Prostate Cancer Treatment & Management

Treatment of prostate cancer varies by disease stage. See the image below.

Current guidelines on localized prostate cancer from the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) Society of Urologic Oncology (SUO) strongly recommend that selection of a management strategy incorporate shared decision making and explicitly consider the following ^[105] :

• 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:

• Watchful waiting
• Active surveillance
• Radical prostatectomy
• Radiation therapy

Metastatic prostate cancer is rarely curable. ^[106] 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. There is oncologic equipoise of robotic and retropubic 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.

The first patient-driven international prostate cancer quality-of-life study, the Europa Uomo Patient Reported Outcomes Study (EUPROMS), found that except for active surveillance, all treatments for prostate cancer may negatively affect quality of life—especially continence and sexual function—and that for many men these effects may be greater than previously thought. EUPROMS gathered data from 2,943 European men from 25 countries who had been treated for prostate cancer 6 years previously, on average. ^[107]

Urinary incontinence was most affected by radical prostatectomy. Fatigue scores were twice as high with radiotherapy as with surgery, and three times as high with chemotherapy. Both radiotherapy and radical prostatectomy had a severe impact on sexual function—radiotherapy more than radical prostatectomy. Overall, 50% of respondents reported that loss of sexual function (including the ability to have an erection or reach orgasm) was a big (28%) or moderate (22%) problem. The best quality-of-life scores were achieved in patients whose prostate cancer was discovered in an early, curable stage. ^[107]

To view a multidisciplinary tumor board case discussion, see Memorial Sloan Kettering e-Tumor Boards: Unfavorable Intermediate-Risk Prostate Cancer.

Standard treatments for clinically localized prostate cancer include watchful waiting, active surveillance, radical prostatectomy, and radiation therapy. Whether any one of those modalities offers survival benefits over the others remains controversial.

Watchful waiting

Watchful waiting, defined as observation for prostate cancer without definitive local therapy, has been evaluated in several key studies.

In the Prostate cancer Intervention Versus Observation Trial (PIVOT), conducted through the US Department of Veterans Affairs from 1994-2020, 731 men with localized prostate cancer were randomized to radical prostatectomy or observation. ^[108] Initially, there was no difference in survival, but at 22.1 years of follow-up, 68% of men assigned to surgery versus 73% of men assigned to observation had died; mean survival was 1 year longer in the surgical arm. This effect was greatest in men with intermediate-risk disease. ^[69]

However, a significantly higher-than-anticipated portion of patients in each arm of PIVOT died from competing causes (ie, not prostate cancer). The degree of competing risk in the PIVOT trial was higher than in approximately 90% of patients seen in clinical practice, limiting the generalizability of the PIVOT results. ^[109]

In the Veterans Administration Cooperative Urological Research Group (VACURG) trial comparing observation with surgery for non-PSA-screening–detected prostate cancers in 111 patients, minimal to no difference was found in survival at 23 years. The statistical power of this study was limited by the small number of patients involved. ^[110]

The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial provides the most robust data comparing watchful waiting with surgery for non-PSA–detected prostate cancers. After 23.6 years of follow-up in 695 men there was a 12% absolute reduction in the risk of prostate cancer– related death for men undergoing surgery and a gain of 2.9 years in life expectancy. ^[111]

While these studies demonstrate a modest improvement favoring local therapy for non–screening-detected prostate cancer, they also demonstrated that many men might suffer from overtreatment of prostate cancer. This led to the development of active surveillance as a management modality.

Active surveillance

Active surveillance (AS) for prostate cancer encompasses continued monitoring of men with very low, low, and some favorable intermediate-risk prostate cancers after the initial diagnosis. ^[112] Surveillance generally includes continued PSA monitoring at set intervals, confirmatory prostate biopsy, and repeat prostate biopsies at predetermined time points (generally at least 12-24 months apart), with the goal of delaying potential curative intervention if needed without missing the window for a cure. No single AS strategy is currently recommended, and the time to discontinue AS has not been established; however, AS is recommended by numerous international organizations. ^[113]

Several long-term cohort studies of AS, with varying inclusion criteria, have demonstrated the consistent safety of AS. Overall, 27-53% of patients in the large studies have undergone definitive therapy, while the rates of metastasis (0.12-6%) and prostate cancer–related mortality (0-1.5%) have been low. ^[114]

For example, the randomized, controlled ProtecT trial, which compared AS with both surgery and radiotherapy in patients with primarily low-risk prostate cancer, demonstrated that for patients with low-risk prostate cancer, mortality from cancer is low at 10 years, and AS appears as safe as an immediate intervention. Overall, < 1% of patients died from prostate cancer over the study time period. Disease progression was significantly higher in the AS arm than in the intervention arms and about half of the patients in the AS arm went on to receive surgery or radiation therapy. ^[115]

Definitive local therapy

Definitive local therapy for prostate cancer generally involves either surgical removal or irradiation of the prostate, with or without removal or irradiation of the draining pelvic lymph nodes. No head-to-head, randomized, prospective trials comparing radiation with surgery have been conducted, so data for each are generally extrapolated. Patient-centered decision making generally takes into account the differences in short- and long-term adverse effects associated with the different forms of therapy.

Radiation therapy is delivered either from an external source, via implanted radioactive seeds (brachytherapy), or a combination of both, with or without concurrent androgen deprivation therapy (ADT) for a set period of time. It is important to note that radiation therapy delivery methods, fractionation, and dosing have continued to evolve over time. This article will not review the technical differences between therapies; however, at present, 3-dimensional conformal radiation therapy and intensity-modulated radiation therapy with high-dose (hypofractionated) therapy are generally utilized. Proton-beam therapy as well as brachytherapy through a variety of seed types may also be considered. ^[116]

The approach for radiation therapy is primarily determined by risk stratification, as discussed in detail below. Current radiation therapy protocols generally consider the addition of 4-36 months of ADT (castration), based on risk stratification. The selection of modality is generally driven by disease characteristics, differences in adverse effects, and patient preference. National Comprehensive Cancer Network (NCCN) and European Urology Association (EUA) guidelines regarding risk-stratified therapy are presented in the guidelines section. 

In general, radiation therapy and surgery have similar effects on quality of life. Radiation therapy adverse events can be modulated by the type of radiation utilized. In general, both surgery and radiation pose risks of erectile dysfunction and bladder neck contracture. Surgical therapy is associated with immediate operative risks (eg, pain, infection), erectile dysfunction, and persistent incontinence. ^{[117, 118, 119]}

Radiation therapy is uniquely associated with a higher risk of persistent fecal urgency and incontinence of gas, secondary malignancy in the radiation field, and hemorrhagic cystitis. ^{[120, 121, 122]} A systematic review and meta-analysis of radiation therapy for prostate cancer found that external beam radiation therapy (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. ^[123]

Surgical therapy

In general, surgical therapy for prostate cancer involves the removal of the prostate, seminal vesicles, and the draining pelvic lymph nodes (when risk indicates removal) with re-anastomosis of the bladder to the urethra. Historically, prostatectomy has been performed via open surgical approaches, including perineal, suprapubic, retropubic, infrapubic, transrectal, ischiorectal, and sacral. ^{[124, 125]} Over time, however, radical retropubic prostatectomy (RRP) became the gold standard for prostate cancer surgery, and those other approaches were largely abandoned. ^[126]

Since the introduction of the robotic surgical platform at around the turn of the 21st century, robotic prostatectomy (RP) has rapidly become an established modality, increasing from 67% of prostatectomies in 2010 to 85% in 2013. ^{[127, 128]} RP has consistently demonstrated oncologic safety equivalent to that of RRP, with decreased blood loss favoring RP. Refinement of RP with techniques for sparing the peri-prostatic nerves, bladder neck, and space of retzius, as well as continued evaluation and understanding of anatomy, have led to improved outcomes with respect to erectile function, continence, and surgical margin positivity. ^{[129, 130, 131, 132]}

Given the continued innovation in this area, with new robotic platforms and approaches, specific rates of complications and surgical margin positivity are now user and approach dependent and should be reviewed with patients by the performing surgeon. Generally speaking, outcomes after prostatectomy for patients with low- and intermediate-risk disease are favorable. Of patients with high-risk disease undergoing prostatectomy, approximately 25-50% will experience disease recurrence over 10 years, while 1 in 4 may experience disease-related mortality. However, those statistics generally derive from retrospective series and show significant heterogeneity.

