 9 months), and Gleason score (8–10 vs 5–7) are among the important factors for predicting the development of metastatic disease and survival. There is a wide variation in the PSA value seen at the onset of bone metastases; one study documented an average PSA of 33 at this onset; however, about 25% of men will develop skeletal metastases with a PSA of less than 10, and another 25% will not develop metastases even with a PSA of 50 to 90. Thus, PSA alone does not necessarily predict the onset of metastatic diseases, and other factors such as PSA doubling time, life expectancy, comorbidities, and patient concern often dictate when hormonal therapy is initiated. 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. Ongoing randomized phase III studies are also testing the role of docetaxel with androgen deprivation therapy in this setting, but the role of chemotherapy in the nonmetastatic setting remains experimental. 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. The initial study results from the Eastern Cooperative Oncology Group (ECOG) phase III CHAARTED trial, presented at ASCO 2014, showed for the first time that the addition of docetaxel to androgen deprivation therapy can improve overall survival in select patients who present with metastatic, hormone-sensitive prostate cancer, changing the treatment landscape for these patients. As newer systemic treatment strategies and agents have been approved by the FDA, Basch et al report, therapy guidelines have recently been updated by ASCO to include enzalutamide, sipuleucel-T, abiraterone acetate, radium-223, docetaxel, and cabazitaxel as established evidence-based approaches for sequential use in men with metastatic castrate-resistance prostate cancer (mCRPC), each of which has demonstrated improvements in overall survival. 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. TABLE 5: Hormonal approaches to the treatment of advanced prostate cancer LHRH analogs. LHRH agonists, such as leuprolide and goserelin, interfere with the normal pulsatile secretion of luteinizing hormone from the pituitary gland, resulting in an eventual decline in serum testosterone levels. The effect is reversible with cessation of therapy. Because luteinizing hormone is initially increased with LHRH agonists, testosterone levels 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 5). Side effects of androgen deprivation therapy include hot flashes, metabolic-type syndrome and weight gain, loss of libido, loss of peripheral hair growth, gynecomastia, an elevated risk of diabetes, loss of bone mineral density and an increased risk of fracture, and finally an increased risk of cardiovascular complications (including myocardial infarction, stroke, sudden cardiac death, deep venous thrombosis, and angina). The overall risk/benefit profile of androgen deprivation therapy thus depends on an individual man’s preexisting cardiovascular risk and comorbidities, and it should be individually tailored based on this risk assessment. The flare phenomenon can also be avoided through the use of gonadotropin-releasing hormone (GnRH) antagonists. This class of drugs leads to immediate suppression of androgen production without the initial testosterone surge that results with GnRH agonist therapy. Abarelix is a GnRH antagonist that was approved in 2003. However, the manufacturer halted US sales to new patients in 2005. A second agent, degarelix for injection, was approved by the FDA in December 2008. It is currently available in a monthly formulation and is not associated with anaphylaxis. As a receptor antagonist, degarelix reversibly binds to the GnRH receptors in the pituitary gland, immediately suppressing the secretion of LH and follicle-stimulating hormone (FSH), subsequently reducing testosterone levels. Antiandrogens. Antiandrogens function to block the binding of dihydrotestosterone (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, and nilutamide. These agents differ slightly in their affinity for the androgen receptor and their side-effect profiles. For example, nilutamide has been associated with interstitial lung disease and visual adaptation (light-dark) disturbances, whereas flutamide is associated with diarrhea. Antiandrogens as a category have not been as highly associated with cardiovascular risk outcomes, but this may be due to the low numbers of patients treated with antiandrogen monotherapy. Consideration of prophylactic breast irradiation prior to the use of prolonged antiandrogen monotherapy should be considered, given the high risk (> 50%) of developing gynecomastia. Tamoxifen has also been shown to prevent gynecomastia in these men but is associated with other adverse events such as deep venous thrombosis/pulmonary embolism. 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 in metastatic disease 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 (HR, 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 AST, but the approach is not considered standard and its efficacy relative to primary gonadal suppression is not established. 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. CAB. Complete 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 agonists alone vs 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 vs 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. Recent meta-analyses suggest a small but incremental benefit of noncyproterone antiandrogens in combination with GnRH agonists in terms of overall survival (15% to 20% relative risk reduction). This finding led the American Society of Clinical Oncology (ASCO) to advise an informed discussion of the risks and benefits of CAB. Several phase III trials evaluating the role of intermittent androgen deprivation are ongoing. A phase III European trial investigating the use of intermittent hormone therapy in patients with locally advanced or metastatic prostate cancer was reported by Calais da Silva et al in 2009. In this trial, 766 patients were registered, and 626 patients whose PSA level decreased to < 4 ng/mL or to 80% below the initial value after 3 months of induction treatment were randomized to receive continuous vs intermittent hormone therapy. The primary outcome of disease progression was not statistically different between groups. There was also no significant difference in overall survival. Among the 314 patients on intermittent therapy, 50% were off therapy for at least 52 weeks following initial LHRH induction. Patients whose PSA level dropped below 2 ng/mL spent a median of 82% of their time receiving no therapy. Many investigators believe that the advantages observed in trials that include an LHRH antagonist exist because of the “flare phenomenon,” which occurs with LHRH agonists alone and may be lost with a short period of treatment with antiandrogens during the expected flare period. ASCO has published guidelines for the initial management of androgen-sensitive (recurrent, metastatic) prostate cancer. Based on the literature, immediate androgen deprivation was associated with a moderate decrease in prostate cancer mortality and a moderate increase in other causes of mortality. Currently, there is no definitive evidence favoring the early initiation of androgen deprivation in this population. 