Risk category definitions, trial protocols, and clinical outcomes

Recent research data raise questions as to whether clinical trial protocols — and their results — are being skewed (notably for men with so-called “intermediate-risk” disease) by current definitions of risk category.

A randomized clinical trial (RTOG 9910), initiated in the year 2000, was designed to answer the question whether 28 weeks of pre-treatment with androgen deprivation therapy (ADT) is better than 8 weeks of pre-treatment with ADT in men with intermediate-risk prostate cancer receiving primary radiation therapy for prostate cancer. The goal was to achieve a 33 percent decrease in prostate cancer-related deaths after 10 years of follow up. The results, supporting a shorter duration of pre-treatment ADT, were initially presented at the 2013 ASTRO meeting and reported on The “New” Prostate Cancer Infolink at that time. A similar randomized clinical trial (the DART 01/05 trial), the results of which were presented by Zapatero et al. at the 2014 ASTRO meeting, reached a similar finding when intermediate-risk men were treated with higher-dose radiation therapy.

Now, the full, peer-reviewed results of the RTOG 9910 trial have been reported by Pisansky et al. in the Journal of Clinical Oncology. What is especially interesting is Dr. Anthony D’Amico’s accompanying editorial. Dr. D’Amico is well known for his original 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 this editorial, and in another editorial last year, D’Amico 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 the RTOG 9910 trial may differ substantially between the two sub-categories. Favorable intermediate-risk patients possibly require no ADT and only lower dosing (similar to radiation 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 including patients with any of the following characteristics:

  • Clinical stage T2b or T2c, or
  • A PSA level of 10 to 20 ng/ml, or
  • A Gleason score of 7

(If multiple risk factors are present in a specific patient, the clinician may optionally deem such a patient to be high risk.)

D’Amico advocates for the intermediate-risk subgrouping proposed last year by Zumsteg et al. (from the Memorial Sloan-Kettering Cancer Center):

Unfavorable Intermediate Risk:

  • NCCN intermediate risk, as defined above, plus
  • Predominant Gleason grade 4 (i.e., Gleason score 4 + 3 = 7), or
  • Percentage of positive biopsy cores ≥ 50 percent, 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 = 7), and
  • Percentage of positive biopsy cores < 50 percent, and
  • No more than one NCCN intermediate risk factor

If the information on percentage of positive biopsy cores was collected and is available for analysis, D’Amico would like to see a post-analysis of the data from the RTOG 9910 trial 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 radiation therapy, and the above-mentioned DART 01/05 trial of long-term vs short-term ADT with high-dose radiation therapy.

Another drawback associated with the RTOG 9910 study, as reported by Pisansky et al., is that only doses of 70 Gy were used, whereas 80 Gy has better oncological outcomes. This was proven by data from the RTOG 0126 trial, presented at the ASTRO meeting in September 2014, 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 (and other forms of treatment too) that the study 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 et al.’s proposed improvement in risk stratification is already outdated by the growing use of multiparametric MRI-targeted biopsies. For example, is 50 percent of positive biopsy cores still a useful cutoff point when more cores are taken in suspicious areas?

Dr. Laurence Klotz and his colleagues in Canada have argued that favorable intermediate-risk patients also can safely choose active surveillance as a management strategy, 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 patients — active surveillance, watchful waiting (if life expectancy is low), radical prostatectomy, focal therapy, brachytherapy alone, SBRT, IMRT, and PBRT are all reasonable choices. Treatment choices for both unfavorable intermediate-risk and high-risk men are also the same — brachytherapy or PBRT with boost radiation therapy, SBRT, IMRT (all with adjuvant ADT), radical prostatectomy, or watchful waiting (if life expectancy is low). One could reasonably argue that only two risk categories are really necessary — favorable risk and unfavorable risk. This binary distinction has, in fact, been used in a number of clinical trials.

It is not necessary to have consensus on risk stratification. Indeed, even within the NCCN network, the University of California at San Francisco uses the so-called CAPRA scoring system, and Memorial Sloan-Kettering Cancer Center now uses Zumsteg et al.’s intermediate-risk distinction. It is, however, useful for non-academic clinicians trying to apply the findings of such research studies to have a common terminology and to make clear distinctions about when and why they might (or perhaps should) change treatment decisions. D’Amico’s opinions on this subject are likely to carry a lot of weight.

Editorial note: The above commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink and includes minor editorial modifications by the sitemaster.

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