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Conclusions

The

findings covered in this report are summarized in Table

B.

Key

Question 1. What are the comparative risks, benefits, and outcomes of

therapies?

No one

therapy can be considered the preferred treatment for localized prostate cancer

due to limitations in the body of evidence as well as the likely tradeoffs an

individual patient must make between estimated treatment effectiveness,

necessity, and adverse effects. All treatment options result in adverse effects

(primarily urinary, bowel, and sexual), although the severity and frequency may

vary between treatments. Even if differences in therapeutic effectiveness

exist, differences in adverse effects, convenience, and costs are likely to be

important factors in individual patient decisionmaking. Patient

satisfaction with therapy is high and associated with several clinically

relevant outcome measures. Data from nonrandomized trials are inadequate to

reliably assess comparative effectiveness and adverse effects. Additional

randomized controlled trials (RCTs) are needed.

Limitations

in the existing evidence include the following:

Few randomized trials directly compared the

relative effectiveness between (rather than within) major treatment

categories.

Many randomized trials are inadequately powered

to provide long-term survival outcomes, with the majority reporting

biochemical progression or recurrence as the main outcomes.

Some randomized trials were old, conducted prior

to prostate cancer detection with PSA testing (i.e., studies before the

current era, when tumors are diagnosed in an earlier stage, giving more

lead time, and there is a higher percentage of benign tumors, resulting in

length bias and overdiagnosis), and used technical aspects of treatment

that may not reflect current practice; therefore, their results may not be

generalizable to modern practice settings.

Wide variation existed in reporting and

definitions of outcomes.

There was little reporting of outcomes according

to major patient and tumor characteristics.

Emerging technologies have not been evaluated in

randomized trials.

Randomized

comparisons across primary treatment categories

Radical prostatectomy compared

with watchful waiting (2 RCTs). Compared with men who

used watchful waiting (WW), men with clinically localized prostate cancer

detected by methods other than PSA testing and treated with radical

prostatectomy (RP) experienced fewer deaths from prostate cancer,

marginally fewer deaths from any cause, and fewer distant metastases. The

greater benefit of RP on cancer-specific and overall mortality appears to

be limited to men under 65 years of age but is not dependent on baseline

PSA level or histologic grade. Two RCTs compared WW with RP. The

Scandinavian Prostate Cancer Group (SPCG) trial found significantly lower

incidences of all-cause deaths (24 vs. 30 percent), disease-specific

deaths (10 vs. 15 percent), and distant metastases (14 vs. 23 percent) for

subjects treated with RP than for subjects assigned WW after a median

followup of 8.2 years. Surgery was associated with greater urinary and

sexual dysfunction than WW. An older trial of 142 men found no significant

differences in overall survival between RP and WW after a median followup

of 23 years, although small sample size limited study power.

Radical prostatectomy vs.

external beam radiotherapy (1 RCT). One small (N=106),

older trial indicated that, compared with EBRT, RP was more effective in

preventing progression, recurrence, or distant metastases in men with

clinically localized prostate cancer detected by methods other then PSA

testing. Treatment failure at 5 years of followup, defined as acid

phosphatase elevation on two consecutive followup visits or appearance of

bone or parenchymal disease with or without concomitant acid phosphatase

elevation, occurred in 39 percent for EBRT compared with 14 percent for

RP.

Cryotherapy, laparoscopic or

robotic assisted radical prostatectomy, primary androgen deprivation

therapy, high-intensity focused ultrasound (HIFU), proton beam radiation

therapy, or intensity modulated radiation therapy (IMRT) (0 RCTs).

It is not known whether these therapies are better or worse than other

treatments for localized prostate cancer because these options have not

been evaluated in RCTs.