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/day cause significant cardiovascular mortality, DES has fallen out of favor as a first-line therapy to induce castration. Ketoconazole. 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 complete androgen blockade. Abiraterone acetate. Recent evidence suggests that androgen production is not limited to the testicles and adrenal glands, but that prostate cancer and the surrounding microenvironment can contribute to androgen synthesis in an autocrine/paracrine manner. This is mediated by overexpression of key androgen synthetic enzymes such as cytochrome P450 17-hydroxylase/lyase (CYP17) and other enzymes, overexpression of androgen transport molecules that allow cancer cells to import circulating androgen precursors, and reductions in androgen-metabolizing enzymes that degrade androgens. Given these findings, combined with additional findings of androgen receptor (AR) mutations, amplifications, and splice variants that can lead to constitutive or overactive AR signaling, there have been significant recent efforts to inhibit AR signaling in tumors that were previously deemed hormone-refractory but are now classified as castration-resistant, a more biologically correct term. One such CYP17 inhibitor is abiraterone acetate, an oral agent with potent CYP17 inhibitory activity that leads to a dramatic reduction in systemic androgen levels. Feedback upregulation of adrenocorticotropic hormone (ACTH) can be seen with this agent alone; thus low-dose prednisone is combined with abiraterone to prevent adrenal insufficiency as well as to reduce the mineralocorticoid excess (hypertension, fluid retention, hypokalemia) seen with abiraterone. The use of prednisone also improves upon the overall efficacy of this agent. Additional CYP17 inhibitory agents are in development, such as TAK-700 (orteronel). Abiraterone acetate has now been FDA-approved for use in both the pre-chemotherapy setting as well as in the post-docetaxel setting for men with mCRPC (see below). Enzalutamide. This novel androgen-signaling inhibitor (formerly known as MDV3100) has the ability to bind the amplified AR, prevent nuclear translocation, and result in cytocidal effects in preclinical models of CRPC, even in cellular models that are bicalutamide-resistant. Phase I/II studies have demonstrated efficacy and safety in the pre-docetaxel and post-docetaxel CRPC setting, and results from AFFIRM, a large phase III trial, demonstrated a nearly 5-month improvement in overall survival compared with placebo in the post-docetaxel metastatic CRPC setting. After priority review, the FDA approved enzalutamide in August 2012 for patients with metastatic CRPC previously treated with docetaxel. The side effect profile includes fatigue, fall risk, a low incidence of seizures (< 1%), and hot flushing. PSA responses occurred in 50% of men, and pain palliation, soft tissue responses, delays in progression-free survival (8 months), and delays in skeletal-related events have been notable in the post-docetaxel mCRPC setting, accompanied by a 4- to 5-month improvement in survival. The pre-docetaxel mCRPC trial (PREVAIL) was also recently reported to be positive, resulting in a 30% improvement in relative hazard of death over time and more than 80% reduction in the risk of progression over time as compared with placebo (see below). Thus, the likely use of enzalutamide will be in the pre-docetaxel treatment space, and the relative merits of using either abiraterone or enzalutamide first will be determined based on the overall risk/benefit of these drugs for individual men, although initial retrospective studies have suggested cross resistance between these two novel agents. Comparative effectiveness studies and combination/sequential studies are needed. Currently, this agent is in phase III trials in the pre-docetaxel M0 CRPC setting, head to head against bicalutamide in the STRIVE randomized phase II trial, and in phase II trials investigating the earlier use of this agent as adjuvant therapy, for radiosensitization, and prior to surgery, and in a phase IV trial to determine the risk of enzalutamide inducing seizures. These studies will clarify the role of enzalutamide in non-CRPC populations. TABLE 6: The incidence of complications from advanced prostate cancer with immediate vs deferred androgen deprivation Chemotherapy Early use of docetaxel. At this time, the standard of care is to use docetaxel only in men with mCRPC. There are no published data to support its early use in the hormone-naive metastatic setting, in the rising PSA setting, in the adjuvant/neoadjuvant setting, or in men without metastatic disease and CRPC. However, findings from the ECOG CHAARTED trial were reported by Sweeney et al at ASCO 2014. This study randomized 790 men with metastatic hormone-sensitive prostate cancer and a high metastatic burden (visceral disease, high bone burden) to standard ADT alone or ADT with 6 cycles of docetaxel without prednisone. This study was enriched for patients with high-volume metastatic disease (66% of patients in the combination arm and 64% of patients in the ADT-alone arm), defined as patients with either visceral metastatic disease or more than four bone metastases and at lease one bone metastasis beyond the axial skeleton. Overall survival was improved for those treated with the combination of docetaxel and ADT (HR, 0.61; 95% CI, 0.47–0.80; P = .0003). The median overall survival for patients treated with docetaxel and ADT was 57.6 months, compared to 44 months for those treated with ADT alone, an improvement of 13.6 months. Patients who had a high volume of metastatic disease in particular showed an improvement in median overall survival of 17 months (49.2 months vs 32.2 months; HR, 0.60; 95% CI, 0.45–0.81; P = .0006). Written publication and further maturation of these data are still pending, but the trial results suggest that docetaxel can be considered in addition to ADT in the upfront setting, for patients with high-volume metastatic disease at the time of diagnosis. Early vs late treatment. Whether to treat patients early with hormonal therapy or wait until they become symptomatic has been tested in a large European trial conducted by the Medical Research Council (MRC). Men were randomized to receive immediate hormonal therapy (orchiectomy or an LHRH analog) vs 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 6). 