Neuromuscular Toxicity and Dose-Volume Relationships Following SBRT for Bone Oligometastases: Post-Hoc Analysis of Two Ongoing Clinical Trials

Abstract

<h3>Purpose/Objective(s)</h3> Growing evidence suggests that stereotactic body radiotherapy (SBRT) is effective for oligometastatic disease. Currently, there is limited data to define dose-volume relationships between muscle and adipose tissues and neuromuscular toxicities. In this post hoc analysis, we evaluated these associations in patients enrolled in two phase II clinical trials (NCT03575611, NCT03599765) where bone oligometastases were ablated with SBRT. <h3>Materials/Methods</h3> We reviewed three-fraction SBRT treatment plans for bone oligometastases where total dose ranged from 24-36 Gy. We contoured muscle and adjacent soft tissue receiving at least 10Gy based on anatomical function (e.g., hip flexors) and defined the largest-volume group as the most-affected functional muscle group (MFMG). Muscle and adipose tissues within MFMGs (MFMG-m and MFMG-a respectively) were further delineated by semi-automated contouring scripts using previously validated CT Hounsfield unit ranges for muscle (-29 to +150 HU) and adipose (-190 to -30 HU). Associations between neuromuscular adverse events (AE) (graded by Common Terminology Criteria for Adverse Events version 5) with dose to 2cc-30cc of contoured volumes (D2cc-D30cc) and clinical variables (BMI, ECOG, etc.) were assessed using two-sided Mann-Whitney U tests. Results were considered significant at P<0.0071 with Bonferroni correction. <h3>Results</h3> We evaluated 43 treatment plans for 37 patients with target lesions in the pelvic girdle (n=18), rib (n=15), femur (n=4), lumbar vertebra (n=2), scapula (n=2), and sternum (n=2). Three patients (8.1%) experienced grade 3 hip pain, 1 patient (2.7%) had grade 2 hip pain, and 2 patients (5.4%) had grade 1 hip or rib pain. There were no grade 4 or 5 AEs. Median time to AE was 2.3 months (range: 1.2–4.5 months). Patients with AEs had significantly higher MFMG D25cc (median = 28.4 vs 18.6Gy; p=0.004), MFMG-m D25cc (median = 27.7 vs 17.3Gy; p=0.006), and MFMG-a D5cc (median = 30.2 vs 18.9Gy; p=0.006) compared to pain-free patients. We identified a dose/volume threshold at MFMG D25cc > 25 Gy, where 5/11 (45.5%) treatment plans above and 1/32 (3.1%) below this threshold led to AEs, corresponding to an odds ratio of 25.8. There was no relationship between AEs and BMI, ECOG score, or demographics. No local tumor recurrences occurred with median follow-up of 15.5 months (range: 3.1–35.4 months). Two patients with grade 3 AEs after SBRT to pelvic girdle lesions had 3- and 5-month follow-up MRIs which identified soft tissue edema consistent with our findings. <h3>Conclusion</h3> Preliminary results from two prospective trials suggests that SBRT for bone oligometastases can be conducted safely with excellent tumor control and minimal toxicity. We propose that MFMG D25cc be limited to 25 Gy to avoid symptomatic neuromuscular toxicity. Future studies are needed for dose criteria verification.