Defining Very-High-Risk Localized Prostate Cancer

Approximately one out of every six men diagnosed with prostate cancer is classified as having high-risk disease. The current National Comprehensive Cancer Network (NCCN) defines high-risk disease as prostate cancer that meet one of the following features: clinical stage ≥T3 disease, Gleason sum of 8-10, or PSA >20 ng/ml [1]. Traditionally, high-risk prostate cancer was more commonly treated with androgen deprivation therapy (ADT) and radiotherapy (RT) rather than radical prostatectomy (RP) as it was thought that surgical management was less likely to improve long term survival [2]. More recently, Loeb et al. showed that surgery (RP) can provide improved long term survival in a subset of high-risk men: 10 year biochemical recurrence-free survival (BFS) of 68% and metastasis-free survival (MFS) of 84% [3]. Several additional studies further supported the favorable long term clinical outcomes following RP, thus providing high-risk patients with an attractive alternative to combination external beam RT and ADT [4, 5].

Although many high-risk patients who elect to undergo RP have excellent oncologic outcomes and do not require further adjuvant cancer-directed treatments, significant heterogeneity in clinical outcomes exists [6]. For example, patients with a Cancer of the Prostate Risk Assessment (CAPRA) score of 0-2 have less than a 25% chance of biochemical recurrence at 10 years following radical prostatectomy compared to greater than 75% chance in patients with a CAPRA score of 7-10. Similarly, Dr. Phillip Pierorazio lead a study at Johns Hopkins that showed a significant variation in cancer-specific survival at 15 years post radical prostatectomy between patients with seminal vesicle or lymph node involvement (37%-73%) compared to those without (76-96%) [7].The heterogeneity of clinical outcomes observed in these studies suggested potentially additional sub-groups within the high risk cohort of prostate cancer patients.

Debasish Sundi, MD

Therefore, Dr. Debasish Sundi and colleagues performed a study to identify pre-operative characteristics that could better predict which patients would most benefit from radical prostatectomy and which patients may require multimodal therapy [8]. After univariate and multivariable analyses of extensive pre-operative characteristics in over 700 high-risk patients, the study determined that patients with primary Gleason pattern 5 on biopsy, ≥5 biopsy cores containing Gleason sum 8-10, or multiple NCCN high-risk features ("very high risk" criteria) carried threefold higher risks for prostate cancer metastasis (distant disease spread), and death due to prostate cancer.  For example, at 10 years after treatment, the rate of metastasis in high risk patients was 22%, compared to 63% in very high risk patients.

Figure 1. Kaplan–Meier curves showing significantly better biochemical free survival (BFS), metastasis free survival (MFS), cancer specific survival (CSS), and overall survival (OS). All analyses were performed exclusively on differences of clinical outcomes within the NCCN high risk cohort. JHU very-high-risk group were defined as patients with primary Gleason pattern 5 on biopsy, ≥5 biopsy cores containing Gleason sum 8-10, or multiple NCCN high-risk features. JHU high-risk group were the remaining NCCN high risk patients that did not meet the very-high risk criteria. [8]

Patients with very-high-risk prostate cancer may require more aggressive therapies in order to achieve optimal oncologic outcomes. Multimodal treatment approaches such as combination radiotherapy/hormonal therapy or surgery with early adjuvant therapy should be considered. Furthermore, patients with very high risk prostate cancer may also be ideal candidates for clinical trials that incorporate neoadjuvant and/or novel multimodal treatment approaches.

Summary:  

• Significant variations in clinical outcomes and cancer-specific survival exist within the NCCN high-risk group
• Patients with one of the following characteristics are thought to have very high risk prostate cancer and may benefit most from multimodal therapy and/or clinical trials:
• Primary Gleason primary pattern 5 on biopsy
• ≥5 cores containing Gleason sum 8-10 cancer on biopsy
• 2 or more of the following characteristics: 
• clinical stage ≥T3 stage
• Gleasonsum8-10
• PSA >20ng/ml

There are several exciting clinical trials currently ongoing at Johns Hopkins' Sidney Kimmel Comprehensive Cancer Center for patients with high-risk or advanced prostate cancer:

1. Neoadjuvant Study of Androgen Ablation Combined with Cyclophosphamide and GVAX Vaccine for Localized Prostate Cancer https://clinicaltrials.gov/ct2/show/NCT01696877?term=high+risk+prostate+cancer&state1=NA%3AUS%3AMD&rank=13
2. Randomized Salvage Radiation Therapy Plus Enzalutamide Post Prostatectomyhttps://clinicaltrials.gov/ct2/show/NCT02203695?term=high+risk+prostate+cancer&state1=NA%3AUS%3AMD&rank=14
3. A Pre-surgical Study of LDE225 in Men With High-risk Localized Prostate Cancerhttps://clinicaltrials.gov/ct2/show/NCT02111187?term=high+risk+prostate+cancer&state1=NA%3AUS%3AMD&rank=6

This blog was written by Vinson Wang, Medical Student at the Johns Hopkins University School of Medicine.  Vinson recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Very High Risk Prostate Cancer" from which this blog is inspired. Vinson is looking forward to a career in urology.











References:

1. Mohler JL, Kantoff PW, Armstrong AJ, et al. Prostate cancer, version 2.2014. J Natl Compr Canc Netw. 2014;12(5):686–718.
2. Gerber GS, Thisted RA, Chodak GW, Schroder FH, Frohmuller HG, Scardino PT, et al. Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis. EurUrol 1997;32:385-90.
3. Loeb S, Schaeffer EM, Trock BJ, Epstein JI, Humphreys EB,Walsh PC. What are the outcomes of radical prostatectomy for high-risk prostate cancer? Urology 2010;76:710-4.
4. Zwergel U, Suttmann H, Schroeder T, Siemer S, Wullich B, Kamradt J, et al. Outcome of prostate cancer patients with initial PSA> or =20 ng/ml undergoing radical prostatectomy. EurUrol 2007;52:1058-65.
5. Spahn M, Joniau S, Gontero P, Fieuws S, Marchioro G, Tombal B, et al. Outcome predictors of radical prostatectomy in patients with prostate-specific antigen greater than 20 ng/ml: a European multi-institutional study of 712 patients. EurUrol 2010;58:1-7.
6. Cooperberg MR, Cowan J, Broering JM, Carroll PR. High-risk prostate cancer in the United States, 1990-2007. World J Urol. 2008;13:211–218. doi: 10.1007/s00345-008-0250-7. 
7. Pierorazio P.M., Guzzo T.J., Han M., Bivalacqua T.J., Epstein J.I., Schaeffer E.M., Schoenberg M., Walsh P.C., Partin A.W. Long-term survival after radical prostatectomy for men with high Gleason sum in pathologic specimen. Urology. 2010;76:715–721.
8. Sundi D, Wang VM, Pierorazio PM, Han M, Bivalacqua TJ, Ball MW, Antonarakis ES, Partin AW, Schaeffer EM, Ross AE. Very-high-risk localized prostate cancer: definition and outcomes.Prostate Cancer Prostatic Dis. 2014 Mar;17(1):57-63.