Radiation therapy

Radiotherapy also offers the potential for curative treatment of localized prostate cancer. It may be delivered in the form of 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) with hypofractionation.

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. ^[133] 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. ^[134]

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. ^[135]

In a study by Pisansky et al of 1489 intermediate-risk prostate cancer patients, disease-specific survival was not significantly different whether total androgen suppression (TAS) was given for 8 weeks or for 28 weeks prior to radiation therapy. ^[136] 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. ^[136]

Taken together, radiation therapy is generally given for 4-36 months, depending on the risk group of the patient. 

Radiation therapy versus surgery

In 2014, the Agency for Healthcare Research and Quality (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. ^[137]  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 track 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 the quality of life complicate comparison using uncontrolled studies.

Radiation as adjuvant or salvage therapy after surgery

Several randomized trials have evaluated the use of adjuvant radiation therapy to the prostatic bed following surgery for patients at high risk of recurrence (generally those with positive surgical margins or with seminal vesical invasion). Those include EORTC 22911, ^[138] SWOG 8794, ^[139]  ARO 96-02/AUO AP 09/95, ^[140] and FinnProstataX, ^[141] as well as the ongoing RAVES, GETUG-AFU 17, and RADICALS-RT studies. Recent research has further highlighted the role of early salvage radiation therapy (PSA < 0.5) with concomitant ADT for those with biochemical recurrence after prostatectomy, to avoid overtreatment associated with adjuvant radiotherapy. This is reflected in the current AUA/ASTRO guidelines. ^[142]

Emerging therapies

Several emerging therapies for the management of localized prostate cancer are gaining traction, though they are not yet routinely recommended for that purpose. These include whole-, hemi-, and partial-gland ablative therapies such as cryoablation, high-intensity focused ultrasound (HIFU), and photodynamic therapy. ^[143] They are generally utilized in patients with low-risk prostate cancer. Long-term safety and efficacy data remain largely elusive. ^{[144, 145, 146, 147, 148]}

However, on 4-year follow-up of the prospective, randomized PCM301 trial in men with low-risk prostate cancer, cancer progression rates (overall and by grade) were significantly lower in patients who underwent partial gland ablation with vascular targeted photodynamic therapy (n=207) versus those who underwent active surveillance (n=206). Consequently, fewer patients in the ablation cohort required conversion to radical therapy (24%, vs 53% in the surveillance cohort; hazard ratio 0.31, 95% confidence interval 0.21-0.46). ^[149]

AUA/ASTRO/SUO guidelines on advanced prostate cancer separate management considerations into the following four disease states, which encompass the entire continuum of advanced prostate cancer ^[150] :

1. Biochemical recurrence without metastatic disease, after exhaustion of local treatment options
2. Metastatic hormone-sensitive prostate cancer
3. Non-metastatic castration-resistant prostate cancer
4. Metastatic castration-resistant prostate cancer

These disease states are defined by the following:

• Primary tumor status
• Presence or absence of distant disease on imaging (metastatic versus nonmetastatic)
• Testosterone levels (noncastrate versus castrate)
• Prior chemotherapy exposure ^[151]

Biochemical recurrence without metastatic disease after exhaustion of local treatment options 

Biochemical recurrence is defined as a rise in PSA to 0.2 ng/mL and a confirmatory value of 0.2 ng/mL or greater following radical prostatectomy,  or a rise of 2 ng/mL or more above the nadir PSA after radiation therapy. Not all men who have a rising PSA will develop metastases, and for that reason not all such men require treatment. The risk of metastases and death depend on the patient’s Gleason score, the length of time between the nadir PSA and the onset of the PSA’s rise, and the PSA doubling time. ^[152]

Patients who have PSA (biochemical) failure following radical prostatectomy and have no evidence of metastatic disease have the options of watchful waiting, radiation therapy, or hormone ablation as salvage therapy. Similarly, patients who have PSA failure following radiation therapy have the following options:

• Watchful waiting
• Brachytherapy
• Prostatectomy
• Cystoprostatectomy
• Cryotherapy
• Hormone ablation

The pretreatment Gleason score, clinical stage, PSA level, and percentage of positive core biopsy results have been found to be reliable predictors of failure following local therapy. Unfortunately, no means of identifying recurrences limited to the pelvis is reliable. Although a Gleason grade of 7 or less is associated with a better prognosis than a grade of 8 or more, the survival likelihood associated with a rise in the PSA level is greater if the rise occurs more than 2 years after local treatment than if it occurs less than 2 years afterward.

The decision algorithm for the initiation of treatment for biochemical failure is controversial. Factors to consider include the following:

• Type of local therapy previously instituted (if any)
• Patient's life expectancy
• Intention and likelihood of cure
• Risk for increased morbidity
• Patient's quality of life

For patients with a rising PSA after failure of local therapy and no demonstrated metastatic disease by conventional imaging, the AUA recommends observation or enrollment in a clinical trial. A balance between disease control and minimization of the toxicity and intolerance of the treatment is difficult to maintain. Androgen blockade, while able to limit disease progression and reduce urinary outlet obstruction, produces a number of adverse effects. Unlike treatment of men with a biochemical recurrence following prostatectomy, where early salvage radiation with or without adjuvant ADT remains the preferred treatment strategy, there are currently no systemic treatments with proven efficacy in men without metastatic disease who are not candidates for additional local therapy.

Two large observational studies have assessed the question of salvage systemic therapy in this population, and neither found an advantage for earlier treatment in terms of metastasis or survival. ^{[153, 154]} Initiation of ADT is not recommended in the absence of visible metastases for men who have completed maximal local therapy, but if it is used, intermittent ADT may be offered instead of continuous ADT.

