Sunday, August 28, 2016

The optimal brachytherapy ADT pre-treatment for intermediate risk patients depends on whether they are “favorable” or “unfavorable.”

Anthony D’Amico has been advocating breaking up the intermediate risk category into “favorable” and “unfavorable,” and now offers yet another circumstance where the optimal treatment is different for each of the two groups, this time with brachytherapy.

First, let’s get clear about his definitions. He starts with the current NCCN definition of intermediate risk:
  • Clinical stage T2b or T2c, or
  • A PSA level of 10 to 20 ng/ml, or
  • A Gleason score of 7
(If multiple risk factors are present in a specific patient, the clinician may optionally deem such a patient to be high risk.)

D’Amico advocates for the intermediate-risk sub-grouping proposed last year by Zumsteg et al. (from the Memorial Sloan-Kettering Cancer Center):

Favorable Intermediate Risk:
  • NCCN intermediate risk, as defined above, but only those with
  • Predominant Gleason grade 3 (i.e., Gleason score 3 + 4 = 7), and
  • Percentage of positive biopsy cores < 50%, and
  • No more than one NCCN intermediate risk factor

Unfavorable Intermediate Risk:
  • NCCN intermediate risk, as defined above, plus
  • Predominant Gleason grade 4 (i.e., Gleason score 4 + 3 = 7), or
  • Percentage of positive biopsy cores ≥ 50%, or
  • Multiple NCCN intermediate risk factors

Keane et al. did a retrospective study using the dataset at Harvard of intermediate risk men treated with brachytherapy between 1997 and 2013. In that cohort, 1,902 fell into the “favorable intermediate risk” category, and 608 fell into the “unfavorable intermediate risk” category. After a median 7.8 years of follow-up, there 29 deaths attributable to prostate cancer. They found that:
·      Among “favorable intermediate risk” patients, there was no significant difference in prostate cancer mortality due to using ADT before brachytherapy vs, brachytherapy alone.
·      Among “unfavorable intermediate risk” patients, there was a significant decrease in prostate cancer mortality if they were pre-treated with ADT rather than if there was a combination therapy with external beam radiation (adjusted hazard ratio=0.34)

The authors conclude:
Neoadjuvant ADT does not appear to reduce PCSM risk in men undergoing brachytherapy for favorable intermediate-risk PC and should not be considered a standard; however, it appears superior to neoadjuvant RT in men with unfavorable intermediate-risk PC undergoing brachytherapy, making neoadjuvant ADT and brachytherapy a preferred option in these men.”

There are a few of important caveats:
·      This was a retrospective database analysis and not a randomized clinical trial, so the conclusions must be taken as provisional. This analysis is especially prone to selection bias: patients were chosen for their treatment based on an assessment of its probability of success.
·      There were only 29 deaths from prostate cancer in the follow-up period, so it is difficult to project what might have happened as the patients were tracked longer.
·      This study did not include a subgroup treated with all three therapies – early ADT and external beam RT and a brachytherapy boost. We saw in the ASCENDE-RT trial that that triple combination was very potent.

In spite of those caveats, there is nevertheless evidence of something very interesting happening here – the two subgroups that we had previously been treating equivalently respond, in fact, to very different treatment protocols.

We have seen in earlier studies (Castle et al. and Edelman et al.) that ADT confers no benefit when added to external beam radiation treatment unless the Gleason score is at least 4+3 or there is a large volume of cancer. This study provides evidence that that is also true for brachytherapy.

Unfavorable intermediate risk prostate cancer, on the other hand, seems to respond very well to the addition of ADT to brachytherapy. There is a randomized clinical trial (RTOG 0815) designed to determine if there is a benefit to adding ADT to dose-escalated external beam RT for intermediate risk patients as a whole, and sub-group analyses for unfavorable intermediate risk patients if there is a specific benefit. Zumsteg et al. demonstrated a benefit in a retrospective analysis.

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