Magnetic Resonance Imaging-Directed Stereotactic Body Radiation Therapy Microboost in Concert With Pelvic Nodal Irradiation for Prostate Cancer in the Higher-Risk Spectrum: Toxicity

Abstract

Purpose

Recent publications have renewed interest in prophylactic pelvic radiation therapy for higher-risk prostate cancer, as well as dose escalation for magnetic resonance imaging (MRI)-defined intraprostatic lesions. Here, we explore the use of pelvic nodal irradiation with a 3-fraction stereotactic body radiation therapy (SBRT) boost to the prostate and seminal vesicles, with a simultaneous MRI-directed focal intraprostatic lesion-ablative microboost (MIB).

Methods and Materials

We evaluated an institutional registry of patients undergoing pelvic nodal radiation followed by an SBRT boost to the prostate and seminal vesicles from April 2021 to March 2023. The study was approved by the local institutional review board (study #00001269). All patients were treated with pelvic nodal irradiation followed by a 3-fraction SBRT boost. The prostate SBRT boost dose was primarily 2100 cGy in 3 fractions (an accommodated range of 1800-2100 cGy). A subgroup of 15 patients received an MIB to an additional dose of 2300 cGy in 3 fractions (range, 2100-2400 cGy). The distribution of adverse event grades for acute and late gastrointestinal (GI) and genitourinary (GU) toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

Results

Fifty-eight patients underwent pelvic nodal irradiation followed by an SBRT boost to the prostate, with the distribution of risk groups as follows: patients were either in the high (36.2%, n = 21) or very high (34.5% n = 20) risk groups, whereas those with known nodal disease (19.0%, n = 11) or intermediate risk (10.3%, n = 6) comprised the rest of the study population. Most patients received androgen-deprivation therapy. The prostate SBRT boost dose was primarily 2100 cGy in 3 fractions. Fifteen patients received an MIB to an additional dose of 2300 cGy in 3 fractions. A median follow-up of 8.7 months was used to document the incidence of GU and GI toxicity. The distribution of GI and GU toxicity showed no significant difference between the MIB and non-MIB subcohorts at either the acute (<90 days) or late (>90 days) time points. Two grade 3 toxicities were observed, both in the non-MIB cohort. Grade 2+ GI and GU toxicities were not significantly different between the 2 groups, as assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

Conclusions

In the early follow-up period, we observed no significant difference in GI or GU toxicity between those who underwent MIB and those who did not. These results suggest that MRI-directed SBRT MIB did not increase GI toxicity and may even reduce GU toxicity compared with standard treatment. Future research should explore long-term side effects, with attention to the Expanded Prostate Cancer Index Composite (EPIC) scores and oncologic outcomes of this novel method of dose escalation.

Introduction

External beam radiation therapy (EBRT) is the first-line option for high-risk prostate cancer (PCa), as well as nonoperable cases of low- and intermediate-risk PCa.¹ Dose escalation of radiation to the prostate is at the forefront of radiation therapy (RT) research due to improvements in oncologic outcomes compared with standard radiation doses. Early randomized trials have demonstrated improved biochemical disease-free survival (bDFS) with dose-escalated EBRT in the management of low- to very-high-risk PCa, with minimal impact on toxicity.2, 3, 4 Whole-gland dose escalation up to 80 Gy has been shown to yield better bDFS, but with a small yet significant risk of increased acute and late gastrointestinal (GI) and genitourinary (GU) toxicity.⁵ Stereotactic body radiation therapy (SBRT) enables the delivery of ultrahypofractionated high-dose radiation with precise patient setup and image guidance techniques and has emerged as an excellent method for prostate dose escalation.

