Addition of Multifocal MRI-Directed SIB to SBRT Shows Acceptable Toxicity Profile in Prostate Cancer

Although the addition of multifocal MRI-directed simultaneous integrated boost (SIB) to stereotactic body radiation therapy (SBRT) was not associated with additional acute toxicity compared with unifocal SIB in patients with prostate cancer, questions remain regarding the risk of late-onset toxicity and oncologic efficacy, according to Joshua C. Hurwitz.

Investigators conducted a single-center retrospective analysis assessing the safety of this approach vs unifocal SIB in patients with prostate cancer who had PI-RADS 3+ lesions identified on pretreatment MRI. Findings presented at the 2023 ASTRO Meeting revealed higher crude rates of grade 2 genitourinary (GU) toxicities vs grade 2 gastrointestinal (GI) toxicities in the overall population, at 51% vs 6%, respectively, with the multifocal approach, but this was in line with what has previously been reported with unifocal SIB. No difference in median SIB volume between multifocal and unifocal SIB was observed, at 1.47 cc vs 1.72 cc, respectively (P = .57), and SIB volume was not linked with increased risk of grade 2 GU toxicity (P = .28). At a median follow-up of 33 days, no grade 3 or higher acute toxicities were observed in either arm.

Additional univariate and multivariate analyses did not suggest that the multifocal approach was associated with increased risk of grade 2 GU toxicity vs the unifocal approach, at 35% vs 67%, respectively (P = .09).

“[Multifocal SIB with SBRT] is something we’ve incorporated into our practice because it’s not detrimental to the patients,” said Hurwitz, who is a medical student at NYU Grossman Long Island School of Medicine. “We’ll hopefully be able to [conclusively] demonstrate that it is [more] beneficial [with continued research].”

In an interview with OncLive®, Hurwitz discussed prior research from the phase 3 PACE-B (NCT01584258) and FLAME (NCT01168479) trials that provided the impetus for this analysis, detailed key toxicity and quality-of-life (QOL) data for multifocal vs unifocal SIB presented during the meeting, and discussed next steps for expanding this research to a larger cohort of patients with prostate cancer.

OncLive: Could you discuss the rationale for this analysis, including any relevant recent data with SBRT that supported its inception?

Hurwitz: SBRT as a definitive treatment in prostate cancer has been well established for some time now. At the 2022 ASTRO Meeting, the oncologic results of the PACE-B trial were presented for the first time. They showed excellent oncologic control with SBRT at a dose of 36.25 Gy in 5 fractions to control prostate cancer vs a conventional fractionation scheme. That was exciting, because it confirmed what we already knew, and what we had already incorporated into our practice at NYU Grossman Long Island School of Medicine. It’s one of the largest and most robust phase 3 studies [on this subject] to date.

Additionally, the FLAME trial looked at [adding a focal] boost to the dominant intraprostatic lesion, [which is] a PI-RADS lesion as discovered on MRI. PI-RADS is a diagnostic radiology term that can show or delineate where the tumor is located in the gland and where local recurrence is most likely to occur. The FLAME trial [utilized] conventional fractionation, but it showed excellent oncologic and toxicity outcomes. That prompted the [phase 2] hypo-FLAME trial [NCT02853110], which was essentially the same thing but utilized hypofractionated treatment at 36.25 Gy for 5 fractions, as the PACE-B trial did. We don’t have oncologic data from this trial yet, but the toxicity results were excellent. They boosted the PI-RADS all the way up to 50 Gy, [which is a] high ablative dose. Hopefully good oncologic data will [be reported from this trial] down the line.

[Based on these data], we decided to target multiple PI-RADS lesions in the patients who have multiple PI-RADS lesions, and we don’t necessarily mean all PI-RADS lesions. We’re focused on grade 3 or higher PI-RADS lesions, as those are more likely to be where local recurrence occurs. We started doing multifocal boosts in the patients who had multifocal dominant PI-RADS lesions, [and assessed whether] a multifocal boost was associated with higher toxicity relative to the universal boost.

Please briefly detail the design of this analysis. What patients were included?