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 the MRC study 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. A randomized EORTC study (30891) of early vs deferred androgen deprivation therapy for men with localized prostate cancer not amenable to local treatment did not show a prostate cancer–specific survival advantage to the immediate use of androgen deprivation therapy in these men. Balancing comorbidity and the risk of cardiovascular complications is an important consideration in the timing of androgen deprivation therapy in this population, given the competing causes of mortality. 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 et al published an adjuvant study that evaluated immediate hormonal therapy vs 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. Immunotherapy. In 2010, sipuleucel-T became the first autologous cellular therapy approved for use in patients with solid tumors. The phase III IMPACT trial demonstrated a 4.1-month survival advantage over sham vaccination. Thus, autologous dendritic cell therapy vaccination (three infused doses over 4 weeks following initial leukapheresis), utilizing a prostatic acid phosphatase–granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion protein to stimulate immune cells, has become a standard of care prior to docetaxel in men with asymptomatic to minimally symptomatic mCRPC. Men with pain requiring narcotics, with visceral metastases, and with a life expectancy < 6 months are not eligible for this therapy. Of note, vaccination did not lead to PSA declines, tumor responses, improved palliation, or delayed tumor progression by our current measures, and thus this therapy should be regarded as adjunctive to other current therapies that are more cytoreductive and palliative. Sipuleucel-T therapy involves an initial leukapheresis whereby a small fraction of leukocytes are removed by a pheresis procedure, typically through the American Red Cross, and sent to the manufacturer, Dendreon, for modulation. During a proprietary next step, the white blood cells are then pulsed with an antigen cassette composed of prostatic acid phosphatase (PAP) fused to GM-CSF, an immune adjuvant. After 3 days, these newly primed CD54-positive cells, which have been stimulated and expanded ex vivo, are shipped back to the patient and infused in a local treatment facility. This process is then repeated two more times during a 1-month procedure. Side effects have included infusional reactions (fever, headache, perioral numbness, chills, muscle aches, and back pain) that are typically mild and transient (1–3 days) and can be treated with acetaminophen or NSAIDs. Other side effects may include the need for a central line for leukapheresis in about 25% of men, which may require heparin and may increase the risk of infection. In a double-blind, placebo-controlled, multicenter phase III trial, 512 patients were randomly assigned in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients). The median survival was 4.1 months longer in the sipuleucel-T group than in the placebo group (25.8 months vs 21.7 months). The estimated probability of survival 36 months after randomization was 31.7% in the sipuleucel-T group and 23% in the placebo group. A major question regarding sipuleucel-T is the timing of treatment initiation given the availability of newer hormonal agents such as abiraterone and enzalutamide. A retrospective subset analysis by Schellhammer et al of the phase III IMPACT trial of sipuleucel-T suggested a greater survival improvement in treatment of men with a lower PSA. For example, the HR and improvement in median survival for men with a PSA under 22 ng/mL were 0.51 and 13 months, as compared to men with a PSA over 134 ng/mL (for whom the HR was 0.84 and median survival was 2.8 months), illustrating that immunotherapy may result in greater relative benefits when used early in the disease process, a time when tolerance is not as overwhelming and when men have a longer expected survival time. These results should be prospectively validated, but they suggest that use of sipuleucel-T should be prioritized to men with asymptomatic mCRPC, a low burden of disease, and a low PSA level, and without visceral, particularly liver metastatic, disease. 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–III studies of intermittent androgen deprivation therapy (IADT) have demonstrated feasibility and safety with suggestion of improved quality of life without negative effects on time to disease progression or survival. More recently, the phase III SWOG/NCIC/UK cooperative group trial of continuous vs intermittent androgen deprivation therapy in men with M0 PSA recurrent prostate cancer was reported. In this trial, 690 patients randomized to the intermittent therapy arm were found to have improved quality of life with less sexual dysfunction, hot flashes, and improved physical function and fatigue. There was no significant difference in time to disease progression or overall survival. The final results of several ongoing phase III trials in metastatic disease and PSA-only relapse will better define the role of intermittent androgen deprivation; however, most trials suggest that IADT is non-inferior to continuous ADT in M0 disease and may result in improved quality of life and reduced cost. With the currently available information, intermittent androgen deprivation may be considered in most patient settings as a standard of care for nonmetastatic disease. However, for M1 disease, the results of the recently presented SWOG 9346 trial have challenged this dogma and suggest that intermittent therapy in the face of metastatic disease may result in a higher risk of death from prostate cancer. In this trial of more than 3,000 men with M1 disease starting ADT, 1,749 men were randomized to intermittent ADT vs continuous ADT, with resumption of ADT being performed if the PSA rose to the baseline value or a PSA of 20. In this study, while there were some improvements in fatigue, libido, emotional function, and erectile function in the IADT arm, IADT was found not to be noninferior according to the study design, with a HR of 1.09 (95% CI, 0.95–1.24). This translated into a 0.7-year improvement in survival with continuous therapy. However, therapeutic equivalence could not be excluded in this trial. Unplanned subgroups unexpectedly showed worse outcomes with IADT in patients with nodal and axial metastatic bone disease, suggesting that IADT should only be considered in men with M1 prostate cancer who experience severe side effects from ADT and under informed consent about the overall risks/benefits of this approach. 