WCB 2021 - Online

Session Item

May 07
08:45 - 10:00
Single dose vs fractionated HDR monotherapy for prostate cancer
09:21 - 09:39
HDR prostate brachytherapy and fractionation; does it matter?
Jeremy Millar, Australia


HDR prostate brachytherapy and fractionation; does it matter?
Authors: Jeremy Millar(Central Clinical School , Monash University, Melbourne, Australia)
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Abstract Text

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.