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Chou R, Dana T, Bougatsos C, et al. Treatments for Localized Prostate Cancer: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Oct. (Evidence Syntheses, No. 91.)

Cover of Treatments for Localized Prostate Cancer

Treatments for Localized Prostate Cancer: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation [Internet].

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4Discussion

Summary of Review Findings

The results of the evidence review are summarized in Table 11.

Table 11. Summary of Evidence.

Table 11

Summary of Evidence.

PSA-based screening identifies prostate cancer that is not clinically evident and, in some cases, may never have been diagnosed without screening. Over three quarters of men with localized prostate cancer undergo prostatectomy or radiation therapy.85,86 Treatment studies can therefore help inform screening decisions by providing information about potential benefits and harms of interventions once prostate cancer is detected.

Only one good-quality randomized trial compared an active treatment for localized prostate cancer with watchful waiting.35 It found that prostatectomy was associated with decreased risk of all-cause and prostate cancer-specific mortality after 15 years of followup, though based on subgroup analyses, benefits appeared to be limited to younger (ages <65 years) men. Because the RCT did not enroll men specifically with screen-detected prostate cancer, and evaluated populations with a substantially higher rate of T2 relative to T1 cancer compared with recent screening trials, its applicability to screening is uncertain. Although cohort studies consistently found that prostatectomy and radiation therapy were associated with decreased risk of all-cause and prostate cancer-specific mortality compared with watchful waiting, estimates were susceptible to residual confounding by indication, even after statistical adjustment.

Commonly selected therapies for localized prostate cancer are associated with clinically important harms. Treating approximately three men with prostatectomy, seven with radiation therapy, or two to three with ADT instead of watchful waiting would each result in one additional case of erectile dysfunction, and treating approximately five men with prostatectomy instead of watchful waiting would result in one additional case of urinary incontinence. Estimates for urinary incontinence and erectile dysfunction were similar based on pooled analyses and when results were synthesized more qualitatively (using medians and ranges). Prostatectomy and radiation therapy were not associated with worse outcomes on most measures related to general health-related quality of life compared with watchful waiting, suggesting that negative effects related to specific harms may be offset by positive effects, perhaps related to less worry about untreated prostate cancer. Prostatectomy was also associated with perioperative (30-day) mortality (about 0.5%) and cardiovascular events (0.6% to 3%), radiation therapy with bowel dysfunction, and ADT with gynecomastia and hot flashes.

The evidence on treatment-related harms reviewed for this report appears to be most applicable to open retropubic radical prostatectomy and EBRT, though details about specific surgical or radiation therapy techniques and dosing regimens were frequently lacking. We found little evidence with which to evaluate newer techniques for prostatectomy (including nerve sparing approaches that utilize laparoscopy, either robotic-assisted or freehand) compared with watchful waiting, but found no pattern suggesting that more recent studies reported different risk estimates compared with older studies. Limited data suggest that low-dose brachytherapy may be associated with fewer harms compared with high-dose brachytherapy or EBRT.64 A potential harm of radiation therapy not addressed in this review is secondary posttreatment carcinogenic effects.87,88

Although ADT is the next most commonly utilized therapy for localized prostate cancer following prostatectomy and radiation therapy,86 its use is comparatively infrequent, and it is not recommended as primary therapy17,18 due to evidence suggesting ineffectiveness,44 as well as an association with important adverse events such as coronary heart disease, myocardial infarction, diabetes, and fractures when used in the treatment of more advanced prostate cancer.79–81

Evidence on benefits and harms associated with cryotherapy and HIFU is very limited, with no studies comparing these therapies with watchful waiting.

Limitations

We excluded nonEnglish-language articles, which could result in language bias, though we identified no nonEnglish-language studies that would have met inclusion criteria. We included cohort studies of treatments, which are more susceptible to bias and confounding than well-conducted randomized trials. However, confounding by indication may be less of an issue in studies that evaluate harms,89 and analyses stratified by study design did not suggest differential estimates. If patients are selected for a specific prostate cancer treatment in part based on a lower perceived risk for harms, the likely effect in observational studies would be to underestimate risks. For mortality outcomes, which may be more susceptible to confounding by indication, we only included studies that performed statistical adjustment. Finally, studies did not distinguish well between active surveillance and watchful waiting. Active surveillance might be associated with more harms (due to repeat biopsies or subsequent interventions) compared with watchful waiting, and studies with well-described active surveillance interventions that are consistent with current definitions for this therapy are needed.29

Emerging Issues

Therapies for localized prostate cancer continue to evolve. Newer techniques for prostatectomy include minimally invasive approaches that utilize laparoscopy, either robotic-assisted or freehand.90 With regard to EBRT, efforts to define optimal doses and techniques (e.g., short-course, image-guided regimens) continue. In addition, use of brachytherapy for localized prostate cancer has increased markedly. One large survey of radiation oncology centers found that 36% of patients with localized prostate cancer received brachytherapy as a component of care in 1999 compared with 3% in 1994.91 Cryotherapy, HIFU, and vascular-targeted photodynamic therapy are newer therapies for localized prostate cancer that have not yet come into widespread use.92

Future Research

Evidence from well-conducted randomized trials would be helpful for better characterizing the harms associated with treatments for localized prostate cancer. When available, results from the Prostate Cancer Intervention Versus Observation Trial (PIVOT), which compared prostatectomy with watchful waiting for screen-detected cancer, may help clarify which patients will benefit from prostatectomy or other active treatments, potentially reducing harms from unnecessary treatment.93 Additional research is needed on the harms associated with newer surgical techniques (such as robotic-assisted laparoscopic surgery) and radiation therapy regimens, as well as new and emerging therapies, in order to better understand comparative harms. Improved standardization of methods for defining whether a patient has urinary incontinence or erectile dysfunction and improved characterization of the specific techniques and interventions evaluated would be very helpful for interpreting results of future studies. For example, more standardized definitions of watchful waiting and active surveillance (and better reporting of the methods used) would help distinguish between these two types of therapies and facilitate analyses to determine whether they are associated with differential risks of harms.

Conclusions

Additional research is needed to understand the benefits of treatments for screen-detected, localized prostate cancer. Commonly selected therapies for localized prostate cancer are associated with an increased risk of important harms. More research is needed to understand whether newer therapies and techniques for treating localized prostate cancer are associated with fewer harms.

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