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 likely significant comorbidities. However, a patient with multiple metastatic sites will need immediate treatment, generally with orchiectomy, LHRH agonists or antagonists, 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. Degarelix or ketoconazole may be considered as initial systemic therapies for patients presenting with spinal cord compression as the first sign of prostate cancer, as well as combined androgen blockage. For patients who have a high volume of metastatic disease (with visceral metastases or widespread bone metastases at the time of diagnosis), docetaxel may be considered in addition to ADT. Palliative radiation in this setting should also be considered. Given the overall limitations of hormone therapy, all appropriate patients should be offered access to clinical trials. Intermittent ADT should be considered in men with M0 disease and in some men with low-volume M1 disease who have ADT-related toxicity. 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 MRC 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 It is important to realize that there has been a shift in terminology from “androgen-independent” or “hormone-refractory” prostate cancer to a newer term: castration-resistant prostate cancer. This change reflects an understanding that prostate cancer often remains dependent on androgenic signaling, even in the presence of castrate levels of testosterone. Tumors may produce their own androgens through autocrine signaling, amplify low levels of testosterone ligand signaling through AR mutations or duplications, and may have activation of the AR through other ligands. Thus, progression of disease despite castration does not necessarily imply resistance to all hormonal strategies, as exemplified by the response to antiandrogens, ketoconazole, and newer second-generation agents such as enzalutamide or abiraterone acetate. Thus, true hormone-refractory disease may refer to disease that has progressed despite therapies employing all known hormonal strategies. 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 chemotherapy for men with metastatic androgen-independent prostate cancer, to improve survival. The survival advantage of docetaxel is not limited by the number of prior hormonal therapies. However, as exemplified by recent novel antiandrogens (enzalutamide) and adrenal/autocrine synthesis-inhibiting agents (abiraterone acetate), men with castration-resistant disease remain sensitive to agents targeting the androgen receptor, and this remains a rich area of clinical investigation. In phase I/II trials, the novel oral antiandrogen enzalutamide demonstrated striking PSA declines (50% to 70% achieved a > 30% decline) and partial tumor responses both in the pre-docetaxel and post-docetaxel settings (see below), with responses that were durable in many men for over 6 months. The drug can prevent androgen-induced nuclear translocation and has shown tumoricidal activity even in bicalutamide-resistant model systems. Abiraterone acetate with prednisone has demonstrated similar outcomes in these settings as well, showing that hormonal sensitivity may remain even among docetaxel-resistant men. Phase III trials of these agents are completed or ongoing (Table 8). For patients with a rising PSA level only, timing of chemotherapy is even less clear. The ECOG 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. Ongoing randomized studies of androgen deprivation therapy with and without chemotherapy should address this question within the coming few years. 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 changed significantly in 2004 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 7). Investigators from the SWOG 9916 trial randomized patients to receive mitoxantrone plus prednisone vs docetaxel (60 mg/m2) plus estramustine 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 used in combination with docetaxel in the front-line setting, given the lack of additional efficacy and the certain added toxicity. TABLE 7: Standard chemotherapy regimens for prostate cancer A second international randomized phase III trial (TAX327) by Tannock et al showed a similar survival benefit of 3 months with docetaxel (at 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 peripheral neuropathy, both of which can be dose-limiting. Additional toxicities include constipation, tearing due to docetaxel deposition in tear ducts, onycholysis, and fluid retention (peripheral or pulmonary edema, pleural effusion). Weekly docetaxel with prednisone (30 mg/m2) for 5 of 6 weeks provided an intermediate level of control and survival that was not statistically different from that with mitoxantrone and prednisone, despite favorable PSA declines and tumor and pain responses. Weekly docetaxel is less well tolerated, and early treatment discontinuation likely limits this schedule’s utility. The activity of docetaxel following abiraterone acetate is unknown. A 5-year update of this study has confirmed a 3-month survival advantage to every-3-week docetaxel in the overall study population. Additional benefits of docetaxel over mitoxantrone included superior PSA responses, improved pain and quality-of-life responses, greater durability of response, and improved radiographic responses. 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 for men without normalized PSA levels-nearly a twofold difference. Current studies indicate that, of all current surrogate markers in this disease, a 30% or greater decline in the serum PSA level within 3 months of treatment initiation may be the best predictor of overall survival and may be used to assist in prognostication after treatment initiation. Although not a credentialed surrogate for FDA approval, this level of PSA decline was shown in both pivotal studies to be highly associated with survival as compared to other outcomes and PSA metrics, including the traditional confirmed > 50% decline in PSA level and pain responses. The timing of docetaxel initiation is controversial, given its known toxicities and the many active hormonal and now immunologic therapies that can be administered prior to docetaxel. However, it has been demonstrated that the absolute survival advantage of docetaxel is greatest (3 to 4 months) in men with minimal symptoms, whereas men who have impaired performance status or pain due to cancer are not able to tolerate 10 full cycles well and often have a reduction in the overall survival benefit (1- to 2-month advantage). Thus, the early timely use of docetaxel in men with clear prostate cancer progression based on PSA or radiographic disease is warranted for palliation and prevention of pain onset as well as improved survival. There are also recent data from Kellokumpu-Lehtinen et al to support an every-2-week docetaxel