Draft Key Questions
Disposition of Comments Report
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To comprehensively update a 2008 systematic review on treatments for cancer confined to the prostate gland, which is the definition of clinically localized disease.
We searched MEDLINE®, PreMEDLINE, Embase®, the Cochrane Library, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment Database, gray literature, and the U.K. National Health Service Economic Evaluation Database for reports published from January 1, 2007, through March 7, 2014.
We synthesized evidence from randomized controlled trials (RCTs) and nonrandomized comparative studies published in English that evaluated treatments and reported clinical or biochemical outcomes in patients with clinically localized prostate cancer.
Eight RCTs and 44 nonrandomized comparative studies evaluating numerous treatment options met inclusion criteria. However, because most comparisons were represented by only one or two studies, the strength of evidence (SOE) was insufficient for the majority of comparisons.
Two RCTs, the Scandinavian Prostate Cancer Group-4 (SPCG-4) and the Prostate Intervention Versus Observation Trial (PIVOT) compared radical prostatectomy (RP) and watchful waiting (WW) in localized prostate cancer patients. No meta-analysis was done because of the heterogeneity of included patients. While the SPCG-4 study found that RP reduced prostate cancer–specific mortality at 12 and 15 years, the PIVOT trial found no statistically significant difference at 12 years. The SPCG-4 study found that RP reduced all-cause mortality at 15 years, but neither the SPCG-4 nor the PIVOT trial found any significant difference at 12 years. The SOE for these outcomes was insufficient. However, both trials found significant reductions in progression to metastases in the RP group compared with the WW group (SOE: moderate). In the SPCG-4 trial, subgroup analyses showed reduced all-cause mortality among patients younger than 65 years and among patients with low tumor risk. In the PIVOT, reduced all-cause mortality was identified among men with prostate-specific antigen >10 ng/mL and among men with intermediate tumor risk.
One RCT that compared three-dimensional conformal radiotherapy (3D-CRT) with 3D-CRT plus androgen-deprivation therapy (ADT) reported an improvement in overall survival and prostate cancer–specific mortality among men who received combined therapy (SOE: low). Six nonrandomized comparison studies reported that all-cause and prostate cancer–specific mortality was lower in patients treated with RP than in patients treated with external beam radiation therapy (SOE: low).
The definition and severity of adverse events varied greatly across studies. Adverse events such as urinary incontinence and erectile dysfunction were reported mostly among men who underwent RP. Additionally, adverse events such as genitourinary toxicity, gastrointestinal toxicity, and erectile dysfunction were reported among men who received radiation therapy.
This systematic review update found that the evidence for most treatment comparisons is largely inadequate to determine comparative risks and benefits of therapies for clinically localized prostate cancer. This conclusion is similar to that of the 2008 review, which found that no single therapy can be considered the preferred treatment for localized prostate cancer because of limitations in the body of evidence as well as the likely tradeoffs a patient must make between estimated treatment effectiveness, necessity, and adverse effects. Although limited evidence appears to favor surgery over WW or external beam radiotherapy, or favors 3D-CRT plus ADT over 3D-CRT 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 can control for many of the known and unknown confounding factors that can affect long-term outcomes are needed to evaluate comparative risks and benefits of therapies for clinically localized prostate cancer.