Novel Gradient-based Approach to Spatially Fractionated Radiotherapy: Implementation and Preliminary Clinical Results

Background and purpose Bulky tumors often present limited treatment options and poor response to conventional radiotherapy due to hypoxia, radioresistance, and dose delivery challenges near organs at risk. Spatially fractionated radiation therapy (SFRT) has shown promising results by creating heterogeneous intratumoral dose distributions that enhance local control while minimizing toxicity and stimulating immune response. We introduce a novel gradient-based approach, spatial stepwise gradient radiation therapy (2SG-RT), designed to simplify planning, preserve the biological advantages of dose heterogeneity, and facilitate integration into routine clinical workflows. Materials and methods Twenty-nine patients with pathologically confirmed malignant neoplasms manifesting as bulky tumors at various sites underwent 2SG-RT between November 2021 and April 2024. Target volumes were delineated in a stepwise manner, generating nested concentric planning target volumes (PTVs) for dose escalation, guided by PET-CT or CT-defined hypoxic/necrotic regions. Standard prescriptions were 12 Gy to the innermost PTV, 6-9 Gy to intermediate volumes, and 3-4 Gy to the outer PTV. Treatment planning employed intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) to achieve the intended dose gradient while minimizing exposure to organs at risk, followed by conventional external beam radiation therapy (EBRT) with homogeneous dose. Results Among 29 patients (median age 70 years), median follow-up was four months. Median initial tumor volume was 118 cc. Median doses delivered with 2SG-RT were 12 Gy to the innermost PTV, 9 Gy to the intermediate PTV, and 3 Gy to the outer PTV. Radiologic assessment showed complete response in 34.5% of patients, partial response in 48.3%, and stability in 10.3%; two patients could not be assessed due to early death. Median tumor volume reduction was 75%. Symptom relief was complete in 44.8% and partial in 31% of patients. Treatment was well-tolerated with no grade 3-4 toxicities. Estimated equivalent uniform doses (EUD) and equivalent dose in 2 Gy fractions (EQD2) calculations indicated that the initial 2SG-RT fraction delivered, on average, a 106% higher biological dose than a single conventional fraction, while the full treatment regimens were comparable (mean difference 7.9%). Conclusion 2SG-RT is a feasible and promising approach to SFRT, offering efficiency, adaptability, and applicability across diverse bulky tumors. It facilitates precise dose delivery, enhances planning and verification efficiency, and may support subsequent radiotherapy or systemic treatments in patients otherwise limited to palliative care. Preliminary clinical outcomes and EUD analyses suggest potential immune-mediated effects, warranting further investigation. Prospective comparative studies with longer follow-up are needed to validate these findings and clarify the clinical impact of 2SG-RT.