chemotherapy regimen of 50 mg/m2, the use of which a randomized phase II–III trial demonstrated response rates, survival, and progression rates equivalent to the standard 3-weekly regimen but with a lower degree of marrow suppression and neutropenic fever. For elderly men or men at high risk of toxicity/marrow suppression, this every 2-week-regimen is reasonable. Several nomograms currently exist for men with mCRPC that can predict overall survival (Halabi; Memorial Sloan-Kettering Cancer Center; Armstrong, TAX327). These studies indicate that the presence of visceral metastatic disease, anemia, performance status, PSA level, PSA doubling time, elevated alkaline phosphatase, low albumin, Gleason score, the presence of significant pain, the type of progression, and lactate dehydrogenase level are highly predictive of survival and can be used to predict prognosis. In addition, circulatory tumor cells are FDA-approved as prognostic markers of survival in men receiving docetaxel. These cells can be enumerated in 7.5 mL of whole blood either prior to systemic chemotherapy or while the patient is receiving chemotherapy, and the number of circulating tumor cells (CTCs) in whole blood correlates strongly with overall survival. Although CTCs are not credentialed at this time as surrogates and thus have not been used or studied to guide therapeutic choices in men with CRPC, the ability to detect and characterize these cells holds promise as a predictive and intermediate biomarker to aid in personalized medicine approaches. These cells can be further characterized in research settings for molecular profiling, indicating their potential to help guide systemic therapy in the future. 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. Toxicities of mitoxantrone include a cumulative cardiotoxicity, typically after 10 to 12 cycles of therapy. Thus pretreatment ejection fraction assessment is recommended in all men as well as serial ejection fraction assessments every 4 to 5 cycles or based on new onset of cardiac symptoms. Given the approval of cabazitaxel (see discussion later in this chapter), use of mitoxantrone has generally been limited to third-line therapy, or for palliative therapy in men who are not candidates for microtubule-targeting therapies because of neuropathy, for example. 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 mCRPC with a more potent bisphosphonate, zoledronic acid. 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. Zoledronic acid did demonstrate a delay in the need for radiation to bone, pathologic fracture onset, and bone pain, providing some evidence of clinical benefit over time. At this time, the recommendation for zoledronic acid in prostate cancer is limited to men with mCRPC, pending ongoing randomized studies in the hormone-sensitive population. 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, use of 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). Denosumab. A novel approach to the prevention of bone loss and skeletal events in recurrent prostate cancer involves the use of an inhibitor antibody to block RANKL (receptor activator of nuclear factor-ÎºB ligand), a molecule involved in osteoclast-mediated bone resorption and remodeling. This antibody, termed denosumab, has demonstrated an ability to improve bone mineral density in men undergoing androgen deprivation theapy, as well as an improved capability in preventing pathologic fractures, the need for radiation or surgery to bone, or spinal cord compression (so-called skeletal-related events) and restoring bone density as compared with zoledronic acid in head-to-head studies. While osteonecrosis is also a side effect with this compound (1% to 4% risk over time), its subcutaneous administration and lack of kidney toxicity have led to an approved and now standard role for this agent for the prevention of skeletal events in men with castration-resistant prostate cancer. Further studies of the role of denosumab in the prevention of metastasis and hormone therapy–induced clinical fractures will help to guide the rational use of this agent, which is given by subcutaneous injection. Side effects of denosumab include hypocalcemia and hypophosphatemia and osteonecrosis of the jaw, with risks similar to or slightly greater than those of zoledronic acid. Second-line therapy after docetaxel Cabazitaxel with prednisone. In 2010, it was demonstrated that a novel synthetic taxane, cabazitaxel, demonstrated improved overall survival compared with mitoxantrone in men with mCRPC whose disease had progressed on docetaxel chemotherapy. As reported by de Bono et al in a randomized, open-label, phase III study of 755 patients (377 in the mitoxantrone group, 378 in the cabazitaxel group), the overall survival benefit was 2 months (from 12.7 to 15.1 months; HR, 0.70; 95% CI, 0.59–0.83; P < .0001), and improvements in PSA response, tumor response, and progression-free survival were notable. Each regimen was similarly palliative, but the duration of response favored cabazitaxel. Cabazitaxel is given intravenously at 25 mg/m2 every 3 weeks with prednisone dosed at 5 mg orally twice daily. The risk of neutropenia and sepsis due to myelosuppression in this heavily pretreated group of men is high (7% to 8%) and prophylactic GM-CSF should strongly be considered. Other toxicities include neuropathy, fatigue, diarrhea, nausea, and vomiting. Continuation of testosterone suppression was required. Cabazitaxel has demonstrated activity in docetaxel-resistant cell lines and was approved by the FDA in 2010 for second-line treatment of men with chemorefractory CRPC. A nomogram published in JNCI by Halabi et al in 2013 is a useful tool to estimate prognosis of men treated with cabazitaxel in this second-line setting. Abiraterone acetate with prednisone. In April 2011, the FDA approved the androgen synthesis inhibitor abiraterone acetate in combination with low-dose prednisone for the treatment of men with mCRPC who have received prior chemotherapy containing docetaxel. Autocrine and/or paracrine androgen synthesis is known to be enhanced in the tumor microenvironment during castration-resistant progression in many men, and abiraterone acetate inhibits a key step in testosterone/dihydrotestosterone precursor synthesis, notably the cytochrome P450 c17 (lyase, hydroxylase) enzyme. Blockade of this enzyme is known to reduce testosterone production from the adrenal gland and is thought to reduce intratumoral synthesis as well, mediated by a reduction in AR activity, as described by Attard et al. The FDA approval is based on the results of a randomized, placebo-controlled, multicenter trial reported by de Bono in 2011, in 1,195 patients with metastatic CRPC previously treated with docetaxel-containing regimens. Patients were