Randomized

comparisons within primary treatment categories

Radical prostatectomy combined

with neoadjuvant androgen deprivation therapy (5 RCTs). The

addition of neoadjuvant hormonal therapy to RP did not improve survival or

cancer recurrence rates, defined by PSA recurrence, but increased AEs. One

small RCT comparing RP alone and RP combined with neoadjuvant ADT found no

overall or disease-specific survival benefit with the addition of

neoadjuvant ADT after a median followup of 6 years. The addition of

neoadjuvant ADT did not prevent biochemical progression compared with RP

alone in any of the four trials. The trial comparing 3 months and 8 months

neoadjuvant ADT with RP reported greater AEs in the 8-month group than the

3-month group (4.5 percent vs. 2.9 percent) and higher incidence of hot

flashes (87 percent vs. 72 percent).

External beam radiotherapy:

comparison of EBRT regimens (5 RCTs). No RCTs compared

EBRT and WW. It is not known if using higher doses of EBRT by increasing

either the total amount or type of radiation (e.g., via high-dose

intensity modulated or proton beam or by adding brachytherapy) improves

overall or disease-specific survival compared with other therapies. No

EBRT regimen, whether conventional, high-dose conformal, dose

fractionation, or hypofractionation, was superior in reducing overall or

disease-specific mortality. Increasing the total amount of radiation or

adding brachytherapy after EBRT decreased cancer recurrence compared with

lower doses of radiation. One trial (N=936) found that the probability of

biochemical or clinical progression at 5 years was lower in the long-arm

group (66 Gy in 33 fractions) than the short-arm group (52.5 Gy in 20

fractions). Conventional-dose EBRT (64 Gy in 32 fractions) and

hypofractionated EBRT (55 Gy in 20 fractions) resulted in similar PSA

relapse. One trial (N=104) found that brachytherapy combined with EBRT

reduced biochemical or clinical progression compared with EBRT alone. One

trial (N=303) found that high-dose EBRT (79.2 Gy that included 3D

conformal proton 50.4 Gy with 28.8 Gy proton boost) was more effective

than conventional-dose EBRT (70 Gy that included 19.8 Gy proton boost) in

the percentage of men free from biochemical failure at 5 years (80 percent

in the high-dose group and 61 percent in the conventional-dose group).

Effectiveness was evident in low-risk disease (PSA <10 ng/ml, stage

≤T2a tumors, or ≤Gleason 6) and higher risk disease. Acute

combined gastrointestinal (GI) and genitourinary (GU) toxicity was lower

in the long arm (7.0 percent) than in the short arm (11.4 percent). Late

toxicity was similar. There were no significant differences between

conventional and hypofractionated EBRT with the exception of rectal

bleeding at 2 years after therapy, which had a higher prevalence in the

hypofractionated group. Acute GI or GU symptoms of at least moderate

severity were similar in the trial comparing high and conventional doses.

External beam radiotherapy

combined with androgen deprivation therapy compared with EBRT alone (3

RCTs). ADT combined with EBRT (ADT + EBRT) may decrease

overall and disease-specific mortality but increase AEs compared with EBRT

alone in high-risk patients defined by PSA levels and Gleason histologic

score (PSA >10 ng/ml or Gleason >6). One RCT (N=216) found that

conformal EBRT combined with 6 months of ADT reduced all-cause mortality,

disease-specific mortality, and PSA failure compared with conformal EBRT

alone after a median followup of 4.5 years. There were significant

increases in gynecomastia and impotence in the ADT + EBRT group compared

with EBRT alone. One RCT (N=206) found that 6 months of ADT + EBRT did not

significantly reduce disease-specific mortality compared with conformal

EBRT alone in T2b and T2c subjects after a median followup of 5.9 years.

Six months of combination therapy reduced clinical failure, biochemical

failure, or death from any cause compared with EBRT alone in subjects with

T2c disease but not in T2b subjects.

Different doses of adjuvant

external beam radiotherapy combined with brachytherapy (1 RCT).

