Active surveillance in intermediate risk prostate cancer: is it safe?

1 University of Melbourne, Department of Surgery, Austin Health, Melbourne, Australia; 2 Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; 3 Olivia NewtonJohn Cancer Research Institute, Melbourne, Australia ___________________________________________________________________________________

found that 46% of patients with biopsy GS 3+4 cancer have unfavourable disease at final pathology (6). When applying the University of Toronto, Royal Marsden Hospital and Prostate Cancer Research International Active Surveillance (PRIAS) criteria (7) 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 (8). The Cancer Council Ontario (CCO) currently recommends active treatment (surgery or radiotherapy) for patients with intermediate-risk localized prostate cancer (9).
A number of studies also support the role of surgery in men in this intermediate risk group. The PIVOT study found men with intermediaterisk tumours who underwent radical prostatectomy (PSA 10.1 to 20.0ng/ml, GS 7, or a stage T2b tumour) had a 31% relative reduction in allcause mortality, as compared with those assigned to observation (HR 0.69; 95% CI, 0.49 to 0.98; ARR 12.6%) (10). PCa mortality in this group was not significant despite a similar trend. This was compared with the Scandinavian Prostate Cancer Group 4 (SPCG-4) trial of radical prostatectomy versus watchful waiting in men with prostate cancer, which showed the benefit of surgery in relation to death from PCa was largest in those with intermediate-risk prostate cancer (relative risk, 0.38) (11). There was a significant absolute reduction in men with intermediate risk disease in overall mortality, rate of death from PCa, and in the risk of metastases (11%).
Klotz et al. performed a large cohort Canadian study with 993 patients and up to 16 years of follow-up, with 25% of the patients fulfilling the D'Amico criteria for intermediate risk (5). There were 15 deaths (2.8%) due to PCa in total, all of whom had confirmed metastases before death. 12 (44%) of the 28 patients with metastases had a Gleason score of 3+4 at diagnosis; with a median time to metastasis was 7.3 years (95% CI, 5.81 to 8.76 years). Only 2 of the 28 patients who developed metastasis were not upgraded to GS 7 before developing metastatic disease, neither of whom had surgical grading. Klotz (12).

DIsCussIOn
Although the lifetime risk of receiving a diagnosis of prostate cancer is about 17%, the risk of dying from the disease is approximately 3%, suggesting that conservative management may be appropriate for select men (13). Thus, the way forward for AS must be lighted by improved tools for risk stratification at diagnosis and for early identification of progressive disease (14). A recent systematic review of novel tools for improving patient selection and monitoring low-risk prostate cancer by AS found that magnetic resonance imaging (MRI) has a high specificity for low-risk prostate cancer and new serum markers are associated with unfavourable disease (15). The potential of multi-parametric MRI lies in its high negative predictive value (80-90%) for the intermediate endpoint of disease upgrading, which may make it useful as an AS endpoint predictor (16). It is also beneficial in identifying anterior and higher volume tumours, as well as aiding in disease reclassification. A significant proportion of low risk patients do harbour more aggressive disease, and MRI can provide better risk stratification in both low and intermediate risk patients. This observation is demonstrated by several series of patients meeting AS criteria who underwent radical prostatectomy, revealing Gleason score upgrading in 23%-56% (17). Klotz et al. observed that 16% of patients had histological progression (2). Such observations encourage the need for future research of both MRI and molecu-lar biomarkers such as PCA3 or PSA isoforms in these patients.
When managed with non-curative intent, intermediate-risk PCa is associated with 10-year and 15-year prostate-cancer-specific mortality rates of 13 and 19.6% (18). Thus, men with this disease are at risk of developing incurable disease in the future as they may miss the window of curability when opting for AS (8). Thomsen et al. estimated average 5-year and 10-year probabilities of discontinuing AS at 33% (14%-41%) and 55% (40%-59%) respectively, with a majority undergoing delayed curative treatment (RP or RT) (19). Thus, AS can only be warranted in select intermediate risk PCa patients, with consideration for individual tumour metrics, patient age and overall health, as well as patient preferences and the potential side effects of curative treatments. For those young patients (<65) with longer qualityadjusted life expectancy in this group, surgery should still be considered the definitive approach.

COnCLusIOns
At least 50%-60% of individuals diagnosed with PCa ultimately die of other causes, and as a result, AS has become a chosen management option for low risk PCa patients (20). The latest literature however, demonstrates surgery as the mainstay of treatment in intermediate risk patients, with the role of AS limited to select men in this group. The use of MRI and prostate serum and genetic markers are still being evaluated, and until that time, it is recommended that definitive intervention remain the optimal choice of management in this group of patients.