In prostate cancer, urinary and sexual function were worse with prostatectomy than active monitoring or radiotherapy

Question In men with clinically localized prostate cancer, what are the effects of active monitoring, radical prostatectomy, and external-beam radiotherapy on patient-reported outcomes? Methods Design Randomized controlled trial (Prostate Testing for Cancer and Treatment [ProtecT] trial). Current Controlled Trials ISRCTN20141297; ClinicalTrials.gov NCT02044172. Allocation Concealed.* Blinding Blinded* {questionnaire data entry staff and outcome assessors for cause of death}. Follow-up period 6 years. Setting Screening population in the UK. Patients 1643 men 50 to 69 years of age (median age 62 y, median prostate-specific antigen [PSA] level 4.6 ng/mL) who received a diagnosis of localized prostate cancer after PSA screening. Intervention Active monitoring with PSA measurements every 3 months for 1 year, then every 6 to 12 months, with patient review when PSA increased by 50% in the past 12 months (n =545); radical prostatectomy (n =553); or radiotherapy with 3 to 6 months of neoadjuvant androgen-deprivation therapy plus external-beam 3-dimensional conformal radiotherapy (total dose 74 Gy in 37 fractions) (n =545). All groups were offered androgen-deprivation therapy at PSA levels 20 ng/mL or lower, if indicated. Outcomes Outcomes were urinary, sexual, and bowel function, and health-related quality of life at baseline, 6 and 12 months, and annually from 2 to 6 years. Patient follow-up 86% (intention-to-treat analysis). Main results The main results are in the Table. Conclusion In men with prostate cancer, urinary function and sexual function over 6 years were worse with prostatectomy than with active monitoring or radiotherapy; bowel function at 6 months was worse with radiotherapy. Health-related quality of life did not differ among groups. Active monitoring vs radical prostatectomy vs external-beam radiotherapy in men with clinically localized prostate cancer Outcomes Main results Urinary incontinence Incontinence was increased at 6 mo with prostatectomy and remained worse than active monitoring or radiotherapy at all time points. Erectile function Erectile function was substantially reduced at 6 mo with prostatectomy or radiotherapy; it recovered slightly and then decreased again with radiotherapy, and remained worse with prostatectomy. Over time, erectile function gradually decreased with active monitoring. Bowel function Bowel function scores did not change over time with active monitoring or prostatectomy but were slightly worse with radiotherapy at 6 mo. Health-related quality of life Groups did not differ. Commentary The ProtecT randomized trial provides high-quality evidence to inform future clinical and health policy decisions regarding treatment for men with clinically localized PSA-detected prostate cancer. The results should be interpreted in the context of 2 previous landmark studies of radical prostatectomy versus watchful waiting: the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), conducted before widespread PSA testing (1), and the Prostate Cancer Intervention versus Observation Trial (PIVOT), conducted in the early PSA testing era (2). ProtecT compared radical surgery, radiotherapy, and active monitoring (using PSA measurements but not the periodic prostate biopsies commonly done in the USA) and found no difference in overall or prostate cancer mortality at 10 years. Absolute differences were <1%. Prostate cancer mortality was rare in all 3 treatment groups and was eclipsed 10-fold by all-cause mortality. Disease progression and development of metastatic disease favored surgery or radiotherapy. Absolute differences, especially in metastatic disease, were small (<4%) and defined by asymptomatic increases in PSA levels and findings on diagnostic imaging studies. SPCG-4, and perhaps PIVOT, suggests that these small differences may translate into future mortality benefits with much longer follow-up. However, only the small number of men with very long life expectancies could realize such a delayed benefit. Most men will experience harm without benefit, further highlighting the importance of preventing overdiagnosis and overtreatment of prostate cancer. The suggestion in the accompanying editorial that radiotherapy is superior to surgery based on statistical trends is not supported by ProtecT findings (3). Mortality and cancer outcomes may distract from the important patient-reported outcomes discussed in the study by Donovan and colleagues, including Expanded Prostate Cancer Index Composite scores for up to 6 years of follow-up with response rates >85%. Until now, the best evidence on quality-of-life outcomes for contemporary treatment modalities came from observational studies (e.g., Sanda and colleagues [4]) that were confounded by men choosing their treatments, as reflected in their different baseline characteristics. Donovan and colleagues clearly define the short- and long-term trade-offs faced by patients with prostate cancer who must choose among these 3 options. Where do we go from here? The discussion about the best way to treat clinically localized prostate cancer is inextricably tied to the PSA screening controversy. Detection that triggers prostate biopsy is increasing through the use of new and more sensitive technology (e.g., magnetic resonance imaging) (5) and lower PSA thresholds. Contributing to this debate will be the cluster-randomized Comparison Arm for ProtecT (CAP) trial of prostate cancer screening in primary care centers in the UK, which will be published in early 2017 (6). The CAP results should be interpreted in the context of systematic reviews of existing screening trials for which extended follow-up data may also be available (7). In the meantime, results of ProtecT provide further support for informed decision-making and careful patient selection to reduce prostate cancer overdiagnosis and overtreatment (8). Physicians who treat men with prostate cancer need to fully understand the evidence on treatments for localized prostate cancer and the other health challenges facing patients. Watchful waiting and noninvasive active surveillance approaches should be recommended more frequently, and thresholds for intervening with curative intent should be raised rather than lowered. Local treatment with curative intent should focus on men with higher-risk disease who are in good health and have a life expectancy 15 years (8), resisting the urge to treat every man with biochemical or asymptomatic progression. For men with PSA-detected localized prostate cancer, ProtecT provides convincing evidence that less can be more.