Grid/Lattice radiotherapy: Innovation with evidence or innovation ahead of evidence?

Radiation tolerance in the context of toxicity in large fields used in abdominal and pelvic masses had been a big concern. To reduce the toxicities, a moving strip technic was developed in the Co-60 era.1, 2 In a pilot study, Mohiuddin et al.3 used multiple nonconfluent beam by circular holes and called it ‘grid therapy’ to overcome this issue. This megavoltage grid therapy technique for massive tumors gave good palliation with reduced toxicities. This opened a new avenue for palliative treatment using microbeam, Tomotherapy, and proton therapy.4-6 In modern days, instead of blocks, multileaf collimator (MLC) available on most linear accelerators have been used for grid therapy.7, 8 Recently this technique is coined as spatially fractioned, grid, lattice therapy which is described in a recent book by Zhang and Mayr.9 Radiation treatment approaches with grid/lattice therapy technique have not been validated in any clinical trial. In a recent study with 176 patients, 1-year survival rate was mere 37% with significant recurrences.10 Additionally, there is no large study providing its efficacy. Furthermore, its scientific theory is unclear and contrary to believe that radiation dose in tumor should be uniform. Some have coined it as abscopal effect. This article debates scientific validity of the clinical outcome if any without a clinical trial. Arguing in favor of grid/lattice therapy is Dr Mansoor M. Ahmed, PhD, a research professor and director of the Division of Radiation Biology at Albert Einstein College of Medicine, New York. He has worked in spatially fractionated radiation therapy (SFRT), including GRID and LATTICE approaches, for over 25 years. His research began in 1999 with early GRID therapy studies and has since focused on understanding the biological mechanisms behind these treatments, including TNF-α, TRAIL, and ceramide pathways. In 2014, his team showed connections between SFRT and immune responses that helped shape current research directions. Before joining Einstein in New York, he served as Program Director at the National Cancer Institute's Radiation Research Program (2012-2023). He has published extensible on this topic and received the NIH Director's Award of Merit in 2019. He held faculty positions at the University of Miami and University of Kentucky. His current work focuses on developing radiation therapy approaches for difficult-to-treat tumors, including recent studies on combining radiation timing with immune responses. Arguing against the preposition is Dr Mohamed E. Abazeed, MD, PhD, a radiation oncologist and physician scientist who uses multi-modal approaches to improving the personalization of cancer treatments. He received his MD/PhD degrees from the University of Michigan with a research focus in model system genetics. As a Leonard B. Holman Research Fellow in the Harvard Radiation Oncology Program, he conducted his training at the Broad Institute with a focus on cancer genomics and computational biology. His current research efforts are focused on improving therapies for thoracic cancers, including the initiation of investigator-initiated biomarker and augmented intelligence studies. With expertise in computational biology, genetics, and imaging, Dr. Abazeed and his team have applied and developed tools to advance approaches for personalized cancer treatment, especially for patients treated with radiation. Dr. Abazeed is currently the Chair and William N. Brand Professor at department of Radiation Oncology at Northwestern University Feinberg School of Medicine and the Co-Leader of the Lung Cancer Program in the Robert H. Lurie Cancer Center in Chicago. Advanced, bulky tumors (> 5–10 cm) remain among the most pressing challenges in radiation oncology. Conventional radiation therapy (RT) techniques frequently fail, either delivering inadequate tumor control or producing unacceptable toxicity. Grid/SFRT, with over a century of clinical application and decades of mechanistic investigation, provides a compelling alternative that merits serious consideration as part of the standard of care. The early GRID method also carried inherent limitations: the high-dose beams traversed normal tissues, exposing patients to unnecessary toxicities. With the advent of 3D SFRT techniques, including Lattice Radiotherapy (LRT),9 these drawbacks have been largely overcome. Modern approaches can focus ablative doses within defined intratumoral sub-volumes while preserving surrounding tissues and organs. This transformation opens the possibility of using Grid/SFRT not only for palliation but also as a component of curative-intent strategies. Conventional palliative RT that provides limited symptomatic relief with minimal tumor control, or No treatment at all, due to the anticipated futility of conventional regimens. The outcome gap in this patient population underscores the urgent need for innovative approaches. Modern SFRT provides a third path: the ability to deliver higher intratumoral doses while maintaining or even lowering normal tissue exposure. Clinical series have demonstrated improved local responses and survival outcomes, though larger multi-institutional validation remains essential.11-14 Historical analogy: Radiation therapy itself was widely practiced long before the discovery of DNA structure and the elucidation of molecular mechanisms in the 1950s. In comparison, the mechanistic knowledge supporting SFRT today is far stronger than what existed during the formative