Approach Considerations Current guidelines on localized prostate cancer from the American Urological Association (AUA) strongly recommend that selection of a management strategy incorporate shared decision making and explicitly consider the following [68] : Cancer severity (risk category) Patient values and preferences Life expectancy Pretreatment general functional and genitourinary symptoms Expected post-treatment functional status Potential for salvage treatment Standard treatments for clinically localized prostate cancer include the following: Active surveillance Watchful waiting Radical prostatectomy Radiation therapy Hormone therapy Whole-gland cryotherapy is also used, but its adverse effects are considerable and survival benefit compared with active surveillance has not been shown. Newer therapies, such as proton-beam radiation and high-intensity focused ultrasound are being used, but long-term survival and complication rates have not been presented in well-done studies. For locally advanced prostate cancer, radiation therapy along with androgen ablation is generally recommended, although radical prostatectomy may be an appropriate alternative to radiation therapy in some cases. A combination of external radiation, brachytherapy, and hormone therapy is also being used, but it is unclear whether it offers advantages over hormone therapy and external radiation alone, and it does increase complications. Metastatic prostate cancer is rarely curable. [69] Management of these cases typically involves therapy directed at relief of particular symptoms (eg, palliation of pain) and attempts to slow further progression of disease. Comparisons between treatments for prostate cancer are complicated by the stage-migration and lead-time bias associated with the adoption of prostate-specific antigen (PSA)–based screening and the resultant increase in the detection of small, clinically localized cancers. In addition, treatment selection has become more complicated as options have increased. Surgical treatment currently includes nerve-sparing techniques, laparoscopic procedures, robotically-assisted procedures, and the classic retropubic prostatectomy and perineal prostatectomy. Multiple forms of radiation therapy are currently available. These include the following: Conventional radiation therapy Three-dimensional (3-D) conformal radiation therapy Intensity-modulated radiation therapy Temporary and permanent brachytherapy Proton-beam radiation Stereotactically guided radiation Hormone therapy for prostate cancer is also known as androgen deprivation therapy (ADT). It may consist of surgical castration (orchiectomy) or medical castration. Agents used for medical castration include luteinizing hormone–releasing hormone (LHRH) analogues or antagonists, antiandrogens, and other androgen suppressants. Localized Prostate Cancer Whether one of the several different modalities used for treating localized prostate cancer offers survival benefits over the others remains controversial. The choice of definitive therapy has been suggested to make a significant difference in long-term survival in less than 10% of patients. This means that most patients are cured either because the treatment was effective or because they had a non–life-threatening tumor and the treatment was unnecessary. The remainder of patients are not cured, either because they had unsuspected micrometastases or because the local therapy did not eradicate all of the malignant cells. Current AUA guidelines (2017) consider active surveillance, radiation therapy, and radical prostatectomy to be acceptable treatment options for localized prostate cancer. However, the guidelines do not recommend any one of these therapies over the others. Instead, they advise that patients be informed of the benefits and drawbacks to the most commonly accepted interventions. [68] One aspect of counseling that the AUA guidelines do not discuss is how to provide this information to patients. Rather than simply listing the potential side effects of each intervention, patients are likely to benefit from being given the odds of developing each complication and the odds that the treatment will result in recurrence of cancer, reduce the development of metastases, and improve overall survival. The AUA guidelines do, however, emphasize that high-risk treatment should never be administered to low-risk patients. First-line hormone therapy is seldom indicated in patients with localized prostate cancer. In a population-based cohort study of older patients with localized prostate cancer, Lu-Yao and colleagues found that primary ADT did not improve long-term overall or disease-specific survival. The study involved 66,717 men 66 years of age and older and was conducted in predefined geographical areas of the United States covered by the Surveillance, Epidemiology, and End Results (SEER) Program. [70] A review of US Department of Veterans Affairs (VA) data