A new review published recently in the British Journal of Cancer addresses appropriate current practice regarding the use of neoadjuvant and adjuvant androgen deprivation therapy (ADT) in combination with radiation therapy in the management of patients with high-risk localized and locally advanced forms of prostate cancer.
Payne and Mason begin by noting the historic role of ADT in the treatment of advanced and metastatic forms of prostate cancer. However, over the past 20 years there has been increasing evidence to support the combination of ADT with various forms of radiation therapy for the treatment of localized and locally advanced prostate cancer. These uses of ADT in combination with radiation therapy include:
- The use of ADT for as little as a month prior to brachytherapy (neoadjuvant ADT) to simply shrink large prostates down to about 45 cm3 or smaller, and thus increase the effectiveness and safety of brachytherapy
- The use of ADT before external beam radiation therapy (neoadjuvant ADT) to improve rates of biochemical recurrence-free survival in men receiving external beam radiation therapy as first-line treatment for (usually intermediate- and high-risk forms of) localized prostate cancer
- The use of ADT before, during, and after external beam radiation therapy (neoadjuvant and adjuvant ADT) to improve rates of biochemical recurrence-free and overall survival in men receiving external beam radiation therapy for locally advanced forms of prostate cancer
- The use of ADT before, during, and after external beam radiation therapy (neoadjuvant and adjuvant ADT) to improve rates of biochemical recurrence-free and overall survival in men receiving external beam radiation as salvage therapy after prior failure of other forms of first-line therapy (e.g., radical prostatectomy)
Indeed, there are multiple ways in which ADT can now be combined with radiation therapy to treat a wide range of men with prostate cancer at various stages in its progression — and there are many forms of ADT that can now be used in such treatment strategies.
The full text of this review article is not easily accessible on line, but Payne has provided a little more information from the paper in a “Beyond the Abstract” commentary on the UroToday web site.
Like many radiation oncologists, Payne now considers that, “The use of neoadjuvant or adjuvant … ADT … in combination with radiotherapy … is now … the standard of care in patients with high-risk localized or locally advanced prostate cancer.” Others might debate that under selected circumstances, but it is certainly the case that combinations of radiotherapy and ADT are highly appropriate treatment options for a wide variety of men with higher-risk and locally advancing forms of prostate cancer today. The hard thing is selecting the very best combination if a combination is appropriate and minimizing any risk from the side effects of ADT wherever possible.
As yet unanswered questions identified by Payne in addressing the most appropriate uses for combinations of ADT with radiation therapy include the following:
- How do we select the most appropriate patients for neoadjuvant or adjuvant ADT, given that there is no universally accepted definition of high risk or, indeed, locally advanced disease?
- When should adjuvant therapy be started and for how long should it be continued?
- Should neoadjuvant and adjuvant therapy be used in combination?
- How should we be thinking about combining newer hormonal agents (abiraterone acetate, orteronel, and MDV3100) with radiation therapy in appropriately selected patients?
The original article by Payne and Mason includes a full discussion on the many combination trials from which we now have long-term data, such as RTOG 86-10, TROG 96.01, RTOG 85-31, EORTC 22863, RTOG 92-02, SPGC-7/SFUO-3, and PR3/PR07. For this reason alone, this may be a good reason for support group leaders to track down a full-text copy of this review.
There are good clinical reasons for continuing to look hard at the potential for combinations of radiation therapy and ADT in the management of localized and locally advanced forms of prostate cancer:
- We know that ADT can reduce prostate size, allowing greater focus of radiation therapy.
- We know that modern forms of radiation therapy can be delivered with very high accuracy (compared to even the late 1990s).
- We know that ADT can significantly impact the micrometastases associated with high-risk and locally advanced disease.
- We know that the LHRH antagonist degarelix can lower PSA and testosterone levels faster than the LHRH agonists.
- We know that under certain circumstances the combination of ADT with radiation therapy can significantly extend disease-specific and overall survival.
The critical question is going to be whether greater sophistication in the use of various combinations of radiation therapy and ADT can show greater benefits in delaying biochemical progression, delaying the onset of metastasis, and delaying the need for chemotherapy. Such progress certainly ought to lead to further extensions in disease-specific and overall survival.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: "high risk", ADT, androgen deprivation, localized, locally advanced, outcomes, radiation therapy, survival |
THE "NEW" PROSTATE CANCER INFOLINK 
My high-risk case was pretty complex. I got neoadjuvant ADT (Zoladex, with Casodex for part of the time), two rounds of HDR brachytherapy, and 3D-EBRT (I cannot remember how many times), with concurrent Zoladex. In June I shall get the last 12-week shot of Zoladex, for 3 years of adjuvant ADT. The text you summarize strengthens my conviction that I got the most agressive current treatment. An added benefit, I think, was that my biopsy stage was either T2a or T2c , probably the former. Until I saw this post, almost everything I had read about the combination of radiotherapy and adjuvant ADT pertained to T3. I was told that this stage difference was an attempt to extend the good results involving T3 to the hopefully more tractable lower stage. I had no problem with accepting this.
The question that really interests me is the duration of neoadjuvant hormone therapy with radiation for high-risk, locally advanced disease.