randomly allocated (2:1) to receive either abiraterone acetate orally at a dose of 1,000 mg once daily (n = 797) or placebo once daily (n = 398). Patients in both arms (abiraterone acetate and placebo) received prednisone 5 mg orally twice daily because of the ability of prednisone to improve both the safety and efficacy profile of abiraterone acetate as well as to serve as an efficacy control group, given the modest but known efficacy of prednisone alone in this population. Treatment continued until disease progression (defined as a 25% increase in PSA level over the patient’s baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), unacceptable toxicity, initiation of new treatment, or withdrawal. Patients with prior ketoconazole treatment for prostate cancer were excluded, although as Ryan et al discuss, abiraterone acetate is known to have some benefit in these patients, albeit probably to a lower degree. A prespecified interim overall survival analysis was performed when 552 events had occurred. This analysis demonstrated a statistically significant improvement in overall survival in patients receiving abiraterone acetate compared with those on the placebo-containing arm (HR, 0.646; 95% CI, 0.543–0.768; P < .0001). Median overall survival was 14.8 vs 10.9 months in the abiraterone and placebo arm, respectively. Abiraterone acetate was also shown to result in improved pain palliation and had a significant delay in the time to pain progression compared with prednisone alone. Improvements in progression-free survival (5.6 months vs 3.6 months) and PSA responses (29% vs 6%) were also noted. All subgroups based on baseline characteristics (age, performance status, PSA, pain intensity, visceral metastases) demonstrated improvements in outcomes over prednisone alone. The most common adverse reactions seen with abiraterone/prednisone (> 5%) were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection. The most common adverse drug reactions resulting in drug discontinuation were increased aspartate aminotransferase and/or alanine aminotransferase levels, urosepsis, and cardiac failure (each in < 1% of patients taking abiraterone). The most common electrolyte imbalances in patients receiving abiraterone were hypokalemia (28%) and hypophosphatemia (24%). Following interruption of daily corticosteroids and/or with concurrent infection or stress, adrenocortical insufficiency (< 1%) has been reported in clinical trials in patients receiving abiraterone acetate at the recommended dose in combination with prednisone. It is recommended that close monitoring of serum electrolytes and liver enzymes be conducted during therapy with abiraterone. Abiraterone should be taken in a fasting state due to the higher levels of drug exposure when taken with food. Interestingly, bone scan healing flares are commonly seen early on with abiraterone (and cabazitaxel), despite pain and PSA reductions, indicating the need to obtain confirmatory bone scans that show additional new lesions before stopping therapy in the absence of other evidence of clinical progression. Thus, following docetaxel chemotherapy for mCRPC, the hormonally active androgen synthesis inhibitor abiraterone acetate has demonstrated clinical benefit and therefore represents a new standard of care in this setting. The NCCN Prostate Cancer Guidelines also acknowledge that some men with mCRPC are not candidates for chemotherapy (docetaxel or mitoxantrone) because of comorbidities, peripheral neuropathy, or concerns over tolerability and risk/benefit. In these men, abiraterone acetate with prednisone may be an appropriate therapy, given its survival benefits, palliative benefits, and reasonable toxicity profile. Abiraterone pre-docetaxel. In 2012, data were presented from the phase III Cougar 302 trial of abiraterone/prednisone vs prednisone alone, which was a randomized international study of men with mCRPC in the pre-docetaxel clinical state. These men had minimally symptomatic disease (ie, little pain from their prostate cancer) and no visceral metastatic disease. Results were presented by Ryan et al at the 2012 meeting of ASCO and published in early 2013. In this trial, 1,088 men were randomized 1:1 to abiraterone/prednisone vs prednisone with a co-primary endpoint of overall survival and progression-free survival. This study was placebo-controlled and blinded, and it was stratified based on performance status. The progression-free survival definition was a composite radiographic definition that accounted for the known bone scan flares that occur with this agent in the short term, and did not include PSA criteria. Dosing is 1,000 mg daily without food, with prednisone given at 5-mg twice daily. With 311 mortality events, the survival data were immature; however, the study was stopped and unblinded early by the data and safety monitoring board due to the positive results for both progression-free survival and all secondary outcomes, combined with a strong trend to improved survival. Specifically, progression-free survival was improved (HR, 0.43; 95% CI, 0.35–0.52; P < .0001) with a likely 7- to 10-month improvement in progression-free survival observed. Overall survival was improved (HR, 0.75; 95% CI, 0.61–0.93; P = .0097) but this did not meet prespecified criteria (alpha of 0.0008) at the time of the ASCO presentation. PSA responses (50% or greater decline) were observed in 62% vs 24% of patients, respectively, while radiographic RECIST responses were observed in 36% vs 16% of patients (P < .0001 for each endpoint). Improvements in time to performance status deterioration, time to chemotherapy administration, and time to pain onset were all improved, reflecting a clear clinical benefit. Notably, this trial was not compared with docetaxel and had limited eligibility for a head-to-head comparison with chemotherapy. Nevertheless, given the established palliative role and improved survival with abiraterone even in the post-docetaxel space, many patients and providers will prefer a trial of abiraterone prior to docetaxel unless there is evidence for rapid visceral or pain progression requiring immediate chemotherapy. No biomarkers have yet been identified that can select a man with CRPC for abiraterone or chemotherapy, and these studies are now warranted. Toxicities of this agent in the pre-docetaxel space were as expected, with evidence of mineralocortocoid excess (hypertension, edema, hypokalemia) occurring in 2% to 3% of men, grade 3/4 elevated liver enzymes in 3% to 6% of men, and cardiac disorders (atrial fibrillation, CHF) in 19% of men (6% grade 3/4). In addition to the efficacy of abiraterone observed in this trial, the 8-month progression-free survival observed with prednisone alone testifies to the efficacy of corticosteroids in