by Loeb et al found that conservative management of low-risk prostate cancer increased significantly from 2005 to 2015. Over that decade, the use of conservative management in men younger than 65 years rose from 27% to 72%; in men 65 years or older, it rose from 35% to 79%. Conservative management consisted mostly of active surveillance; watchful waiting was more likely to be used in men older than 75 years and those with a higher PSA level and greater comorbidity. [71] Intermediate-risk disease In patients with intermediate-risk localized prostate cancer, appropriate treatment options include active surveillance, interstitial prostate brachytherapy, external beam radiation therapy, and radical prostatectomy. Cryotherapy should also be discussed. [68, 72] Treatment should be based in part on the patient’s preferences and functional status. A patient who chooses conventional external beam radiation therapy may have improved survival by combining it with 6 months of hormone therapy. Active surveillance Active surveillance differs from watchful waiting. With watchful waiting, patients forgo close follow-up and primary treatment. Instead, palliative treatment is provided if local or metastatic progression occurs, as indicated by symptoms. With active surveillance, the physician monitors the course of the disease over time and intervenes with treatment if the disease begins to progress. Active surveillance is increasingly being recommended for men with very-low-risk disease (ie, T1c, 2 or fewer biopsy cores positive, no core with >50% involved, Gleason 3+3/grade group 1, and a PSA density < 0.15 ng/mL/g) or low-risk disease (T1-2a disease, a Gleason score of 2-6, and a PSA level below 10 ng/mL. The National Comprehensive Cancer Network (NCCN) notes that active surveillance is usually appropriate for men with very-low-risk and low-risk prostate cancer who have a life expectancy of 10 years or more. [73] Progression of local disease may be indicated either by increased tumor volume or changes in the Gleason score. PSA doubling times are also being used, although some studies have questioned their reliability for this purpose. The optimal management of men on active surveillance is evolving, although no randomized studies have yet been conducted. Monitoring typically consists of PSA testing every 3 months and repeat biopsy at 12- to 24-month intervals. Biopsy findings are the most important factor in deciding whether to pursue treatment. A rapid PSA level rise or patient choice can also prompt the physician to proceed to treatment. [74] Current NCCN recommendations for active surveillance (based on lower-level evidence) include the following [75] : PSA no more often than every 6 mo unless clinically indicated DRE no more often than every 12 mo unless clinically indicated Repeat prostate biopsy no more often than every 12 mo unless clinically indicated However, the NCCN recommends a repeat biopsy within 6 months of diagnosis if the initial biopsy included fewer than 10 cores. Repeat biopsies are not indicated in patients whose life expectancy is less than 10 years. [75] Watchful waiting Watchful waiting is typically recommended to patients of advanced age and to those who have significant, life-limiting comorbidities or a life expectancy of less than 10 years. These patients will most likely experience worse quality of life if their cancer is treated than if they wait for disease progression. They have a very high chance of dying from another cause, and treatment of their prostate cancer could actually worsen comorbid (eg, cardiac) disease and hasten death. In a 2009 study—the largest US study since the advent of PSA screening—Lu-Yao et al found that the prostate cancer–specific 10-year survival rate in patients managed with watchful waiting was 94%. Median age at diagnosis of the patients in this study was 78 years. [57] Lu-Yao et al noted that outcomes in these patients, who were diagnosed from 1992-2002, were better than outcomes in patients diagnosed in the 1970s and 1980s. Possible explanations for the improvement include additional lead times, overdiagnoses related to PSA testing, grade migrations, and/or advances in medical care. Radical prostatectomy versus watchful waiting Since 1990, only 2 randomized studies comparing radical prostatectomy and watchful waiting have been conducted in men with clinically localized disease. In the first one, which was done in Sweden and included only a small percentage of cases diagnosed by screening PSA (3-5%), overall mortality at 15 years was 46.1% in the surgery group, compared with 52.7% in the watchful waiting group. [68, 76] Prostate cancer mortality was 14.6% versus 20.7%, respectively, meaning that 1 cancer death was prevented for every 18 men treated with surgery. [76] In a subsequent analysis of the data, however, no mortality benefit was seen in men over 65 years. Similarly, a 2008 research summary by the Agency for