Key Findings and Strength of Evidence

This systematic review updates a previous systematic review on treating localized prostate cancer. Fifty-two studies met the inclusion criteria for review for Key Question (KQ) 1 regarding comparative effectiveness of various therapeutic options. Thirteen of the 52 studies also met the inclusion criteria for KQ 2 regarding patient characteristics that impact response to treatment, and 20 of the 52 studies met the inclusion criteria for KQ 4 regarding the impact of tumor characteristics. Studies that addressed KQ 1 reported data for patient-oriented outcome measures such as overall survival, all-cause mortality, prostate cancer–specific mortality, metastases, quality of life (QOL), and adverse events. Evidence addressing KQ 2 or 4 came solely from subgroup analyses of larger studies that addressed KQ 1. Although these subgroup analyses reported data on overall survival, all-cause mortality, or prostate cancer–specific mortality for specific patient subgroups, they did not report adverse events that occurred in these subgroups.

Key Question 1

For the comparison of radical prostatectomy (RP) versus watchful waiting (WW), the Prostate Cancer Intervention Versus Observation Trial (PIVOT) reported data on all-cause mortality, prostate cancer–specific mortalities, and progression to metastases at the end of the 12-year followup period and the Scandinavian Prostate Cancer Group-4 (SPCG-4) trial reported data on these same outcomes at the end of the 12- and 15-year followup periods. Neither study, however, compared RP to active surveillance.

Although patients with some similarities were enrolled in these two important trials, major differences exist in the enrolled populations. The SPCG-4 trial began in 1989 when prostate-specific antigen (PSA) screening was not widespread; only 5 percent of tumors in SPCG-4 were screen-detected. In contrast, 76 percent of men had prostate cancer detected by screening in PIVOT. Not surprisingly, men with nonpalpable tumors (T1c) comprised 50 percent of the PIVOT population, but only 20 percent of SPCG-4. Although the SPCG-4 trial's eligibility criteria specified clinical stage T1 or T2 disease, nearly half the patients undergoing RP were found to have extracapsular extension (pT3, tumor extending beyond capsule) compared with only 6 percent of patients in the PIVOT study.

In addition to the differences in patient characteristics enumerated above, the protocol for the WW arms differed between the SPCG-4 trial and PIVOT. In the SPCG-4 trial, which included patients in an unscreened population, transurethral resection of the prostate (TURP) was recommended as the initial treatment for men with symptoms suggesting urinary obstruction. Orchidectomy was recommended for symptomatic local recurrence and disseminated disease.

In PIVOT, which primarily included men with screen-detected prostate cancers, patients with symptomatic local progression were treated first with alpha blockers or a mechanical intervention such as TURP or stents. If these measures failed to control local symptoms, prostatectomy was permitted. Hormonal therapy was considered first-line therapy for patients with disease progression requiring nonmechanical therapy, with radiation therapy or chemotherapy permitted when hormonal therapy failed.

While both trials reported similar hazard ratios for prostate cancer–specific mortality, the hazard ratio for all-cause mortality was higher in the PIVOT than the SPCG-4. This suggests that prostate cancer death in the PIVOT may have been diluted by deaths from other causes or competing risks, which speaks to the underlying health of men in both randomized controlled trials (RCTs) being different and the question of whether the PIVOT data can apply to a healthy cohort. Furthermore, in the PIVOT study, the median survival was assumed to be 15 years in the original study design and 10 years in the updated design. The PIVOT investigators failed to accrue its targeted enrollment of 2,000 patients to surgery or observation.

The SPCG-4 trial reported that both overall and prostate cancer–specific mortalities were statistically significantly lower among men who underwent RP compared with WW at 15-year followup. The SPCG-4 trial also reported that at 12-year followup, prostate cancer–specific mortality was statistically significantly lower among men who underwent RP, but no statistically significant difference in overall mortality was found between the compared interventions. At the 12-year followup, the PIVOT found no statistically significant difference in overall or prostate cancer–specific mortality between RP and WW. The strength-of-evidence grade for each of these reported outcomes is insufficient. The evidence on overall QOL based on the PIVOT²⁵ and SPCG-4³³ trials is insufficient to permit conclusions, although there was low strength of evidence that one component of QOL (urinary incontinence) occurs more frequently with RP than with WW.