When I went through treatment, the consensus was 18 to 36 months based on three or four different studies; however, there were no comparative studies to suggest the optimum period. More recently, I am seeing some of the UCSF doctors recommend 12 months or less to minimize co-morbidities, with the belief that benefits beyond 12 months are marginal. Any thoughts from this brains trust?
Rick:
I personally believe that more than 2 years of continuous neoadjuvant and adjuvant ADT in association with radiation in high-risk, locally advanced prostate cancer is probably unethical unless the patient is known to have significant node-positive disease today.
The precise “best practice” for men with lower levels of risk is frankly not known because there are still few definitive, directly comparative data.
The lack of comparative studies is precisely the problem. … I got nine 3-month shots; about half way through, the 3-year study came out so I e-mailed Mack Roach to ask whether I should be contemplating the longer period. He pointed out that there is little difference in the results between the various studies, so no way of knowing the optimum.
@Rick D. I am writing this in December 2013. One study I read about several days ago found no significant difference between 18 and 36 months of ADT, with EBRT. I don’t remember the details. The writers did mention that this result might be due to some unknown factor in the selection of patients. But this winds up by basically claiming that we still do not know which is best. I got 36 months and cannot tell if I am any better off than I’d be if I had gotten 18 months. In terms of my quality of life now, the main problem is cancer-related-fatigue. But little is known about that.
George:
Here’s a link to our original commentary on that study from just under a year ago.
Tx for responding.
Mike — if you want to send Berger my e-mail address so we can dialog directly rather than through the site, that is fine by me.
Wishing you and yours a happy holiday and healthy New Year.
rd
Dear Sitemaster,
I read that but forgot it. This is getting me curious, as I might be comparing apples with pears.
I did get three years of ADT, combined with EBRT, but with added HDR brachytherapy. The dose escalation was 20 Gy in two fractions, with an empty interval of 2 weeks. I don’t know the dosage of the EBRT, since my notes are unreadable. (I will ask about that in January.) I was told that this combination of values for dose escalation and ADT is pretty new. The latest result I could find on this trimodal therapy is dated 2011. That study used 2 years of ADT on high-risk patients but with a dose escalation of 19 Gy in four fractions The doctors here are familiar with this study. So my problems are these: what was the EBRT dosage, what was the effect of the slightly higher dose escalation and time interval (the LQ model has parameters for these), and most importantly, does the higher values for ADT and HDR induce any kind of advantage of three years over two? My guess is that the latter is unknown and that I’m part of some sort of experiment. I do not mind.
Rick:
George will have your e-mail address by the time you get up to open your presents this morning!
Hippy happy!
George:
What is going on here is that the radiotherapists around the world have been “playing” with a variety of combinations of different types of EBRT with or without diffferent types of brachytherapy and with or without ADT for various lengths of time. However, the quality of the studies that have been carried out (in terms of numbers of patients enrolled and rigor about the enrollment criteria) has varied; few of the studies have 10-year follow-up data; etc.
The objective, of course, is to identify a “best” combination for specific patient categories in terms of both long-term survival and minimal side effects. I don’t think there is clarity about any of this yet, and it is extremely difficult to compare data from the different trials with any great degree of confidence. Tony D’Amico from Harvard, who is often the commentator when data on this topic are presented at various conferences, has always taken the position that until there are 10-year follow-up data, we should be cautious about the over-interpretation of data from all these trials. I tend to agree with him, but I think it is clear that 3 years of ADT is now probably needed only in men with high-risk disease (along with whatever type of radiation is being used).
Thanks. I agree, given the papers I have seen. Many are explicit that 2 or 3 years of ADT should probably be used for high-risk patients at most. In fact, when I discussed this with a Dutch oncologist about 3 years ago, he said, “I hear 18 months is also OK.” He is a good, lively person who would not mislead me. I told him I was high risk.
At that time I did not follow this up, since I was more interested in HDR brachytherapy. Since then I have seen references to 6, 12, 18, 24, and 36 months. Since I am high risk, and realised that the total combination I got was one of a good number of possibilities, I didn’t mind the choice of 36 months. More importantly, I am at stage T2, probably T2c.
Now, when I moved to Sweden in January 2009, a paper by Anders Widmark et al. had just been placed on line. I was told that my treatment was partly inspired by the good results Prof. Widmark reported. His group examined only T3 cases (locally advanced), using ADT and EBRT, no HDR. That paper used a phrase like “continuous” to describe the ADT period. That got me curious, I asked what that meant, and was told “until death.” Today I doubt that this reply was accurate, since after all, the trial was terminated; I assume that some subjects completed treatment, before death. I then figured that the trimodal treatment with 3 years ADT and on me, at T2 with Gleason sum 4 + 4 and initial PSA 31 ng/ml, was a test to see if Widmark et al.’s good results could be improved upon when combined with HDR and used on high-risk T2 cases. I was told that I was right.
All this was well before I knew a thing about the confusing set of tests and articles (some had not yet been published). A bit less than 1 year ago, I showed one oncologist the latest paper I could find about trimodal therapies. That is the 2011 paper I mentioned above. Then I decided that the optimal interval for ADT is not only unknown but possibly in part dependent on the details of the total treatment. Especially since one paper found no advantage with ADT in similar settings at all! This explains the “problems” I mentioned above.