the management of these men. Based on the efficacy demonstrated in the Cougar 302 study, abiraterone acetate in combination with prednisone gained FDA approval on December 10, 2012, for treatment of patients with mCRPC prior to chemotherapy. Enzalutamide. On August 31, 2012, the FDA approved enzalutamide (formerly known as MDV3100) for the treatment of men with mCRPC who have received prior docetaxel chemotherapy. Approval was based on the results of the AFFIRM randomized, phase III, placebo-controlled trial that is now published in this post-chemotherapy setting (see Scher et al, NEJM 2012). In this trial, 1,199 men were randomized to enzalutamide or placebo in a 2:1 ratio and the primary endpoint was overall survival. Median survival was improved with enzalutamide, from 13.6 to 18.4 months (HR, 0.63; P < .001). Survival was improved in all subgroups analyzed, including men with poor performance status, high or low PSA values, visceral metastases, significant pain, and more than two prior chemotherapy regimens. Secondary endpoints were also significantly improved, including the proportion of men with a ≥ 50% PSA decline (54% vs 2%), radiographic response (29% vs 4%), radiographic progression-free survival (8.3 months vs 2.9 months), and the time to the first skeletal-related event (16.7 months vs 13.3 months). Quality of life was improved with enzalutamide over placebo therapy as measured by validated surveys, and adverse events were mild, but included fatigue (34% vs 29%), diarrhea (21% vs 18%), hot flushes (20% vs 10%), headache (12% vs 6%), and seizures (0.6% vs 0%). The incidence of cardiac disorders did not differ between the arms. Dosing of enzalutamide is 160 mg daily. Of note, patients in this AFFIRM study were maintained on GnRH agonist/antagonist therapy and could also receive bone supportive care medications. The seizure risk cited in the full prescribing information for XTANDI is 0.9%. Thus, enzalutamide represents a new treatment option for men in the post-docetaxel mCRPC setting and is also a reasonable choice in men who are not candidates for chemotherapy. As previously noted, level 1 evidence to support routine use of enzalutamide in the pre-docetaxel setting will be based on results of the phase III randomized clinical study, PREVAIL, the results of which were published by Beer et al in 2014. In this study, 1,717 patients were randomized to enzalutamide 160 mg daily or placebo. The study was stopped early after meeting primary efficacy endpoints of progression-free survival and overall survival. Radiographic progression-free survival was improved in patients receiving enzalutamide (HR, 0.19; 95% CI, 0.15–0.23; P < .001), as was overall survival (HR, 0.71; 95% CI, 0.60–0.84; P < .001). Treatment with enzalutamide also met all secondary endpoints, improving time until initiation of chemotherapy, time until functional decline based on the FACT-P score, time until the first skeletal-related event, and time until PSA progression. A total of 59% of patients reated with enzalutamide experienced an objective response, including 20% complete responses. Similarly to adverse events in the AFFIRM trial, the most common adverse events were fatigue, back pain, constipation, arthralgia, anorexia, and hot flushes. Grade 3 or 4 cardiac events were seen in 3% of patients, and less than 1% of patients experienced seizure during treatment with enzalutamide. Thus, the rational use of both abiraterone and enzalutamide is in the pre-docetaxel mCRPC treatment space, based on their favorable safety profiles, improvements in survival and multiple other key clinical efficacy parameters, and the ability of these agents to defer chemotherapy, often for prolonged periods of time. Cross-resistance between abiraterone and enzalutamide. Concern exists regarding clinical cross-resistance between abiraterone and enzalutamide, based on multiple case series documenting an inferior response rate and time to progression with subsequent therapy on one agent following progression on the other. PSA response rates of 20% to 40% with times to progression of 4 to 5 months are expected with crossover therapy after resistance to one agent. Several retrospective studies have suggested cross-resistance with sequential use of both agents, in either order. At this time, it is not possible to predict benefit to one drug over another based on clinical parameters or based on prior response to the other agent, illustrating the need for the development of predictive biomarkers of AR activity, AR mutations and deletion variants, and AR-independent tumor growth. The AR splice variant AR-V7 lacks the ligand binding domain and localizes to the nucleus without binding androgens. AR-V7 was recently associated with primary resistance to both abiraterone and enzalutamide, in a study reported by Antonarakis et al. The detection of AR-V7 in circulating tumor cells in patients with mCRPC treated with enzalutamide resulted in shorter median clinical or radiographic progression-free survival times (2.1 months vs 6.1 months, P < .001) as well as median overall survival (5.5 months vs ot reached, P = .002). Similarly, the presence of AR-V7 in patients with mCRPC treated with abiraterone was also prognostic for shorter median clinical or radiographic progression-free survival (2.3 months vs not reached, P < .001) and shorter median overall survival (10.6 months vs not reached, P = .006). Therefore, molecular changes in AR can potentially predict for resistance to the novel hormonal therapies, and ongoing correlative science studies should be able to validate this work and develop clinically available biomarkers to categorize patients and predict response to these therapies based on the presence of these AR variants. An ongoing study in the ALLIANCE US cooperative groups is examining whether upfront combination therapy with abiraterone plus enzalutamide vs enzalutamide followed by subsequent therapy will improve survival, and a host of predictive biomarkers are incorporated into this trial to address these important questions of sequential vs combination therapy. Novel therapies Several newer therapies for men with prostate cancer are under investigation, with some available as single agents and some to be given with chemotherapy. Since docetaxel is the only approved chemotherapy in the front-line setting to date that is associated with a survival advantage in patients with mCRPC, it has become the “backbone” upon which novel therapies and response modifiers are added in an attempt to improve patient outcomes. To date, all docetaxel-based combination phase III trials have been negative for their primary outcome of improving survival, including VEGF-targeted therapies, lenalidomide, src family kinase inhibition with dasatinib, endothelin