An open-label trial by Crook et al in 1,386 patients with a PSA rise to > 3 ng/mL more than 1 year following primary or salvage radiation for localized prostate cancer found that at a median follow-up of 6.9 years, there was no difference in survival between intermittent versus continuous ADT (median 8.8 versus 9.1 years, (HR= 1.02; 95% CI, 0.86 to 1.21). There was also no difference in prostate cancer–specific survival (hazard ratio [HR]=1.18; 95%CI 0.90 to 1.55). Intermittent therapy was associated with better scores for hot flashes (P < 0.001), desire for sexual activity (P < 0.001), and urinary symptoms (P=0.006) compared with continuous therapy. ^[155]

In this study, intermittent therapy consisted of an 8-month treatment cycle. At the end of the 8-month cycle, treatment was discontinued if there was no evidence of clinical disease progression, the PSA level was < 4 ng/mL and did not increase more than 1 ng/mL. The PSA threshold to reinitiate the next cycle of ADT was 10 ng/mL. ^[155]

 

Androgen deprivation is considered the primary approach to the treatment of metastatic prostate cancer. However, androgen deprivation therapy (ADT) has been found to be palliative, not curative. Prior to the development of newer therapies, overall survival for patients with metastatic prostate cancer ranged from 24-36 months. In recent years, however, several new therapies have been approved that prolong survival in men whose disease progresses on ADT. In patients with metastatic hormone-sensitive prostate cancer (mHSPC), castrate levels of testosterone (< 50 ng/dL) may be achieved with LHRH analogues, gonadotropin-releasing hormone (GnRH) antagonists, or orchiectomy. These treatments are considered equivalent in cancer control, although they have never been compared in large randomized controlled trials.

Combined androgen blockade

Combined androgen blockade (CAB) recognizes the 5-10% contribution of adrenal androgens to total body testosterone. Considerable controversy has surrounded this approach despite a total of 27 prospective randomized studies. Most of these studies showed no benefit from CAB, but 3 showed significant 3-6 month increases in survival with the use of an LHRH agonist combined with an antiandrogen. ^[156]  

Current AUA guidlines note that first-generation antiandrogens (bicalutamide, flutamide, nilutamide) should not be offered in combination with LHRH agonists in patients with mHSPC, except to block testosterone flare. The addition of an antiandrogen to LHRH agonist treatment can minimize the risk of the flare response (ie, temporary rise in testosterone levels) that can occur with LHRH treatment. There is limited evidence of the clinical utility of this approach. As opposed to LHRH agonists alone, GnRH antagonists and orchiectomy as monotherapy have a rapid onset of action and avoid a testosterone flare, making them useful in situations needing rapid hormone ablation such as impending spinal cord compression.

Early versus delayed treatment

In the years following the introduction by Huggins and Hodges of hormone therapy for prostate cancer, ^[157]  early institution of such treatment was recommended, based on comparison with historical controls. Later, the Veterans Administration Cooperative Urology Research Group (VACURG) studies resulted in the recommendation to defer hormone therapy until symptomatic progression occurred; this was thought to avoid the promotion of early androgen resistance in prostate tumors. ^[158]

Subsequently, the controversy of the appropriate timing of ADT was renewed because of the advent of an LHRH antagonist and LHRH agonists. Laboratory studies demonstrated that early hormone therapy does not confer early resistance. Moreover, clinical trials found that it provided significantly longer survival with fewer complications (eg, pathologic fractures, spinal cord compression, ureteral obstruction) than did deferred treatment. ^{[159, 160]}

Intermittent androgen suppression

Intermittent androgen suppression has been assessed in prospective, randomized studies as a possible means of minimizing the side effects of ADT. As previously discussed, Crook et al found that intermittent androgen suppression was noninferior to continuous therapy with respect to overall survival. ^[155]  In a Spanish study, a greater number of cancer deaths in the intermittent treatment arm was balanced by a greater number of cardiovascular deaths in the continuous treatment arm. ^[161]

In both studies, intermittent therapy resulted in better quality of life. Indeed, this benefit might be more pronounced than was seen in these studies, because the testosterone level does not return to baseline in about one third of men on intermittent therapy.

However, survival in men with metastatic hormone-sensitive prostate cancer may be shorter when ADT is given intermittently rather than continuously, according to a large study of 770 men treated with intermittent therapy and 765 men treated with continuous therapy, who were followed for a median of almost 10 years (average survival, 5.1 vs 5.8 years, respectively—a 10% higher relative risk for death). Intermittent therapy was associated with better erectile function and mental health at month 3 but not thereafter. ^[162]

National Comprehensive Cancer Network (NCCN) guidelines advise that for men with nonmetastatic prostate cancer, intermittent ADT is considered as safe as continuous ADT. The NCCN recommends that intermittent ADT be considered in men with metastatic disease. ^[58]

Addition of androgen pathway–directed therapy or chemotherapy

mHSPC remains incurable. While ADT, with or without nonsteroidal antiandrogens, has been the backbone of mHSPC treatment for many decades, ADT alone is no longer considered sufficient treatment for mHSPC. In the past 5 years, multiple studies have shown that additional therapy with either docetaxel or androgen pathway–directed therapy (abiraterone acetate plus prednisone, apalutamide, enzalutamide) significantly extends overall and progression-free survival. 

Androgen suppression plus abiraterone acetate with prednisone

In February 2018, the FDA approved abiraterone acetate (Zytiga) in combination with prednisone for patients with metastatic high-risk castration-sensitive prostate cancer, based on findings from the LATITUDE trial. In this double-blind, placebo-controlled, phase III trial in 1199 men with metastatic, castration-sensitive prostate cancer, the addition of abiraterone acetate and prednisone to ADT significantly increased overall survival and radiographic progression-free survival. Median overall survival was significantly longer in the abiraterone group versus the placebo group (not reached vs. 34.7 months). Median radiographic progression-free survival was 33 months in the abiraterone group versus 14.8 months in the placebo group. ^[163]

In addition, the abiraterone group had significantly better outcomes in all secondary end points, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P< 0.001 for all), along with next symptomatic skeletal events. ^[163]

In the STAMPEDE trial, the addition of abiraterone acetate and prednisolone at the initiation of primary ADT was associated with a 71% relative improvement in the time to treatment failure, which translated into a 37% difference in overall survival. Three-year survival rates were 83% with combination therapy versus 76% with ADT alone, and treatment failure–free survival rates at 3 years were 75% vs 45%, respectively. STAMPEDE included 1917 men with newly diagnosed, locally advanced or metastatic prostate cancer, or relapsed disease with high-risk features. ^[164]

Androgen suppression plus enzalutamide

In the open-label, randomized, phase III ENZAMET trial,1125 men were randomized to receive testosterone suppression plus either open-label enzalutamide (160 mg daily) or standard care with a nonsteroidal antiandrogen (bicalutamide, nilutamide, or flutamide). The primary end point was overall survival (OS). With a median follow up of 34 months, there were 102 deaths in the enzalutamide group versus 143 deaths in the standard care group (HR= 0.67; 95%CI 0.52 to 0.86; P= 0.002). Kaplan-Meier estimates of OS at 3 years were 80% in the enzalutamide group and 72% in the standard care group. ^[165]

In the double-blind, phase III ARCHES trial, conducted in 1150 men with mHSPC, the risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT compared with placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; P < 0.001; median not reached vs 19.0 months). The benefit of enzalutamide extended to patients with low-volume disease and/or prior docetaxel therapy. ^[166]

Both enzalutamide and apalutamide do present a small risk of seizures, so patients with a seizure disorder should instead choose a regimen such as abiraterone acetate plus prednisone or docetaxel.