However, both trials reported consistent findings regarding a significant reduction in progression to metastases in the RP group compared to the WW group. This consistency, combined with medium risk of bias and precision, means that the strength of evidence is moderate for this outcome. Given the clinical heterogeneity between these trials, the results suggest that the findings for this outcome may apply to a wide range of patients with clinically localized prostate cancer. Although this is not a QOL assessment, it has serious QOL implications because bone metastasis is a significant determinant of QOL in men with prostate cancer. Nevertheless, we note that these findings should always be interpreted with caution. Potential issues regarding applicability to current clinical practice will be further discussed in the following sections.

For the comparison of radical retropubic prostatectomy (RRP) versus brachytherapy (BT), the evidence on the only reported outcome, QOL at 1-year followup, is insufficient for drawing any conclusion.

For the comparison of three-dimensional conformal radiation therapy (3D-CRT) alone versus 3D-CRT combined with androgen-deprivation therapy (ADT),³⁵ the data on overall survival, all-cause mortality, and prostate cancer–specific mortality from a single low risk-of-bias trial favor the combined treatments with a low strength-of-evidence grade. For the comparison of external beam radiotherapy (EBRT) alone versus EBRT combined with ADT,⁴³ a single medium risk-of-bias RCT favored the combined treatments for overall survival, all-cause mortality, and prostate cancer–specific mortality. However, the strength of evidence was insufficient to allow a conclusion. These findings should be interpreted using thorough consideration of the specific patient populations and the treatment methods used in the trials. In both studies, the dose of radiation therapy was lower than is currently known to be effective. The applicability of these trials will be further discussed in the following sections.

Overall, the RCT-based evidence favors the combined therapies. However, the low or insufficient strength-of-evidence grades in the existing evidence suggest that the comparative effectiveness of EBRT versus EBRT plus ADT is still uncertain and will need future studies for validation.

Our review used nonrandomized trials to permit conclusions for treatment comparisons with insufficient RCT-based evidence. As with the RCTs, the strength of evidence from nonrandomized studies was often insufficient to address the treatment comparisons of interest. The main reasons for the insufficient strength-of-evidence gradings include the medium to high risk of bias in the majority of the individual studies included in the evidence base and the small number of studies addressing each treatment comparison. In two instances we were able to draw a conclusion, based on six studies of high risk of bias but with consistent findings. RP was favored over EBRT for both all-cause mortality^36-40 and prostate cancer–specific mortality.^37-42 However, we note that radiation dosage was not reported in some studies and a proportion of patients received a lower dose than what is currently considered effective. Furthermore, despite statistical attempts to adjust for known confounders, most observational studies are vulnerable to bias from unknown confounding factors.

Adverse events were defined and reported rather differently across the interventions compared and across the studies reviewed. This made synthesis of findings difficult, but some patterns could be discerned. Overall, urinary incontinence and erectile dysfunction were frequently reported among men who underwent RP. Genitourinary toxicity, gastrointestinal toxicity, and erectile dysfunction were frequently reported among men who received radiation therapy.

Table 36 summarizes the main findings and strength of evidence for KQ 1.

Table 36

Summary of the main findings for Key Question 1.

Findings in Relationship to What Is Already Known

The 2008 systematic review that the current report updates concluded that no single therapy could be considered the preferred treatment for localized prostate cancer because of limitations in the body of evidence as well as the tradeoffs an individual patient must make when considering treatment options. Following publication of the PIVOT, some experts have suggested that patients found to have low- to intermediate-risk localized disease should be encouraged to consider active surveillance and that older patients or those with comorbid conditions should wait for symptoms to appear. Despite the availability of 12-year follow up data from PIVOT and 15-year data from SPCG-4, we believe that uncertainty remains.

