SBRT Dose Escalation

Is there an optimum treatment dose for SBRT? At the low end of the spectrum, Alan Katz found that 35Gy in 5 fractions gave equivalent oncological outcomes with less toxicity compared to 36.5 Gy. At the other end of the dose spectrum, a clinical trial pushed the dose as high as 50 Gy in 5 fractions with disastrous consequences (see this link).  A trial of high dose rate brachytherapy, which is radiologically similar to SBRT, failed to find an optimum dose.

But radiation safety is not only just about dose. We saw that two treatment schedules using the same prescribed dose (40 Gy in 5 fractions) had disparate toxicity outcomes (see this link). In fact, the 12 month toxicity outcomes of Dr. King's high-risk study were recently presented and look excellent (see this link). It's also worth noting once again the outcomes of the 5-year multi-institutional SBRT clinical trial that used 40 Gy in 5 fractions and had excellent oncological and toxicity outcomes (see this link).

Helou et al. reported the outcomes of their SBRT (they call it SABR, but it's the same thing) trials at the Sunnybrook Health Sciences Centre in Toronto, Canada. There were sequential trials conducted from 2006-2014:

• 35 Gy/5 fractions/29 days - 82 low risk men only
• 40 Gy/5 fractions/11 days or 29 days - 177 low and intermediate risk men

A few (12) men had up to 6 months of androgen deprivation to shrink their prostates prior to radiation.

As an early measure of oncological effectiveness, they used PSA at 3 years (PSA3Y) after radiation. After correcting for the other variables like age, baseline PSA, T stage, and ADT use, the dose received remained the biggest predictor of PSA3Y. Median PSA3Y was:

• 0.64 ng/ml in those who received 35 Gy
• 0.27 ng/ml in those who received 40 Gy
• The difference was significant in both low risk men and intermediate risk men

The use of PSA3Y as a surrogate endpoint for biochemical recurrence is controversial. Because prostate cancer progresses very slowly and radiation, at the very least, reduces the cancer burden, it can take at least 5 years, and as long as 10 years, before we start to see concrete evidence that such therapy is curative. Also, a longer time until the nadir is achieved has been found to be correlated with failure-free survival (see this link). Nadir PSA has been proven to be a strong predictor of a lasting cure (see this link), but no one can tell when the nadir will be reached. In a recent study comparing the PSA at 1000 days after SBRT or HDR brachytherapy to the PSA at 1000 days after conventional IMRT, Kishan et al. reported that the PSA was lower for SBRT/HDR-BT. While the downward slope was about the same for the first 1000 days, the slope was steeper afterwards for SBRT/HDR-BT, indicating that a lower nadir would be achieved.

After correcting for confounders like age, baseline urinary function, and time between treatments, late term urinary toxicity of grade 2 or higher was 17 times greater among those who received 40 Gy compared to those who received 35 Gy.

The authors previously reported late term rectal toxicity. After 2 years, the cumulative probability of  grade 2 or higher rectal toxicity was suffered among:

• 5% of the men who received 35 Gy with 4mm margins
• 27% of the men who received 40 Gy with 5 mm margins
• 42% of the men who received 40 Gy with 5 mm margins +  30 Gy to seminal vesicles received 

Grade 3 and 4 rectal toxicity was especially high (10%) in the group that had their seminal vesicles irradiated. There were 3 cases of fistulas that may be attributable to rectal biopsies. [Patients should be very careful about the use of any kind of instrumentation within at least 6 months of radiation. That includes cystoscopies and colonoscopies.] Since this study, the authors have changed their radiation planning to include faster (VMAT) linacs and improved rectal dose constraints. Other changes that might mitigate rectal toxicity may include use of intrafractional tracking, rectal immobilization, and a rectal spacer.

There was clearly a trade-off between SBRT dose and late-term side effects of treatments. Perhaps we will one day be able to identify those cancers that are curable with a lower dose, and treat only those with the more radio-resistant cancers with a higher dose. Some believe that such techniques as simultaneous integrated boosts or heterogeneous planning may cure the cancer in the prostate better with less damage to organs at risk. But they remain to be proved in randomized clinical trials.

Note: Thanks to Dr. Andrew Loblaw for allowing me to review the full text of the study.