Androgen suppression plus docetaxel

Since 2015, two clinical trials demonstrated the benefits of adding docetaxel chemotherapy to ADT for mHSPC patients.The phase III E3805/ CHAARTED trial (ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) randomized 790 patients with mHSPC to six cycles of docetaxel plus ADT or ADT alone. Intended to enroll only patients with high disease burden, defined by the presence of visceral metastases (a bone metastasis burden beyond the axial skeleton) or a high number of lesions, the trial was later amended to enroll patients with low disease burden as well. At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (HR=0.72; 95%CI 0.59 to 0.89; P= .0018). This benefit was most apparent and significant among patients with high disease burden and was maintained in these patients at 54-month follow up. However, patients with low disease burden had no survival benefit after docetaxel addition ^[167] . 

Similar survival outcomes were seen with the docetaxel and docetaxel plus zoledronic acid arms in the large multicenter multi-arm MRC STAMPEDE (Medical Research Council Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial, which enrolled 2,962 patients with metastatic, nodal, or high- risk localized disease. At a median follow up of 43 months, median OS was 71 months for ADT alone compared with 81 months for standard of care plus zoledronic acid plus docetaxel (HR=0.78; 95%CI 0.66 to 0.93; P=0.006). ^[168]

Like many chemotherapy agents, docetaxel has a significant toxicity profile that needs consideration. In the STAMPEDE trial, the most frequently reported adverse events in the docetaxel group included febrile neutropenia (15%), general disorder (including lethargy, fever, asthenia—7%), and gastrointestinal disorder (including diarrhea, abdominal pain, constipation, vomiting—8%). ^[168]  

Relugolix

Relugolix is the first oral androgen deprivation therapy approved by the FDA for advanced prostate cancer. It is a gonadotrophin-releasing hormone (GnRH) receptor antagonist that decreases gonadotropin release (ie, luteinizing hormone, follicle stimulating hormone), thereby decreasing the downstream production of testosterone by the testes in men. 

Approval of relugolix was based on the HERO clinical trial (n = 622). In HERO, sustained testosterone suppression at 48 weeks was achieved in 96.7% of relugolix-treated patients compared with 88.8% with leuprolide. Risk of major adverse cardiovascular events was 54% lower with oral relugolix compared with leuprolide injections. ^[169]

Eventually, almost all metastatic prostate cancers become resistant to androgen ablation. In patients with castrate serum testosterone levels (less than 50 ng/dL), castrate-resistant prostate cancer is defined as 2-3 consecutive rises in PSA levels obtained at intervals of greater than 2 weeks and/or documented disease progression based on findings from computed tomography (CT) scan and/or bone scan, bone pain, or obstructive voiding symptoms.

Rarely, a rise in PSA may reflect failure of LHRH treatment to control testosterone secretion, rather than the development of castrate-resistant disease. Therefore, the testosterone level should be measured when the PSA rises. If the serum testosterone level exceeds castrate levels, changing the antiandrogen therapy may drop the PSA and delay the need for other therapy.

Prior to the development of the most recent therapies, the median time to symptomatic progression after a rise in the PSA level of more than 4 ng/mL was approximately 6-8 months, with a median time to death of 12-18 months. Since then, however, the latter figure has increased.

Little information is available about the impact of maintaining hormone suppression when androgen-independent progression occurs, but the general consensus among specialists is that the treatment should continue. The reasoning is that tumor cells are still hormone sensitive and may grow faster if the testosterone is permitted to rise.

Non-chemotherapy options that provide palliation and improve quality of life include the following:

• Megestrol
• Nonsteroidal antiandrogens
• Corticosteroids
• Ketoconazole
• Radiation therapy
• Bisphosphonates
• Suramin
• Estrogen

None of those have been shown to improve survival, although few of them have been properly assessed for that endpoint.

A subset of men who have developed castration-resistant prostate cancer will have a rising PSA, but no visible metastatic disease on conventional imaging. In these patients a PSA doubling time of ≤10 months is associated with a high risk of developing metastatic disease or dying from prostate cancer. ^[170] Along with serial PSA measurements at 3-6 month intervals, patients should undergo convential imaging every 6-12 months to assess for metastatic disease.

In patients with castration-resistant prostate cancer treated with enzalutamide prior to chemotherapy in the PREVAIL trial, radiographic progression occurred in 24.5% of patients without PSA progression, suggesting that routine imaging can identify a significant portion of patients who would otherwise not be identified. ^[171] The AUA/ASTRO/SUO guidelines stratify treatment decisions based on risk for developing metastatic disease. Patients with a PSA doubling time ≤10 months are deemed high risk and should be offered apalutamide, darolutamide, or enzalutamide with continued ADT.

Docetaxel

Therapeutic options for patients with castration-resistant prostate cancer have changed significantly, beginning with the approval of docetaxel in 2004. Two randomized studies have shown that this drug improves survival. ^[172]  In the Southwestern Oncology group trial SWOG 99-16, median survival was 2 months longer with docetaxel plus estramustine than with mitoxantrone plus prednisone (17.5 vs 15.6 months). ^[173]  Gastrointestinal and cardiovascular side effects were more common in the group receiving docetaxel, however.

In the TAX 327 trial, median survival was 16.5 months in patients given mitoxantrone, 17.4 months in those given weekly docetaxel, and 18.9 months in those given docetaxel every 3 weeks. All 3 groups also received prednisone. ^[174]  A follow-up analysis confirmed these findings, with median survival of 16.3 months in the mitoxantrone arm, 17.8 months in the weekly docetaxel arm, and 19.2 months in the every-3-weeks arm. ^[175]

Other therapies now approved for androgen-independent prostate cancer include the following:

• Sipuleucel-T (Provenge)
• Abiraterone acetate (Zytiga, Yonsa)
• Enzalutamide (Xtandi)
• Cabazitaxel (Jevtana)
• Mitoxantrone
• Apalutamide (Erleada)
• Rucaparib (Rubraca)
• Olaparib (Lynparza)

As previously mentioned, early results from a randomized, controlled trial indicated that in patients with hormone-sensitive metastatic prostate cancer, those who are treated with docetaxel at the beginning of standard hormone therapy with ADT have improved survival compared with those treated with hormone therapy alone. ^[167]

In the phase III COMET-1 study, the tyrosine kinase inhibitor cabozantinib did not significantly improve overall survival compared with prednisone in heavily treated patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving bone scan response, which was the secondary trial end point. However, grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone. ^[176]  

Lutetium Lu 177 vipivotide tetraxetan

Lutetium Lu 177 vipivotide tetraxetan is indicated for the treatment of men with prostate-specific membrane antigen (PSMA)-positive, metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy. It is a radioligand therapeutic agent. The active moiety is the radionuclide lutetium-177, which is linked to a moiety that binds to PSMA, a transmembrane protein expressed in prostate cancer, including mCRPC. Upon binding to PSMA-expressing cells, the lutetium-177 delivers beta-minus radiation to the cells, as well as to surrounding cells, inducing DNA damage that can lead to cell death. 

Approval was based on the phase 3 VISION trial. Compared with patients receiving standard care (n = 196), patients who received lutetium Lu 177 vipivotide tetraxetan plus standard care (n = 581) had significantly prolonged imaging-based progression-free survival (median, 8.7 vs 3.4 months; P < 0.001) and overall survival (15.3 vs. 11.3 months; P < 0.001). ^[177]   

Sipuleucel-T

Sipuleucel-T is a therapeutic vaccine that was approved by the FDA in April 2010 for asymptomatic or minimally symptomatic prostate cancer with metastases resistant to standard hormone treatment. The National Comprehensive Cancer Network supports its use in men with good performance status, a life expectancy of more than 6 months, no hepatic metastases, and no or minimal symptoms. ^[58]

Sipuleucel-T must be prepared individually for each patient. To create Sipuleucel-T, peripheral blood mononuclear cells, including antigen-presenting cells (APCs), are extracted from the patient using leukapheresis and are incubated with prostatic acid phosphatase, an antigen expressed in prostate cancer tissue. The product, which now contains activated APCs, is then reinfused into the patient.