The 2008 report also compared RP with WW, primarily based on the evidence at the 10-year followup from the SPCG-4⁹⁴ and another small trial.⁹⁵ With the 12- and 15-year data from the SPCG-4 trial and the 12-year data from the PIVOT, the RCT-based findings from this comparative effectiveness review extend those from the 2008 report on the same comparison.

For the comparison of radical retropubic prostatectomy (RRP) versus brachytherapy, the 2008 report found no evidence from RCTs.²² In this report, the evidence on the only reported outcome, QOL at 1-year followup, is insufficient for drawing any conclusion.

Two RCTs^96,97 in the 2008 report compared EBRT plus ADT with EBRT alone. One RCT⁹⁶ reported that EBRT plus 6 months of ADT reduced all-cause mortality, prostate cancer–specific mortality, and PSA failure compared with EBRT alone at 4.5-year followup. Another RCT⁹⁷ reported that EBRT plus 6 months of ADT reduced clinical failure, biochemical failure, or death from any cause compared with those outcomes with EBRT alone in men with stage T2c but not T2b prostate cancer.

For the comparison of ADT versus ADT in combination with EBRT, the 2008 report did not identify any evidence from RCTs.²² In this report, the evidence on the only reported major outcome, prostate cancer–specific mortality, is insufficient for drawing any conclusion.

The only RCT reviewed in the 2008 report that performed a subgroup analysis by any patient characteristics is the SPCG-4 trial. The subgroup analysis of the earlier SPCG-4 trial data found that the difference in prostate cancer mortality between RP and WW appeared to be primarily in patients younger than 65 years. The updated SPCG-4 analysis agrees with this finding and extends it to overall mortality as well, but the PIVOT did not find a difference in these outcomes when stratifying by age. Overall, these RCTs reviewed in the current report and in the 2008 report were not well-powered to detect statistical significance in patient-oriented outcomes in subgroup analyses. The strength of the RCT-based evidence in the current report is insufficient for us to draw any conclusion for KQ 2.

We did not identify any comparative study that directly examined how provider characteristics influence the effectiveness of different treatments. As a result, this review does not add new information to that reported in the 2008 report on the same KQ.

The only RCT reviewed in the 2008 report that performed a subgroup analysis according to any tumor characteristics is the SPCG-4 trial. The subgroup analysis of the earlier SPCG-4 trial data was based on the data at 10-year followup, which is overridden by the undated SPCG-4 trial data reported in this review.

One small RCT in the 2008 report compared RP to EBRT and found that patients undergoing RP had less progression and recurrence and fewer distant metastases. This is supported by low-strength evidence from nonrandomized studies in this update which found lower overall mortality and prostate cancer–specific mortality among patients treated with RP.

Applicability

We considered applicability of study findings using the PICOTS framework (patients, intervention, comparisons, outcomes, timing, and settings) as described by Atkins et al.⁹⁸ The evidence-based conclusions are applicable only to the types of patients enrolled in the studies underlying those conclusions, the types of clinical settings in which the studies were conducted, the types of interventions being compared, and the particular outcomes and followup period reported. Table 37 is a summary of factors that may restrict the applicability of the findings from the RCTs discussed in the previous section. Although the restrictions on the applicability of the conclusions may vary across the evidence bases for different treatment comparisons, some restrictions may be common to most of these evidence bases. All but one of the RCTs included in this review recruited their subjects before 2002. Since then, the treatment options compared in this report have greatly evolved. For example, open surgery was the main treatment for radical prostatectomy in the reviewed RCTs. However, in recent years, robotic-assisted surgery has become the dominant technique for radical prostatectomy in the United States.

Table 37

Factors affecting the applicability of the evidence from randomized controlled trials.

Similarly for EBRT, BT, and other treatments, advances in technologies and knowledge may allow many of the currently available treatments to better target the cancer, thereby improving the effectiveness and patient tolerance of the treatments. For example, current radiotherapy dosing protocols are based on patient or tumor characteristics (e.g., age, comorbidity status, clinical stage of the tumor, Gleason score), thus allowing higher doses than those administered in most of the radiotherapy studies reviewed in this CER update (see Table D-1 and Table D-2 in Appendix D). Because evidence based on dated medical techniques may not apply to current practice, future studies are required for validating the comparative effectiveness and safety of the current and emerging treatment techniques (e.g., robotic-assisted surgery, proton beam therapy, stereotactic body radiation therapy).

