SABR for High-Risk Prostate Cancer: A Prospective Multilevel MRI-Based Dose Escalation Trial

Abstract

Purpose: Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa.

Methods and materials: This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate <33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events.

Results: Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively.

Conclusions: SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity.

Figure 1

Integrating diagnostic mpMRI, radiation planning MRI, and CT to delineate lesion(s). Images of a 65-year-old patient with elevated PSA (5.25 ng/mL) and grade group 4 cancer. Diagnostic mpMRI revealed a PI-RADS 5 lesion in the left mid gland peripheral zone shown as a homogeneous, moderately hypointense lesion (red contour) on axial T2-weighted images (A); hyperintense on high b-value diffusion weighted images (B) and hypointense on apparent diffusion coefficient map (C) images. After androgen deprivation and hydrogel spacer placement, and before radiation therapy initiation, radiation planning MRI axial T2-weighted images (D) indicate adequate spacer (S) distribution in the rectoprostatic space and decrease in prostate (P) and lesion size. Although less conspicuous than on diagnostic MRI, the correlation between studies allows us to delineate lesions on treatment planning MR images. Given its vulnerability to artifacts caused by metal, axial gradient-echo MR imaging (E) can easily identify the fiducial markers (yellow arrow) and facilitate fusion of the MRI and radiation planning CT (F) datasets. Radiation plans showing intralesional boost to contoured tumors (red contour G and H), urethral dose sparing (yellow contour G and H), and treatment of pelvic lymph nodes (cyan contour I). Isodose lines show location of 24Gy and 39Gy rectal constraints (I) of the same axial slice as G.

Figure 2

Maximum physician-reported CTCAE acute (A) and late (B) GU and GI toxicities. Acute toxicity by cohort (C).

Figure 3

Patient-reported outcomes on IPSS symptom score questionnaire with 95% CI at baseline, maximum 90 days post-treatment, and 18 months post-treatment (A). Average IPSS, maximum 90-day IPSS, and change in IPSS from baseline to maximum 90-day with 95% CI within each cohort(B).

Figure 4

Patient-reported EPIC score reaching MCIC using the anchor-based method. A threshold change for MCIC of 5 for the bowel domain and 6 for the urinary domain was used (A). Percent of patients who reached MCIC within the first 90 days stratified by cohort in the GU domain (B) and the GI domain (C).