Healthcare Research and Quality (AHRQ) concluded that men with clinically localized prostate cancer detected by methods other than PSA testing who were treated with radical prostatectomy had fewer deaths from prostate cancer, marginally fewer deaths from any cause, and fewer distant metastases, than did men who underwent watchful waiting. [77] As in the Swedish study, the AHRQ report noted that the advantage of radical prostatectomy with regard to lower cancer-specific and overall mortality rates appears to be limited to men younger than 65 years. The advantage was unrelated to baseline PSA level or histologic grade. The AHRQ found insufficient evidence to determine whether radiation or hormone therapy results in fewer deaths or cancer progressions than does watchful waiting. [77] The AHRQ also pointed out that radical prostatectomy, radiation therapy, and hormone therapy result in more long-term adverse effects than watchful waiting. These include sexual, urinary, and bowel problems. [78] PIVOT Unlike the above reports, the Prostate Intervention Versus Observation Trial (PIVOT), the only such randomized study performed in screened men, showed no statistically significant difference between radical prostatectomy and watchful waiting with respect to either all-cause mortality (47% versus 49.9%, respectively) or prostate cancer–specific mortality (5.8% versus 8.4%, respectively) after a median follow-up of 10 years. PIVOT included 731 men aged 75 years or younger with localized prostate cancer, a PSA level below 50 ng/mL, and a life expectancy of at least 10 years. [33] A subgroup analysis of PIVOT revealed a statistically significant reduction in overall mortality in men with a PSA greater than 10 ng/mL at diagnosis (61 of 126 men vs 77 of 125 men) but not in men with a PSA of 10 ng/mL or less (110 of 238 men vs 101 of 241 men). These results must be interpreted carefully, however. Age (< 65 vs ≥65 years), Gleason score, comorbidity, race, and performance score did not affect the efficacy of either treatment. [33] Longer-term follow-up data from PIVOT confirmed the initial observation that for men with low-risk early-stage prostate cancer, surgery does not reduce the risk for death compared with observation. The 19.5-year cumulative incidence of death with surgeryversus observation was 61.3% versus 66.8%, respectively (hazard ratio [HR], 0.84; P = 0.06). Quality-of-life analysis in PIVOT subjects found that urinary incontinence and erectile and sexual dysfunction were each greater with surgery than with observation. [34] Vascular-targeted photodynamic therapy Vascular-targeted photodynamic therapy is an investigational technique being studied in Europe. In this technique, a light-responsive drug (padeliporfin) is infused intravenously; optical fibers are inserted into the prostate transcutaneously, to cover the desired treatment zone; and laser light is then used to activate the drug. A phase 3 randomized controlled trial in patients with low-risk, localized prostate cancer (Gleason grade 3) found that at a mean follow-up interval of 24 months, disease progression had occurred in 58 of the 206 men in the vascular-targeted photodynamic therapy group compared with 120 of the 207 men in the active surveillance group (28% versus 58%, respectively; adjusted risk ratio 3.67, P < 0.0001). [79] The most common grade 3–4 adverse effects in the study were prostatitis, acute urinary retention, and erectile dysfunction, which occurred at similar rates (< 1% to 2%) in the vascular-targeted photodynamic therapy group and the active surveillance group. The most common serious adverse event in the vascular-targeted photodynamic therapy group, retention of urine occurred in 15 patients but resolved within 2 months in all cases. Radiation Therapy External-beam radiation therapy Radiation therapy also offers the potential for curative treatment of localized prostate cancer. It may be delivered in the form of external-beam radiation therapy (EBRT) or brachytherapy (ie, the insertion of radioactive seeds into the prostate gland). EBRT techniques include 3-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT). Higher-dose-rate therapy using stereotactic guidance is being used despite lack of data on long-term survival or complication rates. In general, after 2 years, the quality-of-life profile for IMRT and surgery are similar, although radiation therapy does pose a slightly higher risk of persistent fecal urgency and incontinence of gas. [80] Proton-beam therapy is theoretically an excellent modality for EBRT, providing an ideal dose distribution. In a phase 2 study in patients with organ-confined prostate cancer, Nihei et al found that acute, transient grade 2 rectal and bladder toxicity developed in 0.7% and 12% of patients, respectively, who underwent proton-beam therapy; at 2 years, late grade 2 or greater rectal and bladder toxicity developed in 2% and 4.1% of patients, respectively. [81] A