Additionally, patients studied in the RCTs included in this review may have a different risk profile from patients currently being diagnosed with prostate cancer. Ten to 15 years ago, prostate cancers were primarily detected by digital rectal examination or tissue specimens obtained during TURP for treating benign prostatic obstruction. Currently, the vast majority of prostate cancers detected in the United States are found via PSA-level testing. Men often start to receive PSA tests in their 40s and continue taking the test on a regular basis until their 80s. As a result, the patients whose diagnosis is established today can be younger and have more confined cancers than those studied in the reviewed RCTs. This trend restricts the applicability of the reviewed evidence, which was based mostly on studies using older and sicker patient populations.

Because of the intensified concern about overdiagnosis of prostate cancer in recent years, the manner in which PSA testing is used for screening prostate cancer and the criteria for establishing an abnormal PSA test result may continue to change. Patient and tumor characteristics among men with prostate cancer diagnosed in the future are likely to be different, not just from those in the past but even from men so diagnosed today.

Finally, we note that even in well-designed RCTs that found an apparent advantage of one intervention over another, subgroup analyses raise the possibility that not all patients in the target population will derive equal or even any observed benefit. This is of particular importance given the potential morbidities associated with prostate surgery and radiation therapies, which may be avoided if a more conservative intervention such as active surveillance is deemed appropriate.

To summarize, most current RCTs were initiated many years ago, and diagnosis and treatment have evolved. Given that it is now possible to detect smaller-volume tumors and that histologic grading is less likely with low-grade tumors than with intermediate-grade tumors, the long-term, patient-oriented outcomes of detected prostate cancer in men managed with observation are likely much better than they were when these studies were initiated and the risk of overdiagnosis and overtreatment greater (this includes the harms of active surveillance with biopsies, which can lead to infection and hospitalization). Therefore, any benefit of early intervention is likely to be less in absolute terms and require a longer time period to accrue and, per se, any harms would carry even more weight.

Implications for Clinical and Policy Decisionmaking

Our review suggests that in comparison with WW, RP appears to lead to a reduced all-cause or cancer-specific mortality in at least some patients with localized prostate cancer after a 15-year followup.³³ However, the strength of evidence from the SPCG-4 trial³³ is graded as insufficient (evidence does not permit a conclusion), and the evidence does not clearly identify the subgroup(s) of patients for which this finding is applicable. However, SPCG-4 and PIVOT together provided consistent, moderate-strength evidence that fewer patients treated with RP developed distant metastases at 12 to 15 years compared to patients receiving WW.

Our review was unable to draw any conclusion on global QOL. Therefore, it is unclear how patients as a whole can balance the tradeoff between the potential benefit in long-term survival and the potential harms (e.g., urinary incontinence, sexual dysfunction) associated with RP surgery. In the end, the treatment decision rests with each individual patient and the patient's family and physicians. These stakeholders' personal preferences and values play a significant role in this decisionmaking process. This may be particularly true for patients with life expectancies of less than about 15 years.

This review and the 2008 report both attempted to evaluate whether a particular patient group (in terms of age, race, general health status, and various tumor risk factors) might benefit more from a compared intervention. Addressing this question would help patients and clinicians make better-informed treatment decision. However, the evidence reviewed does not provide any consistent conclusion on this issue. For example, the SPCG-4 trial found that RP led to significantly lower all-cause and cancer-specific mortalities compared with WW among patients younger than 65 years of age but not among the older patient group.²⁵ However, the PIVOT study did not have the same finding.³³ The PIVOT study found that RP did not reduce all-cause or cancer-specific mortality among men with PSA levels of less than 10 ng/mL but resulted in a significant reduction among men with PSA levels of more than 10 ng/mL. However, this finding is not confirmed by the SPCG-4 trial, which found a mortality reduction with RP in both subsets of patients. Despite these differences in findings, the two trials also show some overlap in findings (reduced mortality with RP) for the subgroup of patients with PSA levels of more than 10 ng/mL. Given the low prostate cancer–specific mortality in men in PIVOT (early PSA era), the likelihood is very low for more than a small mortality benefit for early intervention, especially in men with low PSA/low-risk disease; moreover, harms are associated with surgery or radiation therapy. Nevertheless, enough inconsistency remains in the evidence that clear guidance regarding the appropriate patient population for RP is difficult to establish.