One small trial comparing different doses of supplemental EBRT, 20 Gy

(N=83) vs. 44 Gy (N=76), adjuvant to brachytherapy (103Pd) implant

found no significant differences in the number of biochemical failure

events and freedom from biochemical progression at 3 years.

Brachytherapy compared with

brachytherapy (1 RCT). No RCTs compared brachytherapy

alone with other major treatment options. Preliminary results from one

small trial (N=126) comparing 125I with 103Pd

brachytherapy found similar biochemical control at 3 years. There was a

trend toward more radiation proctitis, defined as persistent bleeding,

with 125I.

Adjuvant androgen deprivation

therapy with bicalutamide combined with standard care: RP, EBRT, or WW (3

RCTs). Androgen deprivation with bicalutamide alone or

in addition to RP or EBRT did not reduce cancer recurrence or mortality.

There was no difference in total number of deaths between the bicalutamide

and placebo groups for men receiving RP or EBRT at the median followup of

5.4 years. Among WW subjects, there were significantly more deaths with

bicalutamide compared with placebo. The addition of bicalutamide to

standard care did not reduce progression.

Comparative

outcomes data from nonrandomized reports

To

supplement RCT findings and summarize the literature on treatment for localized

prostate cancer, we used the database of the Clinical Guideline Panel for

Treatment of Clinically Localized Prostate Cancer of the American Urological

Association. This work relied on data extracted from 436 articles published

between 1991 and April 2004 on T1-T2 prostate cancer. Over 80 percent were case

series and only 6 percent were controlled trials. Data interpretation is

limited by variability in result reporting, lack of controls, and likelihood

that the database contained results from multiple publications using identical

or nearly identical populations. Overall and disease-specific mortality were

infrequently reported. When reported, there was extremely wide variation within

and between treatments, making overall estimates of outcomes difficult. There

was not standardized reporting of biochemical outcomes, with more than 200

definitions of “biochemical no evidence of disease (bNED)”

reported. Results demonstrated extremely wide and overlapping ranges of

outcomes at 5 and 10 years within and between treatments.

Adverse

effects were reported, but definitions and severity varied widely. It was not

possible to provide precise estimates regarding comparative effectiveness or

specific AEs for each treatment option. Urinary dysfunction appeared to be more

common in men treated with RP than in men treated with EBRT. Sexual dysfunction

was common following all treatments. Impotence rates ranged from less than 5

percent to approximately 60 percent in the few studies reporting on men

undergoing nerve-sparing RP.

Additional

estimates for U.S.

population-based AEs at 5 years following treatment were obtained from a large

survey of Medicare-eligible men who had undergone treatment for localized

prostate cancer. Urinary dysfunction, defined as no control or frequent leaking

of urine, occurred in 14 percent of men undergoing RP and 5 percent undergoing

EBRT. Use of pads to stay dry was greater after RP (29 percent) than EBRT (4

percent). Bowel dysfunction was lower in men receiving RP than EBRT, although

the only significant difference was related to bowel urgency (18 percent vs. 33

percent). Erection insufficient for intercourse occurred in approximately

three-quarters of men regardless of treatment. When adjusting for baseline

factors, erectile dysfunction (ED) was greater with RP (odds ratio=2.5,

95-percent confidence interval=1.6, 3.8).

Cryosurgery. No randomized trials evaluated

cryosurgery, and the majority of reports included patients with T3-T4 stages.

Overall or prostate-cancer-specific survival was not reported. Progression-free

survival in patients with T1-T2 stages ranged from 29 to 100 percent. AEs were

often not reported but, when described, included bladder outlet obstruction (3

to 21 percent), tissue sloughing (4 to 15 percent), and impotence (40 to 100

percent). Outcomes may be biased by patient and provider characteristics.

Laparoscopic and robotic assisted prostatectomy.

