The SMILE trial is underway to compare two different fractionation schedules of stereotactic body radiation therapy (SBRT) for the management of non-spine bone metastases. This international, multicenter, open-label, randomized, controlled phase 3 non-inferiority clinical trial aims to determine if a shorter 3-fraction regimen can provide similar benefits to a more conventional 5-fraction regimen, potentially reducing side effects and treatment burden.
Trial Design and Methods
The trial compares a 3-fraction regimen (Arm A) delivering 9 Gy x 3 fractions (BED10: 51.3 Gy) to a 5-fraction regimen (Arm B) delivering 7 Gy x 5 fractions (BED10: 59.5 Gy) to the treatment site. Patients are immobilized in a stable supine position using devices ensuring set-up reproducibility. Target volume delineation involves defining the gross tumor volume (GTV) based on planning CT and co-registered MRI and/or PET/CT, with specific margins added to create the clinical target volume (CTV) and planning target volume (PTV).
Organs at risk (OAR) are contoured according to institutional standards, and dose constraints adhere to published data. Treatment planning involves 3D-conformal planning with a type C dose calculation algorithm utilizing static, rotational, or robotic intensity-modulated radiotherapy. On-board imaging is required before each fraction to account for set-up errors and allow for online positional correction.
Outcomes and Assessments
The primary outcome is pain response at the treatment site, defined as a ≥2-point improvement on the visual analogue scale (VAS) at 3 months post-treatment. Secondary outcomes include acute and late toxicities, fracture rates, quality of life assessments using EORTC QLQ-C15-PAL, QLQ-BM22, and EQ-5D-DL, local metastasis control, and long-term pain response. Follow-up assessments occur at 3, 6, and 12 months post-treatment.
Sample Size and Statistical Analysis
The trial plans to enroll 162 patients, with statistical analyses conducted on intent-to-treat (ITT), per-protocol (PP), and safety-analysis sets. The non-inferiority margin is set at 10%, with the goal of establishing non-inferiority of the 3-fraction regimen compared to the 5-fraction regimen. An interim analysis with 128 patients (64 per arm) will be sufficient to reach 80% power at a significance level of 5% with a possible drop rate of 10%.
Patient Care and Adherence
During the trial, standard supportive care measures, including analgesics and anti-inflammatory medications, are permitted. Adherence to interventions is supported through close monitoring of treatment attendance, side effects, and regular follow-up appointments. After the trial, patients will be monitored for long-term side effects and continued pain management.