years of the field. Dose heterogeneity rationale: Tumor dose uniformity may facilitate response prediction but is not inherently advantageous for tumor control. Purposeful heterogeneity that increases intratumoral dose while maintaining low surrounding exposure can produce superior biological and clinical outcomes—even by the principle of traditional radiobiology. Mechanistic evidence: Modern investigations have uncovered multiple interrelated biological processes triggered by SFRT15: These findings form a coherent and biologically plausible rationale for SFRT. Indeed, our current mechanistic insight into SFRT surpasses what was available when modalities like stereotactic body radiotherapy (SBRT) or intensity modulated radiation therapy (IMRT) were first integrated into standard practice. Most of modern linacs with IMRT/VMAT capabilities and particle RT systems are well suited for delivering 2D or 3D SFRT. Automated planning systems now can generate SFRT treatment plans robustly, with improved consistency and quality. Consensus guidelines and QA protocols from professional societies standardize implementation and safety. Image-guided RT equipment and motion management system allow for accurate SFRT delivery. Patient-specific quality assurance for SFRT follows established IMRT/VMAT-based SRS and SBRT QA protocols, utilizing portal dosimetry systems (including EPID-based verification with gamma analysis), radiochromic film, and high-resolution diode array-based detectors to ensure dosimetric accuracy, reproducibility, and error detection capability across institutions. These advances eliminate the technical obstacles to broader clinical application. Some have characterized the discrepancy between SFRT's slow adoption and the rapid acceptance of IMRT or SBRT as a “double standard.” However, a more accurate frame may be that SBRT and IMRT were natural evolutions under the established radiobiological models, whereas SFRT represents a conceptual shift. The better comparison, in the context of “double standard”, may be to the early era of radiation therapy, when practice outpaced biological understanding. Today, we know more about SFRT's biology, although much more to be known, than our predecessors knew about conventional radiation when it was established as a clinical standard. SFRT-induced mediation—leveraging bystander and abscopal phenomena to induce systemic antitumor effects. Physical and biological dose enhancement—achieving tumoricidal dose escalation while respecting normal tissue tolerance. This dual framework could potentially expand SFRT's application beyond palliation, into curative-intent therapy, adjuvant settings, and integrated multimodality approaches. For bulky, advanced, and radioresistant tumors, the current “standard” is often no effective treatment at all. Modern SFRT, refined with modern techniques, supported by mechanistic insights, and enabled by contemporary planning and QA infrastructure, offers a scientifically grounded alternative. The question is no longer whether SFRT works, but whether we as a field can justify withholding it while patients face limited or futile options. Implementation of SFRT, both as a palliative and potentially curative modality, represents not only a clinical opportunity but an ethical imperative. Grid therapy's spatial dose modulation is conceptually elegant but radiobiologically imprecise. It relies on the assumption that islands of high-dose exposure interspersed with low-dose “valleys” will induce favorable bystander and abscopal effects. However, this paradigm remains speculative, largely derived from in vitro models or small retrospective cohorts. Unlike IMRT or SBRT, which are optimized to maximize tumor dose while conforming to organ-at-risk (OAR) constraints, grid therapy often results in highly heterogeneous dose distributions. In an era where dose precision, conformity, and biologically effective dose (BED) calculations are foundational to planning, this heterogeneity poses a significant clinical risk, especially for tumors in proximity to critical structures. Grid therapy is incompatible with modern image-guided and adaptive techniques. Technologies such as MR-Linac and CBCT-based ART have revolutionized the ability to personalize treatment in real time based on anatomical changes and tumor response. In contrast, grid therapy offers no mechanism for dose adaptation, motion management, or volumetric image guidance. Its implementation requires predesigned collimation with little flexibility for evolving target volumes or shifting anatomy. This technical mismatch relegates grid therapy to an antiquated modality with poor interoperability in today's radiation oncology ecosystem. The therapeutic rationale behind grid therapy, the treatment of bulky tumors where conventional fractionation is ineffective, is increasingly outdated. SBRT or hypofractionated regimens with dose painting is supported by robust radiobiological models and advanced imaging now offer superior solutions for delivering ablative doses with precision.19 Furthermore, advances in systemic therapy, including immunotherapy, radiosensitizers, and targeted therapies, provide complementary strategies for addressing radioresistant disease without the need to resort to experimental and logistically burdensome approaches like grid therapy.20 Fourth, while some small institutional series suggest potential tumor response with grid therapy, these studies are almost universally non-randomized, underpowered, and heterogeneously reported. There is no Level I evidence