Bookshelf

Overall mortality/survival: In SPCG-4, RP reduced overall mortality compared with WW after a median followup of 8.2 years. In VACURG, there was no significant difference in median overall survival.

Disease-specific mortality: In SPCG-4, RP reduced prostate-cancer-specific mortality compared with WW.

Incidence of distant metastases: In SPCG-4, RP reduced the incidence of distant metastases compared with WW.

Urinary incontinence and sexual dysfunction were greater after RP in SPCG-4.

Relative effectiveness of RP compared with WW for overall and disease-specific survival may be limited to men under 65 years of age based on subgroup analysis from the SPCG-4.

Overall mortality/survival: RP with ADT did not improve overall survival compared with RP alone after a median followup of 6 years.

Disease-specific survival: RP with ADT did not reduce disease-specific mortality compared with RP alone.

Biochemical/clinical progression or recurrence: RP with ADT did not prevent biochemical progression compared with RP alone in any of 4 RCTs.

Distant metastases: The addition of ADT did not reduce the risk of developing distant metastases in 2 trials reporting.

Adverse effects and toxicity: There was no difference between 8-month and 3-month ADT in the type and severity of AEs. 8-month ADT resulted in more AEs than 3-month ADT. (AE defined as the first occurrence of an event and higher incidences of hot flashes.)

Biochemical/clinical progression or recurrence: RP was more effective than EBRT in preventing progression at 5 years.

Incidence of distant metastases: RP reduced distant metastases compared with EBRT.

Comment: Only 97 subjects included in analysis; excludes 9 subjects who failed to receive any treatment. Prostate cancers not detected by PSA testing. Refinements in RP and EBRT may make results inapplicable to current practice.

Overall mortality/survival: No difference in overall mortality between groups (median followup of 5.7 years).

Disease-specific survival: No significant difference in PC deaths between groups.

Biochemical/clinical progression or recurrence: At 5 years, biochemical or clinical progression was 53% in the long arm compared with 60% in the short arm.

Distant metastases: No significant difference in distant failure events between groups at the median followup of 5.4 years.

Adverse effects and toxicity: Acute (≤5 months) combined gastrointestinal and genitourinary toxicity was lower in long arm than in short arm. Late toxicity was similar in both arms.

Biochemical/clinical progression or recurrence: Iridium brachytherapy implant combined with EBRT reduced biochemical or clinical progression compared with EBRT alone over a median followup of 8.2 years in T2 subjects.

Biochemical/clinical progression or recurrence: No difference in PSA relapse events between conventional and hypofractionated EBRT.

Adverse effects and toxicity: No differences between groups with the exception of rectal bleeding at 2 years, which had a higher prevalence in the hypofractionated group.

Trial 1: Overall mortality/survival: No difference in overall survival between conventional- and high-dose EBRT at 5 years.

Trial 1: Disease-specific survival: No significant reduction in PC deaths noted between groups.

Trial 1: Biochemical/clinical progression or recurrence: High-dose therapy was more effective in controlling biochemical failure than conventional dose. Superior effectiveness was evident in both low-risk disease (PSA <10 ng/ml, stage ≤T2a tumors, or Gleason ≤6) and high-risk disease. Trial 2: There was no benefit with the use of high-dose EBRT among low-risk subjects. Overall, freedom from failure significantly better in the high-dose group.

Trial 1: Adverse effects and toxicity: No differences between treatments in acute and late GU morbidity. Differences remained significant for late Grade 2 GI morbidity.

Trial 1: Overall mortality/survival: ADT + EBRT reduced all-cause mortality compared with EBRT alone after a median followup of 4.5 years.

Disease-specific mortality: ADT + EBRT reduced disease-specific mortality compared with EBRT alone.

Biochemical/clinical progression or recurrence: ADT + EBRT reduced PSA failure compared with EBRT.

Adverse effects and toxicity: ADT + EBRT resulted in more AEs, including gynecomastia and impotence, than EBRT alone.

Trial 2, T2 disease only: Disease-specific survival—difference in prostate cancer deaths was not significant with addition of 6 months ADT to EBRT vs. EBRT alone after a median followup of 5.9 years.

Biochemical/clinical progression or recurrence: EBRT + ADT reduced clinical failure at any site, biochemical failure, and death from any cause for subjects with T2c disease but not for T2b.

Comment: Both trials were underpowered to detect survival differences.

Biochemical/clinical progression or recurrence: The actuarial estimate of freedom from biochemical failure was lower for the 3-month group than the 8-month group among low-risk subjects (N=92, PSA <10 ng/ml, stage T1c to T2a tumors, Gleason ≤6) but not when including T3 subjects

Biochemical/clinical progression or recurrence: Biochemical progression was similar for both treatments at 3 years.

