ADT + radiation vs. ADT alone in men with high-risk, localized prostate cancer

As we reported at the time, at the annual meeting of the American Society for Clinical Oncology, in June this year, Warde et al. presented the initial survival data from a large, multi-center trial of androgen deprivation therapy (ADT) + radiation compared to ADT alone for patients with high-risk, localized prostate cancer. Some additional data from this trial are to be presented at the upcoming annual meeting of the American Society for Radiation Oncology (to be held in San Diego). But the “hype” around the results of this study appears to be a little overblown.

The lead author of the study data to be presented in San Diego (Malcolm Mason, MD, a radiation oncologist at Cardiff University in Wales) is quoted on Medscape and in a media release from ASTRO as saying, “We feel that these results are practice-changing. The standard of treatment for patients with high-risk localized prostate cancer who are fit to receive radiation therapy — which is not every man — should now be combination hormone therapy plus radiation.”

The problem, in our view, is that first-line, long-term hormone therapy alone has not be considered an appropriate first-line therapy for high-risk patients with localized disease for years. It may arguably have been a valid option back in 1993 when this study was first initiated in the UK, Canada, and the USA, but even then there were indications that combining radiation with ADT or combining surgery with adjuvant radiation was a potentially better option, and few specialists would have considered ADT alone to be an appropriate form of care for the majority of men with high-risk, localized prostate cancer since the year 2000.

It is certainly true that the appropriate management of high-risk, localized prostate cancer is still a “hotly debated topic” and that “there is much variation in the treatment of men with localized high-risk prostate cancer.” However, the debate is now focused on issues such as whether to combine surgery with adjuvant radiation, or radiation with neoadjuvant ADT, or surgery with adjuvant radiation and neoadjuvant ADT, or to even to take advantage of some of the more recent forms of targeted therapy, in this group of patients, based on their precise clinical characteristics, their age, their comorbidities, and their personal comfort levels with the various possible options. Few patients who fall into the high-risk category would now be considered as appropriate for immediate, long-term ADT as first-line therapy, if for no other reason that intermittent ADT would appear to be a better choice if ADT had to be considered at all.

In this study, high-risk patients with localized prostate cancer were defined to include three groups of patients:

  • Those with clinical stage T3/T4 disease
  • Those with clinical stage T2 disease and a PSA level > 40 ng/ml
  • Those with clinical stage T2 disease and a PSA level> 20 ng/ml and a Gleason score of 8 to 10.

And here is what this study has and has not established, as of today:

  • It has confirmed for us that combining ADT with radiation therapy is more effective than ADT alone in the first-line treatment of patients meeting these criteria for high-risk, localized prostate cancer.
  • It has not, in any way, established long-term ADT + radiation therapy as the most appropriate form of treatment for men with high-risk, localized prostate cancer.
  • It has not established the appropriate dose of radiation to be used in combination with ADT in such patients (because the trial was designed long before techniques were available to deliver high-dose radiation of up to 80 Gy to the prostate).
  • It has not given us any additional insight into the length of time that such patients should be treated with hormone therapy (or whether they could be managed with intermittent ADT over some undefined time period).

To quote Dr. Anthony Zeitman, the president of ASTRO, we can also clearly agree that this study confirms that “[W]e really can help men with locally advanced disease. We shouldn’t regard them as just needing palliative treatment — they really can be cured.”

The fundamental problem with this study is that it has taken 17 years from initiation to reporting of the initial results of the trial. In those 17 years there have been major changes in  how we define high-risk, localized disease, and in the incidence of the type of patient who met the original definition of high-risk, localized disease adopted for this study. Other trials are starting to mature that have taken similarly long periods of time to give us results. It will be important for the prostate cancer community to interpret these data in an appropriate context, and not to “hype” results which would have been exciting 15 years ago but are merely of confirmatory significance today. “Practice changing” is not (in our view) an appropriate descriptor today for the results of this trial.

The full text of a helpful review article by Fang et al. dealing with the role of ADT in the management of patients with localized and locally advanced, high-risk prostate cancer appeared in the August issue of Oncology and is available on line. Fang and her colleagues also address the importance of the cardiovascular side effects of ADT.

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