This current review also evaluated RCTs that compared EBRT alone versus EBRT combined with ADT⁴³ and 3D-CRT alone versus 3D-CRT combined with ADT.³⁵ The evidence based on both RCTs^35,43 suggests that the results for overall survival and prostate cancer–specific mortality favored the combined treatments. The subgroup analysis in one RCT³⁵ also suggests that the advantage of 3D-CRT combined with ADT may only occur among patients with no comorbidity or a minimal comorbidity score for the outcome of all-cause mortality. The evidence in another RCT⁴³ suggests that the advantage of EBRT combined with ADT may occur only among white patients for the outcome overall survival and among white patients and men older than 70 years of age for the outcome of prostate cancer–specific mortality. However, this evidence is weak and requires further validation by new studies before it can be used to form clinical guidance for choosing appropriate cases for the treatments. Similarly, the evidence for other treatment comparisons covered in the current review also needs further validation, particularly via rigorously designed RCTs, to form a more reliable foundation for making clinical recommendations. The ongoing U.K. trial of RP versus EBRT and AS (ProtectT [Prostate testing for cancer and Treatment] study) when completed could add to the body of evidence (see Table G-2).

Limitations of the Comparative Effectiveness Review Process

This section discusses challenges that we encountered conducting this systematic review and how we addressed them. They included: (1) how to synthesize findings in an evidence base with numerous treatment comparisons and considerable clinical heterogeneity in patient populations even among studies that made the same treatment comparisons; (2) how to handle issues regarding applicability of findings of long-term studies to current clinical practice; and (3) expanding the scope of this update from studies of patients diagnosed with stage T1–T2 prostate cancer to include stage T3a following reviewer input.

After discussion with clinical expert consultants, we decided against conducting meta-analysis of RCTs with similar treatment comparisons and outcomes (e.g. SPCG-4 and PIVOT) because of clinical heterogeneity in the patient populations (see Discussion for more details). The team believes that a meta-analytic summary effect size would provide an illusion of precision regarding differences between interventions when the level of benefit of a given intervention is likely to be affected by patient and tumor characteristics. Instead, we performed a qualitative synthesis of findings from similar RCTs and separately for observational studies that had similar comparisons and outcomes. This allowed us to reach some conclusions that we could not have reached had we analyzed all individual studies separately.

Issues with lack of applicability of long-term data from RCTs and nonrandomized studies to current clinical practice meant that any conclusions based on findings from such studies needed to be caveated carefully. We have attempted to do this throughout the report.

Although the original scope including patients with stage T1–T2 prostate cancer was agreed on by the Key Informants, comments received by a few reviewers during the draft's public posting led us to expand the scope to include patients with stage T3a prostate cancer. This was supported by a 2013 National Comprehensive Cancer Network guideline that classified clinically localized prostate cancer as stages T1–T3a. We addressed this issue by re-reviewing a large number of abstracts and full publications previously excluded as being outside the original scope of the report. Studies we identified as fitting within the expanded scope were added to the report.

Limitations of the Evidence Base

This current review has several limitations. First, although more RCTs were available for this review than for the 2008 report, the amount of evidence from well-designed RCTs that directly compare different treatments, particularly emerging technologies (e.g., proton beam therapy, high-intensity focused ultrasound [HIFU]), is still small. The few RCTs that met the inclusion criteria for the review compared only a few treatments of interest (e.g., RP vs. WW, EBRT alone vs. EBRT plus ADT, 3D-CRT vs. 3D-CRT plus ADT). Questions about the effectiveness and safety of new and emerging treatment methods are largely unanswered by the RCTs.