An updated report of a randomized, placebo-controlled study by Kantoff et al showed median survival of 25.8 months versus 21.7 months and a survival probability at 36 months of 32.1% versus 23% in the sipuleucel-T and placebo arms, respectively. ^[178]  The study included a crossover design, which means the true benefit is likely to be higher. A subset analysis found that survival in men with a PSA level below 22 ng/mL was 13 months longer in the sipuleucel-T group than in the control group.

One aspect of sipuleucel-T treatment that has made its acceptance difficult is that it does not appear to produce either a PSA or an objective disease response; the benefit is limited to overall survival. Consequently, other therapies can be instituted after the sipuleucel-T treatment regimen has been completed.

Adverse events that have been reported more often with sipuleucel-T than with placebo include chills, pyrexia, headache, influenzalike illness, myalgia, hypertension, hyperhidrosis, and groin pain. The majority of these were low grade and resolved within 1-2 days. ^[178]

Abiraterone acetate

Abiraterone acetate (Zytiga), an inhibitor of androgen biosynthesis, was approved by the FDA in April 2011 for use in combination with prednisone for the treatment of patients with mCRPC who have received prior chemotherapy containing docetaxel. Abiraterone blocks CYP17A1, an enzyme that is important in the synthesis of testosterone by the adrenal gland and by prostate cancer cells. This results in blocking all testosterone production.

Approval of abiraterone was based on the results of a randomized, controlled trial that showed improved survival in 1195 patients with castrate-resistant prostate cancer who were treated with this combination. ^[179]  More recently, a large, international, randomized trial found a median overall survival period of 15.8 months in men receiving abiraterone, compared with 11.2 months in the placebo group. ^[180]

Men receiving abiraterone also had a significantly longer time to PSA progression, a longer progression-free survival, and a higher PSA response. The adverse  effects occurring more frequently in the treated group were related to decreased mineralocorticoid effects and included hypertension, fluid retention, and hypokalemia. ^[180]

In December 2012 the FDA expanded the approved use of abiraterone to treatment of men with late-stage (metastatic), castrate-resistant prostate cancer prior to receiving chemotherapy. The expanded indication was based on a study in which patients who received abiraterone had a median overall survival period of 35.3 months, compared with 30.1 months for patients receiving placebo, and had better radiographic progression–free survival. ^[181]

An ultramicronized abiraterone tablet (Yonsa) was approved in May 2018 for mCRPC in combination with methylprednisolone. The ultramicronized formulation may be administered with or without food, whereas the original tablet formulation (Zytiga) must be administered 1 hour before or 2 hours after meals.

Enzalutamide

Enzalutamide acts by inhibiting the binding of androgens to the androgen receptor and inhibits translocation of the androgen receptor into the nucleus. A stage III trial in 1199 men with castration-resistant prostate cancer after chemotherapy showed median overall survival of 18.4 months in the enzalutamide group versus 13.6 months in the placebo group. Patients receiving the active drug also had a higher PSA and quality-of-life response and a longer time to PSA progression, longer radiographic progression-free survival, and longer time to first skeletally-related event. Fatigue, diarrhea, and hot flashes were more common in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide. ^[182]

Enzalutamide proved superior to bicalutamide in the TERRAIN clinical trial, a double-blind, randomized phase II study in 375 asymptomatic or minimally symptomatic men with prostate cancer progression on ADT. Median progression-free survival was significantly longer with enzalutamide than bicalutamide (15.7 versus 5.8 months; hazard ratio [HR], 0.44; P< 0.0001). However, 68% of patients in the enzalutamide group and 88% of those in the bicalutamide group discontinued their assigned treatment before study end, mainly due to progressive disease. ^[183]

In  2018, the FDA approved an expanded indication for enzalutamide in CRPC to include patients with nonmetastatic castration-resistant prostate cancer. Approval was based on the PROSPER trial. In the 1401-patient trial, enzalutamide decreased the risk for distant metastasis or death by 71% (HR, 0.29; 95% confidence interval [CI], 0.24 - 0.35; P < 0.0001), with a median metastasis-free survival of 36.6 compared with 14.7 months in the placebo group (an improvement of 21.9 months). ^[184]

In 2019, FDA approval was further expanded to include metastatic castration-sensitive disease. Approval was based on the ARCHES trial, in which median radiographic progression-free survival was not reached (NR) in the enzalutamide arm, compared with 19.4 months in the placebo arm. ^[185]

Cabazitaxel

Cabazitaxel is another taxane that acts as a microtubular inhibitor. In a study of 755 men with mCRPC that had progressed despite docetaxel treatment, the median overall survival period was 15.1 months in patients receiving cabazitaxel, versus 12.7 months in those receiving mitoxantrone. Median progression-free survival was also longer with cabazitaxel. Both groups also received prednisone. The most common clinically significant grade 3 or higher adverse events with cabazitaxel were neutropenia and diarrhea. Febrile neutropenia was also more common with cabazitaxel. ^[186]

Apalutamide

Apalutamide, an androgen receptor inhibitor, was approved by the FDA in February 2018 for treatment of nonmetastatic castration-resistant prostate cancer. The FDA based its approval on safety and efficacy data from the phase 3 SPARTAN (Selective Prostate Androgen Receptor Targeting With ARN-509) trial, in which median metastasis-free survival (the primary endpoint), was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (P < 0.001). That translated into a 72% reduction in the relative risk for metastasis or death with apalutamide (HR, 0.28; 95% CI, 0.23 - 0.35). ^[187] .

In the SPARTAN trial, 806 men were randomized to receive treatment with apalutamide (240 mg per day) and 401 to receive placebo; all participants also received hormone therapy, either gonadotropin-releasing hormone analogue therapy or surgical castration. All the participants had undergone previous definitive treatment, either surgery or radiotherapy, for prostate cancer, but their PSA scores had doubled within 10 months or less following treatment, despite hormone therapy. ^[187]

Darolutamide

Similar to apalutamide, darolutamide was approved for patients with nonmetastatic castration-resistant prostate cancer.

