Over the years, several randomized trials have shown the benefit of combining androgen deprivation therapy (ADT) with radiation therapy (RT) for the first- and second-line treatment of men with prostate cancer. However, new data from the William Beaumont Hospital in Michigan is now questioning whether adjuvant ADT actually has the same level of benefit in first-line therapy of men with intermediate- and high-risk disease treated with dose-escalated radiotherapy (RT).
The study from Krauss et al. is “only” a retrospective analysis, but it offers some intriguing suggestions.
Between 1991 to 2004, Krauss et al. report that a total of 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. The intermediate-risk patients had a Gleason score of 7, a PSA level of 10.0-19.9 ng/ml, or clinical stage T2b/c. The high-risk patients had a Gleason score of 8-10, a PSA level ≥ 20, or clinical stage T3. In addition, the authors were able to categorize the patients by Gleason score alone, by the presence (or absence) of palpable disease, and by PSA level to further define subgroups potentially benefiting from ADT.
The results of their analysis showed the following:
Median follow-up was 5 years.
420 patients received ADT + dose-escalated RT.
624 patients received dose-escalated RT alone.
When all patients were considered as a single group, there were no identifiable advantages in any clinical endpoints associated with ADT at 8 years.
When patients were considered based on their risk group (intermediate risk or high risk) or on the type of radiation therapy received, there were also no identifiable advantages in any clinical endpoints associated with ADT.
Patients with palpable disease and a Gleason score of 8 or higher had a lower clinical failure rate and a trend toward improved survival when they also received ADT.
Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was administered.
The authors conclude that the benefits of ADT in the setting of dose-escalated RT remain poorly defined, and go on to suggest that more clinical trials are needed to address this issue.
So how can multiple randomized clinical trials show a real survival benefit for the combination of RT and ADT but this study suggest only a minimal advantage?
Obviously, one of the issues here relates to stage shifting over time and the increasing accuracy and quality of radiation therapy between the early 1990s and 2004. Most of the major randomized trials that explored the potential of adding hormone therapy to RT were planned and initiated as long ago as the late 1980s. Many of the men in these trials had palpable, locally advanced disease (stage T3) and were treated with relatively low doses of radiation compared to those used today. The data from Beaumont Hospital includes such patients but their overall database also includes patients with forms of prostate cancer that were potentially less advanced (even though they still had intermediate- or high-risk disease).
The “New” Prostate Cancer InfoLink has long been concerned about the over-use of ADT including the long-term use of adjuvant ADT in men undergoing RT for potentially localized disease. It is already clear that the 3 years of adjuvant ADT originally used in the trial conducted by Bolla and his colleagues is probably “overkill,” and that much briefer periods of adjuvant hormone therapy are possible and appropriate. The data published by Krauss et al. throw a further spanner into the works. It seems to us that there are no longer any clear data on best practices when it comes to the addition of hormone therapy to radiation treatment. Unanswered questions seem to include:
Who really needs it?
What is the real clinical benefit by patient type?
Is there really a survival benefit for men diagnosed today with much less bulky disease that in the past?
If there is a benefit (in definable patient types), how long does hormone therapy need to be given to gain that benefit?
At the very least, it would be interesting to see a similar retrospective analysis of radiotherapy data from another major radiotherapy center over a similar time period. Another center might be able to demonstrate quite different outcomes.
One of the other complications to all of this relates to another great unanswered question, which is whether early hormone therapy in itself really offers a survival benefit to men diagnosed with locally or regionally advanced disease (clinical stage T3 and/or node-positive disease). We still have only a modicum of data suggesting that this is the case.