Analyses of
prostate cancer radiation-response have suggested a high sensitivity to
increased fractional doses; in other words, a low alpha-beta ratio in the
linear-quadratic model. Assuming this “LQ” model, higher effective doses to the
cancer (“Biologically-equivalent dose”, or BED)—with a higher therapeutic
ratio—would be achieved by increasing the fraction size, and decreasing the
total dose.
High Dose-Rate (HDR) brachytherapy (“brachy”)—as “boost” to external beam
radiotherapy (EBRT)—has been a widely-employed standard of care for some groups
of men in some centres since the late 1990s. Consequent to the insight on
prostate cancer radio-sensitivity, there have been multiple reports of large
numbers of men treated with increasingly high HDR brachy doses per fraction,
and fewer numbers of fractions. Most of these reports have been single-arm
series reporting increasing doses, but at least two randomised trials comparing
brachy combined with external beam, with “equivalent” doses of EBRT alone, have
favoured the brachy “boosts”. Typical reported doses given in combination with
EBRT increased from ranges such as four-times 5 Gy, or three-times 6 Gy, to
two-times 9.5–15 Gy. Single fractions of 12.5–15 Gy in combination with EBRT
have become the standard HDR boost dose in randomised trials (RTOG 0924 and
1115).
Increasingly, the EBRT component of the the “EBRT and HDR boost” has been
dropped in favour of higher fractional doses given as HDR brachy “monotherapy”.
Recently this has been taken to the logical extreme of administering prostate
HDR brachytherapy in single fractions of 19–21.5 Gy.
The cancer control in series reporting the outcomes from the large numbers of
men treated in the non-comparative series of HDR-and-EBRT combinations—with
long term followup (up to ten years)—has been encouraging: around 95% for
low-risk men, 90% for intermediate risk and 80% for high-risk. Non-randomised
comparative data also supports the conclusion that disease-control with HDR
boosts might provide better control rates than EBRT alone, or even surgery, in
at least men with high-grade disease.
Similarly, non-comparative reports of fractionated HDR monotherapy for prostate
cancer have also suggested high rates of biochemical control for dose
fractionated schemes such as eight-times 6 Gy, six-times 7 Gy, four-times
8.5–9.5 Gy, three-times 10.5–15 Gy, and two-times 12–13.5 Gy. In contrast a
well-conducted randomised Canadian study reported on the
comparison of a single fraction of 19 Gy (that would be expected—on the basis
of linear-quadratic modelling—to be an iso-effective dose) to the other trial
arm of 27 Gy in two fractions. This study showed inferior disease control
results for the 19 Gy arm. Retrospective series from the United States and from
Spain have also reported biochemical-control results at three- and six-years
for low- and intermediate-risk groups of men treated with 19 Gy as a single
fraction were lower than would be anticipated from reports of other HDR fractionation
schemes.
HDR brachytherapy with decreased fraction numbers (and without external beam)
is convenient for men, especially at the limit of single fractions. In short
term follow-up of many prostate HDR-brachytherapy series, the treatments seem
to be well-tolerated with low rates of acute complications. Late rectal and
urethral injuries continue to occur more than a decade after treatment, and can
be hard to accurately discern without disciplined and standardised followup.
Some series report higher rates of late complications such as urethral
strictures with long-term followup of HDR fractionation schemes with lower
doses per fraction in series longer followup. Late complications from
higher dose-per-fraction schedules and few or single fractions might become
manifest in the next decade as they evolve and are reported.
Dose-fractionation fundamentally affects prostate cancer control rates and the
likelihood of side-effects. HDR brachytherapy treatments with doses such as 15
Gy in one fraction in combination with external beam seems effective and well
tolerated. Fractionated HDR brachy monotherapy seems promising on relatively
short-term followup, but the clinical outcomes from single fraction HDR
monotherapy suggest doses higher than 19 Gy are required and seem discordant
from what would be expected from simple LQ models. Better understanding of
optimal HDR fractionation schedules, of the underlying radiobiological
mechanisms, and their place in relation to other radiation or surgical
treatments will rely on long-term followup of well-designed randomised
comparative trials.
In a wider sense, the continued benefit of brachy for patients with prostate
cancer relies on clinicians being able to give at least one fraction.This
fraction matters.