supporting its use and, critically, nor are there clear guidelines on patient selection, optimal grid design, or clinical endpoints.14 In contrast, modern techniques are backed by randomized trials, consensus guidelines, and dosimetric validation, enabling reproducibility and standardized care across institutions. Finally, from an operational perspective, SFRT continues to present workflow and QA complexities that must be weighed against its uncertain clinical value. Although advances in MLC-based virtual grids and planning automation have reduced some of the logistical barriers cited historically, implementation remains nontrivial. Commissioning, small-field dosimetry,21 and plan verification require additional resources and individualized oversight. In an era where radiation oncology is advancing toward automation, adaptability, and patient-centered precision, SFRT represents a departure from the efficiency and standardization that characterize mature technologies. Until evidence demonstrates a clear therapeutic advantage, expanding its use beyond protocol-driven settings risks adding operational burden without proven clinical benefit. In conclusion, while grid therapy represents an intriguing concept with niche applications, its continued use is misaligned with the trajectory of modern radiation oncology. Precision, adaptability, and evidence-based practice are the pillars of contemporary care. Grid therapy fails to meaningfully support any of these pillars. Future research is better directed toward integrating biologically guided imaging, AI-driven adaptation, and molecularly informed radiotherapy and not reviving antiquated modalities with speculative mechanisms. The opening statement by Dr Abazeed against Grid/SFRT characterizes the approach as radiobiologically speculative, technically antiquated, and clinically redundant in the era of conformal IMRT/SBRT. That framing overlooks the last several years of prospective feasibility work, consensus standard-setting, and growing clinical experience across photon and proton platforms.14, 22, 23 Far from being a historical curiosity, contemporary SFRT is a family of image-guided, TPS-planned techniques (GRID, LATTICE, minibeam/microbeam) designed to address a persistent unmet need: safe dose-escalation or rapid cytoreduction in very large or radioresistant tumors where uniform ablative dosing is not achievable without excessive toxicity. Recent literature reviews and consensus documents outline indications, planning/dosimetric metrics, and trial designs, positioning SFRT as an evolving, translationally informed option to complement—not replace—standard conformal therapy. Large-volume disease remains a blind spot for conventional SBRT: once targets exceed safe organs-at-risk (OAR) constraints or motion envelopes, purely uniform high-BED prescriptions become impractical. LATTICE and GRID explicitly tackle that geometry by delivering high-dose vertices (or beamlets) within gross disease while keeping valleys and peripheral margin doses OAR-constrained—often as a brief induction (e.g., 1–5 fractions) followed by conventional or hypofractionated consolidation. Multiple prospective and structured single-institution series (including Phase I LATTICE SBRT in very large tumors) have demonstrated feasibility and acceptable acute toxicity, with consistent radiographic debulking and symptomatic relief signals in bulky tumors across histologies. These experiences are not Level I evidence and should not be oversold, but they do provide a reproducible safety foundation and a biologically rational path for expansion into multi-institutional trials—exactly the progression recommended by recent NRG/AAPM and international consensus work.14, 22, 23 The “bystander/abscopal” language that critics call speculative is now backed by a maturing preclinical and translational literature specific to spatially heterogeneous dose delivery.15 Minibeam/microbeam experiments consistently show normal-tissue sparing with preserved function despite very high peak doses, while tumoricidal effects correlate with structured heterogeneity and immunogenic cell death. Emerging immuno-oncology data indicate that intratumoral dose heterogeneity can enhance antigen release, dendritic priming, and T-cell infiltration—providing a mechanistic link between SFRT patterns and systemic antitumor responses. Importantly, the literature recognizes that valley dose and peak-to-valley dose ratio (PVDR) influence response, so contemporary SFRT planning uses (e.g., than practice with what The consensus is not that but that biologically guided heterogeneity is an of discovery with the call for prospective studies with immune and imaging Modern SFRT is not with It is in using MLC-based virtual grids or LATTICE vertices with published on beam and to ensure accurate valley and small-field with plans are and to the in the tumor and to has beyond toward (e.g., at in and that are robust to small SFRT (e.g., modality where and can support valley and sparing when these advances the that SFRT is or they show that as in SBRT, on planning, imaging, and The that SFRT no mechanism for dose adaptation, motion management, or volumetric image the era of blocks, not current 25 SFRT are (or where to gross tumor and motion is as in SBRT with or and of LATTICE vertices or patterns is when using the adaptive in use for Recent consensus documents explicitly outline to SFRT patterns within conventional including to SFRT induction with conformal consolidation. 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