Second, all but one of the reviewed RCTs were conducted more than 10 years ago. The manner in which PSA testing was used for detecting prostate cancer and the treatment techniques used may not reflect current practices, so the RCT results may not be generalizable to current practice settings.

Third, there was little reporting of outcomes according to major patient and tumor characteristics. The reviewed RCTs that performed subgroup analyses according to patient or tumor characteristics often do not have adequate power to detect significant effects within the subgroups.

Fourth, wide variation existed in reporting and definitions of outcomes and tumor characteristics (e.g., PSA recurrence level) and patient characteristics (e.g., age, comorbidity status), which make evidence synthesis difficult. We therefore recommend a standardization of definitions of tumor characteristics such as PSA recurrence level and improvement in reporting of clinical outcome data.

Fifth, this review included only studies published in English and also used specific sample-size cutoffs as criteria to exclude small-sized nonrandomized comparative studies. Inclusion of small-sized studies and those published in other languages may have resulted in additional conclusions or may have contradicted some conclusions. Furthermore, this review limited evidence to studies that reported data only for T1–T3a disease separately from T3b or T4 disease. Studies with more than 15 percent of T3/T4 population that did not specifically report data separately for T1–T3a were excluded. As a result, some information potentially relevant to the topic of this review may not have been captured.

Sixth, because prostate cancer–specific mortality is subject to ascertainment bias, all-cause mortality, which is not subject to ascertainment, may be a more consistent outcome measure. A major concern with the outcome all-cause mortality is evaluating comorbidity status using a validated measure. Most of the included studies reported using various criteria to evaluate comorbidity status.

Seventh, the reported outcomes for the RCTs and non-RCTs in the studies reviewed demonstrate the diversity of the endpoints that study investigators considered, some of which (e.g., biochemical progression) are clinically irrelevant in terms of metastases-free, symptom-free, and overall survival.

Eighth, although evidence from included RCTs suggests that observation should be offered to men with low-risk tumors, it is becoming increasingly clear that some in the intermediate-risk category may also be candidates for such an approach (pointing to the limitations of the risk-assessment scheme described earlier in our Background section). Indeed, some trials we described support the notion that treating some men who have intermediate-risk disease may have little to no impact on prostate cancer–specific survival compared with observation (see nonrandomized comparative study by Abdollah et al.⁵⁹).

Ninth, although our review gave the first priority to evidence from RCTs in drawing conclusions, we also reviewed useable evidence that was available from the nonrandomized comparative studies. However, of all the comparisons that we identified across the 44 nonrandomized comparative studies, only a few nonrandomized studies compared interventions that overlapped with the RCTs. Three of four nonrandomized studies compared RP to WW and reported that RP was associated with a reduction in all-cause and prostate cancer–specific mortality. Although the fourth study agreed using a propensity score analysis, an instrumental variable analysis by the same study did not find a significant difference between interventions.⁷³ Given that the patient population in this latter study was derived from a database of patients 65 years or older, the findings in this analysis are comparable to those of the SPCG-4 trial³³ for patients aged 65 years or older.

Finally, we acknowledge that tumors in patients with clinically localized prostate cancer undergoing radiation therapy as primary therapy are likely to be understaged and that a fair comparison of radiation with or without androgen deprivation to RP might best be done in a population with nonmetastatic disease. However, that was not the population specified in our review protocol. Until staging systems reframe prostate cancer staging in this way (i.e., metastatic vs. nonmetastatic), we believe that evaluating this comparison will be difficult.

Research Gaps

A fundamental research gap involves the development of better methods for staging prostate cancer that is detectable but not metastatic. With current technology, such staging is not straightforward, and choosing treatment based on stage for those patients will be difficult until more precise imaging/diagnostic methods are available. As noted earlier, patients who receive radiation therapy are often understaged, which increases the difficulty in judging the relative effectiveness of this treatment in patients with clinically localized prostate cancer.

