UCLA Journal of Radiation Oncology APRIL 2023 - Flipbook - Page 15
UCLA RADIATION ONCOLOGY JOURNAL
However, the target dosing we sought to
employ in MIRAGE was more aggressive
than had been used in either of the
previous studies. Specifically, we planned
to deliver 40 Gy to the entire PTV, while the
PACE-B trial delivered 36.25 Gy to the PTV
and the Amsterdam trial delivered 36.25
Gy to the PTV but reduced the dose around
the urethra to 32.5 Gy. This escalated dose
was chosen because we anticipated that we
would treat patients with more aggressive
disease than those treated on these prior
studies, and our own research as well as
work from others have suggested a doseresponse with respect to biochemical
control after prostate SBRT.11 12
guided SBRT (22.4% vs. 47.1%, vs P = .01).15
It was concluded that 154 patients would
be needed to have a conditional power of
89% to detect the hypothesized difference
in toxicity, and therefore the trial was
closed to accrual early.
Importantly, however, all trials of doseescalation in prostate radiation oncology
have identified that an increase in dose
also leads to an increase in toxicity.13
Notably, toxicity following radiation
depends not only on the total dose of
radiation, but also the dose per fraction.
As such, the effective difference for the
bladder, urethra, and rectum between
the MIRAGE target dose and the earlier
doses ranges anywhere from 8 Gy to 14 Gy
depending on assumptions about tissue
radiosensitivity.
Of the 156 patients who received prostate
SBRT on the MIRAGE trial, only 19%
had favorable intermediate risk disease,
supporting our decision to treat to a higher
dose on this trial. With regards to other
relevant variables, 44% had placement of a
rectal hydrogel spacer, 24% received nodal
radiation, 26% received a simultaneous
integrated boost to the dominant lesion,
and 68% received hormonal therapy, with
no significant differences between arms
for any of these parameters.
We know from multiple studies of
radiation dose escalation that such large
increases in dose will lead to increased
toxicity.14 Therefore, we pre-specified that
after 100 patients were eligible for analysis,
we would perform an interim “futility”
analysis to assess conditional power and
re-estimate sample size. As it so happened,
by the time 100 patients were eligible for
this analysis (which occurred 90 days after
the 100th patient was treated), 156 patients
had already been enrolled and treated.
The analysis found that acute grade ≥2 GU
toxicity was significantly reduced in men
receiving MRI-guided SBRT versus CT15
While trials are always vulnerable to
the vicissitudes of fate and fortune, it
is important to underscore in this case
that the trial was closed because the
effect size observed on interim analysis
(24.7% absolute difference) exceeded the
hypothesized difference (14% absolute
difference), suggesting enough patients
had already been enrolled to detect the
superiority of MRI-guided SBRT.
Prior to randomization, we stratified
based on baseline International Prostate
Symptom Score (IPSS) and prostate gland
size, which are both known to impact posttreatment toxicity; these were thus also
balanced between arms.
Before discussing the results of the final
analysis, it is particularly important to
discuss blinding. Ideally, a randomized
trial would be double-blind to limit biases.
In this case, the interventions being
investigated were different enough (one
requiring an invasive procedure to place
fiducial markers, the other requiring
multiple MRIs) that patient blinding would
be impractical.