Adverse effects and toxicity: No significant difference in radiation proctitis with ¹²⁵I vs. ¹⁰³Pd.

Comment: Preliminary results, only 126 presented (of which 11 were excluded for this report) of a planned total of 600.

Biochemical/clinical progression or recurrence: No significant differences between 20 Gy and 44 Gy in the number of biochemical failure events and the actuarial estimates of freedom from biochemical progression at 3 years. No significant differences in freedom from biochemical progression based on pretreatment PSA levels (<10 ng/ml or >10 ng/ml).

Overall mortality/survival: At the median followup period of 5.4 years, there was no difference in total number of deaths between the bicalutamide and placebo groups for men receiving RP or EBRT. Among WW subjects, there were more deaths in bicalutamide than placebo group.

Biochemical/clinical progression or recurrence: The addition of bicalutamide to standard care did not reduce objective progression in T2 subjects at 5.4 years.

Overall mortality/survival: Vaccine may reduce overall mortality compared with nilutamide. Fewer overall deaths for vaccine group than nilutamide group.

Disease-specific survival: Vaccine may improve disease-specific survival compared with nilutamide.

Biochemical/clinical progression or recurrence: Vaccine reduces time to treatment failure compared with nilutamide.

Distant metastases: Twice as many metastases on scans for subjects initially treated with vaccine than subjects initially treated with nilutamide.

Adverse effects and toxicity: Both arms reported grade 2 and 3 toxicities - Nilutamide: dyspnea, fatigue, and hot flashes; Vaccine: arthralgia, fatigue, dyspnea, and cardiac ischemia. Grade 2 and 3 toxicities associated with aldesleukin (part of vaccine regimen) included fever, arthralgia, hyperglycemia, lymphopenia, dehydration/anorexia, and diarrhea.

Comment: Very small trial that may not be applicable to men with clinically localized prostate cancer.

The variability in reporting of results, lack of controls, and likelihood that the results from case series contain results from multiple publications using identical or nearly identical populations limit data interpretation.

Overall and disease-specific mortality were infrequently reported. There was extremely wide variation within and between treatments, making estimates of outcomes difficult. More than 200 definitions of bNED (biological no evidence of disease) were used, with extremely wide and overlapping ranges of outcomes within and between treatments.

Adverse event definitions and severity varied widely. Baseline tumor and patient characteristics were usually reported, but outcomes were rarely stratified according to prognostic variables. It is not possible to accurately determine the relative adverse effects of treatments from these data. However, urinary dysfunction (especially incontinence) appeared to be more common with RP and bowel dysfunction with EBRT. Sexual dysfunction was common following all treatments. Impotence rates ranged from <5% to approximately 60% in the few studies reporting on men undergoing nerve-sparing RP.

Death within 30 days of RP is approximately 0.5% in Medicare recipients age 65 and over. Major cardiopulmonary complications occurred in 4% to 10%. 30-day mortality, major morbidity, and need for hospitalization appear higher with RP than for other interventions. Need for surgical repairs is 0.5% to 1%.

Population-based surveys of U.S Medicare-eligible men at 5 years following treatment: Urinary dysfunction, defined as no control or frequent leaking of urine, was more common with RP than EBRT. Bowel dysfunction was slightly lower in men receiving RP than EBRT, although the only significant difference was related to bowel urgency. Erection insufficient for intercourse occurred in three-quarters of men regardless of treatment. Adjusting for baseline factors, the odds of ED were greater with RP.

Bother due to urine dripping or leaking was more than sixfold greater in RP than in EBRT after adjusting for baseline factors. Bother due to bowel dysfunction or sexual dysfunction was similar for RP and EBRT. Satisfaction with treatment was high, with <5% reporting dissatisfaction, unhappiness, or feeling terrible about treatment, although the highest percent was among those treated with RP.

No randomized trials evaluated cryosurgery. Overall or prostate-cancer-specific survival was not reported. Progression-free survival in patients with T1–T2 stages ranged from 39% to 100%. Adverse effects, when described, included bladder outlet obstruction (3%–29%), tissue sloughing (1%–26%), and impotence (40%–100%).

No randomized trials evaluated laparoscopic and robotic assisted RP. 3 reviews from 21 nonrandomized trials and case series mostly originated from centers outside the United States. Laparoscopic RP had longer operative time but lower blood loss and improved wound healing vs. open retropubic RP. Reintervention rates were similar. For robotic assisted laparoscopic RP, total complications, continence rates, positive surgical margins, and operative time were similar to RP. Median length of hospital stay and median length of catheterization were shorter after robotic assisted RP than open RP.