Prostate SBRT is now a first-line therapy for low- and intermediate-risk PCa, supported by level 1 evidence from phase 3 randomized clinical trial data.⁶ High-risk PCa is at the center of an ongoing debate regarding the utility of elective pelvic nodal irradiation (PNI) from an oncologic and toxicity standpoint. The recent publication of a Phase III Outcomes research study on Prostate-Only Versus Whole-Pelvic Radiation Therapy in High-Risk and Very High-Risk Prostate Cancer (POP-RT) has encouraged more practitioners to favor elective nodal irradiation, yielding a relatively favorable toxicity profile for patients while improving local control.⁷

The recent Focal Lesion Ablative Microboost in Prostate Cancer (FLAME) Trial, Hypofractionated Focal Lesion Ablative Microboost in Prostate Cancer (HYPO-FLAME) Trial, and HYPO-FLAME 2.0 series have shown that further dose escalation with a microboost (MIB) to the dominant intraprostatic lesion can improve 5-year bDFS, with a small, nonstatistically significant increase in toxicity.8, 9, 10 This suggests that for localized intermediate- and high-risk PCa patients being treated with EBRT, adding dose escalation with an MIB is a safe option, from a toxicity standpoint, to improve local control.

While oncologic outcomes, such as bDFS, are paramount in patient and clinician treatment decision-making, toxicity metrics have a significant impact on PCa, given the excellent disease-specific outcomes of standard-of-care treatment regimens. The goal of radiation treatment planning is to maximize the dose to the target and reduce the dose to organs at risk (OARs). Even in highly targeted, imaging-guided treatments such as SBRT, it is impossible to completely spare OARs from any radiation dose. This is particularly a challenge in dose escalation to the prostate, where the rectum, bladder, urethra, and bowel are all nearby OARs. Thus, GU, GI, and sexual side effects are closely monitored.

While there is vast support for the use of dose-escalated RT across prostate disease stages, there is a paucity of data showing the impact of simultaneous MIBs on patients with more advanced disease already undergoing pelvic RT and whole-gland boosts. Thus, this study sought to evaluate how the use of simultaneous MIBs in this patient population affects treatment toxicities compared with those just receiving pelvic RT with whole-gland SBRT. This study will enable patients and clinicians to make more informed decisions when considering the use of simultaneous MIBs.

Methods and Materials

Patient eligibility

We conducted a retrospective review using an institutional registry of patients undergoing definitive prostate radiation from April 2021 to March 2023. This study was approved by the local institutional review board (study #00001269). Patients had histologically confirmed PCa, were assessed by a radiation oncologist, and were considered suitable for PNI and SBRT Simultaneous Integrated Boost (SIB). All patients underwent pretreatment evaluations, including clinical examination, Prostate Specific Antigen (PSA) testing, prostate biopsy, a dedicated multiparametric prostate magnetic resonance imaging (MRI), and a Prostate-Specific Membrane Antigen Positron Emission Tomography Scan (PSMA PET).

Simulation, planning, and treatment delivery

All patients underwent computed tomography-based radiation treatment planning simulation using the GE Optima 580 (GE HealthCare). A dedicated multiparametric prostate MRI was acquired, with T2- and diffusion-weighted imaging sequences fused with the simulation computed tomography at the level of the fiducials to aid in target volume delineation. A pre–androgen-deprivation therapy diagnostic MRI was also used to delineate the target volumes. The pelvic nodal clinical target volume was obtained with a 7 mm brush, starting at L4/L5 just distal to the aortic bifurcation, and extending to the common iliac, internal iliac, external iliac, and obturator nodes. PNI was planned using conventional fractionation (180 cGy per fraction) to a total dose of 4500 cGy. The prostate clinical target volume encompassed the entire prostate and the proximal or entire seminal vesicles. A 5 mm isometric expansion, with a more constrained 3 mm posterior margin, was applied to define the planning target volume. The rectum, bladder, urethra, small bowel, penile bulb, and femoral heads were delineated as OARs. The SBRT boost was delivered in 3 fractions, every other day, via CyberKnife (Accuray), at 1800 to 2100 cGy, using fiducial tracking. An isotoxic simultaneous-integrated MIB of an additional 2300 cGy in 3 fractions was delivered to high-risk lesions (Prostate Imaging Reporting and Data System (PI-RADS) 4-5 lesions on MRI or biopsy-proven PI-RADS 3 lesions). There was no limit on target dose heterogeneity.

OAR dosimetric constraints from prior SBRT trials were used.^9,10 The urethra was contoured using MRI fusion. Dose calculations and planning optimization were conducted using Accuray MultiPlan software. A single robotic planning platform was used to evaluate maximum and mean dosimetric parameters.

