SBRT: Optimal Dose

While excellent outcomes of stereotactic body radiation therapy (SBRT) have been reported since it was first used for prostate cancer in 2003, the delivered doses have ranged from 35 Gy in 5 treatments to 40 Gy in 5 treatments. We saw in a University of Texas Southwest (UTSW) study (see this link) that toxicity escalates when doses are greater than 45 Gy.

Memorial Sloan Kettering designed a clinical trial (described here) among low and intermediate-risk men. They started with about 35 men treated at 32.5 Gy and checked for dose-limiting toxicity. When most reached 6 months of follow-up, and fewer than 10% had dose-limiting toxicity, they increased the dose to the next group of 35 men by 2.5 Gy in 5 treatments. In all, they had 136 patients who were followed up for 5.9 yrs, 5.4 yrs, 4.1 yrs and 3.5 yrs with doses of 32.5 Gy, 35 Gy, and 37.5 Gy and 40 Gy, respectively.

Their toxicity and oncological outcomes are reported here and shown in the table below:

	Dose delivered in 5 treatments
	32.5 Gy	35.0 Gy	37.5 Gy	40.0 Gy
Acute toxicity
Urinary – grade 2	16.7%	22.9%	8.3%	17.1%
Rectal – grade 2	0%	2.9%	2.8%	11.4%
Late-term toxicity
Urinary – grade 2	23.3%	25.7%	27.8%	31.4% (1 grade 3 stricture)
Rectal – grade 2	0%	0%	0%	0%
Oncological outcomes
5-year PSA failure	15%	6%	0%	0%
2-year positive biopsy	47.6%	19.2%	16.7%	7.7%

Other than the one urinary stricture, there were no acute or late-term grade 3 (serious) toxicities.

Because follow-up decreased with increasing dose, it is unclear whether the zero biochemical failure rates for doses of 37.5 Gy and 40 Gy will be sustained, but in other studies, almost all SBRT failures had occurred within 5 years. The positive biopsy rates will probably continue to decline with longer follow-up because the non-viable cancer cells can take up to 5 years to clear out. Clearly, 32.5 Gy is too low because of its unacceptable oncological results.

A dose of 40 Gy in 5 treatments has very acceptable toxicity and excellent cancer control. It would be reasonable to use doses as low as 37.5 Gy in patients with insignificant amounts of low grade cancer (who would usually be excellent candidates for active surveillance). Based on the UTSW study, it would be reasonable to escalate the dose as high as 45 Gy in patients judged to have radioresistant cancers.

Optimal prostate dose is also discussed:

SBRT dose escalation trial at Sunnybrook 

SBRT dose escalation trial at UTSW

Potters et al. trial

The multi-factorial nature of SBRT safety

Why we should care about standards of care

Escalated radiation dose doesn't improve 8-year overall survival in intermediate-risk men (but does it matter?)

Survival benefit of dose escalation for higher-risk patients

Can surgery+radiation+ADT provide equal outcomes to brachy boost therapy +ADT in high risk men?

As we saw (see this link) among men with Gleason 9 or 10, brachy boost therapy (BBT: external beam radiation with a brachytherapy boost to the prostate) was shown to provide better oncological outcomes (10-year metastasis-free survival and 10-year prostate cancer-specific mortality (PCSM)) compared to surgery (RP) or external beam radiation (EBRT) alone. Some researchers argue that the comparison was unfair. In that study, 43% of the RP patients received adjuvant or salvage radiation, and virtually all of the BBT patients received 1 year of adjuvant ADT. What if ALL of the RP patients were to receive radiation and ADT?

Tilki et al. did a retrospective study to answer that question. They looked at two groups of Gleason 9/10 patients treated at two institutions between 1992 and 2013:

• 559 men received RP+pelvic lymph node dissection (PLND) at the Martini-Klinik Cancer Center in Hamburg
• 88 received adjuvant EBRT
• 49 received adjuvant ADT
• 50 received both (called MaxRP)
• Median ADT duration - 8.6 months in 49 men with negative lymph nodes
• Median ADT duration - 14.5 months in 39 men with positive lymph nodes

• 80 men received BBT+ADT (called MaxRT) at the Chicago Prostate Center
• Median ADT duration - 6 months

After 5.5 years of median follow-up for MaxRT and 4.8 years of median
follow-up for those receiving RP, they found that the risk of PCSM compared to MaxRT was:

• 2.8 times greater for any RP (statistically significant)
• 0.5 times less for RP+adjuvant EBRT (not statistically significant)
• 3.2 times greater for RP+adjuvant ADT (statistically significant)
• 1.3 times greater for MaxRP (not statistically significant)

The 5-year PCSM was:

• 2% for MaxRT
• 22% for any RP (significantly higher than MaxRT)
• 4% for RP+adjuvant EBRT (not significantly different from MaxRT)
• 27% for RP+adjuvant ADT (significantly higher than MaxRT)
• 10% for MaxRP (not significantly different from MaxRT)

They computed a 76% chance ("plausibility index") that the PCSM was plausibly the same for MaxRT vs. MaxRP.

Kishan et al. supplied numbers from his study that are more directly comparable. They are shown in the table below.

Study	Tilki	Kishan
Sample size	BBT: 80 RP+EBRT: 88 RP+ADT: 49 RP+EBRT+ADT: 50	BBT: 436 RP+EBRT: 272 RP+ADT: 175
ADT duration (median)	BBT: 6 months RP (N1): 14.5 mos. RP (N0): 8.6 mos.	BBT: 12 months
Among RP,% N1	44%	17%
5-year % PCSM	RP (any): 22% BBT: 2%	RP (any): 12% BBT: 3%
Adjusted PCSM Hazard Ratio compared to BBT:	RP+ADT: 3.2 RP+EBRT: 0.5 (not sig.)	RP+ADT: 3.2 RP+EBRT: 2.0

We see that the two studies are really not comparable in some respects. The Kishan study was much larger, and was done among many of the top institutions. The Hamburg patients had a much higher percent of positive lymph nodes, and their mortality was twice as high as in the Kishan study. The Chicago patients only got half as much ADT vs. the Kishan study. Importantly, the Kishan study found that RP+EBRT had PCSM that was twice as high as BBT, while the Tilki study showed no statistically significant difference.

Another important aspect was not reported in either study - the toxicity of treatment. We know that surgery plus radiation has worse urinary and sexual side effects compared to surgery alone.BBT carries risk of higher late-term urinary side effects compared to EBRT alone.

Until we have a randomized clinical trial of BBT vs MaxRP, we will never have certainty, but for now, the Kishan study better reflects expected outcomes of these therapies at top institutions.