Refers to article:
Case Presentation: Intermediate-risk Prostate Cancer in a Fit 66-year-old Man
September 2015 (Vol. 1, Issue 2, pages 207 - 208)
1. Case details
Many urologists will be familiar with this interesting case. As a 66-yr-old man, the patient has good life expectancy, which, using Australian data , I estimate to be around ≥16 yr. He appears to have little sexual or urinary dysfunction, and his father had a good outcome from prostate cancer (PCa) treatment, so I assume this man is expecting cure if possible. His cancer appears to be confined to the prostate on radiologic and statistical grounds, but his tumour has Gleason pattern 4 elements, and maybe the 1-mm biopsy focus is missing the larger 8-mm lesion seen on magnetic resonance imaging (MRI).
Histologically, this man has very low-volume Gleason 3 + 4 PCa. The main dilemma is whether active surveillance (AS) is a safe option. A key concern with the AS approach is the risk of missing the window of opportunity to treat clinically significant PCa, which might eventually lead to PCa-related morbidity and death. Conversely, although intervention with radical prostatectomy or radiation therapy would ensure a good oncologic outcome, it would undoubtedly expose the patient to functional morbidity that would affect his quality of life. Is it possible to offer AS to selected patients such as this who appear to have very low-volume intermediate-risk cancer?
It is already clear that urologists are embracing AS for men with low-risk PCa  and even for selected men with intermediate-risk PCa . For low-risk disease, several large AS studies  have shown this approach to be a safe and feasible management option, with mature data showing 10- and 15-yr actuarial cause-specific survival rates of 98.1% and 94.3%, respectively . However, it is noteworthy that at a median follow-up of 6.4 yr, the same study of 993 men reported 15 deaths from PCa and another 13 patients with metastases. Of these 28 patients, 26 had Gleason 3 + 4 PCa before the development of metastases . It seems reasonable to predict that longer follow-up will reveal more patients with metastases. Consequently, use of AS in younger patients with Gleason 3 + 4 disease, even when of very low volume, remains controversial.
It is also acknowledged that the intermediate-risk category is quite heterogeneous, and there is evidence that selected men with Gleason 3 + 4 PCa may have lower risk disease than others. Gandaglia et al.  demonstrated that patients with organ-confined Gleason 3 + 4 PCa did not have poorer outcomes compared with counterparts with Gleason 3 + 3 disease, and they defined unfavourable disease as Gleason 4 + 3 or non–organ-confined disease on final pathology. Moreover, Ploussard et al.  calculated the risk of missing such clinically significant disease in patients with biopsy-proven Gleason 3 + 4 PCa. When applying very strict selection criteria (PSA ≤10 ng/ml, PSA density ≤0.15 ng/ml per gram, ≤2 cores positive for T1c, and age ≤70 yr), this risk is reduced to < 20%. This compares with a reclassification rate of 28% in patients in the Prostate Cancer Research International Active Surveillance study . In any case, an important message for all men considering AS for localised PCa is that the possibility of understaging and undergrading must always be considered, but in the case of already established intermediate-risk disease, additional caution is warranted because the safety of AS in such patients has not yet been established.
3. Treatment strategy
A number of recent approaches, including multiparametric MRI (mpMRI) of the prostate and genomic testing, have been proposed as potential avenues for predicting such unrecognised high-grade disease. A recent meta-analysis revealed that mpMRI has value in AS management , with negative predictive values for significant disease well above 90% for patients with low clinical risk. However, patients such as this man, with a measurable 8-mm lesion on mpMRI, are at significant risk of having more clinically significant disease than currently suggested . Although the role of mpMRI in selecting and monitoring men on AS for localised PCa is not yet defined, mpMRI appears to add value. The presence of a visible lesion on mpMRI, such as in this case, should certainly prompt concerns about higher volume cancer than the 1-mm Gleason 3 + 4 core identified by conventional transrectal ultrasound–guided biopsy in this patient. This alone is enough to suggest that the patient is not suitable for AS without at least undergoing a targeted biopsy of the lesion.
Several tissue-based genomic assays are now commercially available. It has been shown that the Oncotype DX (Genomic Health, Redwood, CA, USA) genomic prostate score (GPS) is of value in risk-stratifying men with intermediate-risk disease . This 17-gene expression panel is significantly associated with adverse pathologic features at radical prostatectomy with a rise in GPS ≥20; however, the GPS test and other similar tissue-based genomic assays have not been formally evaluated in an AS population.
