Lattice radiotherapy for bulky tumors: A practical clinical guide from evidence synthesis to linac-based implementation in diverse resource settings

ABSTRACT

Bulky tumors, defined as lesions exceeding 5 cm in maximum diameter, remain among the most challenging scenarios in radiation oncology. These tumors are often characterized by extensive hypoxia, radioresistance, and proximity to dose-limiting organs at risk, rendering conventional homogeneous-dose radiotherapy suboptimal. Lattice radiotherapy (LRT), a three-dimensional evolution of spatially fractionated radiation therapy (SFRT), offers a paradigm-shifting approach by delivering ablative doses to discrete high-dose vertices within the gross tumor volume while maintaining low peripheral doses. Since the first clinical application in 2014, the global experience has expanded to over 300 patients across lung, head and neck, gynecological, sarcoma, and other sites, demonstrating tumor volume reductions frequently exceeding 50% with minimal toxicity. Recent meta-analytic data from 187 patients confirm pooled 3-month complete and partial response rates of approximately 37% and 42%, respectively, with severe adverse events below 4%. The radiobiological rationale underpinning LRT encompasses direct ablation of tumor vasculature and hypoxic cores, radiation-induced bystander signaling in low-dose valleys, immunogenic cell death, and the preservation of tumor-infiltrating lymphocytes essential for abscopal responses. Emerging preclinical evidence suggests that coupling SFRT with immune checkpoint inhibitors may potentiate systemic antitumor immunity. Despite these promising signals, the clinical literature remains predominantly comprised of case reports and small retrospective series, with no completed randomized trials. Furthermore, existing reviews have been written from the perspective of well-resourced centers, leaving a significant gap for radiation oncologists practicing in low- and middle-income countries (LMICs) where bulky, advanced-stage tumors are disproportionately prevalent. This narrative review provides a comprehensive, practical clinical guide encompassing the historical evolution from GRID to LRT, the radiobiological framework, a detailed site-by-site evidence synthesis of all published clinical data, a proposed patient selection algorithm, and a novel tiered implementation framework stratified by linear accelerator (LINAC) capability—from basic multileaf collimator (MLC)-based GRID through advanced volumetric modulated arc therapy (VMAT) with image guidance. We also examine the immunotherapeutic frontier and ongoing prospective trials. Our aim is to equip the practicing radiation oncologist, particularly in resource-diverse settings, with the knowledge needed to evaluate, adopt, and implement LRT for their patients with bulky, radioresistant tumors.