Ask the Experts – Vinayak Muralidhar, MD

Expert Perspective
Subclassification of High-Risk Prostate Cancer Validated

Vinayak Muralidhar, MD

Practice Community: Boston

Hospital and Institutional Affiliations: Clinical Fellow in Medicine, Massachusetts General Hospital and Brigham and Women’s Hospital in Boston.

Practice Niche: Radiation Oncology

Dr Muralidhar is the senior author of a study validating the prognostic utility of a subclassification for high-risk prostate cancer. He and his colleagues compared a subgroup of men with favorable high-risk PCa (T1c with either a Gleason score of 4+4 = 8 and a PSA level below 10 ng/mL or a Gleason score of 6 and a PSA level greater than 20 ng/mL) with standard high-risk disease. Median follow-up was 5.7 years. The 8-year prostate cancer-specific mortality rate was significantly lower in patients with favorable high-risk disease than those with standard high-risk disease, but similar to that of patients who had intermediate-risk disease. Study findings were published online February 19, 2020 in Cancer. doi: 10.1002/cncr.32778

Question 1. Did your study reveal any unexpected findings?
In this study, we validated a previously developed subclassification of high-risk prostate cancer into favorable vs standard high-risk disease. Because prior studies had suggested that these groups have very different genomic characteristics and expected outcomes from each other, it was not unexpected that this sub-classification would be validated in this prospectively collected cohort of patients. In fact, the rate of death from prostate cancer at 8 years in the favorable high-risk subgroup in the present study was almost the same as in the initial study that defined this subgroup (2.2% risk of death in the current study compared to 2.1% in the original study). This confirmation of good outcomes in favorable high-risk prostate cancer is very reassuring.
Question 2. Your study found that patients with favorable high-risk disease had a PCSM rate similar to that of intermediate-risk patients. Should management for both groups be the same?
This is an important and difficult question. There are several differences in the management of intermediate-risk and high-risk prostate cancer, especially when using radiation therapy. Our results are very encouraging that patients with favorable high-risk prostate cancer may have similar outcomes to patients with intermediate-risk prostate cancer. However, before we can safely de-escalate treatment for men with favorable high-risk prostate cancer, I think we still need better risk stratification tools which incorporate genomic information and we need to perform non-inferiority randomized clinical trials to test the different management options against each other.
Question 3. Do you recommend a different therapeutic course for men with favorable vs standard high-risk PCa? If so, what is your practice in these cases?
This is another great question. Currently, national guidelines do not make a distinction between favorable and standard high-risk disease. However, there is a lot of variation in how patients with high-risk prostate cancer are managed. For example, when primarily being managed with external beam radiation therapy, the duration of androgen deprivation therapy varies widely across the country and the use of brachytherapy boost also varies widely. While our study does not directly address which therapies should be used in which subsets of patients, the fact that patients with standard high-risk disease have much worse outcomes raises the possibility that those are not the patients where you would want to use shorter durations of ADT or omit a brachytherapy boost.
Question 4. Is the difference in PCSM between favorable and standard high-risk disease reflected in the new Grade Group classification system?
There is not a direct relationship between the difference in PCSM among the subsets of high-risk disease and the new Gleason Grade Group system. However, as you might expect, patients in lower grade groups have lower rates of PCSM. Patients with favorable high-risk disease were defined as those with T1c (non-palpable disease) in Gleason Group 1 (if they had PSA > 20 ng/mL) or Gleason group 4 (if they had PSA < 10 ng/mL). Compared to standard high-risk disease, which is mostly comprised of Gleason groups 4 and 5, patients with favorable high-risk disease have better outcomes.
Question 5. Is the subclassification of high-risk PCa in use at your institution?
Yes, at least some of the physicians at my institution consider this subclassification when it comes up to help think about the patient’s prognosis and the possibility of treatment de-intensification. Prostate cancer treatment can have significant side effects, and having an accurate prognosis is important when counseling a patient about the possible risks and benefits of the various treatment options.


  1. Butler SS, Dee EC, Lamba N, et al. Validation of a subclassification for high-risk prostate cancer in a prospective cohort [published online February 19, 2020]. Cancer. doi: 10.1002/cncr.32778