Given the 20–30% misclassification risk in all AS patients, a confirmatory biopsy within 6–12 mo is an essential tool in the follow-up strategy to reduce the risk of undergrading and understaging of disease. This is particularly true for patients with Gleason 3 + 4 disease, in whom AS would not usually be recommended but may be adopted. This repeat biopsy should target the areas of the prostate that are typically undersampled on initial biopsy, such as the anterior prostate. Transperineal template biopsies have been proposed as a more reliable method of ruling out high-grade tumours . Furthermore, MRI-targeted biopsies, mainly through fusion with real-time ultrasound, significantly improve cancer detection rates and are emerging as a new standard of care .
AS for our patient with very low-volume Gleason 3 + 4 disease is still considered experimental and cannot be safely recommended outside of clinical trials. At the very least, more refined risk stratification using an mpMRI-targeted biopsy (using either visual or machine fusion) should be considered, and genomic classification using the Oncotype DX GPS might also guide decision making. Prospective trials are warranted to support such AS expansion and guide the follow-up for these patients. In the meantime, radical treatment options, whether surgery or radiotherapy, should still be offered as the gold standard for this patient if avoidance of PCa-related morbidity and mortality is a priority for him.
Conflicts of interest
The authors have nothing to disclose.
-  Life expectancy. Australian Institute of Health and Welfare Web site. http://www.aihw.gov.au/deaths/life-expectancy.
-  C.R. Ritch, A.J. Graves, K.A. Keegan, et al. Increasing use of observation among men at low risk for prostate cancer mortality. J Urol. 2015;193:801-806 Crossref
-  M. Weerakoon, N. Papa, N. Lawrentschuk, et al. The current use of Active Surveillance in an Australian cohort of men: a pattern of care analysis from the Victorian Prostate Cancer Registry. BJU Int. 2015;115(Suppl 5):50-56 Crossref
-  M. Bul, X. Zhu, R. Valdagni, et al. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. Eur Urol. 2013;63:597-603 Crossref
-  L. Klotz, D. Vesprini, P. Sethukavalan, et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol. 2015;33:272-277 Crossref
-  G. Gandaglia, G. Ploussard, H. Isbarn, et al. What is the optimal definition of misclassification in patients with very low-risk prostate cancer eligible for active surveillance? Results from a multi-institutional series. Urol Oncol. 2015;33:164
-  G. Ploussard, H. Isbarn, A. Briganti, et al. Can we expand active surveillance criteria to include biopsy Gleason 3 + 4 prostate cancer? A multi-institutional study of 2,323 patients. Urol Oncol. 2015;33:71
-  I.G. Schoots, N. Petrides, F. Giganti, et al. Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review. Eur Urol. 2015;67:627-636 Crossref
-  S.S. Dianat, H.B. Carter, K.J. Pienta, et al. Magnetic resonance-invisible versus magnetic resonance-visible prostate cancer in active surveillance: a preliminary report on disease outcomes. Urology. 2015;85:147-153
-  J. Cullen, I.L. Rosner, T.C. Brand, et al. A biopsy-based 17-gene genomic prostate score predicts recurrence after radical prostatectomy and adverse surgical pathology in a racially diverse population of men with clinically low- and intermediate-risk prostate cancer. Eur Urol. 2015;68:123-131
-  L. Vyas, P. Acher, B. Challacombe, et al. Indications, results and safety profile of transperineal sector biopsies of the prostate: a single centre experience of 634 cases. BJU Int. 2014;114:32-37 Crossref
-  M.M. Siddiqui, S. Rais-Bahrami, B. Turkbey, et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA. 2015;313:390-397 Crossref
a Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia
b Australian Prostate Cancer Research Centre, Epworth Richmond Hospital, Melbourne, Australia
Corresponding author. Division of Cancer Surgery, Peter MacCallum Cancer Centre, St. Andrew's Place, Melbourne, Victoria 3002, Australia. Tel. +61 39936 8032; Fax: +61 39429 4683.
© 2015 European Association of Urology, Published by Elsevier B.V.