Three reviews estimated the effectiveness and AEs of laparoscopic and robotic

assisted prostatectomy from 21 nonrandomized trials and case series. Most

originated from centers outside of the United States. Median followup was

8 months. Laparoscopic RP had longer operative time but lower blood loss and

improved wound healing compared with open retropubic RP. Reintervention rates

were similar. Results from eight nonrandomized reports suggested that total

complications, continence rates, positive surgical margins, and operative time

were similar for robotic assisted and open RP. Median length of hospital stay

(1.2 vs. 2.7 days) and median length of catheterization (7 vs. 13 days) were

shorter after robotic assisted RP than open RP.

Intensity modulated radiation therapy.

There was no direct evidence that IMRT results in better survival or

disease-free survival than other therapies for localized prostate cancer. Based

on nonrandomized data, the absolute risks of clinical and biochemical outcomes

(including tumor recurrence), toxicity, and quality of life after IMRT are

comparable with conformal radiation. There is low-level evidence that IMRT

provides at least as good a radiation dose to the prostate with less radiation

to the surrounding tissues compared with conformal radiation therapy.

Proton EBRT. There were no data from

randomized trials comparing EBRT using protons vs. conventional EBRT or other

primary treatment options. In one randomized trial, men with localized prostate

cancer had statistically significantly lower odds of biochemical failure

(increase in PSA) 5 years after the higher dose of EBRT with a combination of

conformal photon and proton beams without increased risk of adverse effects.

Based on nonrandomized reports, the rates of clinical outcomes and toxicity

after proton therapy may be comparable with conformal radiation. There was no

direct evidence that proton EBRT results in better overall or disease-free

survival than other therapies.

High-intensity focused ultrasound therapy.

There were no data from randomized trials comparing HIFU with other primary

treatment options. Biochemical progression-free survival rates of 66 to 87

percent and negative biopsy rates of 66 to 93 percent were reported from

noncontrolled studies. The absolute risk of impotence and treatment-related

morbidity appeared to be similar to other treatments. Followup duration was

<10 years.

Health status, quality of life, and treatment satisfaction.

Eight studies of health status and quality of life, including a U.S.

population-based survey, were eligible. Bother due to dripping or leaking of

urine was more than sixfold greater in RP-treated men than in men treated with

EBRT after adjusting for baseline factors. Bother due to bowel dysfunction (4

vs. 5 percent) or sexual dysfunction (47 vs. 42 percent) was similar for RP and

EBRT. In a subgroup of men ages 70 and over, bother due to urine, bowel, or

sexual dysfunction was 5.1, 2.4, and 2.8 times higher, respectively, for aggressive

(RP/EBRT) vs. conservative (WW/ADT) therapy. Satisfaction with treatment was

high, with less than 5 percent reporting dissatisfaction, unhappiness, or

feeling terrible about their treatment, although the highest percent was among

those treated with RP. Treatment satisfaction was highly correlated with bowel,

bladder, and erectile function; general health status; belief that the

respondent was free of prostate cancer; and whether cancer treatments limited

activity or relationships. More than 90 percent said they would make the same

treatment decision again, regardless of treatment received.

Key

Question 2. How do patient characteristics affect outcomes?

No RCTs

reported head-to-head comparisons of treatment outcomes stratified by

race/ethnicity, and most did not provide baseline racial characteristics.

Available data were largely from case series. Few studies reported head-to-head

comparisons, and there was limited adjustment for confounding factors. Modest

treatment differences reported in some nonrandomized studies have not been

consistently reported in well-powered studies. There was little evidence of a

differential effect of treatments based on age. While differences exist 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 compared the treatment effects of different therapies across

age groups. Most RCTs did not have age exclusion criteria. The mean/median age

ranged from a low of 63 years for trials of RP to 72 years for trials of EBRT.

Only one RCT provided subgroup analysis according to age. Results suggest that

survival benefits of RP compared with WW may be limited to men under 65 years

of age. Practice patterns from observational studies show that RP is the most

common treatment option in younger men with localized prostate cancer.