inhibition, anti-clusterin, and high-dose vitamin D. Thus, at this time, docetaxel should not be combined with other agents outside of a research study and docetaxel-prednisone remains the front-line treatment of choice for men with mCRPC who have failed to respond to prior hormonal therapy. TABLE 8: Phase III trials in castration-resistant metastatic prostate cancer Based on promising results in phase II testing, several phase III trials investigating therapies given prior to or following docetaxel were opened and are ongoing (Table 8). The earlier use of enzalutamide, abiraterone, ARN-509 (another AR antagonist) is ongoing. Recent data suggest that another androgen synthesis inhibitor, orteronel (TAK700), while active and able to delay progression, did not improve overall survival in two phase III trials in CRPC, and thus will not be available for use in these settings. Immunotherapy phase III trials with CTLA-4 blockade (ipilimumab), Prostvac (PSA immunotherapy), and tasquinimod (an oral anti-angiogenic and immunomodulatory small molecule inhibitor of the myeloid suppressor cell, with a target likely being S100A9 and potentially thrombomodulin) are ongoing. For example, the efficacy and safety of tasquinimod have been demonstrated in a phase II randomized placebo-controlled international trial reported by Pili et al, in which tasquinimod was shown to delay radiographic progression by 5 to 7 months and have an acceptable safety profile. However, agents such as these will need to show an improvement in both progression-free and overall survival to be incorporated into the standard of care in this disease, given the clear disconnect between progression-free and overall survival seen with immune therapies and anti-angiogenic drugs (see biomarker review in Armstrong et al, Eur Urol 2012). Finally, many of these agents are being tested in men with asymptomatic CRPC or minimally symptomatic men with mCRPC (ie, the window prior to docetaxel use), with the aim of delaying chemotherapy use/need. Based on striking bone scan regressions accompanied by improvements in pain levels and anemia, two phase III trials of the c-met/VEGFR2 (vascular endothelial growth factor receptor 2) tyrosine kinase inhibitor cabozantinib were completed in the post-docetaxel setting; however, these studies did not demonstrate a prolongation in survival or durable pain palliation and development of this agent for use in patients with CRPC has stopped. In addition, current trials are investigating the use of systemic agents, including docetaxel, in locally advanced or PSA-recurrent disease, either prior to treatment or as adjuvant therapy following surgery or radiation therapy. Accrual to these trials has been a priority (in RTOG 0521 [now completed], VA 553, and CALGB 90203), 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. RTOG is exploring the role of docetaxel in addition to long-term androgen deprivation therapy for men with locally advanced high-risk prostate cancer who have completed IMRT of the prostate. CALGB 90203 randomized high-risk men (Gleason score > 8 or nomogram-defined high risk) to immediate radical prostatectomy vs docetaxel for 6 cycles with androgen deprivation therapy followed by radical prostatectomy. The use of neoadjuvant or adjuvant docetaxel for high-risk men will be guided by evidence from these trials. The ALLIANCE trial of abiraterone +/− enzalutamide will examine upfront combination therapy vs sequential therapy with these agents. Recent guidelines by the Prostate Cancer Working Group (PCWG) 2 have updated methods for categorizing disease states in men with CRPC (node only, PSA only, locally advanced, bone metastatic visceral disease). In addition, the requirements for confirmation bone scans and changes in the reporting and assessment of disease progression have been updated to be more consistent with our understanding of prostate cancer biology, including the lesion flare response on bone scan with effective therapy, and to prevent the unnecessary early abandonment of potentially active agents based on PSA changes alone. For example, healing of bone lesions may cause an apparent “worsening” of disease on bone scan despite declines in PSA levels and improvement in pain, likely due to osteoblastic activity in regressing tumors. Physicians are encouraged to evaluate these potential flare cases with a confirmatory bone scan 6 or more weeks later; if the patient develops no additional new lesions or disease progression, he should be maintained on therapy. Many older therapies may have been unnecessarily stopped prematurely due to this misclassification of bone scan progression using older criteria. 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 radiation therapy 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 and samarium SM 153 lexidronam. Radium-223. In 2011–2012, the results of the phase III ALSYMPCA trial (Alpharadin in Symptomatic Prostate Cancer) were presented and have led to the regulatory approval of the novel alpha particle emitter radium-223 in men with bone-metastatic symptomatic prostate cancer. Radium-223 is a calcium-mimetic radiopharmaceutical that is incorporated into bone and produces alpha particles capable of tumor killing with a 2–10 cell diameter penetration, and has demonstrated palliative benefits and acceptable safety with minimal myelosuppression in phase I/II trials to date. The ALSYMPCA trial, reported by Parker et al, was a phase III 2:1 randomized trial of radium-223 (50 kBq/kg × 6 every 4 weeks) or placebo in men with bone-metastatic symptomatic CRPC who had failed to respond to docetaxel or who were considered unfit for docetaxel by their treating physicians. Men could also receive concurrent hormonal therapies or radiation or glucocorticoids during this trial. In this trial, 921 men were randomized, 57% of whom had received prior docetaxel. More than 60% of men were able to complete the planned 6-month course of therapy. Overall survival improved from 11.3 months to 14.9 months (HR, 0.695; 95% CI, 0.581–0.832; P = .00007). Improvements were seen in men with prior docetaxel or among those considered not to be docetaxel candidates; benefits seemed particularly robust among men with elevated alkaline phosphatase levels (> 220 U/L), with a survival improving from 8.1 to 11.4 months, while those with normal bone markers had a less substantial and non-significant benefit. Delays in skeletal events were noted and data on pain palliation are not yet available. Toxicities were mild and did include vomiting, diarrhea (25%), and thrombocytopenia (12%). Rates of severe anemia and neutropenia were similar. Thus, this radiopharmaceutical represents a new treatment option for symptomatic men. 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