Approval was based on the phase IIARAMIS trial which evaluated metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks. Patients (n=1509) received either darolutamide or placebo while continuing androgen-deprivation therapy. In the planned primary analysis, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo. Darolutamide was also associated with benefits to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. In men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo. ^[188]

Rucaparib

Rucaparib, a PARP (poly ADP-ribose polymerase) inhibitor, was approved by the FDA in May 2020 for mCRPC associated with a deleterious BRCA mutation (germline and/or somatic) in patients who have been treated with androgen receptor–directed therapy and taxane-based chemotherapy. Accelerated approval was based on an objective response rate (ORR) of 44% from the multicenter, single arm TRITON2 clinical trial. The confirmatory TRITON3 trial is ongoing. ^[189]  

Olaparib 

Another PARP inhibitor, olaparib, was approved in May 2020 for deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated mCRPC that progressed after treatment with enzalutamide or abiraterone. Approval was supported by the PROfound phase III clinical trial, in which olaparib significantly reduced risk of disease progression or death by 66% (HR 0.34, P < 0.0001) compared with abiraterone or enzalutamide. ^{[190, 191]}

Final analysis of PROfound results confirmed the benefit of olaparib in this setting. The median duration of overall survival in patients with at least one alteration in BRCA1, BRCA2, or ATM (n=245) was 19.1 months with olaparib and 14.7 months with control therapy (HR for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P=0.02). In patients with at least one alteration in any of the other 12 prespecified genes (n=142), the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. Substantial crossover from the control group to olaparib (86 of 131 patients) occurred; adjusted for crossover, the HR for death was 0.55 (95% CI, 0.29 to 1.06) in the overall population. ^[192]

Drug sequencing for androgen-independent prostate cancer

The availability of the above new agents presents a challenge for physicians and patients, who must decide on the best sequence and timing for each of them. So far, no studies have been done to determine the best approach. Studies in progress are likely to result in some change to the sequencing of these drugs.

As of October 2012, and excluding cost considerations, men with asymptomatic or minimally symptomatic progressive disease can start with immunotherapy using sipuleucel-T. Since no objective responses are expected, patients can then be given abiraterone acetate.

On September 11, 2014 the FDA expanded the approved use of enzalutamide for the treatment of men with late-stage (metastatic), castrate-resistant prostate cancer prior to receiving chemotherapy. The expanded indication was based on a study in which patients who received enzalutamide reduced the risk of radiographic progression or death by 83% versus placebo, while significantly reducing the risk of death by 29%. ^[193]

Without formal studies to guide recommendations, either drug may be used next, although enzalutamide does not require prednisone, and for that reason it may be most suitable. Hopefully, studies will be done to determine whether men are better off receiving either enzalutamide or abiraterone first or second. Men showing progression on those drugs should then be offered docetaxel followed by cabazitaxel.

For full discussion, see Metastatic and Advanced Prostate Cancer.

In a study of men with newly diagnosed metastatic prostate cancer, treatment with prostate radiation and ADT led to substantially longer survival compared with treatment with ADT alone. In the study, which included 6,382 men, combination therapy yield superior median survival (55 v 37 months) and 5-year overall survival (49% versus 33%) (P < 0.001). ^[194]

In patients with metastatic prostate cancer, radiation is also applied for palliative purposes. It is used in patients with castration-resistant prostate cancer (CRPC) with painful bone metastases, in patients at risk for fracture, and in patients with impending spinal cord compression.

A meta-analysis of the use of radioisotopes to relieve pain from bone metastases found that over 1-6 months, pain may be reduced without an increase in analgesic use; however, severe effects such as leukocytopenia and thrombocytopenia frequently surface. ^[195]

Radium-223 dichloride (Xofigo), formerly alpharadin, is an alpha particle–emitting radioactive therapeutic agent that was approved by the FDA in 2013 for use in men with CRPC, symptomatic bone metastases, and no known visceral metastatic disease. ^[196] Approval was based on the multinational ALSYMPCA trial (ALpharadin in SYMptomatic Prostate CAncer), which is the first randomized phase III trial to demonstrate improved survival of CRPC with a bone-seeking radioisotope. ^[197]

The ALSYMPCA trial was conducted in 19 countries and included 921 patients with prostate cancer that had progressed with symptomatic bone metastases and no known visceral metastases. The trial was halted early after a planned interim analysis found a survival benefit in favor of radium-223. Updated analysis has demonstrated a 3.6-month survival advantage compared with placebo (14.9 vs 11.3 months, respectively).

 

Physicians have suggested that the benefits seen from radiation to the prostate point to the benefits of local therapy, raising the question of whether radical prostatectomy might have the same results. Trials are ongoing, and at present the use of surgery should be considered investigational and conducted only within the context of a trial. However, transurethral resection is sometimes needed in men who develop obstruction secondary to local tumor growth. Bilateral orchiectomy can be used to produce androgen deprivation in patients with widely advanced and metastatic prostate cancer.

Since the introduction of LHRH agonist and antagonist therapies, surgical intervention has been practiced less often. An indication for immediate bilateral orchiectomy is spinal cord compression, because it avoids the potential flare response that can occur during the first 3 weeks of treatment with an LHRH agonist.

 

Surgical and medical castration lead to a number of adverse effects, including the following, that can have a significant impact on a man’s quality of life:

• Anemia
• Breast enlargement
• Cognitive impairment
• Decreased libido
• Decreased muscle mass
• Erectile dysfunction
• Fatigue
• Fractures
• Gastrointestinal tract disturbances
• Gynecomastia
• Hot flashes
• Osteoporosis
• Metabolic syndrome
• Pulmonary edema
• Psychological changes
• Weight gain

In addition, in men with prostate cancer receiving ADT, lean body mass decreases significantly after 12-36 months of treatment. ^[198]

Uncertainty remains about the impact of androgen ablation on cardiovascular morbidity and mortality. However, the combination of weight gain and anemia in men with asymptomatic cardiovascular disease could adversely affect survival in some cases.

The FDA has advised that manufacturers of gonadotropin-releasing hormone (GnRH) agonists, which are approved for palliative treatment of advanced prostate cancer, must add safety warnings about the increased risk of diabetes and certain cardiovascular diseases (eg, myocardial infarction, sudden cardiac death, stroke) in men receiving these medications. The FDA notes that although the risk for these complications appears to be low, physicians should evaluate patients for risk factors for these diseases before prescribing these agents. ^[199]

Patients receiving GnRH agonists should be actively monitored for diabetes and cardiovascular disease and treated when possible. Periodic measurement of fasting glucose, cholesterol, triglycerides, and blood counts should be performed. In addition, the package inserts for all LHRH medications recommend periodically measuring serum testosterone, because levels above 50 ng/dL do occur and may adversely affect long-term survival.

Long-term androgen blockade for prostate cancer may also increase a patient’s risk for colorectal cancer. An observational study by Gillessen et al of men with prostate cancer—identified through the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute—found that after adjustment for confounding variables such as age, socioeconomic status, and the use of radiation therapy, the rate of colorectal cancer was 30-40% higher in men treated with androgen blockade than in those who were not. ^[200]

In a study of the bone density differences between African-American and Caucasian men who were receiving ADT for prostate cancer, Morgans et al found that African-American men had a greater hip bone mineral density and tended to have fewer prevalent vertebral fractures than Caucasian men. However, African-American men experience a decrease in bone mineral density similar to that of Caucasian men despite a lower baseline risk for osteoporosis and fracture. ^[201]

Acute kidney injury

In a case-control analysis of more than 10,000 men with prostate cancer, ADT was significantly associated with an increased risk for acute kidney injury (AKI). Current use of any ADT more than doubled the risk for AKI, compared with such risk in patients who had never undergone ADT. The risk was especially heightened for combination therapies and estrogens.ref197}

In the study, researchers reviewed data from the UK Clinical Practice Research Datalink on 10,250 men newly diagnosed between 1997 and 2008 with nonmetastatic prostate cancer. The overall incidence rate of AKI in the study population was 5.5 per 1000 person-years, compared with 1.8 per 1000 person-years in the general population. The odds of developing AKI with current ADT use, compared with that for persons who never used the therapy, were highest during the first year of treatment. The odds decreased with longer durations but remained statistically significant for up to 3 years, as well as for 3 years and beyond.