Key

Question 3. How do provider and hospital characteristics affect outcomes?

Results

from national administrative databases and surveys suggested that

provider/hospital characteristics, including RP procedure volume, physician

specialty, and geographic region, affect outcomes. (There was no information on

volume and outcomes for brachytherapy, cryotherapy, or EBRT.) Patient outcomes varied in different locations and

were associated with provider and hospital volume independent of patient and

disease characteristics. Screening practices can influence the characteristics

of patients diagnosed and tumors detected. Screening practices and treatment

choices varied by physician specialty and across regions of the United States.

These did not correlate with clinician availability. Clinicians were more

likely to recommend procedures they performed regardless of tumor grades and

PSA levels.

Regional

variation existed in physician availability, ratio of urologists and radiation

oncologists per 100,000 adult citizens based on surveys conducted by the

American Medical Association, screening practice, incidence, mortality, and

treatment selection. The direction of regional variation was not always

consistent. Several studies reported geographic variation at the county, State,

or U.S. Census region level. Overall, many different methods were used to

report geographic variation, so pooling of results was difficult; when results

were pooled, the geographic regions used were quite large.

Surgeon

RP volume was not associated with RP-related mortality and positive surgical

margins. However, the relative risk of surgery-related complications adjusted

for patient age, race, and comorbidity and for hospital type and location was

lower in patients treated by higher volume surgeons. Urinary complications and

incontinence were lower for patients whose surgeons performed more than 40 RPs

per year. The length of hospital stay was shorter in patients operated on by

surgeons who performed more RPs per year. Cost was not associated with surgeon

volume. Surgeon volume of robotic laparoscopic RP was marginally associated

with lower adjusted odds of extensive (but not any or focal) positive margins.

Hospital

volume and teaching status were associated with patient outcomes. Despite

different definitions of “high” and “low” hospital

volumes in individual studies, pooled analysis showed that surgery-related

mortality and late urinary complications were lower and length of stay was

shorter in hospitals that performed more RPs per year. Hospital readmission

rates were lower in hospitals with greater volume. Teaching hospitals had a

lower rate of surgery-related complications and higher scores of operative

quality. Several studies found differences in treatment and outcome based on

whether the patient was seen in an HMO (health maintenance organization) or

fee-for-service organization and whether the patient was a Medicare

beneficiary. Variability in the use of ADT was more attributable to individual

differences among urologists than tumor or patient characteristics.

Key

Question 4. How do tumor characteristics affect outcomes?

Little

data existed on the comparative effectiveness of treatments based on PSA

levels, histologic score, and tumor volume to identify low-, intermediate-, and

high-risk tumors. We focused on baseline PSA levels and Gleason histologic

score. The natural history of PSA-detected tumors is not known because few men

remain untreated for a long period. One report assessed 20-year outcomes in the

United States

from a cohort of 767 men with prostate cancer detected prior to PSA testing and

treated with WW. Histologic grade was associated with overall and

prostate-cancer-specific survival. Men with low-grade prostate cancers had a

minimal risk of dying from prostate cancer (7 percent with Gleason score 2-4

died due to prostate cancer). Men with high-grade prostate cancers had a high

probability of dying from their disease within 10 years of diagnosis,

regardless of their age at diagnosis (53 percent with Gleason score 8-10 died

due to prostate cancer). Estimates from large ongoing screening trials suggest

that PSA increases the time of detection by 5-15 years. Therefore, it is likely

that men with PSA-detected tumors will have better 20-year disease-specific

survival than this cohort.