Results

A total of 58 patients with a median age of 72 years who underwent PNI, followed by an SBRT boost to the prostate, were analyzed in the database as shown in Fig. 1. Demographic data for our patients are shown in Table 1. Most patients were in the high (36.2%, n = 21) or very high (34.5%, n = 20) risk groups, whereas patients with known nodal disease (19.0%, n = 11) or intermediate risk (10.3%, n = 6) comprised the remainder of the study population. The majority of patients in both the MIB and non-MIB groups had a PSA between 10 and 20 (43.8%, n = 14; and 53.8%, n = 14, respectively). Most patients in the MIB group had grade group 5 disease (31.3%, n = 10), whereas most patients in the non-MIB group had grade group 4 disease (73.1%, n = 19). A total of 55 patients received androgen-deprivation therapy for 8 to 36 months, most of whom started in the neoadjuvant setting 2 to 3 months prior to treatment, as detailed in Table E2 (94.8%, n = 55).

Figure 1.

Examples of dose distributions for microboosts (MIB) to 24Gy. The 21Gy, 24Gy, and 25Gy isodose lines are displayed, as well as the contours for the prostatic urethra and the rectum. Rectal spacers are included in all. A) unifocal MIB to left posteromedial base B) unifocal MIB to right posterlateral base C) Multifocal MIB to right posterolateral base and left anterolateral base.

Table 1.

Patient and tumor characteristics

Patient Demographics and Tumor Characteristics	MIB		Non-MIB		P value
	%	n	%	n	-
Focal	68.8	22	-		-
Multifocal	31.3	10	-		-
Total	55.1%	32	44.8	26	-
Median age (y)	72		74.5		.87
Age (y), range	61-88		56-87		-
Age group
<60	0	0	23.1	6	-
60-70	37.5	12	23.1	6	-
>70	62.5	20	53.8	14	-
PSA (ng/mL)
Median PSA (ng/mL)	11.15		11.41		.37
<10	34.4	11	26.9	7	-
10-20	43.8	14	53.8	14	-
>20	21.9	7	19.2	5	-
Grade group					.003
1	9.38	3	0	0	-
2	12.5	4	7.69	2	-
3	21.9	7	3.85	1	-
4	25	8	73.1	19	-
5	31.3	10	11.5	3	-
Median prostate CTV (cc)	71.7		69.7		.13

P values for median age, median PSA, and median prostate CTV were calculated using the Student t-test. P value calculations for the Grade group used the χ² test for count data.

Abbreviations: CTV = clinical target volume; MIB = Microboost; PSA = prostate-specific antigen.

All patients analyzed were treated with an SBRT boost to the entire prostate, ranging from 1800 to 2100 cGy in 3 fractions. Half of the study population (55.2%, n = 32) also received an MIB, with a median dose of 2100 to 2400 cGy. MIB patients primarily received a unifocal boost (68.8%, n = 22), with only one-third receiving a multifocal MIB (31.3%, n = 10) (Fig. 2).

Figure 2.

Consort diagram.

Abbreviations: MIB = microboost; SBRT = stereotactic body radiation therapy.

GI and GU toxicity is detailed in Figure 3, Figure 4, Figure 5, Figure 6. At a median follow-up of 8.7 months, the crude incidence rates for grade 3+ GU and GI toxicity were 3.4% and 1.7%, respectively. All grade 3+ GI and GU toxicities (National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0) (n = 5) were observed in the non-MIB cohort, and there were no grade 4 or 5 GI or GU events. Descriptive toxicity is noted in Tables E3 to E5. There was 1 patient with grade 3 GI toxicity (diarrhea), and 5 patients with grade 3 GU toxicity (1 bladder spasm, 1 urinary tract obstruction, and 2 urinary tract infections). At the median follow-up time, the crude incidence rates for grade 2 GI and GU toxicity were 21.3% and 26.8%, respectively. The most prevalent grade 2 GI toxicity was diarrhea, and the most prevalent grade 2 GU toxicity was urinary frequency. There was no statistically significant difference in GI (P = .559) or GU toxicity (P = .326) between the MIB and non-MIB cohorts, even when they were further categorized by specific toxicity (Tables E1-E3). There were also no statistically significant differences in acute or late GI (Fig. 4) or GU toxicities (Fig. 6) between the 2 cohorts. GU toxicity showed a numerical increase in the non-MIB group (58% vs 34%), with overlapping CIs but a trend toward significance (P ≈ .08). GI toxicity rates were similar between groups (25% vs 27%), with wide overlapping CIs and no statistical difference (Table E6)

Figure 3.