Bone protection in patients receiving androgen blockade

Two drugs, the bisphosphonate zoledronic acid and the RANKL inhibitor denosumab, have been approved to treat osteoporosis secondary to androgen deprivation. Zoledronic acid is administered as an intravenous infusion. Denosumab is administered subcutaneously. These drugs are given along with supplemental vitamin D and calcium. Patients should be monitored regularly for hypocalcemia. Both agents are associated with a low incidence of osteonecrosis of the jaw. Both drugs delay the risk of skeletally-related events by relieving bone pain, preventing fractures, decreasing the need for surgery and radiation to the bones, and lowering the risk of spinal cord compression.

A double-blind, placebo-controlled, multicenter study in men with primary or hypogonadism-associated osteoporosis found that over a 14-month period, treatment with zoledronic acid reduced the risk of vertebral fractures by 67%. New morphometric vertebral fracture occurred in 1.6% of men taking zoledronic acid and in 4.9% taking placebo. Patients receiving zoledronic acid had significantly higher bone mineral density and lower bone-turnover markers. However, the rate of myocardial infarction was higher in the treatment group (1.5% vs 0.3%). ^[202]

A double-blind, placebo-controlled, multicenter study in men undergoing ADT for nonmetastatic hormone-sensitive prostate cancer found that patients receiving denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5% vs 3.9% with placebo). Patients receiving denosumab also had significant increases in bone mineral density in the total hip, femoral neck, and distal third of the radius. ^[203]

In a double-blind, randomized, comparative trial performed in men with hormone-refractory disease, the time to first skeletally-related event was significantly longer with denosumab than with zoledronic acid (20.7 mo vs 17.1 mo, respectively). Hypocalcemia was more common in the denosumab group than in the zoledronic acid group (13% vs 6%, respectively). Osteonecrosis of the jaw occurred infrequently in both groups (2% vs 1%, respectively). ^[204]

Despite the availability of new therapies, most men with metastatic prostate cancer will eventually experience progression of disease. For these patients, palliative care is important, and early consultation with hospice may provide for a smoother transition.

The combination of mitoxantrone and prednisone is an approved treatment for symptoms of metastatic disease but does not improve survival. Bone pain due to metastatic disease requires narcotics, awareness of fractures, and, possibly, palliative radiation.

Urinary retention

Urinary retention may occur secondary to urethral strictures, bladder outlet obstruction, or a blood clot. Cystoscopy or a retrograde urethrogram should be performed to identify the cause. Strictures can be either dilated or treated endoscopically. Outlet obstruction can be managed by transurethral resection. Ureteral obstruction due to lymphadenopathy may be treated with a ureteral stent or percutaneous nephrostomy.

Long-term urinary retention or malignant urinary obstruction due to untreated prostate cancer can lead to chronic renal failure, which manifests as uremic symptoms and an elevated serum creatinine level. Patients on watchful-waiting protocols are at risk for this if they are not closely monitored.

Hematuria

This may manifest as a small element of prostate venous bleeding or it may lead to large clots. Hematuria is more common in patients who have undergone radiation therapy.

Vigorously irrigate the bladder with copious amounts of fluid to remove all evidence of clots. Sterile water is best because it helps to lyse the clot. Use care, however, because absorption of the fluid may occur in situations in which prostatic venous channels are open.

Prostatic bleeding may be treated first with transurethral resection and cauterization. If that is unsuccessful, medications can be attempted. Androgen ablation can be tried if not already in use. Otherwise, aminocaproic acid and megestrol may help some men.

Urinary incontinence

Incontinence from bladder spasm or irritation is common immediately after various prostate treatments. While patients have urinary catheters in place, oxybutynin, tolterodine, belladonna and opium suppositories, and phenazopyridine (Pyridium) may be used to decrease symptoms.

Patients with incontinence secondary to radical prostatectomy or radiation may benefit from placement of a urinary sphincter. In rare cases, urinary diversion may be considered.

Rectal complications

Although uncommon, a urethrorectal fistula may occur after surgery or radiation. Manage the fistula with urinary and fecal diversion using appropriate treatment options.

Rectal bleeding and tenesmus are observed in patients treated with radiation. Steroid enemas and in some cases focal cauterization can alleviate the problem.

Fractures

Patients receiving ADT and those with bone metastasis should receive preventive therapy for fractures. Patients diagnosed with impending paralysis due to spinal cord compression or patients with pathologic fractures should be immediately hospitalized and treated emergently with spinal cord decompression, steroids, and orchiectomy or an LHRH antagonist.

Consultation with a radiation oncologist should be obtained for palliative radiation therapy for bone metastases, for locally extensive tumors, and, on an emergent basis, for spinal cord compression. Consultations with a neurosurgeon for spinal cord compression and an orthopedic surgeon for pathologic fractures are appropriate. Consultation with a medical oncologist may also be considered for chemotherapy when a patient with metastatic disease begins to show disease progression on hormone therapy.

Follow-up is not standardized; however, practitioners use general guidelines that are derived mainly from publications report outcomes on various methods of treatment. In addition, the NCCN, an alliance of 19 cancer centers, publishes follow-up guidelines for the various treatment modalities.

Followup by primary care physicians

The American Cancer Society has released evidence- and expert-based guidelines for the management of prostate cancer survivors by primary care physicians (PCPs), a response to the fact that as the number of men surviving prostate cancer has increased, reliance on PCPs for their care has grown as well. The guidelines address promotion of healthy lifestyles, surveillance for disease recurrence, screening for second primary cancers, and evaluation and management of adverse physical and psychosocial effects caused by the disease and its treatment. Recommendations include the following ^[205] :

• Oncologists should provide PCPs with treatment summaries, as well as recommendations for posttreatment follow-up

• Serum prostate-specific antigen (PSA) levels should be assessed every 6-12 months during the first five years of follow-up and then should be rechecked annually

• Patients should undergo an annual digital rectal examination (DRE)

• Patients undergoing androgen deprivation therapy (ADT) should be periodically monitored for treatment-associated anemia, but routine anemia therapy for asymptomatic patients receiving ADT is not necessary

• Owing to the risks for metabolic syndrome, obesity, and bone loss and fracture associated with ADT, baseline assessments of calcium and vitamin D levels and bone-density scanning should be performed in men undergoing this treatment, and patients should receive dietary counseling, supplements (if needed), and other therapeutic interventions

• Physicians should, during routine care, inquire about the patient’s ability to function sexually; treatment options for sexual dysfunction include phosphodiesterase type 5 (PDE-5) inhibitors

• Patients may suffer from depression and anxiety as a result of sexual dysfunction or bowel and urinary problems, necessitating a counseling referral

Watchful waiting

Patients on watchful waiting are treated only if they develop symptomatic progression of their disease. No curative therapy is administered. A DRE and PSA test are performed periodically to determine when a bone scan and CT scan might be warranted and if hormone therapy is necessary. The results can also be used to determine when bone-directed treatments are appropriate to avoid serious morbidity.

Radical prostatectomy

PSA testing is performed every 3-4 months for the first 2 years after radical prostatectomy, every 6 months for the third and fourth years, and yearly thereafter. DRE has not been shown to offer any added advantage in the detection of local recurrence beyond PSA testing, but most physicians continue to do it.

