Abstract
Recent results of ProtecT trial published after 15 years of follow-up demonstrate the absence of difference in prostate cancer-specific survival between active monitoring, radiotherapy, or prostatectomy for PSA-detected, localized prostate cancer patients. These results definitively confirm the essential role of active surveillance as the gold standard for men with low-risk and highly selected intermediate-risk prostate cancer. It underlines the importance of shared-decision making process with patients.
Optimal management of low- and intermediate-risk localized prostate cancer (PC) is still a challenge when deciding whether to propose radical treatment or offer a monitoring program. The PROstate TEsting for Cancer and Treatment (ProtecT) trial evaluated more than 82,000 men from the UK who underwent PSA testing between 1999 and 2009. Of these 2965 were diagnosed with PC and 1643 were randomly assigned (1:1:1) to active monitoring (AM) (based on regular PSA measurements alone), radiotherapy (RT) (3D conformational, 74 Gy in 37 fractions with 3–6 months of neoadjuvant ADT) or prostatectomy. Primary endpoint was Cancer-Specific-Survival (CSS) and secondary endpoints were death from any cause, development of metastasis, clinical progression and use of long-term ADT. The 10-year outcomes were previously published in 2016 in the New England Journal of Medicine and have been recently updated after 15 years of follow-up. 1
At baseline, most men (77%) presented with ISUP 1 and with stage T1c disease (76%). However, using the D’Amico criteria, 24% and 9.6% of the men had intermediate- and high-risk disease, respectively. According to other classifications (CAPRA and Cambridge Prognostic group), the corresponding rates were 20%–26% and 2%–8%, respectively. One interesting observation is that among the 488 men who had undergone prostatectomy within 1 year after randomization (irrespective of allocation), nearly one third had an increase in the pathological stage (to pT3 or pT4); one third an increase in tumor grade, and a half were found with ISUP 2 or higher.
The 15 year report confirmed a high CSS rate of 97% without any difference between groups (p = 0.53). Death from any cause was also comparable between arms (32% from cardiovascular and respiratory disease and 52% from other malignancies). Despite a higher incidence of metastases (but for some at long intervals of 10–20 years from diagnosis), long-term ADT use and disease-progression in the AM arm, no consequence on survival was seen. At a median follow-up of 15 years, 39% of the men in the active-monitoring group had not undergone radical treatment, and 24% were alive without neither radical treatment nor ADT. This confirms the low lethality of localized PC and its indolent development over several years. Even in case of metastasis, few men die from PC thanks to the development of effective systemic therapies, which could also raise the relevance of Metastasis-Free-Survival as a surrogate of OS for localized low- to intermediate-risk PC.
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In any case,
Special attention must be paid to the population of ProtecT. As nearly 25% of patients had an intermediate-risk disease according to contemporary risk stratification, the extension of active surveillance to this subgroup should be considered. Currently, there is no consensus criteria for selecting the good candidates, and new tools (imaging, genomic scores) are needed. Conversely, 2%–10% of men had a high-risk disease at baseline (according to the contemporary stratification) and as cited above, the histological analysis of prostatectomy revealed a pT ⩾ 3 stage in one third of cases. The low number of high-risk patients in ProtecT is clearly insufficient for considering a surveillance strategy in this setting, but underlines the indolent evolution in some PC even in the presence of unfavorable criteria.
Simultaneous to the publication of the above oncological outcomes by Hamdy et al., Donovan et al. published patient-reported outcomes (with a 80% response rate) with a 12-year follow-up. 5 These results deserve to be considered together because they are the keystone of the wide interpretation of the ProtecT trial. Without any surprise, patients in the prostatectomy arm presented with a higher 12-year rate of urinary leakage requiring pads than in the RT or AM groups (24%, 8%, and 11% respectively). While sexual function was equally low in the three arms by year 12, the time profile was different. The reduction in sexual function was more pronounced immediately after surgery before a little recovery and finally a slow decline. In the RT arm, the combination of neoadjuvant ADT induced an immediate reduction with some recovery during several years before a gradual decline. Interestingly, men in the AM group presented an harmonious and gradual decline over time. If we focus on the bowel function by year 12, twice as many men had fecal leakage in the RT arm versus in the other groups (12% vs 6%). These data indicate that although urinary, bowel, and sexual domains naturally decline over time, radical treatment induce a clear impact which must be part of the shared-decision making process with patients. Overall, these results show that radical treatments (RT or prostatectomy) may induce harms even in the long term. This has two direct implications: firstly, they must be considered at the time of diagnosis to provide patients with the best possible guidance in their choice of active surveillance versus radical treatment. Secondly, in case of radical treatment, this demonstrates the need for a long-term follow-up.
The ProtecT trial definitively confirms the essential role of active surveillance, which should be offered to all low-risk and to selected intermediate-risk men with PC. It underlines the importance of considering the benefit/risk ratio when radical treatment is proposed, since many patients could suffer from long-term symptoms without any oncological benefit.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