No randomized trials evaluated primary ADT. A previous AHRQ evidence report examined randomized trials of different methods of ADT for advanced prostate cancer. Survival after treatment with a luteinizing hormone-releasing hormone agonist was equivalent to survival after orchiectomy. The available LHRH agonists were equally effective, and no LHRH agonist was superior to others when adverse effects are considered.

Adverse effects of ADT include ED, loss of libido, breast tenderness, hot flashes, depression and mood changes, memory difficulties, fatigue, muscle and bone loss, and fractures.

No randomized trials compared HIFU with other treatments. 2 case series found biochemical progression-free survival ranged from 66%–87%.

2 studies found mild or moderate urinary incontinence occurred in 1.4%–18.6% of men, and the rate of urethral stenosis differed from 3.6%–27.1%. Impotence was reported by 2%–52.7% in 2 studies.

No randomized trials compared clinical outcomes after proton beam radiation therapy vs. other treatments. 1 systematic review of nonrandomized studies found no direct evidence of comparative effectiveness of protons vs. photons in men with prostate cancer. 2 nonrandomized clinical trials, Phase II and several case series from 1 center, reported clinical outcomes in patients with localized prostate cancer after combined proton and photon radiation therapy. 86%–97% of subjects were disease free at the end of followup, and 73%–88% did not have biochemical failure. Distant metastases were diagnosed in 2.5%–7.5% of men. Less than 1% had GI and urinary toxicity. Absolute rates of outcomes after proton radiation appear similar to other treatments.

No randomized trials compared clinical outcomes after IMRT vs. other treatments. Case series report similar biochemical-free survival after IMRT compared with conformal radiation. There was no difference in survival without relapse between IMRT and conformal radiation at 25–66 months followup. The rate of distant metastases was 1%–3% after IMRT in case series.

Acute GI and urinary toxicity were reported in case series. The percents of Grade 1 and 2 acute GI toxicity were 22% and 4%, respectively, and rectal bleeding, 1.6%–10%. Acute urinary toxicity, Grade 1, was detected in 37%–46% after different doses of IMRT. Percentages were 28%–31% for GU toxicity Grade 2. Absolute risk of late toxicity was <20%.

Case series data suggested that IMRT provides at least as good a radiation dose to the tumor with less radiation to the surrounding tissues (where radiation is undesirable) compared with conformal radiation.

Quality of life measures were comparable or better after IMRT vs. conformal radiation.

Data were largely from observational studies.

Mostly based on case series data, with few studies reporting head-to-head comparisons and limited adjustment for confounding factors.

The most commonly reported patient characteristics used as stratifying factors for therapeutic outcomes were age and race/ethnicity.

No RCTs reported head-to-head comparisons of treatment outcomes stratified by race/ethnicity. Baseline characteristics of populations varied across studies.

While there may be differences in the incidence and morbidity of prostate cancer across racial or ethnic groups, there is little evidence of substantial differences in the effects of treatment by racial or ethnic group. Reports of modest treatment differences in some studies have not been consistently reported in well-powered studies.

1 randomized trial evaluated survival with RP vs. WW according to age in men. Subgroup analysis indicated that overall and disease-specific survival benefits of RP when compared with WW were limited to men <65 years of age. Only 5% of enrollees had prostate cancer detected by PSA testing.

3 observational studies reported results of multiple treatments on sexual function stratified by age group. 1 study compared RP, EBRT, and WW and found no evidence that the effects of the treatments on potency varied by age. 2 observational studies comparing patients with nerve-sparing vs. patients with partial or non-nerve-sparing RP lacked adequate sample size and adjusted for baseline characteristics, making it impossible to draw robust conclusions.

While there are differences in the incidence and morbidity of prostate cancer based on patient age and there are differences in the treatments offered to men at different age ranges, few studies directly compare the treatment effects of different therapies across age groups. Practice patterns show RP is the most common treatment option in younger men with localized prostate cancer. However, in older men (>70), radiation therapy and WW become more commonly used treatment options. Differences in practice patterns appear to be based more on differences in preferences of patients and providers related to age, lifestyle, and life expectancy than regarding particular age-independent treatment benefits and side effects.

Surveys and large national administrative databases indicate that screening practices varied by physician specialty.

Clinicians were more likely to recommend procedures they performed for patients with the same tumor grades and PSA levels.

Several studies found differences in treatment and outcome based on whether the patient was seen in an HMO or fee-for-service organization and whether the patient was a Medicare beneficiary.

One survey and use of administrative data indicated that variability in use of ADT was more attributable to individual differences among urologists than tumor or patient characteristics.