Distribution of gastrointestinal (GI) toxicity by timing. There is no significant difference between the microboost (MIB) and non-MIB subcohorts.

Figure 4.

Kaplan-Meier distribution of the incidence of gastrointestinal (GI) toxicity (at 9 months).

Abbreviations: MIB = microboost.

Figure 5.

Kaplan-Meier distribution of the incidence of genitourinary (GU) toxicity (at 9 months).

Abbreviations: MIB = microboost.

Figure 6.

Distribution of genitourinary (GU) toxicity by timing. There is no significant difference between the microboost (MIB) and non-MIB subcohorts.

Discussion

This study demonstrates the safety of simultaneous dominant intraprostatic lesion MIBs in patients with clinically localized high-risk PCa undergoing definitive RT. Treatment-related toxicity was low across all cohorts, including the dose-escalated MIB group. There were low rates of grade ≥2 GU and GI toxicities, which correspond to recent trials exploring prostate dose escalation with elective pelvic therapy. POP-RT showed late grade 2+ GI and GU toxicity of 5% and 18%, respectively, in the group receiving pelvic radiation. This is similar to our study, which found cumulative incidences of late grade 2 or higher GI and GU toxicity of 9.1% and 11.3%, respectively, in the standard arm, versus 6.7% and 8.6%, respectively, in the MIB arm.

This statistically nonsignificant difference between the MIB and non-MIB cohorts largely remained, even when toxicities were further classified by individual toxicity and time of onset. The only statistically significant difference between the 2 cohorts was observed when all GU toxicity, including grade 1, was compared, with the MIB group having a 54.4% rate compared with 45.6% in the non-MIB cohort (P = .03). While notable, this difference has questionable clinical significance, given that this difference was largely driven by grade 1 toxicities, which are highly subjective and do not warrant any clinical management.

The safety profile of our regimen is notable when compared with recent prostate SBRT studies, which typically focus on lower-risk populations. The PACE-B trial, a phase 3 randomized study in low- to intermediate-risk patients, reported a cumulative incidence of late RTOG (Radiation Therapy Oncology Group) grade ≥2 GU toxicity of 26.9% for SBRT (36.25 Gy/5 fractions) versus 18.3% for conventional or moderately hypofractionated RT, with point prevalence at 5 years converging (7.3% vs 4.5%, P = .11).⁶ The HYPO-FLAME trial, targeting intermediate- and high-risk patients with 35 Gy/5 fractions and a SIB up to 50 Gy, reported 34% acute grade ≥2 GU toxicity, whereas HYPO-FLAME 2.0, using a compressed semiweekly schedule, observed a higher rate of 47.5% (P = .01).^10,11 The Jackson et al¹¹ meta-analysis, encompassing 38 prospective studies of 6116 patients (38% high risk), reported low acute grade ≥3 GU toxicity (0.5%) and late grade ≥3 GU toxicity (2.0%; 95% CI, 1.4%-2.8%), with late grade ≥3 GI toxicity at 1.1% (95% CI, 0.6%-2.0%). Our acute grade ≥2 GU toxicity rate of 28% is comparable to PACE-B and HYPO-FLAME, and the absence of grade ≥3 GU toxicity aligns with the meta-analysis,¹¹ despite our inclusion of high- and very-high-risk patients and PNI.^6,8 The negligible GU toxicity further highlights the safety of our approach, likely driven by precise dosimetry and urethra contouring.