To further address the KQs of this review, additional RCTs are needed. In Table G-1 and Table G-2 in Appendix G, we summarize nine ongoing clinical trials. Ideally, future RCTs should (1) recruit patients with PSA-detected prostate cancer and (2) compare patient-focused outcomes (e.g., all-cause and cancer-specific mortalities, QOL) between treatment options and techniques used in the current practice with a long followup. To improve applicability, future RCTs should recruit more patients from populations that have been underrepresented in previous trials (e.g., African Americans). Furthermore, new RCTs are needed to evaluate new and emerging technologies such as proton beam therapy and HIFU, because these technologies are costly and lack an adequate evidence base to assess the balance of benefits and harms. These RCTs should use standardized or validated patient outcome measures, have adequate power to detect significant treatment effect, and define patient subgroups of interest a priori. They should also enroll patients that are representative of current clinical practice using similar enrollment criteria that would allow comparison of the patients' outcomes across studies.

However, RCTs have had challenges achieving target enrollments for comparing different treatment options. For example, the PIVOT investigators did not achieve their stated target enrollment of 2,000 patients. This might suggest that comparative-effectiveness research to guide treatment decisions will likely require well-designed observational studies as well.

Observational studies with better design and methodology (e.g., cancer registries and large prospective population-based cohort studies, use of propensity score or instrumental variables, use of validated QOL measures) may provide useful evidence, particularly in cases in which large differences in outcomes might exist. Observational studies may help estimate treatment effectiveness in high-priority patient and tumor subgroups that have not been adequately addressed in RCTs. Findings from observational studies may also help generate hypotheses and design better RCTs. We noted and reported that some observational studies conflicted in their findings based on the analytic methods employed (e.g., instrumental variable analysis vs. propensity scoring vs. multivariable regression analysis). Most of the existing evidence from nonrandomized comparative studies comes with treatment selection biases. These studies also inconsistently defined and reported outcomes.

For this update, we did not identify any studies that compared active surveillance to current treatment therapies. Because WW or observation is not active surveillance, more studies are needed to assess the effectiveness of active surveillance. These studies might necessitate adequate consideration of multiparametric magnetic resonance imaging as a tool to enhance observation or active surveillance. Additional research comparing observation or active surveillance to any early intervention is warranted to avoid potential overdiagnosis and overtreatment in men with PSA-detected cancer (especially low PSA/low-risk disease, but possibly intermediate PSA/intermediate-risk disease as well). Future RCTs that compare early intervention to active surveillance or other early interventions should target patients with higher PSA/higher-risk disease, given that the benefits in this group remain uncertain.

Furthermore, because prostate cancer is a significant cause of mortality among men, a research need remains for better prognostic surrogate markers to predict the risk of recurrence among patients with clinically localized prostate cancer. Finally, some studies discussed in this report suggest that outcomes of surgery and radiation are influenced by center and surgeon case volume and expertise. However, most of these studies did not provide information about practice of care that could have influenced the results. Future studies are needed to fill this gap.

Conclusions

Overall, the body of evidence for treating prostate cancer continues to evolve, but the evidence for most treatment comparisons is largely inadequate to determine comparative risks and benefits. Although limited evidence appears to favor surgery over WW or EBRT, or favors radiotherapy plus ADT over radiotherapy alone, the patients most likely to benefit and the applicability of these study findings to contemporary patients and practice remain uncertain. More RCTs and better-designed observational studies that reflect contemporary practice and can control for many of the known/unknown confounding factors that can affect long-term outcomes may be needed to evaluate comparative risks and benefits of therapies for clinically localized prostate cancer. We also believe an urgent need exists for clinicians to provide an improved way to categorize patients with prostate cancer into different groups based on associated risk factors. All of the treatments currently available for clinically localized prostate cancer can cause bothersome complications, including sexual, urinary, and bowel dysfunction. Patients should be informed and have active involvement during the decisionmaking process and consider the benefits and harms of the treatments.