SBRT for High-Risk Patients

As we have seen, SBRT is a preferred therapy for low and intermediate-risk patients (see this link). It is effective, safe, convenient, and relatively inexpensive. However, its use for high-risk patients remains controversial.

Amar Kishan has accumulated data from 8 institutions that have used SBRT for 344 high-risk patients. They were treated as follows:

• They received from 35 Gy-40 Gy in 5 treatments (7-8 Gy per treatment)
• 72% received adjuvant ADT for a median of 9 months
• 19% received elective nodal radiation

After a median follow-up of 49.5 months:

• 4-year biochemical recurrence-free survival  (bRFS)was 82%
• Higher dose, longer ADT, and nodal radiation were associated with better bRFS
• 4-year metastasis-free survival was 89%
• Late grade 3 GU toxicity was 2.3%
• Late grade 3 GI toxicity was 0.9%
• Toxicity was associated with dose and ADT use

Although the results of different prospective trials aren't comparable, the following table gives an idea of 4-6 year outcomes of prospective trials of high-risk patients using various therapies.

	Follow-up	bRFS	BED	ADT (median)	Late GU Toxicity Grade ≥3
SBRT (1)	4 yrs	82%	198-253 Gy	9 mos.	2.3%
Surgery+SRT (2)	5 yrs	78%	154 Gy	6 mos.	8% (3)
HDR-BT (4)	5 yrs	91%	227-252 Gy	6.3 mos.	3-16%
LDR- Brachy Boost (5)	5 yrs	86%	227 Gy	12 mos.	19%
HDR-Brachy Boost (6)	6 yrs	88%	267 Gy	12 mos.	2.5%
IMRT (7)	5 yrs	88%	174 Gy	28 mos.	2.5%

SBRT = stereotactic body radiation therapy,. External beam radiation (EBRT) concentrated in 5 treatments

bRFS= biochemical (PSA) recurrence-free survival

BED= biologically effective dose (comparable effectiveness)

ADT= androgen deprivation therapy used for a limited time to improve outcomes

late GU toxicity ≥3 = serious urinary side effects requiring intervention, occurring more than 3 months after therapy

HDR-BT = high dose rate brachytherapy (temporary implants)

LDR-BT = low dose rate brachytherapy (permanent implants/seeds)

Brachy Boost therapy - External beam radiotherapy (EBRT) with a boost of radiation to the prostate using brachytherapy 

IMRT = intensity-modulated radiation therapy, usually given in about 40 treatments

(1) https://www.redjournal.org/article/S0360-3016(21)00068-7/pdf

(2) https://riskcalc.org/ProstateCancerAfterRadicalProstatectomyNew/ with GS 8

(3) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00111-X/fulltext

(4) https://www.redjournal.org/article/S0360-3016(11)00552-9/abstract

(5) https://www.redjournal.org/article/S0360-3016(16)33484-8/abstract

(6) https://www.thegreenjournal.com/article/S0167-8140(18)30238-X/fulltext

(7) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70045-8/fulltext

As we've seen (see this link), brachy boost therapy is the gold standard for long-term recurrence-free survival. At about 5 years, however, all therapies seem to be about equally effective, with biochemical recurrence-free survival in the range of 78-91%. However, they differ markedly in the incidence of serious late-term urinary side effects. For LDR Brachy Boost therapy, the risk of urinary retention is high, while the risk of incontinence and urinary retention is elevated among patients having salvage radiation (SRT). External beam monotherapy, using either IMRT or SBRT, had a low risk of serious late-term urinary side effects (and almost no risk of serious rectal side effects).

IMRT, as a primary therapy for high-risk patients, requires long-term use of ADT to be effective. The DART RADAR trial showed that for high-risk patients, 6 months of adjuvant ADT wasn't nearly enough. Nabid suggests that 18 months of adjuvant ADT may be optimal when paired with IMRT. SBRT seems to be equally effective with less adjuvant ADT, but the optimal duration is yet to be determined.

The question that will only be resolved with longer follow-up is whether the recurrence rates are stable after 4 years, or whether they will deteriorate with longer follow-up. In the ASCENDE-RT trial of brachy boost therapy vs external beam radiation only, biochemical recurrence rates were similar after 5 years. Recurrence increased at a rate of 5% per year among those treated with EBRT alone, but only at a rate of 1% per year if they got the brachy boost. There was similar stability of outcomes when HDR brachytherapy was used. Recurrence after salvage radiation increased from 22% at 5 years to 30% at 10 years. There is every reason to believe that SBRT, which uses biologically effective doses (BED) of radiation similar to brachy boost therapy, will follow a stable recurrence pattern over time, but that remains to be shown.

Ensuring the safety of patients is critical, and high-risk patients are usually treated with wider margins that can affect toxicity. As we saw, SBRT there are many factors that must be considered when giving radiation this intense (see this link).

The first randomized trial (see this link) of radiation delivered in 6 treatments compared to 39 treatments to intermediate to high-risk patients proved that the cancer control and toxicity were similar. Another randomized trial (PACE-B) has already shown that the toxicity is lower with SBRT. An ongoing arm of that trial (PACE-C) is focusing on high-risk patients.

NCCN has included SBRT as a reasonable standard-of-care option for high-risk patients (Table 1 Principles of Radiation Therapy PROS-E 3 of 5 in NCCN Physicians Guidelines 3.2020). Due to the pandemic, an international panel of radiation oncologists is recommending that high-risk patients consider its use (see this link).