For the most part, the study [included] all comers with prostate cancer. [We didn't restrict [the population] to [those with] localized prostate cancer, but we did include a patient who had regional disease. It was a small study of 35 patients. We also didn’t specify with National Comprehensive Cancer Network risk guidelines whether [patients’ disease] needed to be low, intermediate, or high, although [we] mostly focused on intermediate- and high-risk [disease]. Patients had to have a PI-RADS lesion discovered on MRI prior to radiation. When we planned the treatment, we were able to use the CT-MRI fusion to delineate the PI-RADS lesions and design the multifocal boost if they had multiple lesions, or the unifocal boost if we were only boosting 1 lesion.

What was reported regarding the impact of this approach on acute toxicities, as well as GU and GI toxicities relative to unifocal boost?

We focused on GU and GI toxicity for the most part. We did record but did not report on sexual and general toxicities, as they were limited in the cohort overall. We also reported on QOL outcomes, which are intimately linked. QOL may be better for teasing out some subtle differences that are not as easily picked up in the clinic. Using CTCAE [criteria] as grading for patient outcomes, we saw no grade 3 toxicity at all in this study, regardless of multifocal vs unifocal boost. We were really encouraged by the limited toxicity. We did have relatively higher rates of grade 2 GU toxicity, which can sometimes be expected with SBRT. There are also some questions as to how CTCAE grading is performed, because the biggest clinical difference between grade 1 and grade 2 [categorization] is whether medical management is necessary. [Many] patients are put on alpha blockers or 5-alpha–reductase inhibitors, which automatically upstages their toxicity to grade 2.

[Overall,] we reported favorable GU toxicity and very limited GI toxicity, which was encouraging. Most patients did receive a rectal spacer for this treatment, but it was not associated with a decrease in GI toxicity in our study. Because there was a higher rate of GU toxicity, we wanted to see whether the multifocal boost was associated with the increase. Univariate analysis and multivariate analysis [showed that it] was not. Ultimately, that was the primary outcome of the study, and we were encouraged by the results.

Could you briefly discuss the QOL data obtained from this study?

We used EPIC scores to assess QOL, [which are a] standard [scoring system in] prostate cancer. The majority of patients did [have] baseline EPIC scores, and we have some follow-up for them. We saw that the multifocal boost group did have a greater transient drop in scores vs the unifocal boost group in the months immediately following treatment. However, as we followed patients out to the 18-month to 2-year range, the EPIC scores in the urinary domain fully recovered. There was no significant change in the GI domain scores from baseline in either group. Regarding urinary domain scores, patients with a multifocal boost had a higher baseline function rate [vs those with a unifocal boost], so there was essentially more to lose. These are limited data and our median follow-up was 8 months in the study. We’re mostly looking at acute toxicity here. We’re encouraged by [the fact that] toxicities are more likely to occur early. With these QOL data, we can already see trends back toward normalization to baseline at the 2-year mark.

What next steps are planned for this research?

We’ve now established a registry of these patients who are receiving multifocal or unifocal SIB with our SBRT. We are massively expanding the number of patients in this cohort as we continue to treat them based on the clinical indications from their MRIs and the identification of PI-RADS 3-5 lesions. We’re excited to continue following this group going forward. Hopefully [these results] can translate to a much larger cohort of patients with more significant follow-up.

What is the clinical significance of these findings?

We would like our colleagues to know that [utilizing multifocal] boost in areas of greater risk of recurrence to a higher dose within the prostate gland is feasible and is not associated with any increase in toxicity. We can certainly [apply radiation to] the whole gland at the ablative dose of 36.25 Gy. However, as we did in our research, we can also take these PI-RADs lesions up to 42.00 Gy and potentially have better biochemical disease-free survival and decreased biochemical progression moving forward. [This is not confirmed], but we can extrapolate results from the FLAME trial.

What other research efforts are you most excited about?

Some of the residents at NYU Langone’s Tisch Hospital presented some interesting breast cancer radiation research [at the 2023 ASTRO Annual Meeting]. One of the posters that struck home looked at prone positioning in accelerated partial breast irradiation. NYU’s Perlmutter Cancer Center has been doing this for a long time. They presented several posters demonstrating success [with this technique] both [in terms of] oncologic control and toxicity outcomes.

Reference

Hurwitz JC, Santos V, Akerman M, et al. Multifocal MRI-directed simultaneous integrated boost (SIB) in the treatment of prostate cancer with stereotactic body radiation therapy (SBRT). Int. J. Radiat. Oncol. 2023;117(2):E395. doi:10.1016/j.ijrobp.2023.06.1521