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.
