A randomized clinical trial (RTOG 9910) published by Pisansky et al sought to answer the question of whether 28 weeks of pre-treatment androgen deprivation therapy (ADT) is better than 8 weeks of pre-treatment ADT in intermediate risk men receiving primary radiation therapy (RT) for prostate cancer. The goal was to achieve a 33% decrease in PC-related deaths after 10 years of follow up. The results, supporting shorter duration pre-treatment ADT, were presented at the 2013 ASTRO meeting and reported in the New Prostate Cancer Infolink. A similar randomized clinical trial, DART 01/05 presented at the 2014 ASTRO meeting, reached a similar finding when intermediate-risk men were treated with higher-dose radiation.
Now, Pisansky's peer-reviewed results have been published in the Journal of Clinical Oncology. What is especially interesting is Anthony D'Amico's accompanying editorial. Dr. D'Amico is well known for his risk stratification of prostate cancer into low, intermediate, and high-risk categories. He, along with the National Comprehensive Cancer Network (NCCN), have since modified their original categories to include very low risk, low risk, intermediate risk, high risk, and very high-risk categories. In the editorial, and in one last year, he makes the case for breaking up the intermediate-risk category into favorable intermediate-risk and unfavorable intermediate risk. He believes that the findings in such studies as Pisansky's may differ substantially between the two sub-categories. Favorable intermediate-risk patients possibly require no ADT and possibly lower dosing (similar to RT treatment for low-risk patients), while unfavorable intermediate-risk patients may respond more like high-risk patients to longer duration ADT coupled with higher doses of radiation.
The NCCN intermediate-risk group is currently defined as having any of the following:
- Stage T2b or T2c, or
- PSA 10- 20 ng/ml, or
- Gleason score = 7
(If multiple risk factors are present, the clinician may optionally deem it high risk)
D'Amico advocates the intermediate-risk subgrouping proposed by Zumsteg et al at Memorial Sloan Kettering (MSK) last year:
Unfavorable Intermediate Risk:
- NCCN intermediate risk, as defined above, plus
- Predominant Gleason grade 4 (i.e., Gleason score 4+3), or
- Percentage of positive biopsy cores≥ 50%, or
- Multiple NCCN intermediate-risk factors
Favorable Intermediate Risk:
- NCCN intermediate risk, as defined above, but only those with
- Predominant Gleason grade 3 (i.e., Gleason score 3+4), and
- Percentage of positive biopsy cores <50%, and
- No more than one NCCN intermediate risk factor
If the information on percentage of positive biopsy cores was collected, he would like to see a post-analysis with the new proposed subgroupings. He also calls for post-analysis of other studies among intermediate-risk men, like the recently completed RTOG 0126 trial of dose escalation, the ongoing RTOG 0815 trial of short term ADT with high dose RT, and the above-mentioned DART 01/05 trial of long-term vs short-term ADT with high dose RT.
Another drawback associated with the Pisansky study is that only doses of 70 Gy were used, whereas 80 Gy has better oncological outcomes. This was proven by RTOG 0126 presented in September, but had already been incorporated into standard-of-care practice by many clinicians based on earlier studies. It is often the case in long-term clinical trials of radiation therapies that the findings have become irrelevant by the time they are published owing to technological advances, and enhancements in our understanding of oncology. It may be that Zumsteg's proposed improvement in risk stratification may already be outdated by the growing use of multiparametric MRI-targeted biopsies -- is 50% positive biopsy cores still a useful cutoff point when more cores are taken in suspicious areas?
Dr. Klotz has argued that favorable intermediate-risk men also can safely choose Active Surveillance, given close monitoring with multiparametric MRI. With that inclusion, there really are no treatment choices that are different for low risk and favorable intermediate-risk men - Active Surveillance/Watchful Waiting (if life expectancy is low), RP, focal therapy, brachy monotherapy, SBRT, IMRT, or PBRT. Treatment choices for both unfavorable intermediate-risk and high-risk men are the same - brachy or PBRT boost therapy, SBRT, IMRT (all with adjuvant ADT), RP, or Watchful Waiting (if life expectancy is low). One could reasonably argue that only two risk categories are necessary - favorable risk or unfavorable risk. This binary distinction has been used in a number of clinical trials.
It is not necessary to have consensus on risk stratification. Indeed, even within the NCCN network, UCSF uses a CAPRA scoring system, and MSK uses Zumsteg's intermediate risk distinction. It is, however, useful to clinicians trying to apply the findings of such research studies to have a common terminology and to make distinctions where they might change treatment decisions. D'Amico's opinions on this subject carry a lot of weight.