Radiation therapy

In patients who have been treated with EBRT, DRE and PSA are performed every 3-6 months for 5 years and then annually thereafter. Evidence is lacking that periodic prostate biopsies following radiation therapy are beneficial.

After brachytherapy, PSA testing is performed every 3-6 months for 2 years and then annually thereafter. Here too, no studies have proved that there is a benefit to performing a prostate biopsy unless the PSA begins to rise and the patient is considered a candidate for salvage prostatectomy.

Biochemical recurrence

A biochemical recurrence (ie, measurable PSA) is considered to have occurred following radical prostatectomy if the PSA level is greater than 0.2 ng/mL or is above the minimal detectable level of the assay. For example, using ultrasensitive PSA assays, a cutoff of 0.01 ng/mL or 0.05 ng/mL can be used.

The definition of a biochemical recurrence following radiation is more complex, and significant debate still surrounds this topic. Options for determining biochemical recurrence include the following:

• 2-3 consecutive rises in the PSA level following a nadir (ASTRO definition)
• Rise of 2 ng/mL or more above the nadir PSA level (Phoenix definition) ^[206]
• An absolute cutoff of 0.2, 0.5, or 1 ng/mL

Biochemical recurrence should prompt closer follow-up and consideration of alternative therapies. When the PSA level begins doubling every 10-12 months or reaches some minimal level ranging from 10-20 ng/mL, imaging studies may be performed, as follows:

• Bone scan
• CT scan of the abdomen and pelvis
• Potentially, transrectal ultrasonography–guided rebiopsy of the prostate or prostatic fossa in patients treated with radical prostatectomy
• ProstaScint scan

The ProstaScint scan is most commonly used in patients who have biochemical recurrence without evidence of metastases and who may be candidates for EBRT. The ProstaScint scan is especially useful for identifying localized recurrence and lymphatic spread.

Other imaging studies include positron emission tomography (PET) scanning and magnetic resonance imaging (MRI) spectroscopy. PET scanning uses cancer metabolism to illuminate cancer spread to other organs. MRI spectroscopy combines anatomic information with metabolic activity to detect residual cancer in the gland.

Multiparametric MRI (mpMRI) may have a role in detecting clinically significant prostate cancer in men with elevated PSA levels. ^[207] Recommendations on a standardized method for the conduct, interpretation, and reporting of prostate MRI for cancer detection and localization have been agreed on, using formal consensus methods.

Possible preventive measures for prostate cancer include lifestyle modification and chemoprevention with 5-alpha-reductase inhibitors (5-ARIs). Use of 5-ARIs, however, has proved problematic. Lifestyle measures such as weight loss in obese patients and physical activity can be recommended unequivocally because of their multiple benefits.

Lifestyle measures

Diets associated with a reduced risk of prostate cancer in epidemiologic studies are composed mainly of vegetables, fruits, grains, and fish. Tomatoes (because of their lycopene content), broccoli, green tea, and soy have all been hypothesized to be beneficial.

Increased risk has been shown with high-fat diets, excessive intake of estrogens and phytoestrogens, and the consumption of burned or charred foods. Obesity appears to be the diet-related factor most strongly associated with prostate cancer, so overall energy intake is important.

Because a high-fat diet is linked with a higher incidence of prostate cancer, a low-fat diet may be beneficial for men at high risk of developing prostate cancer (ie, those with a positive family history, African Americans) and for patients undergoing treatment for advanced prostate cancer. However, no prospective studies have proved that dietary modification provides a benefit.

Nutritional supplements also have not proved beneficial in research studies. The Physicians' Health Study II, a long-term, randomized, controlled trial involving male physicians, found that neither vitamin E nor vitamin C supplementation reduced the risk of prostate or other cancers. ^[208]

Similarly, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized placebo-controlled trial involving 35,533 relatively healthy study participants from 427 US sites, found that neither selenium nor vitamin E (alone or in combination), at the doses and formulations used, prevented prostate cancer. ^[209] See Prostate Cancer and Nutrition for more information on this topic.

Physical activity appears to lower prostate cancer risk. A meta-analysis by Liu et al found a small, but significant, association between physical activity and prostate cancer in men aged 20-45 years. ^[210]

Improving diet and increasing physical activity to reduce prostate cancer risk will also reduce cardiovascular risk. This is a significant benefit, as cardiovascular disease is the cause of death in many men with prostate cancer.

5-alpha-reductase inhibitors

The 5-ARIs, approved by the FDA for benign prostatic hyperplasia (BPH) and alopecia, include finasteride (Proscar, Propecia) and dutasteride (Avodart, Jalyn).

The use of 5-ARIs to prevent prostate cancer was studied in 2 large, randomized, controlled trials, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. In both of these studies, men taking dutasteride or finasteride had a decreased incidence of prostate cancer overall, but they also had an increased incidence of high-grade prostate cancer over participants who received placebo. ^{[211, 212]}

PCPT randomized almost 19,000 men in the United States at low risk of prostate cancer to receive either finasteride or placebo for the primary prevention of prostate cancer over a 7-year period. Although there was a significant reduction in the risk of prostate cancer, this benefit was observed only for low-grade disease, while there was an increase in the risk of Gleason grade 7-10 disease. ^[213] Several subsequent analyses of the data suggest that the risk of higher-grade disease was associated with increased cancer detection owing to prostate volume decreases rather than direct effects of the medication. ^[214]

The REDUCE trial evaluated dutasteride for the primary prevention of prostate cancer in 6,700 men at a slightly higher risk of prostate cancer than the PCPT trial and over 4 years of follow-up. Dutasteride treatment was associated with an overall reduction in low-grade prostate cancer diagnosis but no increase in higher-grade disease.

Because both trials demonstrated a reduction in the risk of low-risk prostate cancer only, and both medications have potential adverse effects, neither one is currently recommended for prostate cancer prevention. Some evidence does suggest that, for men on these medications, a rising PSA level might be more sensitive for the detection of clinically relevant prostate cancer. ^[215]

The American Society of Clinical Oncology (ASCO) Health Services Committee (HSC), the ASCO Cancer Prevention Committee, and the American Urological Association Practice Guidelines Committee jointly convened a panel of experts who used the results from a systematic review of the literature to develop evidence-based recommendations on the use of 5-ARIs for prostate cancer chemoprevention. ^[216]

The panel concluded that asymptomatic men with a PSA level of 3 ng/mL or less who are undergoing regular PSA screening or who are planning to undergo such screening annually may be aided by a discussion of the benefits of using 5-ARIs for prostate cancer prevention and of the risks associated with the drugs, such as the development of high-grade prostate cancer.

On June 9, 2011, the FDA announced revisions to the prescribing information for 5-ARIs to include a warning regarding a possible increased risk of high-grade prostate cancer with these agents. ^[217] The revised prescribing information recommends that prior to initiating therapy with 5-ARIs, an appropriate evaluation be performed to rule out other urologic conditions, including prostate cancer, that might mimic BPH. Finasteride and dutasteride were denied approval for prostate cancer prevention.

In contrast, a 2012 placebo-controlled study of dutasteride on prostate cancer progression in men with low-risk disease who chose to be followed up with active surveillance found that at 3-year follow-up, 38% of men in the dutasteride group and 48% of controls had prostate cancer progression. No prostate cancer–related deaths or metastatic disease occurred; 5% of patients in both groups experienced cardiovascular adverse events. The investigators concluded that dutasteride could be a beneficial supplement to active surveillance. ^[218]