Physician availability, prostate cancer screening, incidence, and mortality varied in U.S. Census regions. The ratio of urologists and radiation oncologists per 100,000 adult citizens was highest in the Middle Atlantic and lowest in the West North, while the prevalence of PSA testing was higher in the South and lower in North East regions. Prostate cancer incidence was highest in the Middle Atlantic and lowest in the Mountain region. Incidence of localized prostate cancer did not differ by regions. The highest age-adjusted mortality was observed among African-American males in the South Atlantic and in the East South.

Treatment selection varied substantially among U.S. regions. The probability of receiving EBRT as primary treatment was the lowest in the Mountain region and highest in New England. Less than 11% of patients with localized prostate cancer received brachytherapy, with significant variations between the Middle Atlantic and West South. The lowest prevalence of primary ADT was in the Middle Atlantic, while the West South was highest. WW was most prevalent in the West, Mountain, and Pacific regions. Prevalence of RP was highest in the Mountain region and lowest in the Middle Atlantic. Age-adjusted rates of RP were lower than the national average in the North East and in New England. There was a consistent relative decrease in utilization of RP in the North East and increase in the West compared with the U.S. average.

Hospital volume was associated with patient outcomes. Pooled analysis showed a significant relative reduction in surgery-related mortality corresponding to the number of RPs performed annually in hospitals. The number of RPs performed annually in hospitals was associated with significant absolute reduction in complication rates. Patients operated on in hospitals with fewer procedures per year had increased use of adjuvant therapy compared with those treated in hospitals that performed more RPs per year. There was a decrease in length of stay in hospitals above vs. below the mean number of procedures. Hospital readmission rates were also estimated to be lower in hospitals with greater volume.

Teaching hospitals had a lower rate of surgery-related complications and higher scores of operative quality.

Surgeon volume was not associated with surgery-related mortality and positive surgical margins.

Patients who were operated on by surgeons with higher RP volume experienced lower rates of complications. The relative risk of surgery-related complications adjusted for patient age, race, and comorbidity, and hospital type and location was lower in patients treated by higher volume surgeons (more than 40 vs. 40 or less surgeries per year).

The rate of late urinary complications and incontinence was lower for patients whose surgeons had higher RP volume.

The length of hospital stay was shorter in patients operated on by surgeons who performed more than 15 (4^th quartile) vs. fewer than 3 surgeries (1^st quartile) per year.

There were no data for volume and other forms of prostate cancer treatment

Higher Gleason histologic scores are associated with greater risk of prostate-cancer-related death and disease progression or recurrence, regardless of treatment.

The risk of prostate cancer death over 20 years in non-PSA-detected prostate cancer with Gleason score 2–4 managed with WW is less than 10%.

The risk of prostate cancer death over 10 years in non-PSA-detected prostate cancer with Gleason score 8–10 treated with WW is about 50%.

The risk of overall or prostate cancer death over 10 years for PSA-detected prostate cancers according to Gleason histologic grade treated with WW is not adequately known.

It is not possible to determine the relative effectiveness of treatments according to Gleason histologic score. Subset analysis from 1 randomized trial found that the relative effectiveness of RP vs. WW was not associated with Gleason score in men whose prostate cancer was detected by methods other than PSA testing.

The risk of prostate cancer death and disease progression or recurrence is associated with PSA levels and rate of PSA rise.

Evidence is not sufficient to accurately determine the relative effectiveness of treatments according to baseline PSA levels in men with PSA-detected disease. Subset analysis from 1 randomized trial found that the relative effectiveness of RP vs. WW was not associated with baseline PSA in men whose prostate cancer was detected by methods other than PSA testing.

There are no data on the relative effectiveness of treatment options according to screened vs. nonscreen detected prostate cancer.

The vast majority of men with newly diagnosed prostate cancer are asymptomatic and have clinically localized disease detected by PSA testing.

Screening with PSA testing detects more prostate cancer and cancers of smaller volume, earlier stage, and at an earlier time period in a man's life compared with digital rectal examination. PSA detects prostate cancer 5–15 years earlier than digital rectal exam.

Subset analysis of 1 randomized trial found that the relative effectiveness of RP vs. WW for clinically localized prostate cancer did not vary by tumor stage.

Prostate cancer that has spread locally outside of the prostate gland or metastasizes may cause symptoms such as bone pain, edema, and/or hematuria. Prognosis in men with locally advanced or metastatic disease is not as good as for men with clinically localized disease, and treatment options used for localized prostate cancer (e.g., RP, brachytherapy, prostate-targeted EBRT) are often not feasible.

A risk classification incorporating Gleason histologic score, PSA level, and tumor stage is associated with the risk of disease progression or recurrence, regardless of treatment.