Refers to article:
A New Risk Classification System for Therapeutic Decision Making with Intermediate-risk Prostate Cancer Patients Undergoing Dose-escalated External-beam Radiation Therapy
Accepted 8 March 2013
December 2013 (Vol. 64, Issue 6, pages 895 - 902)
Prostate-specific antigen (PSA) failure following definitive local therapy for intermediate-risk prostate cancer (PCa)  defined as a PSA level >10 but ≤20 ng/ml, a biopsy Gleason score (GS) 7, or clinical tumor (T) category 2b or 2c is variable, with 5-yr rates ranging from 2% to 70%  . Investigators have shown that some of this variation can be explained by considering whether GS 7 is predominately Gleason 4 + 3  , whether the percentage of positive biopsies (PPB) is at least 50% versus <50%  , and whether the patient has more than one determinant of intermediate-risk PCa versus a single determinant  .
In the current issue of the Platinum Journal, Zumsteg and colleagues  provide further evidence to substantiate these findings in a population of 1024 men treated with high-dose radiation therapy (RT; ie, 81–86.4 Gy) between 1992 and 2007, with 521 men (51%) also receiving a median of 6 mo of androgen suppression therapy (AST). Using their results and evidence from prior literature , , and , they define favorable intermediate-risk (FIR) PCa as those with GS 3 + 4 or less and <50% PPB and, at most, one determinant of intermediate-risk PCa. The remaining men with intermediate-risk PCa are defined as having unfavorable intermediate-risk (UIR) disease. After a median follow-up of 71 mo, the authors found that patients with UIR PCa had a significant increase in the risk of PSA failure, distant metastasis (DM), and PCa-specific mortality (PCSM) compared with men with FIR PCa; these results were found despite a median of 6 mo of AST use in 58.5% of men with UIR compared with 30.1% (p < 0.001) of men with FIR PCa  .
Stratifying men with intermediate-risk PCa into cohorts of higher risk versus lower risk for PSA recurrence, DM, and PCSM following high-dose RT with or without short-course AST has potential implications for management. Specifically, it has been established from radical prostatectomy (RP) series that approximately one-third of men will be upgraded  at RP due to sampling error associated with standard transrectal ultrasound (TRUS)–guided 12-core prostate needle biopsy (PNB). Consequently, many men with biopsy GS 7 PCa have occult GS 8–10 PCa that will be missed at the initial PNB. Not unexpectedly, prior studies , , and  have shown that the predictors of upgrading at RP for men with intermediate-risk biopsy GS 7 PCa are exactly the same clinical factors (ie, GS 4 + 3  , at least 50% PPB  , or having more than one determinant of intermediate-risk PCa  ) that the authors in the current study  found to be associated with increased risk of PSA recurrence and DM, leading them to designate such men as having UIR PCa. Randomized controlled trials  have shown that survival is prolonged when 28–36 mo, compared with 4–6 mo, of AST is added to RT for men with GS 8–10 PCa, whereas RT and 6 mo of AST, compared with RT and no AST, prolongs survival in men with GS 7 PCa  . It is likely that men with UIR PCa have an increased risk of PCSM because of the presence of undersampled GS 8–10 PCa for which 6 mo of AST in addition to RT may not be sufficient to minimize the risk of PCSM. Consequently, men with UIR PCa who have GS 8–10 PCa that was missed at PNB may be undertreated and placed at increased risk for PCSM.
The question that remains is whether anything can be done for a man with UIR PCa to ascertain whether biopsy GS 8–10 PCa was missed during the standard 12-core TRUS-guided PNB.
Treatment algorithm for unfavorable intermediate-risk prostate cancer
Emerging data suggest that using 3-tesla (3T) multiparametric magnetic resonance imaging (MRI)  and image-guided PNB via a fused MRI/TRUS platform  provides a better method to identify men with biopsy GS 7 PCa who have GS 8–10 PCa that was missed at the initial TRUS-guided PNB due to sampling error. Specifically, the initial data are promising for evaluation of the diffusion weighted imaging (DWI)  component of multiparametric MRI to identify areas of Gleason grade 4 or 5 PCa in men with biopsy GS 3 + 3 PCa by using whole-mounted RP specimens and assessing concordance between regions of high-grade disease in the RP specimen and regions consistent with high-grade tumor on the DWI maps. Although further study is ongoing and needed before such an approach becomes practice, this new treatment algorithm could lead to better outcomes in otherwise healthy men with UIR PCa who are planning to undergo RT:
- 1. Obtain a 3T multiparametric MRI in men with biopsy GS 7 UIR PCa and assess whether areas suspicious for GS 8–10 PCa exist.
- 2. If suspicious areas are noted, then biopsy those areas using an MRI/TRUS fusion platform  or take additional cores from the suspicious areas using a TRUS-based approach.
- 3. If the biopsy is negative for GS 8–10 PCa, then treat with RT and 6 mo of AST.
- 4. If the biopsy is positive for GS 8–10 PCa, then treat with RT and 28–36 mo of AST.
In summary, three clinical factors have been identified in men with intermediate-risk PCa that are known to be associated with upgrading as well as increased risk of PSA recurrence, DM, and PCSM following RT with or without short-course AST , , and , leading to the designation of these cancers by Zumsteg and colleagues  as UIR PCa. These three factors include biopsy GS 4 + 3, at least 50% PPB, and having more than one determinant of intermediate-risk PCa.
Ascertaining who with biopsy GS 7 UIR PCa harbors occult GS 8–10 PCa through the use of modern imaging and image-guided biopsy techniques may be one way to personalize the care of these men and improve their outcomes.
Conflicts of interest
The author has nothing to disclose.
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Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA, USA
Brigham and Women's Hospital and Dana Farber Cancer Institute, Department of Radiation Oncology, 75 Francis St., Boston, MA 02115, USA. Tel. +1 617 732 8821; Fax: +1 617 264 5242.
© 2013 European Association of Urology, Published by Elsevier B.V.