study of radiation therapy for primary prostate cancer treatment by Sheets et al found that, compared with patients undergoing conformal therapy, patients who received IMRT had less gastrointestinal (GI) morbidity and fewer hip fractures and were less likely to undergo additional cancer treatments. They were, however, more likely to develop erectile dysfunction. Patients who received proton therapy had more GI morbidity than did patients receiving IMRT and were more likely to undergo GI procedures. [82] In a multi-center study, Briganti et al found that early salvage radiation therapy is comparable to adjuvant radiation therapy for improving biochemical recurrence–free survival in pT3pN0 prostate cancer patients after radical prostatectomy. Early salvage radiation therapy may reduce the overtreatment associated with adjuvant radiation therapy without compromising disease control in these patients. [83] Complications of EBRT include cystitis, proctitis, enteritis, impotence, urinary retention, and incontinence. Rates depend on the total dose and the technique used. A systematic review and meta-analysis of radiation therapy for prostate cancer found that EBRT, but not brachytherapy, was consistently associated with increased odds for a second malignancy of the bladder, colon, and rectum. Absolute rates were low, however: 0.1-3.8% for bladder, 0.3-4.2% for colorectal, and 0.3-1.2% for rectal cancers. [84] Brachytherapy In 2011, the American Society for Radiation Oncology (ASTRO) and the American College of Radiology (ACR) issued a practice guideline for transperineal permanent brachytherapy of prostate cancer. These guidelines established standards for the safe and effective performance of brachytherapy for patients with organ-confined prostate cancer. [85] See External Beam Radiation therapy in Prostate Cancer and Brachytherapy (Radioactive Seed Implantation Therapy) in Prostate Cancer for more information on these topics. Radiation therapy plus androgen ablation therapy Androgen ablation has been shown to improve survival in men with localized disease who are treated with external radiation. D’Amico et al reported higher overall survival with the combination of radiation therapy and 6 months of ADT in men with intermediate-risk prostate cancer. Median follow-up was 7.6 years. [86] A study by Jones et al found that for patients with stage T1b, T1c, T2a, or T2b prostate cancer and a PSA level of 20 ng/mL or less, short-term ADT increased overall survival in intermediate-risk—but not low-risk—men. The 10-year rate of overall survival was 62% with combination therapy, versus 57% with radiation therapy alone; 10-year disease-specific mortality was 4% and 8%, respectively. In this study, ADT was given for 4 months, starting 2 months before radiation therapy. [87] In a study by Pisansky et al of 1480 intermediate-risk prostate cancer patients, disease-specific survival in patients who underwent 28 weeks of preradiation total androgen suppression (TAS) was not significantly different from that achieved in patients with only 8 weeks of TAS prior to radiation therapy. [88] Patients in the study were randomized to 8 or 28 weeks of TAS with LHRH agonist, along with a daily nonsteroidal antiandrogen, prior to radiation treatment. This was followed in both groups by an additional 8 weeks of androgen suppression, administered concurrently with radiotherapy. Pisansky and colleagues found that the 10-year disease-specific survival rate in the study was 95% in the 8-week treatment group and 96% in the 28-week treatment group. The 10-year disease-free survival rates in the 8- and 28-week groups were 24% and 23%, respectively, and the 10-year cumulative incidences of clinical and biochemical relapse were 57% and 60%, respectively. Radiation therapy versus surgery The AHRQ found insufficient evidence to determine whether any type of radiation therapy results in fewer deaths or cancer recurrences than radical prostatectomy does in patients with clinically localized prostate cancer. [78] The importance of dose escalation in disease control complicates the extraction of meaningful conclusions from current radiation therapy treatments (eg, 3D-CRT, IMRT). Brachytherapy has also been compared with surgery in the management of early stage disease. Direct comparisons (ie, prospective, randomized trials) are not readily available, but preliminary data from most centers suggest that permanent prostate implants yield comparable local control and biochemical disease-free rates. Valid comparisons of surgery and radiation therapy are impossible without data from randomized studies that look at long-term survival rather than PSA recurrence. Variation in radiation techniques and dosage administered; the variable use of androgen ablation, which improves survival in intermediate- and high-risk disease; and the variable impact on quality of life complicate comparison using uncontrolled studies.