The favorable toxicity profile of our regimen supports the use of SBRT MIB in certain patient subgroups that have historically been excluded from dose-escalation trials, such as those included in Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy Trial (ASCENDE-RT).¹² ASCENDE-RT compared an EBRT boost with a low-dose brachytherapy boost following pelvic EBRT in patients with intermediate- and high-risk disease. Notably, patients with large prostates (>75 cm3), T3b disease, and those who were unfit for anesthesia were excluded from this study. Our study included patients with prostates >75 cm3 and T3b disease and showed late grade 2 GU toxicity (>90 days postradiation) of only 8.6% (no grade 3 GU toxicity) in the MIB group and 8.1% (with grade 3 toxicity of 3.2%) in the non-MIB group. These are lower than those observed in the ASCENDE-RT group, which reported grade 3 GU toxicity of 18% in the brachytherapy boost group and 5% in the EBRT boost group. Although our study has a significantly shorter follow-up than ASCENDE-RT, improved imaging and treatment delivery with SBRT likely allow for the safe treatment of these patients.

A key feature of our study is the explicit contouring of the urethra, which enabled a stringent dose of radiation (D0.1 cm3) < 40 Gy constraint (median, 38.5 Gy), likely contributing to the favorable toxicity profile despite the high-risk cohort and extended treatment fields. Notably, a comprehensive analysis by Leeman et al¹³ of 23 prospective trials involving patients receiving prostate SBRT found that the maximum urethral dose metric, ranging from 69 to 141.75 Gy (Equivalent Dose in 2Gy fractions (EQD₂), α/β = 3 Gy), was significantly associated with increased risks of acute and late grade 2+ urinary toxicity, with each 1 Gy increase in the maximum urethral dose metric correlating to a 0.8% and 1.0% rise in acute and late grade 2+ toxicity, respectively. Specifically, the Hypofractionated Treatment Effects in the Clinic (HyTEC) report¹⁴ cited in this study suggests constraining the urethral D_max to 38 to 42 Gy in a 4-fraction regimen to maintain acceptable toxicity rates.

All grade ≥3 toxicity events occurred in the MRI-defined non-MIB group (P = .88), potentially due to the isotoxic coverage principle (strict constraints), which prioritizes safe OAR doses over target coverage. This technique was also used in the FLAME and HYPO-FLAME series.¹⁰ Additionally, it is possible that the multiboost plans had more conservative tumor coverage than the unifocal boost plans because they would otherwise deliver too much dose to the rectum and urethra. This approach, combined with precise urethral delineation, positions our regimen as a safe and effective option for prostate SBRT, particularly in high-risk patients requiring PNI.

The primary limitations of this study include a small cohort size, a limited follow-up duration, and evolving treatment paradigms that may affect future applicability. First, the small sample sizes in each cohort restricted the ability to perform subgroup analyses, such as comparisons of toxicity outcomes between patients receiving unifocal versus multifocal MIBs. Second, although the median follow-up was sufficient to capture most acute and late toxicities, it was too short to assess oncologic outcomes, necessitating reliance on historical data for outcome estimates. Third, the relevance of these findings may be impacted by the increasing adoption of pelvic nodal hypofractionation, as supported by recent trials like SATURN (Systemic and Tumor-directed Therapy for Oligorecurrent Metastatic Prostate Cancer), which could shift standard practice and limit generalizability.^12,15

Conclusions

Intraprostatic lesional MIB during a 3-fraction SBRT prostate boost in concert with PNI is a safe method of dose escalation in higher-risk PCa patients. At early follow-up, we observed no significant difference in National Cancer Institute Common Terminology Criteria for Adverse Events toxicity. These findings indicate that MRI-guided SBRT MIB preserves GI tolerability while potentially mitigating GU side effects compared with conventional approaches. Our analysis shows that there is no increased risk of high-grade toxicity when an intraprostatic lesional MIB is applied during a 3-fraction SBRT prostate boost in concert with PNI. Rates of acute and late GI and GU toxicities are also not statistically different between the standard and MIB groups, with late GI and GU toxicity rates being comparable to those in POP-RT. To our knowledge, no study of this size has investigated the toxicity of combining MIBs with SBRT after nodal treatment. Future research should explore long-term side effects and oncologic outcomes of this novel dose-escalation method.