Most RCTs

did not exclude participants based on PSA levels or tumor histology, and few

provided comparative analysis according to these factors. Secondary analysis of

one randomized trial concluded that disease-specific mortality at 10 years for

men having RP compared with WW differed according to age but not baseline PSA

level or Gleason score. Men with Gleason scores 8-10 were more likely to have evidence

of biochemical recurrence than men with Gleason scores 2-6, regardless of

whether treatment was RP alone or RP combined with neoadjuvant hormonal therapy

(NHT). High-dose EBRT was more effective in controlling biochemical failure

than conventional dose therapy in both low-risk disease (PSA <10 ng/ml,

stage ≤T2a tumors, or Gleason ≤6) and higher risk disease. When the

higher risk subjects were further divided into intermediate risk and high-risk

groups, the benefit of high-dose therapy remained for the intermediate-risk but

not for the high-risk patients.

Based on

very limited nonrandomized trial data, disease-specific survival was similar

for men treated with EBRT or with RP in men with baseline PSA >10 ng/ml. Men

with Gleason scores 8-10 were more likely to have biochemical recurrence than

men with Gleason scores 2-6, regardless of type of treatment.

Remaining Issues

Uncertainty

about the comparative effectiveness and harms of the primary treatments for

localized prostate cancer is the major gap in knowledge. This is mainly due to

the paucity of direct head-to-head RCTs and the excess reliance on

nonrandomized data to compare the most common treatment options: WW, RP, EBRT,

brachytherapy, and ADT. Emerging technologies such as IMRT, proton beam

radiation, laparoscopic and robotic assisted prostatectomy, and cryotherapy are

increasingly being used despite the absence of long-term comparative RCTs.

Initiation

and completion of long-term, adequately powered randomized trials (particularly

comparative trials across, rather than within, primary treatment modalities)

are needed. Where randomized trials have been conducted, confirmation (or

refutation) of findings with additional randomized trials is needed because

evidence is often based on results from a single relatively small study. These

trials should standardize reporting of key clinically relevant outcomes,

including overall, disease-specific, and metastatic-free survival; bNED;

adverse effects; and disease-specific quality of life/health status. Ideally,

relative effectiveness and adverse effects would be stratified according to

tumor (PSA, stage, histologic grade) and patient (age, race, comorbidity)

characteristics. A previous RCT comparing RP and brachytherapy was discontinued

due to inadequate recruitment. However, several trials are ongoing, including

comparisons of RP vs. WW, RP vs. EBRT or WW, cryotherapy vs. EBRT, and active surveillance

with delayed intervention vs. early intervention with RP. Results will not be

available for several years. Patients

and their support groups, clinicians, researchers, and funders need to ensure

successful initiation and completion.

High-quality,

large prospective cohort studies or cancer registries that identify men at the

time of diagnosis and proceed to collect comprehensive patient, tumor, and

treatment decision selection characteristics could help target future RCTs to

the most promising research questions. These may be able to provide information

related to important patient characteristics (age, race, comorbidities) or

tumor characteristics (PSA, stage, histologic grade) that may not be adequately

addressed in RCTs currently in progress due to sample size limitations.

Nonrandomized studies should report head-to-head comparisons, adjust for

confounding factors, and use standardized definitions of disease-specific and

biochemical survival, adverse effects, and patient/tumor characteristics.

Identification

of biomarkers to provide reliable estimates about prostate cancer

aggressiveness and the relative effectiveness of treatments is needed. This

would reduce unnecessary interventions while focusing treatment on men most

likely to benefit. A new generation of educational materials is required to

provide balanced information about the risks and benefits of treatments and

assist in patient decisionmaking and incorporation of patient-centric values

(tumor eradication, impact of AEs, anxiety, costs, convenience, etc.). It is

hoped that these materials incorporate findings from comprehensive systematic

reviews that use methods to limit bias and assess quality of evidence. The

resulting patient and provider guides can be developed to summarize these findings

in a format that is understandable and useful for consumers. Structure and

process measures are associated with quality of prostate cancer care. Research

across nationally representative databases using methods of risk adjustment is

needed to clarify geographical differences in patient outcomes. Identification

of factors associated with outcomes and development of systemwide methods for

implementation or improvement are needed.