EBRT works better with ADT for intermediate- and high-risk prostate cancer


The EORTC trial 22991 was designed and implemented to compare external beam radiation therapy (EBRT) + short-term androgen deprivation therapy (ADT) to EBRT alone as first-line therapy in patients with intermediate- and high-risk prostate cancer. The preliminary results of this trial were presented by Bolla et al. at the 2016 Genitourinary Cancers Symposium (abstract no. 22; “EORTC trial 22991: results of a phase III study comparing 6 months of androgen suppression and irradiation versus irradiation alone for localized T1b-cT2aN0M0 prostate cancer”).

There were 819 patients enrolled in this European, multi-institutional study:

  • 407 received EBRT only; 403 received EBRT + 6 months of ADT
  • Radiation dose: 70, 74, or 78 Gy (at discretion of each institution)
  • Pelvic node radiation: at discretion of each institution
  • 75 percent of patients were intermediate risk; 25 percent were high risk

After a median follow-up of 7.2 years,

  • 5-year biochemical progression-free survival was 82.5 percent with the ADT, 69.3 percent without it.
  • Improvement was irrespective of radiation dose.
  • 5-year clinical progression-free survival was improved by 7.9 percentage points.
  • Late urinary toxicity was 5.9 percent with the ADT, 3.6 percent without it (not statistically significant)
  • Severe sexual function impairment was 27.0 percent with the ADT, 19.4 percent without it (statistically significant)
  • Symptoms of hormone treatment, sexual activity, and functioning were impaired at 6 months with ADT, but there was no difference at 2 years.

The authors conclude that:

The addition of 6 months of medical castration to primary irradiation improves bPFS and PFS in intermediate- and high-risk localized T1b-cT2aN0M0 prostatic carcinoma with no persistent detriment on HRQoL or sexual function.

Unfortunately, this preliminary report doesn’t break out the intermediate- and high-risk men separately.

We have previously commented on the DART 01/05 clinical trial, which proved that, at escalated radiation doses, long-term androgen suppression (for 28 months) improved cancer control better than short-term suppression (4 months), at least for high-risk men. The benefit of a longer duration of ADT was not established for intermediate-risk men at 5-year follow-up.

Nabid et al. focused on intermediate-risk men and found a clear benefit to adding 6 months of ADT rather than none (after 10 years of follow-up).

It now seems clear that short-term androgen suppression improves results in intermediate-risk men, while longer androgen suppression is necessary in high-risk men. It would be helpful to know whether the improvement in intermediate-risk men was only among the subgroup classified as “unfavorable intermediate risk.” ADT seems to have a more powerful effect than radiation dose, but it is unclear if that effect is maintained with therapies like stereotactic body radiation therapy (SBRT) and brachytherapy boost that treat with much higher biologically effective doses. We are getting closer to defining an optimal duration of adjuvant ADT by risk level, and future trials using genetic classification data may provide better definition.

Editorial comment: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

5 Responses

  1. Very good efficacy results, even for radiation with older technology

    Allen (and Sitemaster),

    Thank you very much for drawing attention to this important abstract. I was immediately interested when I noticed that Dr. Michael Bolla was the lead author as he has been so involved in important research on radiation for prostate cancer for many years. I’ll post about that separately.

    The efficacy overall results for this group of intermediate- and high-risk prostate cancer patients are impressive, as you reported, for the combined ADT + EBRT radiation group: 5-year biochemical progression-free survival at 82.5 percent, which is 13.2% points better than the non-ADT group. That’s notable as 5 years is long enough to see much of the recurrence picture in some radiation series that have been reported. Indeed, I find it extraordinary in view of the fact that rather obsolete technology was used for most men.

    There have not been many published papers on this trial, but one of them breaks down the numbers of patients getting various doses and types of radiation (3D-CRT vs. IMRT). Here’s a quotation from the abstract:

    “Of 791 patients (vs. 810 in subject abstract #22), 652 received 3D-CRT (70 Gy: 195, 74 Gy: 376, 78 Gy: 81) and 139 received IMRT (74 Gy: 28, 78 Gy: 111).”

    It is clear that most fell well short of the 78 Gy considered as the lower end of the optimal range these days, not to mention that the vast majority received 3D-CRT instead of the IMRT preferred today. There is no doubt that few if any of them benefited from the advanced imaging and target movement control technologies that are common today.

    I hope the paper that will flow from this abstract will give good breakdowns of some important data groups. It would really help to see breakdown by dose, type of EBRT (3D-CRT vs. IMRT), pelvic node, each separated by risk.

  2. Thanks Allen — couple of observations/ questions.

    (1) The abstract does not report incidence of gastrointestinal side effects (bowel, rectal, etc.). … Do you have any more information?

    (2) I also wonder about the optimal ADT period for intermediate- vs high-risk men. Lumping both categories in together does not tell us much about the high-risk men … as you state.

    An earlier Nabid study — PCS IV — indicates that 18 months is as good as 36 months, q.e.d., likely as good as 18 months for high-risk men?

    In this current study, men must all have been categorized as high-risk based on a PSA > 20 or a Gleason scor of > or = 4 + 4 — excluding T3 may make a difference to their recommendation for high-risk men.

    Onward and upwards,

    rd

  3. Extremely High Compliance with Randomized Assignment to Study Arm

    This and a related paper document that 819 patients were randomized to the two arms. Based on the nearly even balance of patients in the two arms, it appears that about 810 patients were in compliance with assignment. Of course it is possible that there were offsetting switches to a non-assigned arm.

    That’s impressive and bolsters confidence in the results!

  4. Side Effect Profile Appears Quite Tolerable for Most Despite Older Technology

    Based on abstract #22 reported here and an earlier paper on this trial about acute treatment side effects, it appears the side effects were rather mild for a a large majority of men despite the older technology used.

    I find that impressive.

  5. Rick D.,

    I’m assuming the reason they didn’t report late term GI toxicity is because there wasn’t any beyond Grade 2 to report. That’s not at all rare.

    On ADT duration … DART 01/05 showed that for high-risk patients, 28 months is better than 4 months with escalated dose levels, and as you said, 18 months is as good as 3 years, and that was even true at low dose levels (70 Gy). So I think 18 months seems like a reasonable minimum for high risk.

    For intermediate-risk, DART 01/05 showed that 28 months was no better than 4 months. And Nabid showed that 6 months was better than none. So something around 4 to 6 months seems appropriate, although my hypothesis is that will only turn out to be beneficial for unfavorable intermediate risk.

    Future randomized controlled trials will probably define it better, but we seem to be narrowing in on the appropriate range.

    Of course that should be adjusted for other risk factors and individual patient characteristics and preferences. And this only applies to conventional dose-rate IMRT.

    I agree that the present study only includes men clinically diagnosed with stage T1c or T2a, thereby excluding those with T2b and T2c, which NCCN would categorize as intermediate risk, and those with T3, which NCCN would categorize as high risk. Those stages are relatively rare at clinical diagnosis, but we don’t know by how much, if any, that might change conclusions for the NCCN risk groups.

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