Radiation therapy, neoadjuvant ADT, and initial PSA response

New data from Zelefsky and his colleagues at Memorial Sloan-Kettering Cancer Center suggest that men who respond well to neoadjuvant androgen deprivation therapy (ADT) have better long-term outcomes after radiation therapy given with curative intent for localized prostate cancer.

What Zelefsky et al. wanted to study was whether their patients’ responses to a short course of neoadjuvant ADT prior to external beam radiation therapy (EBRT) were associated with improved survival and other outcomes after EBRT.

To do this, they looked at data from their institution on 1,046 men, all diagnosed with localized prostate cancer, who were treated with definitive EBRT in conjunction with neoadjuvant and concurrent ADT. The patients were all given a total of 6 months of ADT (3 months during the neoadjuvant phase and 2 to 3 months concurrently with EBRT). Becaus this study includes men who were initially treated several years ago, the vast majority were treated with conformal types of EBRT.

Here are the study findings:

  • The average (median) patient follow-up was 8.5 years.
  • The median dose of radiuation administered per patient was 81 Gy.
  • The actuarial, biochemical relapse-free survival outcome at 10 years was
    • 74.3 percent for patients with pre-EBRT PSA nadirs after 3 months of ADT of ≤0.3 ng/ml
    • 57.7 percent for patients with higher pre-EBRT PSA nadir values
    • This difference was statistically significant (P < 0.001).
  • The actuarial, distant metastases-free survival outcome at 10 years was
    • 81.6 percent for patients with pre-EBRT PSA nadirs after 3 months of ADT of ≤0.3 ng/ml
    • 78.6 percent for patients with higher pre-EBRT PSA nadir values
    • This difference was smaller but was still statistically significant (P < 0.004).
  • There was also a difference in risk for prostate cancer-specific mortality, at
    • 7.8 percent for patients with pre-EBRT PSA nadirs after 3 months of ADT of ≤0.3 ng/ml
    • 13.7 percent for patients with higher pre-EBRT PSA nadir values
    • This difference was again statistically significant (P < 0.009).

The authors conclude that “the pre-EBRT PSA nadir value was a significant predictor of long-term biochemical tumor control, distant metastases-free survival, and cause-specific survival outcomes.” They also note that “Patients with higher nadir values may require alternative adjuvant therapies to improve outcomes.” In other words, such patients may need to stay on ADT or some other form of adjuvant therapy after the initial rdaiation therapy and 6 months of ADT. It is possible that this may depend on the nadir PSA level and the stability of that PSA level after completion of the initial therapy, but the authors do not address that issue in thsi report.

This paper should not be taken to imply that all  men receiving EBRT (or any other type of radiation therapy for that matter) as first-line treatment for localized prostate cancer need to have neoadjuvant short-term ADT. On the other hand, it does appear to show that for those men who are given ADT, a PSA that drops to 0.3 ng/ml or below before they start their radiation therapy is a good signal for a postive long-term outcome.

5 Responses

  1. Thanks for this particular review as it is relevant to my current situation, providing further confirmation that I still have a higher risk case. (It took me about 7 months to reach 0.3, and that after completing radiation. Still, my current pattern is better than I have achieved on three previous rounds of triple ADT without other therapy.)

    My impression is that research has indicated that, for high-risk cases at least, 2 years of supportive ADT is generally superior to 6 months, though one study suggested that results after 18 months of ADT were about the same as those for 2 years. This paper, using a dose at the upper end of current dosing (~78-81 Gy as I understand it), but not as well targeted as with today’s state-of-the-art technology, with good median follow-up of 8.5 years that is well beyond the informative 5-year point for radiation, spotlights the 3-month nadir as a likely key point for navigating the length of ADT needed beyond the 6-month point, if any. My impression is that patients with low-risk cases probably do not benefit much if at all from ADT.

    What an important clue that 3-month nadir may be! In conjunction with the usual risk parameters (PSA, Gleason, stage, perhaps others), that added clue could considerably clarify the length of adjuvant ADT needed.

    I am curious why the abstract did not relate results to the standard risk levels, and I’m wondering if such stratification was done in the paper itself. The only clue about risk in the abstract is that these patients all had localized cancer. First author Dr. Zelefsky is very well known as a leader in radiation and prostate cancer radiation research, and other authors of the paper are also well published in the field, with a lot of their work related to success in the context of risk level, and indeed advancing insights into risk level. Any thoughts or answers about the paper’s treatment of risk levels in conjunction with the nadir?

  2. Jim:

    I can’t really add anything without reading the entire paper, and I don’t have access to this on line myself.

  3. Does this mean that ADT response is a proxy for radiation response? That ADT response indicates a tumor that is outside-of-field? Can one predict radio response from ADT response, regardless of dose and type of radiation? Should radiation field/type/dose be determined by ADT response? As Jim asks, might G score predict everything in the paper without reference to ADT?

  4. I would be extremely surprised if any of this was shown to be the case. What I believe this study shows is only that, in men who are candidates for the combination of neoadjuvant and adjuvant ADT followed by EBRT, the initial response to the ADT allows physicians and their patients to have a better appreciation of whether ADT might need to be continued for more than 6 months in total.

    Now it is certainly true that the Gleason score is one of the factors relevant to whether the patients did or did not need neoadjuvant and adjuvant ADT, and as yet we have seen no data on the range of Gleason scores, PSA levels, and clinical stages of the patients encompassed by this study, but I do not think that Gleason score is likely to be predictive of everything in this paper “without reference to ADT.” We know well that some men have high-risk localized prostate cancer even though they only have a Gleason score of 6 on biopsy … because they have a PSA > 20 ng/ml, or they have T3b or T4 or N+ disease (or both).

  5. It certainly would help to know the actual status of patients prescribed ADT as a prelude to EBRT, since this question is often brought up as to whether or not ADT should be adjuvant therapy, when, and how long.

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