Gleason pattern 4: active surveillance no more

To reduce overtreatment of indolent prostate cancer (PCa), urologists have embraced active surveillance (AS) as a management strategy for low-risk PCa; however, patterns-of-care studies are now showing that AS is also being used for patients with intermediate-risk disease. A contemporary Australian study of 980 men reported that 8.9% of men with intermediate-risk disease were placed on AS, of whom 53.8% had Gleason score (GS) 3+4 PCa and 10.4% had GS 4+3 PCa 1. The most recent update from the CaPSURE database also reflected this trend in AS, but questions remain about the safety of this practice, particularly as the majority of AS protocols worldwide exclude men with GS 4 PCa, unless their life expectancy is limited. Despite long-term data having confirmed the safety and efficacy of AS for low-risk cancers with 10- and 15-year actuarial cause-specific survival rates of 98.1 and 94.3%, respectively 2, the evidence does not extend to supporting its use in intermediate-risk disease. Data from the PIVOT study group indicated that men with intermediate-risk disease who underwent radical prostatectomy had a significant relative reduction of 31% (hazard ratio 0.69, 95% CI 0.49–0.98) in all-cause mortality compared with those who underwent observation 3. A similar trend was observed regarding PCa-specific mortality, but this was not significant. Likewise, the SPCG-4 study group reported that there was a significant absolute reduction in overall mortality, risk of death from PCa and risk of metastasis in the intermediate-risk group who underwent radical surgery 4. Hence, the literature suggests a survival benefit for patients with intermediate-risk PCa who undergo surgery, and it should be strongly reconsidered whether AS is appropriate for patients in this group, especially in younger men with a good life expectancy. Men with intermediate-risk disease are at risk of developing incurable disease in the future as they may miss the window of curability when opting for AS. In the aforementioned Canadian series of 993 patients, Klotz et al. 2 reported that at a median follow-up of 6.4 years, 28 men (2.8%) developed metastatic disease, of whom 15 men died from their PCa 2. The median time to metastasis was 7.3 years (95% CI 5.81–8.76) and it can be reasonably assumed that when follow-up is extended more men will develop metastases. Notably, 44% of men with metastatic disease had GS 3+4 disease at diagnosis and only two men were not upgraded to GS ≥ 7 before developing metastatic disease, neither of whom had surgical grading. Similarly, both the PIVOT 3and SPCG-4 4 studies reported a significant risk reduction of developing metastatic disease of 60 and 43%, respectively, amongst all patients who underwent radical treatment instead of AS. Additionally, this effect was amplified to a 71% relative risk reduction when analysing the intermediate-risk group specifically 3; therefore, the definitive treatment of pattern 4 PCa is recommended in order to prevent the development of incurable metastatic disease in the future. Upgrading disease on AS protocols is a trigger to intervene. Klotz et al. 2 reported that the presence of pattern 4 disease acted as a significant predictor of therapeutic intervention on univariate analysis (odds ratio 1.795, 95% CI 1.216–2.628). It is not clear whether satisfactory oncological outcomes can be achieved at this stage for men whose PCa is upgraded. Furthermore, GS 7 PCa represents a heterogeneous group that is difficult to risk stratify safely. An analysis of 2323 men with GS 3+4 PCa who underwent surgery at six academic centres showed that nearly half the patients had unfavourable disease at final pathology 5. When applying the University of Toronto, Royal Marsden Hospital and Prostate Cancer Research International Active Surveillance (PRIAS) criteria to the above cohort, 78, 59 and 20% of men were eligible for AS, respectively, and the risks of unfavourable disease were decreased to only 42.4, 41.0 and 30.5%, respectively. Only when patients aged <70 years with very favourable disease (cT1c, PSA ≤ 10 ng/mL, PSA density ≤ 0.15 ng/mL/g, ≤2 positive cores) were selected did the risk of unfavourable disease fall below 20% and thus their potential eligibility for AS. Risk stratification of intermediate-risk cancers therefore presents a challenge. The potential of multiparametric MRI lies in its high negative predictive value for the intermediate endpoint of disease upgrading, which may make it useful as an AS endpoint predictor 6. In addition, free PSA and PSA isoforms have been reported to have a similar clinical utility. Although novel biomarkers possess the potential to predict unfavourable findings on repeat biopsy, the data are scarce and have not been used to evaluate long-term endpoints. Further research is required to validate the utility of both multiparametric MRI and biomarkers in this clinical setting. It is recognized that intermediate-risk disease does not always warrant definitive management and that AS may still have a role in older patients with such cancers, in whom higher risks of unfavourable pathology may be accepted. In the Sunnybrook cohort, consisting of a quarter of men with D'Amico intermediate-risk PCa, a low 15-year prostate cancer-specific mortality rate was observed. Furthermore, men aged >70 years in that study were 11.5 (95% CI 5.8–22.8) times more likely to die from causes other than PCa. In comparison, the risk of non-PCa-specific mortality nearly halved in the group aged <70 years (hazard ratio 5.8, 95% CI 2.4–13.8) 2. Although this somewhat justifies the use of AS in the older age group, it also alerts us to the risk associated with placing younger patients on the same management plan. Overall, the literature makes a strong case for definitive intervention for men with intermediate-risk PCa because of their risk of developing incurable disease. In the future it is expected that advances in prostate imaging and biogenomics will improve risk stratification but, until such time, those patients whose disease is classified as Gleason pattern 4 should be offered curative treatment without delay. None declared.

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