A fly in the ointment of RT + adjuvant ADT


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.

13 Responses

  1. I plan to respond again, but I have some early questions/thoughts.

    The period of treatment for this retrospective study was 1991 – 2004, almost guaranteeing that a heavy proportion of EBRT patients were treated with the lower doses of EBRT radiation that are no longer considered adequate. Is there any information on that (wasn’t in the abstract)? If so, that would put this study head-to-head against the studies that did find a benefit, would it not, as Sitemaster notes that at least some of those studies showing a benefit used levels of radiation now judged inadequate.

    Current thinking seems to me to be that at two years of adjuvant hormonal therapy is best, rather than shorter periods, such as six months, which have been used in some studies. The abstract did not state a length or range of length of adjuvant ADT. Is this stated in the full paper?

    Regarding the last issue, I intend to post some thoughts on the survival value of ADT later.

  2. Since I don’t have access to the complete paper, I am not is a position to comment on most of these issues. However, I would not necessarily agree that there is compelling data regarding the need for 2 years of hormone therapy.

    It is my belief (based on the relative paucity of the comparative data) that the period of hormone therapy needs to be carefully customized to the clinical profile of the individual patient. There is still an art to medicine. Absolutes do not necessarily serve the best interest of the individual patient.

  3. To continue the sitemaster’s analogy, as long as your artist is Picasso, it’s fine to trust the artist. But if your artist primarily works in velvet and paints bull dogs playing poker, a reliable set of guidelines is pretty darned important.

  4. A concern I always have when ADT is prescribed either prior to, through, and beyond RT, or even just following RT, is that there is no period of determining if the RT had served sufficiently to have eradicated the cancer. Same applies when RP is administered, physician unsure he got it all because of prostate cancer to margins or extending into fatty tissue, and salvage EBRT is performed; again, accompanied by ADT. Despite Gleason score at diagnosis, when EBRT is prescribed either as monotherarapy or in company with brachytherapy seed implant, why subject the patient to ADT until the effectiveness of EBRT or EBRT/brachy has been determiend? It shouldn’t take long to determine by PSA and other diagnostics if either of these therapies has failed, and if so, THEN ADT could be administered, rather than subjecting the patient to the effects of ADT any sooner than absolutely necessary.

  5. Knowing the length and nature of the ADT is indeed key to knowing whether this is valuable information.

    In my personal case the fact that it included some HRT brachytherapy + EBRT cases may also give me some clues.

    I look forward to someone finding that out and letting us know.

  6. Similar research by Dr Demanes of California Endocurie. He and Martinez have done most of the work on this area. Both are HDR “advocates” if you will. Yes, these older studies likely have GY levels lower than today’s standards. Pretty good evidence that the higher levels have resulted in better cancer control, perhaps reducing any benefit of ADT.

    Bill

  7. Aloha,

    This was the route that was suggested to me in May 2007: start ADT, then, in 3 months, EBRT/IMRT, first month pelvic cavity, second month target the prostate using ultrasound guidance before each session. The ADT was Casodex for 2 weeks, then Lupron Depot for 3 years.

    I suspect that the ADT was intended to stop/shrink the tumor, then hit it with radiation. The ADT was difficult. I asked to stop after 1 year. By the third week of EBRT, I was in a lot of pain for both #1 and #2 toilet trips, which in 2 weeks had increased to 10+ per day.

    For me, at the time and even now, there did/does not seem to be any other way to treat this cancer. The #2 plumbing has shown very little healing since Sept 07. The #1 plumbing starting showing damage in Nov 09. Now it is a wait and see process, a very poor quality of life, with little hope that it will change for the better.

    The treatment in all probability did extend my life.

    Joe

  8. I am wondering if there are any studies comparing 1 year of neoadjuvant and adjuvant ADT to 2 years. Most studies I have seen compare 6 months or less with 2 years or more.

    I am coming up on a decision to continue ADT for a second year following IGRT-IMRT, 78 Gy. My doctors suggest there is a small benefit to the second year if tolerance for ADT is good.

  9. Dear Sam:

    There have been small studies that included data with only 1 year of neoadjuvant and adjuvant ADT, but none (that I am aware of) large enough to provide truly meaningful data. However, what I would tell you in general is that I agree with your doctors. The original studies using adjuvant/neoadjuvant ADT showed a statistically significant survival benefit at 3 years of ADT on top of the radiation for men with locally advanced forms of prostate cancer (clinical stage T2b/T3NxM0). Your potential benefits will depend on exactly why they decided to give you the ADT (your clinical stage, Gleason score, PSA, etc.).

    If you are having little trouble with the side effects of hormone therapy, you would likely improve your long-term outcome by staying on it for a second year. But … if you are having a hard time with the ADT, see if you can come to a compromise with the doctors at an additional 6 months for a total of 18 months. And … if you are having a really hard time with the ADT (i.e., it is really profoundly impacting your quality of life), then just tell the doctors that you can’t do any more unless they can show you a really substantial long-term survival benefit.

  10. Sam:

    This was my dilemma. The best information I found was in this article by Williams et al. (2010). The full article includes a nomogram which takes into account PSA, Gleason score, T stage, age, radiation dose, and ADT duration.

    I bought the full paper (around $30) and printed copies of the nomogram and filled them in with my details and varying the ADT length.

    If you are interested and can’t get a copy of the article, click here to send me an e-mail.

    Cheers

    Jim

  11. Just realized that I never thanked Sitemaster and Jim for their thoughtful replies. I did obtain the study with nomograms which indicated that 18 months would be essentially the same as 24 month for my diagnosis. I am coming up on shot time at 16 months and trying to decide whether to stop or get one 3-month shot or two 1-month shots or just discontinue. The stuff is getting more difficult to tolerate.

    Thanks again to both of you.

  12. Sam:

    Obviously your call on this one … but it seems to me that with one 3-month shot you can both call it quits and assure yourself you have done your best to cover the bases.

    Cheers

    Jim

  13. Thanks Jim. That’s the direction I’m leaning towards. The side effects are becoming cumulative though and starting to bother me more than before.

    Thanks again.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: