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Palliative treatment of advanced cancer using multiple nonconfluent pencil beam radiation: A pilot study
Abstract
In the era of orthovoltage radiation, multiple nonconfluent pencil beam radiation (GRID) therapy was utilized to minimize superficial normal tissue damage while delivering tumorcidal doses at specified depths in tissues. The success of GRID therapy was based on the fact that small volumes of tissues could tolerate high doses of radiation. Since the development of megavoltage radiation and skin sparing, GRID therapy has been abandoned. In a pilot study, the authors adapted the principles of GRID therapy to megavoltage photon beams to treat patients with massive tumors or recurrent tumors after tolerance doses of radiation. Twenty-two patients have been entered in the study. All patients were symptomatic and had exhaustive conventional surgery, chemotherapy, and radiotherapy approaches to treatment. A 50:50 GRID (open to closed areas) was utilized, and a prescribed dose of 1000 to 1500 cGy to the open areas was given using a single photon field. In four patients, a second GRID treated was delivered at a split course interval of 4 weeks. The follow-up in these patients ranges from 1 month to 18 months. The results of treatment have been remarkable with 20 of 22 patients achieving dramatic relief of severe symptoms, and several patients showing significant objective regression. No acute effects have been observed, including those patients having large volumes of the abdomen irradiated. No unusual skin or subcutaneous early or late damage has been observed in follow-up.
... Spatially fractionated radiation therapy (SFRT), the delivery of intentional highly nonuniform tumor dose distributions, presents a major departure from conventionally practiced radiation therapy which seeks the best possible dose homogeneity. SFRT has shown high, and sometimes drastic palliative tumor responses in challenging bulky treatmentrefractory tumors, while causing only minimal toxicity [1][2][3][4][5][6][7][8][9][10][11][12][13]. Investigating the underlying mechanisms of SFRT's profound tumoricidal effects is an area of active and rapidly advancing research. ...
... Building on the encouraging experience in palliation [1][2][3][4], single-institution smaller pilot studies have since explored SFRT in primary (non-metastatic) advanced bulky primary head and neck [5,6,13], lung [20], cervical cancer [8], and sarcoma [9,10,12], treated with curative intent. Longer-term outcome data in these cohorts have shown similarly high responses to SFRT, with high local control and encouraging survival outcomes and limited toxicities in these far-advanced bulky primary tumors [5][6][7][8], as observed in the initial multidisease palliative series [1][2][3][4]. ...
... Building on the encouraging experience in palliation [1][2][3][4], single-institution smaller pilot studies have since explored SFRT in primary (non-metastatic) advanced bulky primary head and neck [5,6,13], lung [20], cervical cancer [8], and sarcoma [9,10,12], treated with curative intent. Longer-term outcome data in these cohorts have shown similarly high responses to SFRT, with high local control and encouraging survival outcomes and limited toxicities in these far-advanced bulky primary tumors [5][6][7][8], as observed in the initial multidisease palliative series [1][2][3][4]. The SFRT pilot experience in bulky advanced gynecologic cancers is promising [8,21,22]. ...
Despite the unexpectedly high tumor responses and limited treatment-related toxicities observed with SFRT, prospective multi-institutional clinical trials of SFRT are still lacking. High variability of SFRT technologies and methods, unfamiliar complex dose and prescription concepts for heterogeneous dose and uncertainty regarding systemic therapies present major obstacles towards clinical trial development. To address these challenges, the consensus guideline reported here aimed at facilitating trial development and feasibility through a priori harmonization of treatment approach and the full range of clinical trial design parameters for SFRT trials in gynecologic cancer. Gynecologic cancers were evaluated for the status of SFRT pilot experience. A multi-disciplinary SFRT expert panel for gynecologic cancer was established to develop the consensus through formal panel review/discussions, appropriateness rank voting and public comment solicitation/review. The trial design parameters included eligibility/exclusions, endpoints, SFRT technology/technique, dose/dosimetric parameters, systemic therapies, patient evaluations, and embedded translational science. Cervical cancer was determined as the most suitable gynecologic tumor for an SFRT trial. Consensus emphasized standardization of SFRT dosimetry/physics parameters, biologic dose modeling, and specimen collection for translational/biological endpoints, which may be uniquely feasible in cervical cancer. Incorporation of brachytherapy into the SFRT regimen requires additional pre-trial pilot investigations. Specific consensus recommendations are presented and discussed.
... Radiation therapy treatment for patients with advanced bulky tumors (≥8 cm) for palliative care or curative intent via spatially fractionated radiation therapy (SFRT), also known as GRID therapy, started in the orthovoltage Era with a grid collimator. 1 Utilizing a physical Cerrobend GRID-block can allow a regrowth of skin and subcutaneous tissue under the blocked area and manage normal tissue toxicity. In the megavoltage Era, the management of unresectable bulky tumors using an open high-energy X-ray field has been converted to a set of pencil beam-type radiation fields using an external physical GRID-block comprising brass, cerrobend, or lead in order to deliver a large single dose of 10-20 Gy. [2][3][4] This large dose can be followed by a conventional radiotherapy treatment of 30-70 Gy, concurrent chemoradiation, or neoadjuvent surgical resection. GRID therapy has resulted in a significant tumor reduction (62%-91%) with a single dose of 15 Gy or higher followed by the conventional radiotherapy with a 78% pain relief response rate, 20% complete clinical response,and 73% rates of mass effect with and without conventional radiotherapy treatment in the curative setting and maintaining the skin toxicity. ...
... Typically, sarcoma and head-and-neck cancer responded very well. [2][3][4][5][6] The underlying mechanisms of the SFRT treatment response have not been fully explored yet. However, there are several speculative theories to contribute the promising clinical outcomes of SFRT therapy. ...
... 11,12 However, there are major limitations of the conventional physical single-field GRID-block therapy:(1) deepseated bulky tumors may only receive a third or less of the prescribed dose of 15 Gy. (2) It is difficult to manage skin toxicity, while escalating the tumor dose, and difficult to spare immediately adjacent critical organs. ...
For fast, safe, and effective management of large and bulky (≥8 cm) non‐resectable tumors, we have developed a conebeam CT‐guided three‐dimensional (3D)‐conformal MLC‐based spatially fractionated radiation therapy (SFRT) treatment. Using an in‐house MLC‐fitting algorithm, Millennium 120 leaves were fitted to the gross tumor volume (GTV) generating 1‐cm diameter holes at 2‐cm center‐to‐center distance at isocenter. SFRT plans of 15 Gy were generated using four to six coplanar crossfire gantry angles 60° apart with a 90° collimator, differentially weighted with 6‐ or 10‐MV beams. A dose was calculated using AcurosXB algorithm, generating sieve‐like dose channels without post‐processing the physician‐drawn GTV contour within an hour of CT simulation allowing for the same day treatment. In total, 50 extracranial patients have been planned and treated using this method, comprising multiple treatment sites. This novel MLC‐fitting algorithm provided excellent dose parameters with mean GTV (V7.5 Gy) and mean GTV doses of 53.2% and 7.9 Gy, respectively, for 15 Gy plans. Average peak‐to‐valley dose ratio was 3.2. Mean beam‐on time was 3.32 min, and treatment time, including patient setup and CBCT to beam‐off, was within 15 min. Average 3D couch correction from original skin‐markers was <1.0 cm. 3D MLC‐based SFRT plans enhanced target dose for bulky masses, including deep‐seated large tumors while protecting skin and adjacent critical organs. Additionally, it provides the same day, safe, effective, and convenient treatment by eliminating the risk to therapists and patients from heavy gantry‐mounted physical GRID‐block—we recommend other centers to use this simple and clinically useful method. This rapid SFRT planning technique is easily adoptable in any radiation oncology clinic by eliminating the need for plan optimization and patient‐specific quality assurance times while providing dosimetry information in the treatment planning system. This potentially allows for dose‐escalation to deep‐seated masses to debulk unresectable large tumors providing an option for neoadjuvant treatment. An outcome study of clinical trial is underway.
... The results of well-conducted GRID radiation therapy studies have the potential to advance the clinical management of bulky and advanced tumors by providing improved treatment response, and to further develop our current radiobiology models and parameters of radiation therapy design. Ó 2020 INTRODUCTION Megavoltage X-ray GRID therapy is a form of spatially fractionated radiation therapy (SFRT) that has been used successfully to manage patients with bulky tumors, which are often refractory to conventional radiation therapy and other cancer therapies (1,2). GRID therapy employs an Xray fluence in a spatially-fractionated irradiation pattern in the shape of a grid (grid pattern). ...
... GRID therapy is not new; GRID radiation fields were initially used to overcome the challenges of treating deep-seated tumors in the kilovoltage X-ray era before the 1950s (5). The technology has subsequently been adapted to megavoltage beams and the first clinical study using megavoltage GRID therapy was published in 1990 (1). Initially, GRID therapy showed success in reducing tumor size and inducing high rates of symptomatic response in very bulky, palliatively treated tumors in patients with metastatic cancer. ...
... Initially, GRID therapy showed success in reducing tumor size and inducing high rates of symptomatic response in very bulky, palliatively treated tumors in patients with metastatic cancer. Over the past 30 years, ample clinical evidence has accumulated for the high symptomatic and clinical response and minimal toxicity of GRID therapy in palliatively and definitively treated tumors with excessive bulk and/or therapy resistance (1,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). More recently, SFRT has also been used as a boost or ''priming'' therapy to improve response to definitive or preoperative radiation in bulky, locally advanced curable tumors (1,(10)(11)(12)(13)(14)(15)(16). ...
The limits of radiation tolerance, which often deter the use of large doses, have been a major challenge to the treatment of bulky primary and metastatic cancers. A novel technique using spatial modulation of megavoltage therapy beams, commonly referred to as spatially fractionated radiation therapy (SFRT) (e.g., GRID radiation therapy), which purposefully maintains a high degree of dose heterogeneity across the treated tumor volume, has shown promise in clinical studies as a method to improve treatment response of advanced, bulky tumors. Compared to conventional uniform-dose radiotherapy, the complexities of megavoltage GRID therapy include its highly heterogeneous dose distribution, very high prescription doses, and the overall lack of experience among physicists and clinicians. Since only a few centers have used GRID radiation therapy in the clinic, wide and effective use of this technique has been hindered. To date, the mechanisms underlying the observed high tumor response and low toxicity are still not well understood. To advance SFRT technology and planning, the Physics Working Group of the Radiosurgery Society (RSS) GRID/Lattice, Microbeam and Flash Radiotherapy Working Groups, was established after an RSS-NCI Workshop. One of the goals of the Physics Working Group was to develop consensus recommendations to standardize dose prescription, treatment planning approach, response modeling and dose reporting in GRID therapy. The objective of this report is to present the results of the Physics Working Group's consensus that includes recommendations on GRID therapy as an SFRT technology, field dosimetric properties, techniques for generating GRID fields, the GRID therapy planning methods, documentation metrics and clinical practice recommendations. Such understanding is essential for clinical patient care, effective comparisons of outcome results, and for the design of rigorous clinical trials in the area of SFRT. The results of well-conducted GRID radiation therapy studies have the potential to advance the clinical management of bulky and advanced tumors by providing improved treatment response, and to further develop our current radiobiology models and parameters of radiation therapy design.
... Spatially fractionated radiation therapy (SFRT), which applies a non-uniform instead of the commonly employed uniform dose pattern to the tumor, has shown promise in improving local tumor control while minimizing toxicity in various bulky advanced malignancies (2)(3)(4)(5). Foundational experience with GRID-based SFRT has long demonstrated unusually drastic and rapid symptomatic responses and favorable local control in palliative treatment for bulky metastatic tumors (2)(3)(4). More recent experience in primary tumors of far-advanced or bulky stages showed similarly high symptom response and local control rates as well as early evidence of long-term survival in a substantial proportion of patients (5)(6)(7). ...
... Spatially fractionated radiation therapy (SFRT), which applies a non-uniform instead of the commonly employed uniform dose pattern to the tumor, has shown promise in improving local tumor control while minimizing toxicity in various bulky advanced malignancies (2)(3)(4)(5). Foundational experience with GRID-based SFRT has long demonstrated unusually drastic and rapid symptomatic responses and favorable local control in palliative treatment for bulky metastatic tumors (2)(3)(4). More recent experience in primary tumors of far-advanced or bulky stages showed similarly high symptom response and local control rates as well as early evidence of long-term survival in a substantial proportion of patients (5)(6)(7). ...
... While three large SFRT series with a total of over 150 palliatively treated patients and far-advanced primary tumors have been published (2)(3)(4)(5), there is less experience in SFRT for disease-specific patient cohorts. Smaller published pilot studies in head and neck (6, 10), lung cancer (11), melanoma (12) and sarcoma (13,14) have shown promising local control and survival outcomes that corroborate the findings of the initial multi-disease palliative and advanced-stage cohorts (2)(3)(4)(5). ...
Spatially fractionated radiation therapy (SFRT) has shown promise in generating high tumor response and local control in the treatment of various palliative and locally advanced bulky tumors. SFRT has not yet been studied systematically in cancer of the cervix. Here we report the first series of patients receiving SFRT for advanced/bulky cervical cancer. Ten patients with far-advanced bulky cervical cancer, stage IIIB-IVA (seven squamous cell and three adeno/adenosquamous carcinomas) received lattice radiation therapy (LRT), a variant of SFRT. The LRT regimen consisted of a dose of 24 Gy in three fractions, given to an average of five high-dose spheres within the gross tumor volume (GTV). The dose in the peripheral GTV was limited to 9 Gy in three factions, using the volumetric modulated arc therapy (VMAT) technique. LRT was followed subsequently by conventionally fractionated external beam irradiation to 44.28 Gy (range: 39.60-45.00 Gy in 1.8 Gy fractions). All patients received concurrent cisplatin chemotherapy. Tumor response was assessed clinically, by morphological imaging (CT, MRI) and 18FDG PET/CT. Tumor control and survival rates were estimated using Kaplan-Meier analysis. All patients had local control at a median follow-up of 16 months (1-77). The two-year disease-specific survival rate was 53.3%. All cancer deaths were due to metastatic failure with local control maintained. Among the three patients who died of disease, all had adeno- or adenosquamous carcinoma histology, and no deaths from disease occurred among the patients with squamous cell carcinoma (P = 0.010). There was no grade ≥3 short-term or long-term treatment-related complications. Intra-treatment morphological tumor regression was highly variable (mean: 54%, range: 6-91%). After therapy, the complete metabolic response was 88.9% (8/9), and one patient out of the nine patients with post-treatment PET-CT had partial response (11.1%). Our preliminary data suggest that LRT-based SFRT is well tolerated in patients with far-advanced bulky cervical cancer and results in favorable tumor responses and high local control. These observations confirm prior reports of favorable tumor control and toxicity outcomes with SFRT in other advanced/bulky malignancies. Our findings are corroborated by high molecular-imaging-based tumor response. These encouraging hypothesis-generating results require cautious interpretation and confirmation with larger patient cohorts, preferably through a multi-institutional controlled randomized clinical trial.
... Published clinical results employing GRID therapy have most commonly focused on its use in the palliative setting. Many reports of patients with large or recurrent tumors treated with GRID therapy showed patients achieving good oncological outcomes [1,[4][5][6]. Placement of 10-15 Gy to Dmax was delivered with a single field and a GRID block with 50:50 (1:1) open to close areas ratio employed. No acute effects and no unusual late damage were observed in a follow-up time range of 1-18 months [4]. ...
... Placement of 10-15 Gy to Dmax was delivered with a single field and a GRID block with 50:50 (1:1) open to close areas ratio employed. No acute effects and no unusual late damage were observed in a follow-up time range of 1-18 months [4]. Subsequently, palliative GRID therapy showed a response rate of more than 90% and complete response (CR) rate of 27% [5]. ...
... Outcomes from tumors with different histological characteristics and treatment sites from historical clinical outcomes from GRID therapy have been summarized by Meigooni et al. [8]. The clinical total response rates with grid therapy were as following: Osteosarcoma (100%), Liposarcoma (50%), Leiomyosarcoma (100%), Colorectal (100%) (4); Sarcoma (94%), SCC (92%), Melanoma (83%), Adenocarcinoma (69%) [4]; Sarcoma (83%), SCC (94%), melanoma (50%) [5]; SCC of H&N (93%) [6]; Parotid (0%), Base of tongue (30%) Maxillary sinus (50%), Nasopharynx, Retromolar trigone, and Larynx (100%) Tonsil (25%) [7]. A few publications have highlighted that SFRT may be useful in radiation-resistant tumors, such as sarcoma. ...
... Spatially fractionated radiotherapy was initially used in the era of low energy x-rays to allow for safe delivery of radiation to internal tumors while allowing for skin and superficial tissue sparing. 1,2 The radiation beam, often delivered through a single field, was spatially fractionated into small beamlets by sieve-like blocking to form a grid pattern (GRID therapy). Tissues, such as skin, in the blocked portion of the treatment field were thought to promote healing/repair of normal tissues irradiated to high dose in the beamlet paths. ...
... In the era of skin-sparing megavoltage photon irradiation, GRID therapy has continued to play a role in radiation oncology, mostly in the treatment of bulky tumors. 1,2 The GRID treatment has typically been delivered in one high-dose (15-20 Gy) fraction, often followed by conventionally fractionated treatment courses which target the entire tumor. The radiation field is partitioned by commercially available blocks or by MLC leaf patterns which reproduce the effect of these blocks. ...
... Many studies have shown excellent tumor response results with this approach and there is a great deal of interest in the radiobiology of GRID treatments. [1][2][3][4][5] Upfront treatment with GRID may influence oxygenation in tumors as well as induce bystander effects. 4,5 Despite the successes with conventional GRID therapy, it has dosimetric limitations in the treatment of very deep-seated tumors. ...
Purpose:
The purpose of this work was to compare the dosimetry and delivery times of 3D-conformal (3DCRT)-, volumetric modulated arc therapy (VMAT)-, and tomotherapy-based approaches for spatially fractionated radiation therapy for deep tumor targets.
Methods:
Two virtual GRID phantoms were created consisting of 7 "target" cylinders (1-cm diameter) aligned longitudinally along the tumor in a honey-comb pattern, mimicking a conventional GRID block, with 2-cm center-to-center spacing (GRID2 cm ) and 3-cm center-to-center spacing (GRID3 cm ), all contained within a larger cylinder (8 and 10 cm in diameter for the GRID2 cm and GRID3 cm , respectively). In a single patient, a GRID3 cm structure was created within the gross tumor volume (GTV). Tomotherapy, VMAT (6 MV + 6 MV-flattening-filter-free) and multi-leaf collimator segment 3DCRT (6 MV) plans were created using commercially available software. Two tomotherapy plans were created with field widths (TOMO2.5 cm ) 2.5 cm and (TOMO5 cm ) 5 cm. Prescriptions for all plans were set to deliver a mean dose of 15 Gy to the GRID targets in one fraction. The mean dose to the GRID target and the heterogeneity of the dose distribution (peak-to-valley and peak-to-edge dose ratios) inside the GRID target were obtained. The volume of normal tissue receiving 7.5 Gy was determined.
Results:
The peak-to-valley ratios for GRID2 cm /GRID3 cm /Patient were 2.1/2.3/2.8, 1.7/1.5/2.8, 1.7/1.9/2.4, and 1.8/2.0/2.8 for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The peak-to-edge ratios for GRID2 cm /GRID3 cm /Patient were 2.8/3.2/5.4, 2.1/1.8/5.4, 2.0/2.2/3.9, 2.1/2.7/5.2 and for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The volume of normal tissue receiving 7.5 Gy was lowest in the TOMO2.5 cm plan (GRID2 cm /GRID3 cm /Patient = 54 cm3 /19 cm3 /10 cm3 ). The VMAT plans had the lowest delivery times (GRID2 cm /GRID3 cm /Patient = 17 min/8 min/9 min).
Conclusion:
Our results present, for the first time, preliminary evidence comparing IMRT-GRID approaches which result in high-dose "islands" within a target, mimicking what is achieved with a conventional GRID block but without high-dose "tail" regions outside of the target. These approaches differ modestly in their ability to achieve high peak-to-edge ratios and also differ in delivery times.
... 4 Interest in SFRT would not be renewed until 1990, when Mohiuddin et al demonstrated the feasibility of this technique with bulky and refractory tumors, historically considered to be resistant to standard fractionated radiation therapy. 5,6 SFRT, in its original form, requires the simple collimation of a broad-based photon beam into pencil beam-shaped, nonconfluent grids to create hexagonal or orthogonal patterns of "hot spots" surrounded by peripheries of nonirradiated tissue (Fig. 1). 7,8 We will refer to this method as GRID and note that it was the original method described by Kohler et al. ...
... GRID therapy was first delivered using attenuation blocks with regularly spaced apertures that can be mounted onto the linear accelerator head (Fig. 1a). 5 Commercially available compensators are made of Cerrobend (Radiation Products Design, Inc, Albertive, MN) or brass (dot Decimal Inc, Sanford, FL). 10,11 Both are made to order with customizable aperture sizes, center-to-center spacing, and holes that follow beam divergence. ...
... The initial Cerrobend block had a 50% open-to-closed field ratio. 5 Evaluation of the Cerrobend block with 1.4-cm hole diameter and 2.1-cm center-to-center spacing demonstrated a valley-topeak ratio of approximately 20% for 6 MV and 25% to 32% for 18 MV at 10-cm depth in a water phantom. 10 Similarly, the brass block with 1-cm hole diameter and 2-cm center-tocenter spacing revealed a valley-to-peak ratio of around 27% for 6 MV and 35% for 18 MV. ...
Spatially fractionated radiation therapy represents a significant departure from canonical thinking in radiation oncology despite having origins in the early 1900s. The original and most common implementation of spatially fractionated radiation therapy uses commercially available blocks or multileaf collimators to deliver a nonconfluent, sieve-like pattern of radiation to the target volume in a nonuniform dose distribution. Dosimetrically, this is parameterized by the ratio of the valley dose in cold spots to the peak dose in hot spots, or the valley-to-peak dose ratio. The radiobiologic mechanisms are postulated to involve radiation-induced bystander effects, microvascular alterations, and/or immunomodulation. Current indications include bulky or locally advanced disease that would not be amenable to conventional radiation or that has proved refractory to chemoradiation. Early-phase clinical trials have shown remarkable success, with some response rates >90% and minimal toxicity. This has promoted technological developments in 3-dimensional formats (LATTICE), micron-size beams (microbeam), and proton arrays. Nevertheless, more clinical and biological data are needed to specify ideal dosimetry parameters and to formulate robust clinical indications and guidelines for optimal standardized care.
... A summary of clinical studies reporting on the response rate and normal tissue complications of GRID RT using photon beams is presented in Table 1. The first clinical findings on the efficacy and safety of GRID RT with megavoltage photon beams were reported by Mohiuddin's group [70][71][72] for palliative patients with bulky tumours who had been treated to tolerance or were refractory to conventional radiotherapy. The first cohort consisted of 22 patients with diverse histologies in a palliative setting [70]. ...
... The first clinical findings on the efficacy and safety of GRID RT with megavoltage photon beams were reported by Mohiuddin's group [70][71][72] for palliative patients with bulky tumours who had been treated to tolerance or were refractory to conventional radiotherapy. The first cohort consisted of 22 patients with diverse histologies in a palliative setting [70]. Treatment was delivered using a hexagonal grid block and MV photons delivering GRID doses ranging from 10 Gy to 15 Gy. ...
The continuously evolving field of radiotherapy aims to devise and implement techniques that allow for greater tumour control and better sparing of critical organs. Investigations into the complexity of tumour radiobiology confirmed the high heterogeneity of tumours as being responsible for the often poor treatment outcome. Hypoxic subvolumes, a subpopulation of cancer stem cells, as well as the inherent or acquired radioresistance define tumour aggressiveness and meta-static potential, which remain a therapeutic challenge. Non-conventional irradiation techniques, such as spatially fractionated radiotherapy, have been developed to tackle some of these challenges and to offer a high therapeutic index when treating radioresistant tumours. The goal of this article was to highlight the current knowledge on the molecular and radiobiological mechanisms behind spatially fractionated radiotherapy and to present the up-to-date preclinical and clinical evidence towards the therapeutic potential of this technique involving both photon and proton beams.
... However, the normal tissue tolerance improves dramatically if the treatment field is divided into numerous small fields using a grid block. Clinical achievements of 6-MV SFGRT have been reported in several papers by Mohiuddin et al. [3][4][5] . Several possible mechanisms have been proposed for the enhancement of treatment efficiency by SFGRT. ...
... Several possible mechanisms have been proposed for the enhancement of treatment efficiency by SFGRT. For patients given SFGRT followed by Conventional Fractionated Radiation Therapy (CFRT), re-oxygenation is expected to improve during the subsequent CFRT after the high local cell elimination from the single high-dose fraction [5] . Also, the bystander apoptosis effect under high radiation dose may reduce the tumor cells in the regions blocked by the grid [6] . ...
Purpose
: Photoneutron production is a common concern when using 18-MV photon beams in radiation therapy. In Spatially Fractionated Grid Radiation Therapy (SFGRT), the grid block in the collimation system modifies the neutron production, photon scattering, and electron contamination in and out of the radiation field. Such an effect was studied with grids made of different high-Z materials by Monte Carlo simulations. The results were also used to evaluate the lifetime risk of fatal cancers.
Methods
: MCNPX® code (2.7.0 extensions) was employed to simulate an 18-MV LINAC (Varian 2100 C/D). Three types of grid made of brass, cerrobend, and lead were used to study the neutron and electron fluence. Output factors for each grid with different field sizes were calculated. A revised female MIRD phantom with an 8-cm spherical tumor inside the liver was used to estimate the dose to the tumor and the critical organs. A 20-Gy SFGRT plan with Anterior Posterior (AP) - Posterior Anterior (PA) grid beams was compared with a Conventional Fractionated Radiation Therapy (CFRT) plan which delivered 40-Gy to the tumor by AP-PA open beams. Neutron equivalent dose, photon equivalent dose, as well as lifetime risks of fatal cancer were calculated in the organs at risk.
Results
: The grid blocks reduced the fluence of contaminant electrons inside the treatment field by more than 50%. The neutron fluences per electron-history in SFGRT plans with brass, cerrobend and lead were on average 55%, 31% and 31% less than that of the CFRT plan, respectively. However, when converting to fluences per delivered dose (Gy), the cerrobend and lead grid may incur higher neutron dose for 20 × 20 cm² field size and above. The changes in neutron mean energy, as well as the correlated radiation weighting factors, were insignificant. The total risk due to the photoneutrons in the SFGRT plans was 87% or lower than that in the CFRT plans. In both SFGRT and CFRT plans, the contribution of the primary and scattered photons to the fatal cancer risk was 2 times or more than the photoneutrons. The total risks from photons in SFGRT with brass, cerrobend, and lead blocks were 1.733, 1.374, and 1.260%, respectively, which were less than 30% of the total photon-risk in CFRT (5.827%).
Conclusion
: In the brass, cerrobend, and lead grids, the attenuation of photoneutrons outweighs its photoneutron production in 18-MV SFGRT. The total cancer risks from photons and photoneutrons in the SFGRT plans were 30% or less of the risks in the CFRT plans (5.911%). Using 18 MV photon beams with brass, cerrobend, and lead grid blocks is still a feasible option for SFGRT.
... Since its early inception over 100 years ago by Kohler (1)(2)(3)(4), spatially fractionated radiation therapy (SFRT) in the form of 2D GRID has been applied clinically, although not as a mainstream radiation therapy modality. While conducting systemic clinical trials has been practically difficult, the reported clinical data have suggested favorable outcomes and clinical value of GRID therapy for the treatment of advanced bulky tumors (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). A recent workshop sponsored by the National Cancer Institute (NCI) and Radiosurgery Society (RSS) for assessment of, and discussion on, the techniques and clinical merits of SFRT resulted in a comprehensive summary report (6). ...
... Over the years, a consensus has been gradually established among the relatively small community of GRID practitioners regarding the GRID dose distribution and the methods of treatment delivery (17,18). In addition to a number of published reviews (6)(7)(8)(9)(10), an article published in this special issue by Zhang et al. updates the collective understanding and technical perspectives on GRID radiation therapy. ...
The concept of spatially fractionated radiation therapy (SFRT) was conceived over 100 years ago, first in the form of GRID, which has been applied to clinical practice since its early inception and continued to the present even with markedly improved instrumentation in radiation therapy. LATTICE radiation therapy (LRT) was introduced in 2010 as a conceptual 3D extension of GRID therapy with several uniquely different features. Since 2014, when the first patient was treated, over 150 patients with bulky tumors worldwide have received LRT. Through a brief review of the basic principles and the analysis of the collective clinical experience, a set of technical recommendations and guidelines are proposed for the clinical implementation of LRT. It is to be recognized that the current clinical practice of SFRT (GRID or LRT) is still largely based on the heuristic principles. With advancements in basic biological research and the anticipated clinical trials to systemically assess the efficacy and risk, progressively robust optimizations of the technical parameters are essential for the broader application of SFRT in clinical practice.
... Clinical results have indicated that megavoltage spatially fractionated radiation therapy (SFRT, or simply called GRID therapy hereafter) provided by modern linear accelerator machines can significantly improve the therapeutic window in the treatment of bulky tumors. [1][2][3][4][5] Researchers have attributed the therapeutic advantages identified in the GRID radiation field to the bystander effect, which is stronger in the high gradient field 6 ; although the underlying reasons for improved responses can be explained by other mechanisms, 7 in which the potential therapeutic advantage of GRID therapy was derived from the radiobiological modeling results based on the different radio-sensitivities of normal and cancerous cells in the target volume. As reported by Zwicker et al. 8 and Zhang et al., 9,10 in theory the GRID therapy takes advantage of the fact that normal cells interspersed in the cancerous cells in the target volume in general have superior repair capabilities over cancer cells. ...
... To date, ample clinical evidence has accumulated for the high symptomatic and clinical response and minimal toxicity of GRID therapy in palliatively and definitively treated tumors with excessive bulk and/or therapy resistance. [1][2][3][4][5][25][26][27][28][29][30][31][32][33] EUD is an important parameter for assessing GRID therapy plan. ...
The purpose of this study was to explore the treatment planning methods of spatially fractionated radiation therapy (SFRT), commonly referred to as GRID therapy, in the treatment of breast cancer patients using multileaf collimator (MLC) in the prone position. A total of 12 patients with either left or right breast cancer were retrospectively chosen. The computed tomography (CT) images taken for the whole breast external beam radiation therapy (WB-EBRT) were used for GRID therapy planning. Each GRID plan was made by using two portals and each portal had two fields with 1-cm aperture size. The dose prescription point was placed at the center of the target volume, and a dose of 20 Gy with 6-MV beams was prescribed. Dose-volume histogram (DVH) curves were generated to evaluate dosimetric properties. A modified linear-quadratic (MLQ) radiobiological response model was used to assess the equivalent uniform doses (EUD) and therapeutic ratios (TRs) of all GRID plans. The DVH curves indicated that these MLC-based GRID therapy plans can deliver heterogeneous dose distribution in the target volume as seen with the conventional cerrobend GRID block. The plans generated by the MLC technique also demonstrated the advantage for accommodating different target shapes, sparing normal structures, and reporting dose metrics to the targets and the organs at risks. All GRID plans showed to have similar dosimetric parameters, implying the plans can be made in a consistent quality regardless of the shape of the target and the size of volume. The mean dose of lung and heart were respectively below 0.6 and 0.7 Gy. When the size of aperture is increased from 1 to 2 cm, the EUD and TR became smaller, but the peak/valley dose ratio (PVDR) became greater. The dosimetric approach of this study was proven to be simple, practical and easy to be implemented in clinic.
... With the development of megavoltage radiotherapy, grid therapy was abandoned temporarily for several years. It was paid attention again in palliative treatments of bulky tumors that do not respond enough to conventional radiotherapy (Mohiuddin et al., 1990(Mohiuddin et al., , 1996. In this modality, using a grid block on the tray of a medical linear accelerator (linac), a single high-dose fraction of 10 -20 Gy is given to the tumor. ...
... In this modality, using a grid block on the tray of a medical linear accelerator (linac), a single high-dose fraction of 10 -20 Gy is given to the tumor. Clinical achievements of 6-MV grid therapy have been reported by Mohiuddin et al. (1990Mohiuddin et al. ( , 1996. Nowadays, researchers are trying to merge grid therapy with carbon-ion therapy and also proton therapy (Gao et al., 2018;Henry et al., 2016;Tsubouchi et al., 2018). ...
The present Monte Carlo study was devoted to the comparison of photoneutron contamination (per 1 Gy photon dose), along the maze of a radiotherapy bunker, between two 18-MV modalities: grid therapy (with grids made of brass, cerrobend, and lead) and conventional radiotherapy. It was turned out that both in grid therapy and in conventional radiotherapy, with increasing distance from the entrance of treatment hall (toward the maze entrance), fluence and ambient dose equivalent of neutrons decrease. Evidence also shows that in grid therapy, independent of materials used in the grid construction, photoneutron contamination along the maze is 45±6 % larger than conventional radiotherapy.
... introDuction Spatially fractionated GRID radiation therapy (SFGRT) is used to treat large and bulky tumors as previously described. 1,2 Conventional treatment uses a cerrobend or brass block for photon beam collimation with the dose prescribed as a single en face field to a maximum dose point (D Max ) or a control point deeper within the tumor using the treatment planning software program. In order to increase dose to the tumor, a number of newer techniques have been described and clinically implemented including non-coplanar MLC fields and parallel opposed GRID. ...
... These clinical results are similar to photon GRID experiences. 1,2 An obvious benefit of proton radiation treatment is that there is no exit dose with particle therapy due to the Bragg peak which allows sparing of deep tissues (Figure 3). This was particularly useful when treating the head and neck area to avoid the brachial plexus or trachea with an anterior oblique field, or when trying to avoid brain when treating near the base of skull with an en face field. ...
Objectives
Approximately 70 patients with large and bulky tumors refractory to prior treatments were treated with photon spatially fractionated GRID radiation (SFGRT). We identified 10 additional patients who clinically needed GRID but could not be treated with photons due to adjacent critical organs. We developed a proton SFGRT technique, and we report treatment of these 10 patients.
Methods
Subject data were reviewed for clinical results and dosimetric data. 50% of the patients were metastatic at the time of treatment and five had previous photon radiation to the local site but not via GRID. They were treated with 15-20 cobalt Gray equivalent (CGE) using a single proton GRID field with an average beamlet count of 22.6 (range 7-51). 80% received an average adjuvant radiation dose to the GRID region of 40.8Gy (range 13.7-63.8Gy). Four received subsequent systemic therapy.
Results
The median follow up time was 5.9 months (1.1–18.9). At last follow up, seven patients were alive and three had died. Two patients who had died from metastatic disease had local shrinkage of tumor. Of those alive, four had complete or partial response, two had partial response but later progressed, and one had no response. For all patients, the tumor regression/local symptom improvement rate was 80%. 50% had acute side-effects of grade1/2 only and all were well-tolerated.
Conclusions
In circumstances where patients cannot receive photon GRID, proton SFGRT is clinically feasible and effective, with a similar side-effect profile.
Advances in knowledge
Proton GRID should be considered as a treatment option earlier in the disease course for patients who cannot be treated by photon GRID.
... However, improving local control of bulky tumors can in many cases improve overall survival (OS) and quality of life (QOL). 1,2 Stereotactic body radiotherapy (SBRT) delivers the ablative dose in several treatments to a relatively small target, which results in a better local control with the high biological equivalent dose (BED). 3 By limiting the dose to the tissue owing to high delivery precision (1 ~ 2 mm or better) and fast dose fall-off around the small target, SBRT helps to avoid serious treatment toxicity. ...
Purpose: Bulky tumor is a challenge to surgery, chemotherapy, and conventional radiation therapy. In this study, we propose a novel therapeutic paradigm using the strategy of Stereotactic Core Ablative Radiation Therapy (SCART), which delivers an ablative dose to a large core of the bulky tumor and a relative low dose at tumor periphery.
Methods and Materials: We pre-defined SCART-treatment volume (STV) at the core of bulky gross tumor volume (GTV) and irradiated with ablative dose. The remaining GTV surrounding STV was defined as Transitional Treatment Volume (TTV). SCART planning process was standardized. Linac-based VMAT, Cyberknife technique, and 6MV photon were adopted. Numerous radiation fields passed TTV, intersected within STV, and generated an ultra-heterogeneous dose distribution, including an ablative dose at STV. The dose quickly fell off at TTV and reached a low and safe level at the edge of GTV, sparing the surrounding tissue.
Results:
In Phase 1 trial, 19 patients with 21 biopsy-proven recurrent or metastatic bulky tumors were enrolled. The five dose levels were 15Gy X1, 15Gy X3, 18GyX3, 21GyX3, and 24GyX3; the GTV’s peripheral dose was limited at 5Gy per fraction. All patients completed treatment with average beam-on time of 8.9min and average treatment time of 18.5min. Mean follow-up time is 15.4 month. No grade-III or higher toxicity was observed. 7/19 patients still survive, with the overall survival of 40% at 30 months. Mean tumor volume shrinks by 60% between initial 301cc and post-SCART volumes of 118cc. Long follow-up showed that 14/21 tumors achieved PR, 2/21 CR, 3/21 SD, and 1/21 PD, leading to an encouraging local control of 95%.
Conclusion:
SCART emerges as a safe and effective strategy for treating bulky malignant tumors, demonstrating excellent local control and overall survival. Multiple treatment courses were feasible. The results from phase-1 study suggest that SCART could revolutionize the treatment landscape for bulky tumors, offering a promising avenue for further exploration and application in clinical practice.
... While scientific evidence of SFRT's biological underpinnings is to date incomplete, we believe that there is already ample clinical evidence of the ability of this modality to achieve high tumoral response rates with low rates of toxicity. Treatments with SFRT have consistently shown promising clinical, radiographic, and pathologic response results in multiple retrospective and prospective series (3)(4)(5)(6)(7)(8). This includes the original 2-D techniques [with a physical block or multileaf collimator (GRID)], which have been widely employed in clinical practice for decades; and the more recent 3-D techniques utilizing intensity modulation (Lattice therapy), which have been practiced for over a decade (3). ...
... In the modern era of megavoltage x-ray radiotherapy, GRID continued to be used for palliative treatment of bulky tumors with favorable clinical outcomes, and was coined Spatially Fractionated Radiotherapy (SFRT). [47][48][49][50][51][52][53][54][55][56][57][58][59][60] The objectives and expectations of SFRT have evolved over time and can currently be categorized into three groups: 1. Delivering partial RT boost; 2. Mediating bystander/abscopal effects; 3. Combination of the first two. The objective-1 inherited the original principle of safe dose escalation with minimal toxicity by spatially segmenting the irradiated field. ...
Purpose
To report a case of large extremity soft tissue sarcoma (2933 cc), safely treated with a novel approach of interdigitating high-dose LATTICE radiation therapy (LRT) with standard radiation therapy as a neoadjuvant treatment to surgery.
Patients and Methods
Four sessions of high-dose LRT were delivered in a weekly interval, interdigitated with standard radiation therapy. The LRT plan consisted of 15 high-dose vertices receiving a dose >12 Gy per session, with 2–3 Gy to the peripheral margin of the tumor. The patient underwent surgical excision 2 months after the new regimen of induction radiation therapy.
Results and Discussion
The patient tolerated the radiation therapy regimen well. The post-operative assessment revealed a negative surgical margin and over 95% necrosis of the total tumor volume. The post-surgical wound complication was mitigated by outpatient wound care. Interdigitating multiple sessions of high-dose LATTICE radiation treatments with standard neoadjuvant radiation therapy as a neoadjuvant therapy for soft tissue sarcoma was feasible and did not incur additional toxicity in this clinical case. A phase-I/II trial will be conducted to further evaluate the toxicity and efficacy of the new treatment strategy with the intent to increase the rate of pathologic necrosis, which has been shown to positively correlate with the overall survival.
... C'est le cas de l'étude de [Mohiuddin et al., 1990], qui ont montré 91% de résolution (partielle ou totale) sur 22 patients des symptômes tels que la douleur, les oedèmes, les saignements ou encore la perte de poids liés à des cancers de stades avancés. ...
La radiothérapie par microfaisceaux synchrotron (MRT pour Microbeam Radiation Therapy) présente des spécificités, telles qu'un important flux de photons, une matrice de faisceaux de taille micrométrique et des photons dans la gamme d'énergie de la centaine de keV, qui rendent les détecteurs couramment utilisés pour le contrôle des traitements en radiothérapie conventionnelle inutilisables. Cette thèse porte sur le développement d'un détecteur portal en diamant pour le monitorage en ligne de chaque microfaisceau individuellement. Notre choix c'est porté sur le matériau diamant pour sa résistance aux radiations, la grande mobilité des charges permettant de limiter les effets de recombinaison ainsi que son numéro atomique proche de celui des tissus humains (Z=6 contre Zeff=7,42 pour les tissus humains). Des caractérisations en laboratoire permettant de s'assurer de la bonne qualité des diamants sont présentées dans un premier temps. Dans un second temps, des expériences sous rayonnement synchrotron à l'European Synchrotron Radiation Facility sur des détecteurs diamant monopixel ont mis en évidence une linéarité de la réponse du détecteur pour des débits de dose compris entre 1 et 10000 Gy/s ainsi qu'une absence d'effets transitoires dans le diamant en début d'irradiation dans les conditions d'irradiation de la MRT. Une faible dépendance en énergie ainsi qu'une résistance aux radiations satisfaisant une utilisation en routine clinique ont également été confirmées. Des simulations Monte-Carlo permettant d'optimiser l'épaisseur du diamant sont également présentées. Enfin ce manuscrit présentera les premières expériences avec un détecteur à pistes et une électronique d'acquisition basée sur un système d'intégration de charge développé au LPSC. Ce détecteur permet la mesure de plusieurs microfaisceaux en simultané. Ces dernières expériences mettent en évidence l'absence de perte de charge dans les zones d'inter-pistes sur le détecteur ainsi que la capacité du détecteur à suivre les variations du flux de photons provoquées par un fantôme simple (fantôme homogène en marche d'escalier). Ces résultats permettent de conclure sur la perspective de tester un détecteur multivoies opérationnel dans un avenir très proche, et son intégration dans le système de contrôle en ligne lors des essais vétérinaires menés à l'ESRF.
... The main mechanism of cell death in the blocked regions is considered to be the bystander effect [16]. Clinical achievements of high-energy SFGRT have been discussed in detail in the literature [17][18][19]. ...
Neutron contamination in radiation therapy is of concern in treatment with high-energy photons (> 10 MV). With the development of new radiotherapy modalities such as spatially fractionated grid radiation therapy (SFGRT) or briefly grid radiotherapy, more studies are required to evaluate the risks associated with neutron contamination. In 15 MV SFGRT, high-Z materials such as lead and cerrobend are used as the block on the tray of linear accelerator (linac) which can probably increase the photoneutron production. On the other hand, the high-dose fractions (10-20 Gy) used in SFGRT can induce high neutron contamination. The current study was devoted to addressing these concerns via compression of neutron fluence (Φn) and ambient dose equivalent ([Formula: see text]) at the patient table and inside the maze between SFGRT and conventional fractionated radiation therapy (CFRT). The main components of the 15 MV Siemens Primus equipped with different grids and located inside a typical radiotherapy bunker were simulated by the MCNPX® Monte Carlo code. Evidence showed that the material used for grid construction does not significantly increase neutron contamination inside the maze. However, at the end of the maze, neutron contamination in SFGRT is significantly higher than in CFRT. In this regard, a delay time of 15 minutes after SFGRT is recommended for all radiotherapy staff before entering the maze. It can be also concluded that [Formula: see text] at the patient table is at least 10 times more pronounced than inside the maze. Therefore, the patient is more at risk of neutrons compared to the staff. The [Formula: see text] at the isocenter in SFGRT with grids made of lead and cerrobend was nearly equal to CFRT. Nevertheless, it was dramatically lower than in CFRT by 30% if the brass grid is used. Accordingly, SFGRT with the brass grid is recommended, from radiation protection aspects.
... Spatially fractionated radiation therapy, also known as GRID therapy, delivers high-dose radiation to small volumes in a manner that creates alternating regions of high and low dose within gross disease [1]. The motivation for using alternating regions of high and low http://theijpt.org ...
Purpose
To compare spatially fractionated radiation therapy (GRID) treatment planning techniques using proton pencil-beam-scanning (PBS) and photon therapy.
Materials and Methods
PBS and volumetric modulated arc therapy (VMAT) GRID plans were retrospectively generated for 5 patients with bulky tumors. GRID targets were arranged along the long axis of the gross tumor, spaced 2 and 3 cm apart, and treated with a prescription of 18 Gy. PBS plans used 2- to 3-beam multiple-field optimization with robustness evaluation. Dosimetric parameters including peak-to-edge ratio (PEDR), ratio of dose to 90% of the valley to dose to 10% of the peak VPDR(D90/D10), and volume of normal tissue receiving at least 5 Gy (V5) and 10 Gy (V10) were calculated. The peak-to-valley dose ratio (PVDR), VPDR(D90/D10), and organ-at-risk doses were prospectively assessed in 2 patients undergoing PBS-GRID with pretreatment quality assurance computed tomography (QACT) scans.
Results
PBS and VMAT GRID plans were generated for 5 patients with bulky tumors. Gross tumor volume values ranged from 826 to 1468 cm3. Peak-to-edge ratio for PBS was higher than for VMAT for both spacing scenarios (2-cm spacing, P = .02; 3-cm spacing, P = .01). VPDR(D90/D10) for PBS was higher than for VMAT (2-cm spacing, P = .004; 3-cm spacing, P = .002). Normal tissue V5 was lower for PBS than for VMAT (2-cm spacing, P = .03; 3-cm spacing, P = .02). Normal tissue mean dose was lower with PBS than with VMAT (2-cm spacing, P = .03; 3-cm spacing, P = .02). Two patients treated using PBS GRID and assessed with pretreatment QACT scans demonstrated robust PVDR, VPDR(D90/D10), and organs-at-risk doses.
Conclusions
The PEDR was significantly higher for PBS than VMAT plans, indicating lower target edge dose. Normal tissue mean dose was significantly lower with PBS than VMAT. PBS GRID may result in lower normal tissue dose compared with VMAT plans, allowing for further dose escalation in patients with bulky disease.
... LRT derived its basis from grid radiotherapy (GRID RT), where a wide radiation beam is passively filtered through a heavy metal block to deliver radiation in beamlets. This technique was popularized in the 1990s by Mohiuddin et al., with patients experiencing good clinical response despite partial irradiation of tumours, albeit at high doses (2). There were subsequently many pre-clinical and clinical studies exploring different aspects of GRID RT (3)(4)(5). ...
... In clinical SFRT, a single SFRT delivery is often followed by a course of conventional chemoradiation therapy. In patients with bulky tumors, both effective palliation and tumor control have been reported [2,11,12,25]. SFRT remains largely unused despite its success in the clinic and its proven technical feasibility in virtually every RT unit in the world. Several obstacles stand in the way of the potentially widespread clinical use of SFRT. ...
Spatially fractionated radiotherapy (SFRT) is characterized by the coexistence of multiple hot and cold dose subregions throughout the treatment volume. In preclinical studies using single-fraction treatment, SFRT can achieve a significantly higher therapeutic index than conventional radiotherapy (RT). Published clinical studies of SFRT followed by RT have reported promising results for bulky tumors. Several clinical trials are currently underway to further explore the clinical benefits of SFRT. However, we lack the important understanding of the correlation between dosimetric parameters and treatment response that we have in RT. In this work, we reviewed and analyzed this important correlation from previous preclinical SFRT studies. We reviewed studies prior to 2022 that treated animal-bearing tumors with minibeam radiotherapy (MBRT) or microbeam radiotherapy (MRT). Eighteen studies met our selection criteria. Increased lifespan (ILS) relative to control was used as the treatment response. The preclinical SFRT dosimetric parameters analyzed were peak dose, valley dose, average dose, beam width, and beam spacing. We found that valley dose was the dosimetric parameter with the strongest correlation with ILS (p-value < 0.01). For studies using MRT, average dose and peak dose were also significantly correlated with ILS (p-value < 0.05). This first comprehensive review of preclinical SFRT studies shows that the valley dose (rather than the peak dose) correlates best with treatment outcome (ILS).
... Because of the small and discrete areas of irradiated healthy tissue by this method, higher doses may be tolerated than by homogeneous irradiation. Published clinical evidence from GRID therapy studies showed beneficial palliative outcomes with reduced toxicity (Mohiuddin et al., 1990;Mohiuddin et al., 1996;Neuner et al., 2012). ...
Spatially fractionated radiation therapy (SFRT or GRID) is an approach to deliver high local radiation doses in an 'on-off' pattern. To better appraise the radiobiological effects from GRID, a framework to link local radiation dose to clonogenic survival needs to be developed. A549 (lung) cancer cells were irradiated in T25 cm$^2$ flasks using 220 kV X-rays with an open field or through a tungsten GRID collimator with periodical 5 mm openings and 10 mm blockings. Delivered nominal doses were 2, 5, and 10 Gy. A novel approach for image segmentation was used to locate the centroid of surviving colonies in scanned images of the cell flasks. GafchromicTM film dosimetry (GFD) and FLUKA Monte Carlo (MC) simulations were employed to map the dose distribution in the flasks at each surviving colony centroid. Fitting the linear-quadratic (LQ) function to clonogenic survival data for open field irradiation, the expected survival level at a given dose level was calculated. The expected survival level was then mapped together with the observed levels in the GRID-irradiated flasks. GFD and FLUKA MC gave similar dose distributions, with a mean peak-to-valley dose ratio of about 5. LQ-parameters for open field irradiation gave $\alpha = 0.16 \pm 0.04$ Gy$^{-1}$ and $\beta = 0.001 \pm 0.004$ Gy$^{-2}$. Using the image segmentation method, the mean absolute percentage deviation between observed and predicted survival in the (peak; valley) dose regions was (8; 10) %, (4; 41) %, and (3; 138) % for 2, 5 and 10 Gy, respectively. In conclusion, a framework for mapping of surviving colonies following GRID irradiation together with predicted survival levels from homogeneous irradiation was presented. For the given cell line, our findings indicate that GRID irradiation, especially at high peak doses, causes reduced survival compared to an open field configuration.
... Mohiuddin et al. ont suivi 87 patients au cours de soins palliatifs avec d'une part des patients traités par la radiothérapie GRID seule (20 %) ou combinée avec une radiothérapie externe (Mohiuddin et al., 1999 patients, 6 avaient déjà reçu une radiothérapie antérieure. L'utilisation de ces traitements supplémentaires rend l'utilité du fractionnement spatial difficile à comprendre, ce qui est récurrent dans les études cliniques existantes sur la thérapie GRID (Mohiuddin et al., 1990;Billena & Khan, 2019). ...
Malgré l’évolution de la radiothérapie (RT), la toxicité aux tissus sains reste une limite en clinique. Les mesures d’Efficacité Biologique Relative (EBR) permettent de prédire les effets biologiques d’un rayonnement d’intérêt par rapport à celui de référence. Elles sont principalement basées sur le test de survie clonogénique qui ne peut suffire à lui seul à prédire le devenir de tissus sains exposés. Les nouveaux appareils de RT utilisent des débits de dose plus élevés sans que les effets biologiques soient bien connus. Le but de ces travaux est d’acquérir des mesures biologiques multiparamétriques à intégrer dans un futur modèle prédictif pour mieux prédire les effets biologiques des protocoles de RT émergents. Pour les irradiations (IR) en dose unique, la modélisation des données in vitro a mis en évidence un effet plus délétère du débit de dose le plus élevé sur la survie clonogénique, la morphologie, la viabilité et le cycle cellulaire, la sénescence et l’expression de gènes signant une dysfonction cellulaire. Ces résultats ont été confirmés in vivo sur un modèle d’IR intestinale. Contrairement au postulat de la CIPR, l’EBR des photons n’est pas de 1 et dépend du débit de dose. Pour les IR fractionnées selon différents protocoles, un impact du débit de dose sur un continuum de “dose biologique équivalente” (BED) a également été démontré in vitro. En revanche, la réponse in vitro et in vivo est différente pour des protocoles à BED équivalente ce qui montre une limite son utilisation pour comparer des protocoles. L’utilisation de mesures biologiques multiples pourrait permettre à terme de mieux prédire les risques potentiels des pratiques actuelles et futures en RT.
... The concept of spatially fractionated radiation therapy (SFRT) was first introduced at the beginning of the 20th century and subsequently re-introduced in the 1970s with Co-60 machines and in the 1990s with LINACs, under the name of GRID therapy (centimeter scale pencil beams) [4,5] or microbeam radiation therapy (with extremely narrow beams of 25-100 µm) [6]. Such techniques take advantage of inhomogeneous dose profiles characterized by peaks and valleys to reduce radiation side effects. ...
Simple Summary
Healthy tissue tolerance to radiation is one of the main limitations in radiotherapy treatment. To broaden the therapeutic index, innovative approaches using non-conventional spatial and temporal beam structure are currently being investigated. Among them, proton minibeam radiation therapy is a promising solution that has already shown a remarkable increase in healthy tissue tolerance in various preclinical models. The purpose of this study is to propose potential strategies to further optimize proton minibeam spatial modulation with the use of magnetic fields. By generating a converging minibeam pattern with dipole magnetic fields, we show that spatial modulation can be improved at shallow depth for the same dose distribution at the tumor location. This indicates that proton minibeam radiation therapy could be efficiently combined with magnetic fields to further increase healthy tissue tolerance.
Abstract
Proton MiniBeam Radiation Therapy (pMBRT) is a novel strategy that combines the benefits of minibeam radiation therapy with the more precise ballistics of protons to further optimize the dose distribution and reduce radiation side effects. The aim of this study is to investigate possible strategies to couple pMBRT with dipole magnetic fields to generate a converging minibeam pattern and increase the center-to-center distance between minibeams. Magnetic field optimization was performed so as to obtain the same transverse dose profile at the Bragg peak position as in a reference configuration with no magnetic field. Monte Carlo simulations reproducing realistic pencil beam scanning settings were used to compute the dose in a water phantom. We analyzed different minibeam generation techniques, such as the use of a static multislit collimator or a dynamic aperture, and different magnetic field positions, i.e., before or within the water phantom. The best results were obtained using a dynamic aperture coupled with a magnetic field within the water phantom. For a center-to-center distance increase from 4 mm to 6 mm, we obtained an increase of peak-to-valley dose ratio and decrease of valley dose above 50%. The results indicate that magnetic fields can be effectively used to improve the spatial modulation at shallow depth for enhanced healthy tissue sparing.
... It employs ''beamlets'' of radiotherapy that are akin to a virtual brachytherapy technique (9). Historically employed in the orthovoltage era to spare areas of skin between beamlets and allow for doseescalation without severe skin reactions, it was repurposed in the megavoltage era as a boost to conventionally fractionated radiotherapy in both the definitive and palliative settings (10)(11)(12)(13)(14)(15)(16). It is most often delivered as a single fraction of 12 to 20 Gy prescribed to Dmax within one to three days prior to a course of conventionally fractionated radiotherapy. ...
Spatially fractionated radiotherapy (GRID) has been utilized primarily in the palliative and definitive treatment of bulky tumors. Delivered in the modern era primarily with megavoltage photon therapy, this technique offers the promise of safe dose escalation with potential immunogenic, bystander and microvasculature effects that can augment a conventionally fractionated course of radiotherapy. At the University of Maryland, an institutional standard has arisen to incorporate a single fraction of GRID radiation in large (>8 cm), high-risk soft tissue and osteosarcomas prior to a standard fractionated course. Herein, we report on the excellent pathologic responses and apparent safety of this regimen in 26 consecutive patients.
... A higher tolerance for spatially segmented than for continuous radiation beams is attributed to undamaged, migratory cells adjacent to the radiation-damaged areas [4,5], but the biological mechanisms are still not completely understood. In minibeam or grid therapy, small non-confluent areas of the skin and subcutaneous normal tissues have been shown to tolerate large radiation doses without significant acute or late normal tissue damage [34][35][36]. This is attributed to the "dose-volume effect" [37], which means that the maximum tolerable doses increase as irradiated tissue volumes are made smaller. ...
Proton minibeam radiotherapy (pMBRT) is an external beam radiotherapy method with reduced side effects by taking advantage of spatial fractionation in the normal tissue. Due to scattering, the delivered small beams widen in the tissue ensuring a homogeneous dose distribution in the tumor. In this review, the physical and biological principles regarding dose distribution and healing effects are explained. In the last decade, several preclinical studies have been conducted addressing normal tissue sparing and tumor control in-vitro and in-vivo, using human skin tissue and mouse or rat models. The major results acquired in these studies are summarized. A further newly emerging therapy method is FLASH radiotherapy, i.e. the treatment using ultra-high dose rates. The possibility of combining these methods in proton minibeam FLASH therapy (pMB FLASH) is worked out. Additionally, technical feasibility and limitations will be discussed by looking at simulations as well as preclinical studies and also pointing out new ways of delivering the desired tumor dose, such as interlacing. We will also highlight the opportunities that emerge regarding high dose radiation, hypofractionation and the combination with immunotherapy.
... 78 A pilot study used GRID therapy as a palliative treatment for sarcomas, recurrent gastrointestinal cancers, liver metastases, melanoma, prostate cancer, renal cell carcinoma, and squamous cell carcinoma. 79 A single radiation dose ranging from 10-15 Gy was given using a grid consisting of 50% open and 50% closed areas. Palliation of symptoms and objective response was observed in 20 out of 22 patients without acute effects. ...
Radiation therapy benefits the majority of patients across the spectrum of cancer types. However, both local and distant tumor recurrences limit its clinical success. While departing from the established tenet of fractionation in clinical radiotherapy, ablative-intensity hypofractionated radiotherapy, especially stereotactic radiosurgery and stereotactic ablative radiotherapy, has emerged as an alternative paradigm achieving unprecedented rates of local tumor control. Direct tumor cell killing has been assumed to be the primary therapeutic mode of action of such ablative radiation. But with increasing recognition that tumor responses also depend on the immunostimulatory or immunosuppressive status of the tumor microenvironment, the immunologic effect of ablative radiotherapy is emerging as a key contributor to antitumor response. More recently, novel radiation modalities, such as spatially fractionated radiotherapy and ultrahigh dose rate FLASH irradiation, that venture even further from conventional paradigms have shown promise of increasing the therapeutic index of radiation therapy with the potential of immunomodulation. Here, we review the immunomodulatory impact of novel radiation therapy paradigms, heretofore considered radiobiological heresies, a deeper understanding of which is imperative to realizing fully their potential for more curative cancer therapy.
... For the past decade, GRID therapy, although not a mainstream treatment modality, has been used by a number of clinicians to treat many patients who they consider would have otherwise been denied other treatment options (20) and they are encouraged by their observations. Mohiuddin et al. (21) reported that among 71 patients and 87 sites treated, presenting with a variety of cancer types treated with GRID therapy with 15 Gy peak dose as a goal there was a 78% response rate for pain and no grade 3 toxicities were observed in any patient. ...
Overview
The National Cancer Institute’s Radiation Research Program in collaboration with the Radiosurgery Society hosted a workshop on Understanding High-Dose, Ultra-High Dose rate and Spatially Fractionated Radiotherapy on August 20-21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically-based clinical trials.
... 3D-MLC Crossfire, Bulky-tumors, cerrobend GRID-block, dose-escalation 1 | INTRODUCTION Spatially fractionated GRID therapy with megavoltage (MV) x-ray beams has proven to be an effective treatment modality for shrinking bulky (>8 cm, in diameter) malignant tumors. 1 Traditional GRID therapy treatments have shown great tumor response of bulky lesions with an overall response rate increase of 62% to 91% when they were treated with a single-dose of GRID therapy (≥15 Gy) followed by conventional extremal beam radiotherapy. 2 Another study of 71 patients with advanced or bulky tumors of varying histologies demonstrated that 78% response rate for pain palliation and 58.5% and 72.5% objective clinical response rate for mass effect after GRID therapy of 10 to 20 Gy dose with or without additional external beam radiation. ...
Purpose:
Treating deep-seated bulky tumors with traditional single-field Cerrobend GRID-blocks has many limitations such as suboptimal target coverage and excessive skin toxicity. Heavy traditional GRID-blocks are a concern for patient safety at various gantry-angles and dosimetric detail is not always available without a GRID template in user's treatment planning system. Herein, we propose a simple, yet clinically useful multileaf collimator (MLC)-based three-dimensional (3D)-crossfire technique to provide sufficient target coverage, reduce skin dose, and potentially escalate tumor dose to deep-seated bulky tumors.
Materials/methods:
Thirteen patients (multiple sites) who underwent conventional single-field cerrobend GRID-block therapy (maximum, 15 Gy in 1 fraction) were re-planned using an MLC-based 3D-crossfire method. Gross tumor volume (GTV) was used to generate a lattice pattern of 10 mm diameter and 20 mm center-to-center mimicking conventional GRID-block using an in-house MATLAB program. For the same prescription, MLC-based 3D-crossfire grid plans were generated using 6-gantry positions (clockwise) at 60° spacing (210°, 270°, 330°, 30°, 90°, 150°, therefore, each gantry angle associated with a complement angle at 180° apart) with differentially-weighted 6 or 18 MV beams in Eclipse. For each gantry, standard Millenium120 (Varian) 5 mm MLC leaves were fit to the grid-pattern with 90° collimator rotation, so that the tunneling dose distribution was achieved. Acuros-based dose was calculated for heterogeneity corrections. Dosimetric parameters evaluated include: mean GTV dose, GTV dose heterogeneities (peak-to-valley dose ratio, PVDR), skin dose and dose to other adjacent critical structures. Additionally, planning time and delivery efficiency was recorded. With 3D-MLC, dose escalation up to 23 Gy was simulated for all patient's plans.
Results:
All 3D-MLC crossfire GRID plans exhibited excellent target coverage with mean GTV dose of 13.4 ± 0.5 Gy (range: 12.43-14.24 Gy) and mean PVDR of 2.0 ± 0.3 (range: 1.7-2.4). Maximal and dose to 5 cc of skin were 9.7 ± 2.7 Gy (range: 5.4-14.0 Gy) and 6.3 ± 1.8 Gy (range: 4.1-11.1 Gy), on average respectively. Three-dimensional-MLC treatment planning time was about an hour or less. Compared to traditional GRID-block, average beam on time was 20% less, while providing similar overall treatment time. With 3D-MLC plans, tumor dose can be escalated up to 23 Gy while respecting skin dose tolerances.
Conclusion:
The simple MLC-based 3D-crossfire GRID-therapy technique resulted in enhanced target coverage for de-bulking deep-seated bulky tumors, reduced skin toxicity and spare adjacent critical structures. This simple MLC-based approach can be easily adopted by any radiotherapy center. It provides detailed dosimetry and a safe and effective treatment by eliminating the heavy physical GRID-block and could potentially provide same day treatment. Prospective clinical trial with higher tumor-dose to bulky deep-seated tumors is anticipated.
... GRID therapy was disparaged or ignored until the 1930s 50 and was used since then and "rediscovered" using Co-60 units and megavoltage beams provided by medical linear accelerators, for example to shrink bulky malignancies for palliative cases (Figure 5a). [49][50][51][53][54][55][56][57][58][59][60][61][62][63] By adjusting the old 2D grid technique into a 3D lattice using multiple high-dose areas (called "vertices"), high-dose radiation is delivered with high-energy photons (6-18 MeV) within the tumour and not in the peripheral areas adjacent to normal tissues. (Figure 5b While LRT is oriented towards improving the effects in the tumour volume, GRID was developed to preserve healthy tissue. ...
After years of lethargy, studies on two non-conventional microstructures in time and space of the beams used in radiation therapy are enjoying a huge revival.
The first effect called ‘FLASH” is based on very high dose-rate irradiation (pulse amplitude ≥10 ⁶ Gy/s), short beam-on times (≤100 ms) and large single doses (≥10 Gy) as experimental parameters established so far to give biological and potential clinical effects. The second effect relies on the use of arrays of Minibeams (e.g., 0.5–1 mm, spaced 1–3.5 mm). Both approaches have been shown to protect healthy tissues as an endpoint that must be clearly specified, and could be combined with each other (e.g., Minibeams under FLASH conditions). FLASH depends on the presence of oxygen and could proceed from the chemistry of peroxyradicals and a reduced incidence on DNA and membrane damage. Minibeams action could be based on abscopal effects, cell signalling and/or migration of cells between “valleys and hills” present in the non-uniform irradiation field as well as faster repair of vascular damage. Both effects are expected to maintain intact the tumour control probability, and might even preserve antitumoural immunological reactions. FLASH in vivo experiments involving Zebrafish, mice, pig and cats have been done with electron beams, whilst Minibeams are an intermediate approach between X-GRID and synchrotron X-ray microbeams radiation. Both have an excellent rationale to converge and be applied with proton beams, combining focusing properties and high dose rates in the beam path of pencil beams, and the inherent advantage of a controlled limited range. A first treatment with electron FLASH (cutaneous lymphoma) has recently been achieved, but clinical trials have neither been presented for FLASH with protons, nor under the Minibeam conditions. Better understanding of physical, chemical and biological mechanisms of both effects is essential to optimize the technical developments and devise clinical trials.
... Despite the advantages of SFGRT[3,4], there are concerns about photo-neutron production in 18-MV SFGRT[5,6], especially when the high-Z materials such as lead, Cerrobend or brass are used for constructing the grid blocks. In order to have a better understanding about these concerns, Monte Carlo (MC) calculations were carried out and photo-neutron production was compared between two treatment modalities: 20-Gy SFGRT in a single fraction and 40-Gy Conventional Fractionated Radiation Therapy (CFRT) in 20 fractions.INTRODUCTION(II)METHODS The MCNPX 2.7.0 code was used to simulate photo-neutron production in the gantry head of an 18-MV LINAC. ...
Our abstract has been included on page 224.
... With the development of megavoltage Radiotherapy using linear accelerators (LINACs), GRID therapy was abandoned temporarily for several years. It was paid attention again in palliative treatments of bulky tumors which do not respond enough to conventional Radiotherapy (CRT) [2,3]. Despite the clinical successes of 6-MV GRID therapy, there are concerns about photoneutron production in 18-MV GRID therapy of deep-seated tumors [4]. ...
... The deep border encompasses the tumor GTV without additional margin, in an approach analogous to that of brachytherapy or SBRT. The dose is delivered most commonly in one fraction of 10-20 Gy [6][7][8][9]. ...
Objectives
The clinical outcomes of patients treated with spatially fractionated GRID radiotherapy (SFGRT) for bulky tumors of the head and neck at a single institution were evaluated retrospectively. Endpoints of interest included tumor response, symptom improvement, treatment tolerance, and adverse events.
Methods
Institutional review board approval was obtained prior to study initiation. The institutional database was queried for patients with tumors of the head and neck treated with SFGRT between August 2007 and April 2015. Medical records of identified patients were reviewed for treatment details and clinical endpoints of interest. SFGRT was delivered in one fraction of 15 gray (Gy) or 20 Gy; 6 megavolt (MV) or 18 MV photon beams were passed through a multileaf collimator (MLC)-based or brass GRID template. All patients had a planned course of conventionally-fractionated external beam radiotherapy (EBRT) to begin on the day following SFGRT delivery.
Results
Twenty-one consecutive patients meeting study criteria were identified. The most common tumor histology was squamous cell carcinoma. Median patient age was 59 years (range 13 - 83 years); median maximum tumor dimension was 9.5 centimeters (cm) (range 5.0 - 25.0 cm). Fifteen patients (71.4%) completed their full course of EBRT. Twelve patients were treated with palliative intent for local tumor symptoms, of which 54.5% experienced some degree of symptom improvement. Of nine patients treated with curative intent, 44.4% achieved a clinical complete response (CR). Concurrent chemotherapy was administered in 12 patients, with all patients being treated having definitively received chemotherapy. Radiation Therapy Oncology Group (RTOG) grade three or higher skin toxicity occurred in five patients; no grade five events were reported.
Conclusions
Our institutional experience suggests that SFGRT is a feasible treatment option for the palliative or definitive management of large tumors of the head and neck. In combination with EBRT, SFGRT can provide timely symptom management and improve patient quality of life in the palliative setting. In the definitive setting, the addition of chemotherapy to SFGRT and EBRT can result in an excellent clinical response. Treatment toxicity was found to be within an acceptable range. When considering SFGRT for patients with these challenging presentations, careful patient selection is needed to identify those who will likely tolerate a full course of EBRT following SFGRT, as these patients are most likely to receive maximal benefit from SFGRT treatment. More data on the feasibility and efficacy of this radiation modality will be helpful for continued optimization of SFGRT delivery and patient selection.
... SFGRT was used in the orthovoltage era to make possible the delivery of an effective radiation dose to deep-seated tumors, avoiding unacceptable skin toxicity [29]. Since the 1990s, SFGRT is used for the treatment of bulky tumors, delivering 10-15 Gy × 1 with multiple beamlets [30]. Several studies combined SFGRT and conventional radio-chemotherapy, confirming its efficacy and safety, reporting overall response rates of 78 to 91% without a notable increase in toxicity compared with conventional treatments (grade 3-4: 5.1%) [31][32][33]. ...
Background
Despite the advances in oncology, patients with bulky tumors have worse prognosis and often receive only palliative treatments. Bulky disease represents an important challenging obstacle for all currently available radical treatment options including conventional radiotherapy. The purpose of this study was to assess a retrospective outcome on the use of a newly developed unconventional stereotactic body radiation therapy (SBRT) for PArtial Tumor irradiation of unresectable bulky tumors targeting exclusively their HYpoxic segment (SBRT-PATHY) that exploits the non-targeted effects of radiotherapy: bystander effects (local) and the abscopal effects (distant).
Materials and methods
Twenty-three patients with bulky tumors received partial bulky irradiation in order to induce the local non-targeted effect of radiation (bystander effect). The hypoxic tumor segment, called the bystander tumor volume (BTV), was defined using PET and contrast-enhanced CT, as a hypovascularized-hypometabolic junctional zone between the central necrotic and peripheral hypervascularized-hypermetabolic tumor segment. Based on tumor site and volume, the BTV was irradiated with 1–3 fractions of 10–12 Gy prescribed to 70% isodose-line. The pathologic lymph nodes and metastases were not irradiated in order to assess the distant non-targeted effects of radiation (abscopal effect). No patient received any systemic therapy.
Results
At the time of analysis, with median follow-up of 9.4 months (range: 4–20), 87% of patients remained progression-free. The bystander and abscopal response rates were 96 and 52%, respectively. Median shrinkage of partially irradiated bulky tumor expressing intensity of the bystander effect was 70% (range 30–100%), whereas for the non-irradiated metastases (intensity of the abscopal effect), it was 50% (range 30–100%). No patient experienced acute or late toxicity of any grade.
Conclusions
SBRT-PATHY showed very inspiring results on exploitation of the radiation-hypoxia-induced non-targeted effects that need to be confirmed through our ongoing prospective trial.
Present study has been retrospectively registered by the local ethic committee under study number A 26/18.
... Spatially fractionated radiotherapy or Grid therapy is a radiation therapy technique for the treatment of bulky and advanced tumours (Mohiuddin et al., 1990) While having therapeutic advantages for normal tissues, this treatment technique is usually used to deliver the required radiation dose with a linear accelerator by using a designed block collimator (Meigooni et al., 2007) A Grid field represents a group of pencil beams giving a high radiation dose (Zhang et al., 2006) Generally, treatments are performed with a single fraction of 10 Gy-20 Gy, prescribed to the depth of the maximum dose, followed by conventional radiotherapy (Zhang et al., 2006). The valley-to-peak dose ratio (VPDR) in the dose distribution of this technique is defined as the ratio of dose in the blocked and the open areas. ...
Objectives: Grid therapy is a radiation therapy technique for the treatment of bulky tumours. The high dose gradients and non-uniformity of dose distributions within the target lead to a challenge in the dosimetry of the Grid radiation fields. The aim of this study is to perform a precise EBT3 Gafchromic film dosimetry for Grid therapy fields using a commercially available flatbed colour scanner. Methods: In this project, samples of the EBT3 Gafchromic films are exposed to Grid radiation fields. The irradiated EBT3 films were read using a flatbed Microtek scanner. The responses of these films (i.e. films from the same batch) as functions of the absorbed dose values are calibrated by irradiation under a fixed standard technique (i.e. 10 × 10 cm² filed, 100 cm SSD, and depth of the maximum dose). These films are also read with the same scanner using the red, green, and blue channels. Four different approaches were used to evaluate film dosimetry for the Grid therapy applications: 1) single channel film dosimetry method (SCM), 2) dual channel film dosimetry method (DCM), 3) linearized dose-response curve method (LRCM), and 4) triple channel film dosimetry method (TCM). A dose of 20 Gy was delivered to the point along the central axis of the grid hole at the depth of maximum dose (dmax) for a 20 × 20 cm² Grid field size. Beam profiles and percentage depth dose distributions of the Grid radiation have been measured in water-equivalent phantom material, using EBT3 films. The accuracy of the relative and the absolute dosimetry of the films were examined by comparison of the TLD measured data with the Monte Carlo simulated values. Results: The results of these investigations show that for a gamma index criterion of 5%/3 mm, the agreements between the MC calculations dose profiles and the SCM, DCM, LRCM, and TCM film dosimetry approaches the passing rates of 91%, 92%, 95%, and 95%, respectively. A much closer agreement was observed for using a linearized dose-response curve and triple-channel methods. Conclusions: Selection of an appropriate methodology in Gafchromic film dosimetry may lead to an accurate dose-response in a high dose gradient radiation field such as Grid therapy.
... GRID therapy was "rediscovered" in the 1970s using Co-60 units 8,9 and later in the 1990s by using megavoltage beams provided by medical linear accelerators (linacs). 10 Linac-based grid therapy is still in use at a few hospitals in the USA, recently also with clinical proton beams, 11,12 to deliver large, single fraction doses to patients with bulky tumours to shrink or palliate the disease with minimum damage to normal tissues. [13][14][15][16][17][18] In parallel developments, pre-clinical research was carried out by Curtis, Zeman and co-workers [19][20][21] at Brookhaven National Laboratory, starting in 1959, in the context of studies on the possible biological effects of cosmic radiation. ...
Extraordinary normal tissue response to highly spatially fractionated X-ray beams has been explored for over 25 years. More recently alternative radiation sources have been developed and utilized with the aim to evoke comparable effects. These include protons, which lend themselves well for this endeavour due to their physical depth dose characteristics as well as corresponding variable biological effectiveness. This paper addresses the motivation for using protons to generate spatially fractionated beams and reviews the technological implementations and experimental results to date. This includes simulation and feasibility studies, collimation and beam characteristics, dosimetry and biological considerations as well as the results of in-vivo and in-vitro studies. Experimental results are emerging indicating an extraordinary normal tissue sparing effect analogous to what has been observed for synchrotron generated X-ray microbeams. The potential for translational research and feasibility of spatially modulated proton beams in clinical settings is discussed.
... This approach, called GRID therapy, 4 is currently used clinically at few hospitals using megavoltage (MV) photon beams delivered by medical Linacs. [5][6][7] GRID therapy (GRT) has been successfully used to deposit high doses in the treatment of bulky tumors, for which conventional approaches fail in their management. [6][7][8] However, the important lateral scattering of MV beams and the relative low fluence of Linacs limits the gain of this technique. ...
Purpose:
The alliance of charged particle therapy and the spatial fractionation of the dose, as in minibeam or Grid therapy, is an innovative strategy to improve the therapeutic index for the treatment of radioresistant tumors. The aim of this work was to assess the optimum irradiation configuration in heavy ion spatially fractionated radiotherapy (SFRT) in terms of ion species, beam width, center-to-center distances, and linear energy transfer (LET), information that could be used to guide the design of the future biological experiments. The nuclear fragmentation leading to peak and valley regions composed of different secondary particles, creates the need for a more complete dosimetric description that the classical one in SFRT.
Methods:
Monte Carlo simulations (GATE 6.2) were performed to evaluate the dose distributions for different ions, beam widths and spacings. We have also assessed the 3D-maps of dose-averaged LET and proposed a new parameter, the peak-to-valley-LET ratio, to offer a more thorough physical evaluation of the technique.
Results:
Our results show that beam widths larger than 400 μm are needed in order to keep a ratio between the dose in the entrance and the dose in the target of the same order as in conventional irradiations. A large ctc distance (3500 μm) would favor tissue sparing since it provides higher PVDR, it leads to a reduced contribution of the heavier nuclear fragments and a LET value in the valleys a factor 2 lower than the LET in the ctc leading to homogeneous distributions in the target.
Conclusions:
Heavy ions MBRT provide advantageous dose distributions. Thanks to the reduced lateral scattering, the use of submillimetric beams still allows to keep a ratio between the dose in the entrance and the dose in the target of the same order as in conventional irradiations. Large ctc distances (3500 μm) should be preferred since they lead to valley doses composed of lighter nuclear fragments resulting in a much reduced dose-averaged LET values in normal tissue, favoring its preservation. Among the different ions species evaluated, Ne stands out as the one leading to the best balance between high PVDR and PVLR in normal tissues and high LET values (close to 100 keV/μm) and a favourable oxygen enhancement ratio in the target region. This article is protected by copyright. All rights reserved.
Spatially Fractionated Radiotherapy (SFRT) has demonstrated promising potential in cancer treatment, combining the advantages of reduced post-radiation effects and enhanced local control rates. Within this paradigm, proton minibeam radiotherapy (pMBRT) was suggested as a new treatment modality, possibly producing superior normal tissue sparing to conventional proton therapy, leading to improvements in patient outcomes. However, an effective and convenient beam generation method for pMBRT, capable of implementing various optimum dose profiles, is essential for its real-world application. Our study investigates the potential of utilizing the moiré effect in a dual collimator system (DCS) to generate pMBRT dose profiles with the flexibility to modify the center-to-center distance (CTC) of the dose distribution in a technically simple way.
We employ the Geant4 Monte Carlo simulations tool to demonstrate that the angle between the two collimators of a DCS can significantly impact the dose profile. Varying the DCS angle from 10∘\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{\circ }$$\end{document} to 50∘\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{\circ }$$\end{document} we could cover CTC ranging from 11.8 mm to 2.4 mm, respectively. Further investigations reveal the substantial influence of the multi-slit collimator’s (MSC) physical parameters on the spatially fractionated dose profile, such as period (CTC), throughput, and spacing between MSCs. These findings highlight opportunities for precision dose profile adjustments tailored to specific clinical scenarios.
The DCS capacity for rapid angle adjustments during the energy transition stages of a spot scanning system can facilitate dynamic alterations in the irradiation profile, enhancing dose contrast in normal tissues. Furthermore, its unique attribute of spatially fractionated doses in both lateral directions could potentially improve normal tissue sparing by minimizing irradiated volume. Beyond the realm of pMBRT, the dual MSC system exhibits remarkable versatility, showing compatibility with different types of beams (X-rays and electrons) and applicability across various SFRT modalities.
Our study illuminates the dual MSC system’s potential as an efficient and adaptable tool in the refinement of pMBRT techniques. By enabling meticulous control over irradiation profiles, this system may expedite advancements in clinical and experimental applications, thereby contributing to the evolution of SFRT strategies.
Small-field dosimetry used in special procedures such as gamma knife, Cyberknife, Tomotherapy, IMRT and VMAT has been in evolution after several radiation incidences with very significant (70%) errors due to poor understanding of the dosimetry. IAEA-TRS-483 and AAPM-TG-155 have provided comprehensive information on small-fields dosimetry in terms of code of practice and relative dosimetry. Data for various detectors and conditions have been elaborated. It turns out that with a suitable detectors dose measurement accuracy can be reasonably (±3%) achieved for 6 MV beams for fields > 1x1 cm2.
For grid therapy, even though the treatment is performed with small fields created by either customized blocks, multileaf collimator (MLC) or specialized devices, it is multiple small fields that creates combined treatment. Hence understanding the dosimetry in collection of holes of small field is a separate challenge that needs to be addressed. It is more critical to understand the scattering conditions from multiple holes that form the treatment grid fields. Scattering changes the beam energy (softer) and hence dosimetry protocol needs to be properly examined for having suitable dosimetric parameters. In lieu of beam parameter unavailability in physical grid devices, MLC based forward and inverse planning is an alternative path for bulky tumors.
Selection of detectors in small field measurement is critical and it is more critical in mixed beams created by scattering condition. Ramification of small field concept used in grid therapy along with major consideration of scattering condition is explored. Even though this review article is focused mainly for dosimetry for low energy megavoltage photon beam (6 MV) but similar procedures could be adopted for high energy beams. To eliminate small field issues, lattice therapy with the help of MLC is a preferrable choice.
Grid therapy recently has been picking momentum due to favorable outcomes in bulky tumors. This is being termed as Spatially Fractionated Radiation Therapy (SFRT) and lattice therapy. SFRT can be performed with specially designed blocks made with brass or cerrobend with repeated holes or using multi-leaf collimators where dosimetry is uncertain. The dosimetric challenge in grid therapy is the mystery behind the lower percentage depth dose (PDD) in grid fields. The knowledge about the beam quality, indexed by TPR 20/10 (Tissue Phantom Ratio), is also necessary for absolute dosimetry of grid fields. Since the grid may change the quality of the primary photons, a new $${\mathbf{k}}_{\mathbf{q},{\mathbf{q}}_{0}}$$ k q , q 0 should be evaluated for absolute dosimetry of grid fields. A Monte Carlo (MC) approach is provided to resolving the dosimetric issues. Using 6 MV beam from a linear accelerator, MC simulation was performed using MCNPX code. Additionally, a commercial grid therapy device was used to simulate the grid fields. Beam parameters were validated with MC model for output factor, depth of maximum dose, PDDs, dose profiles, and TPR 20/10. The electron and photon spectra were also compared between open and grid fields. The d max is the same for open and grid fields. The PDD with grid is lower (~ 10%) than the open field. The difference in TPR 20/10 of open and grid fields is observable (~ 5%). Accordingly, TPR 20/10 is still a good index for the beam quality in grid fields and consequently choose the correct $${\mathbf{k}}_{\mathbf{q},{\mathbf{q}}_{0}}$$ k q , q 0 in measurements. The output factors for grid fields are 0.2 lower compared to open fields. The lower depth dose with grid therapy is due to lower depth fluence with scatter radiation but it does not impact the dosimetry as the calibration parameters are insensitive to the effective beam energies. Thus, standard dosimetry in open beam based on international protocol could be used.
Background and purpose
Spatially fractionated radiation therapy (SFRT) has demonstrated promising clinical response in treating large tumors with heterogeneous dose distributions. Lattice stereotactic body radiation therapy (SBRT) is an SFRT technique that leverages inverse optimization to precisely localize regions of high and lose dose within disease. The aim of this study was to evaluate an automated heuristic approach to sphere placement in lattice SBRT treatment planning.
Materials and methods
A script-based algorithm for sphere placement in lattice SBRT based on rules described by protocol was implemented within a treatment planning system. The script was applied to 22 treated cases and sphere distributions were compared with manually placed spheres in terms of number of spheres, number of protocol violations, and time required to place spheres. All cases were re-planned using script-generated spheres and plan quality was compared with clinical plans.
Results
The mean number of spheres placed excluding those that violate rules was greater using the script (13.8) than that obtained by either dosimetrist (10.8 and 12.0, p < 0.001 and p = 0.003) or physicist (12.7, p = 0.061). The mean time required to generate spheres was significantly less using the script (2.5 min) compared to manual placement by dosimetrists (25.0 and 29.9 min) and physicist (19.3 min). Plan quality indices were similar in all cases with no significant differences, and OAR constraints remained met on all plans except two.
Conclusion
A script placed spheres for lattice SBRT according to institutional protocol rules. The script-produced placement was superior to that of manually-specified spheres, as characterized by sphere number and rule violations.
Spatially Fractionated Radiation Therapy (SFRT) is a form of radiotherapy that delivers a single large dose of radiation within the target volume in a heterogeneous pattern with regions of peak dosage and regions of under dosage. SFRT types can be defined by how the heterogeneous pattern of radiation is obtained. Immune checkpoint inhibitors (ICIs) have been approved for various malignant tumors and are widely used to treat patients with metastatic cancer. The efficacy of ICI monotherapy is limited due to the “cold” tumor microenvironment. Fractionated radiotherapy can achieve higher doses per fraction to the target tumor, and induce immune activation (immodulate tumor immunogenicity and microenvironment). Therefore, coupling ICI therapy and fractionated radiation therapy could significantly improve the outcome of metastatic cancer. This review focuses on both preclinical and clinical studies that use a combination of radiotherapy and ICI therapy in cancer.
Purpose
Spatially fractionated radiation therapy (SFRT) is increasingly used for bulky advanced tumors, but specifics of clinical SFRT practice remain elusive. This study aimed to determine practice patterns of GRID and Lattice radiation therapy (LRT)-based SFRT.
Methods and Materials
A survey was designed to identify radiation oncologists’ practice patterns of patient selection for SFRT, dosing/planning, dosimetric parameter use, SFRT platforms/techniques, combinations of SFRT with conventional external beam radiation therapy (cERT) and multimodality therapies, and physicists’ technical implementation, delivery, and quality procedures. Data were summarized using descriptive statistics. Group comparisons were analyzed with permutation tests.
Results
The majority of practicing radiation oncologists (United States, 100%; global, 72.7%) considered SFRT an accepted standard-of-care radiation therapy option for bulky/advanced tumors. Treatment of metastases/recurrences and nonmetastatic primary tumors, predominantly head and neck, lung cancer and sarcoma, was commonly practiced. In palliative SFRT, regimens of 15 to 18 Gy/1 fraction predominated (51.3%), and in curative-intent treatment of nonmetastatic tumors, 15 Gy/1 fraction (28.0%) and fractionated SFRT (24.0%) were most common. SFRT was combined with cERT commonly but not always in palliative (78.6%) and curative-intent (85.7%) treatment. SFRT–cERT time sequencing and cERT dose adjustments were variable. In curative-intent treatment, concurrent chemotherapy and immunotherapy were found acceptable by 54.5% and 28.6%, respectively. Use of SFRT dosimetric parameters was highly variable and differed between GRID and LRT. SFRT heterogeneity dosimetric parameters were more commonly used (P = .008) and more commonly thought to influence local control (peak dose, P = .008) in LRT than in GRID therapy.
Conclusions
SFRT has already evolved as a clinical practice pattern for advanced/bulky tumors. Major treatment approaches are consistent and follow the literature, but SFRT–cERT combination/sequencing and clinical utilization of dosimetric parameters are variable. These areas may benefit from targeted education and standardization, and knowledge gaps may be filled by incorporating identified inconsistencies into future clinical research.
This review study analyzed preclinical studies available before 2022 on spatially fractionated radiation therapy (SFRT), a promising cancer therapy with a high therapeutic index. We intend to use the results of preclinical studies to shed light on the correlation between SFRT dosimetry and treatment response in the clinic. In particular, we challenge the use of peak dose when prescribing SFRT.
Grid therapy, the first implementation of spatially fractionated radiotherapy (SFRT), is a technique of radiotherapy delivery that results in a heterogeneous dose distribution to a target volume. This chapter provides a historical perspective of the early use of grid therapy, its re‐emergence in the 1990s, its modern day use including proposed radiobiologic effects and open accruing clinical trials, and next steps in this technique. The radiation‐induced bystander effect is defined as the manifestation of radiation injury in cells proximate to irradiated cells, but that were not themselves irradiated, and is mediated by complex signals transmitted directly or indirectly from the nearby irradiated cell(s). Over the past several years, microbeam radiotherapy (MRT) has been further investigated. Minibeam radiotherapy delivers SFRT at interbeam distances approximately double the width of MRT, 500–700 µm, spaced 1–3 mm apart.
Simple Summary
Dose prescription for the inhomogeneous dosing in spatially fractionated radiation therapy (SFRT) is challenging, and further hampered by the inability of several planning systems to incorporate complex SFRT dose patterns. We developed dosing reference tables for an inventory of tumour scenarios and tested their accuracy with water phantom measurements of GRID therapy, delivered by a standard commercial GRID collimator. We find that dose heterogeneity parameters and EUD modeling are consistent across tumour sizes, configurations, and treatment depths. These results suggest that the developed reference tables can be used as a practical clinical resource for clinical decision-making on GRID therapy and to facilitate heterogeneity dose estimates in clinical patients when this commercially available GRID device is used.
Abstract
Computations of heterogeneity dose parameters in GRID therapy remain challenging in many treatment planning systems (TPS). To address this difficulty, we developed reference dose tables for a standard GRID collimator and validate their accuracy. The .decimal Inc. GRID collimator was implemented within the Eclipse TPS. The accuracy of the dose calculation was confirmed in the commissioning process. Representative sets of simulated ellipsoidal tumours ranging from 6–20 cm in diameter at a 3-cm depth; 16-cm ellipsoidal tumours at 3, 6, and 10 cm in depth were studied. All were treated with 6MV photons to a 20 Gy prescription dose at the tumour center. From these, the GRID therapy dosimetric parameters (previously recommended by the Radiosurgery Society white paper) were derived. Differences in D5 through D95 and EUD between different tumour sizes at the same depth were within 5% of the prescription dose. PVDR from profile measurements at the tumour center differed from D10/D90, but D10/D90 variations for the same tumour depths were within 11%. Three approximation equations were developed for calculating EUDs of different prescription doses for three radiosensitivity levels for 3-cm deep tumours. Dosimetric parameters were consistent and predictable across tumour sizes and depths. Our study results support the use of the developed tables as a reference tool for GRID therapy.
Objective:
To develop and characterize novel methods of extreme spatially fractionated kV radiation therapy (including mini-GRID therapy) and to evaluate efficacy in the context of a pre-clinical mouse study.
Approach:
Spatially fractionated GRIDs were precision-milled from 3 mm thick lead sheets compatible with mounting on a 225 kVp small animal irradiator (X-Rad). Three pencil-beam GRIDs created arrays of 1 mm diameter beams, and three 'bar' GRIDs created 1x20 mm rectangular fields. GRIDs projected 20x20 mm2 fields at isocenter, and beamlets were spaced at 1, 1.25, and 1.5 mm, respectively. Peak-to-valley ratios and dose distributions were evaluated with Gafchromic film. Syngeneic transplant tumors were induced by intramuscular injection of a soft tissue sarcoma cell line into the gastrocnemius muscle of C57BL/6 mice. Tumor-bearing mice were randomized to four groups: unirradiated control, conventional irradiation of entire tumor, GRID therapy, and hemi-irradiation (half-beam block, 50% tumor volume treated). All irradiated mice received a single fraction of 15 Gy.
Results:
High peak-to-valley ratios were achieved (bar GRIDs: 11.9±0.9, 13.6±0.4, 13.8±0.5; pencil-beam GRIDs: 18.7±0.6, 26.3±1.5, 31.0±3.3). Pencil-beam GRIDs could theoretically spare more intra-tumor immune cells than bar GRIDs, but they treat less tumor tissue (3-4% vs 19-23% area receiving 90% prescription, respectively). Bar GRID and hemi-irradiation treatments significantly delayed tumor growth (P<0.05), but not as much as a conventional treatment (P<0.001). No significant difference was found in tumor growth delay between GRID and hemi-irradiation.
Significance:
High peak-to-valley ratios were achieved with kV grids: two-to-five times higher than MV grids in literature. GRID irradiation and hemi-irradiation delayed tumor growth, but neither was as effective as conventional whole tumor uniform dose treatment. Single fraction GRID therapy could not initiate an anti-cancer immune response strong enough to match conventional RT outcomes, but follow-up studies will evaluate the combination of mini-GRID with immune checkpoint blockade.
Purpose: Spatially fractionated radiation therapy (SFRT), which delivers highly non-uniform dose distributions instead of conventionally practiced homogenous tumor dose, has shown high rates of clinical response with minimal toxicity in large-volume primary or metastatic malignancies. However, prospective multi-institutional clinical trials in SFRT are lacking, and SFRT techniques and dose parameters remain variable. Agreement on dose prescription, technical administration and clinical/translational design parameters for SFRT trials is essential to enable broad participation and successful accrual to rigorously test the SFRT approach. We aimed to develop a consensus for the design of multi-institutional clinical trials in SFRT, tailored to specific primary tumor sites, to help facilitate development and enhance feasibility of such trials.
Methods and materials: Primary tumor sites with sufficient pilot experience in SFRT were identified, and fundamental trial design questions were determined. For each tumor site, a comprehensive consensus effort was established through disease-specific Expert Panels. Clinical trial design criteria included eligibility, SFRT technology/technique, dose/fractionation, target and normal tissue dose parameters, systemic therapies, clinical trial endpoints, and translational science considerations. Iterative appropriateness rank voting, Expert Panel consensus reviews/discussions and public comment posting were employed for consensus development.
Results: Clinical trial criteria were developed for head and neck cancer and soft tissue sarcoma. Final consensus among the 22 trial design categories each (total of 163 criteria) was overall high to moderate. Uniform patient cohorts of advanced bulky disease, standardization of SFRT technologies and dosimetry/physics parameters, and collection of translational correlates were considered essential to trial design. Final guideline recommendations and degree of agreement are presented and discussed.
Conclusions: This consensus provides design guidelines for the development of prospective multi-institutional clinical trials testing SFRT in advanced head and neck cancer and soft tissue sarcoma through in-advance harmonization of fundamental clinical trial design among SFRT experts, potential investigators and the SFRT community.
Purpose:
GRID therapy is an effective treatment for bulky tumors. Linear accelerator (Linac)-produced photon beams collimated through blocks or multi-leaf collimators (MLCs) are the most common methods used to deliver this therapy. Utilizing the newest proton delivery method of pencil beam scanning (PBS) can further improve the efficacy of GRID therapy. In this study, we developed a method of delivering GRID therapy using proton PBS, evaluated the dosimetry of this novel technique and applied this method in two clinical cases.
Materials/methods:
In the feasibility study phase, a single PBS proton beam was optimized to heterogeneously irradiate a shallow 20x20x12 cm3 target volume centered at a 6 cm depth in a water phantom. The beam was constrained to have an identical spot pattern in all layers, creating a "beamlet" at each spot position. Another GRID treatment using PBS was also performed on a deep 15x15x8 cm3 target volume centered at a 14 cm depth in a water phantom. Dosimetric parameters of both PBS dose distributions were compared with typical photon GRID dose distributions. In the next phase, four patients have been treated at our center with this proton GRID technique. The planning, dosimetry and measurements for two representative patients are reported.
Results:
For the shallow phantom target, the depth-dose curve of the PBS plan was uniform within the target (variation <5%) and dropped quickly beyond the target (50% at 12.9 cm and 0.5% at 14 cm). The lateral profiles of the PBS plan were comparable to those of photon GRID in terms of valley-to-peak ratios. For the deep phantom target, the PBS plan provided smaller valley-to-peak ratios than the photon GRID technique. Pre-treatment dose verification QA showed close agreement between the measurements and the plan (pass rate >95% with a gamma index criterion of 3%/3 mm). Patients tolerated the treatment well without significant skin toxicity (radiation dermatitis grade ≤1).
Conclusions:
Proton GRID therapy using a PBS delivery method was successfully developed and implemented clinically. Proton GRID therapy offers many advantages over photon GRID techniques. The use of protons provides a more uniform beamlet dose within the tumor and spares normal tissues located beyond the tumor. This new PBS method will also reduce the dose to proximal organs when treating a deep-seated tumor. This article is protected by copyright. All rights reserved.
Purpose:
Proton minibeam radiotherapy using sub-millimeter beam dimensions allows to enhance tissue sparing in the entrance channel by spatial fractionation additionally to advantageous proton depth dose distribution. In the entrance channel, spatial fractionation leads to reduced side effects compared to conventional proton therapy. The sub-millimeter sized beams widen with depth due to small angle scattering and enable therefore, in contrary to x-ray microbeam radiation therapy (MRT), the homogeneous irradiation of a tumor. Proton minibeams can either be applied as planar minibeams or pencil shaped with an additional possibility to vary between a quadratic and a hexagonal arrangement for pencil minibeams. The purpose of this work is to deduce inter beam distances to achieve a homogeneous dose distribution for different tumor depths and tumor thicknesses. Furthermore, we aim for a better understanding of the sparing effect on the basis of surviving cells calculated by the linear-quadratic model.
Methods:
Two dimensional dose distributions are calculated for proton minibeams of different shapes and arrangements. For a tumor in 10-15 cm depth, treatment plans are calculated with initial beam size of σ0 = 0.2 mm in a water phantom. Proton minibeam depth dose distributions are finally converted into cell survival using a linear quadratic model.
Results:
Inter proton beam distances are maximized under the constraint of dose homogeneity in the tumor for tumor depths ranging from 4-15 cm and thickness ranging from 0.5-10 cm. Cell survival calculations for a 5 cm thick tumor covered by 10 cm healthy tissue show less cell death by up to 85 %, especially in the superficial layers, while keeping the cell death in the tumor as in conventional therapy. In the entrance channel the pencil minibeams result in higher cell survival in comparison to the planar minibeams while all proton minibeam irradiations show higher cell survival than conventional broadbeam irradiation.
Conclusion:
The deduced constraints for inter-beam distances simplify treatment planning for proton minibeam radiotherapy applications in future studies. The cell survival results indicate that proton minibeam radiotherapy reduces side effects but keeps tumor control as in conventional proton therapy. It makes proton minibeam, especially pencil-minibeam radiotherapy a potentially attractive new approach for radiation therapy. This article is protected by copyright. All rights reserved.
Variation in inhomogeneity quotient, depth doses and skin tolerance values are discussed in relation to sieve ratios.
The need for careful consideration of the aims for which the sieve technique is used and of the indirect effects of radiation in any evaluation of “optimum” dosage level is stressed.
When all sites and types of cancer are included, the cure rate from currently accepted methods of treatment does not exceed 25 per cent. This means that about 75 per cent of all cancer victims must be considered incurable and can be treated only palliatively for prolongation of useful life or relief of symptoms, or both. The value of radiotherapy as a palliative agent is not universally appreciated. There is often a lack of interest in the hopeless or incurable patient and either no active treatment is given or only meaningless token therapy. Recently, renewed interest has been displayed in the use of grids for roentgen therapy of advanced cancers. Grids have been used in roentgen therapy since 1909, when Alban Kohler (1) made his first report. Later, in 1933, Liberson (2) suggested the use of a metallic lead grid and worked out the biological and physical aspects which are, for the most part, valid to this day. Others, including Haring (3), Grynkraut (4), and Jolles (5) have also suggested the use of gri...
To decrease the effects of x-rays on the skin when large fields are used to reach a deep-seated cancer, Alban Kohler (1) in 1909 had devised what has been termed “fractionation of the x-ray dosage in space.” This was done by placing on the skin a steel wire net, the openings of which were 2 mm. wide and the wire proper 1 mm. in thickness. Kohler administered massive doses, ten to twenty times the total dose usually given at that time through a conventional open field. Healing of the skin was initiated in and extended from the surrounding relatively unscathed normal skin. In experimental radiobiology in 1931 (2) and 1938 (3a), doses of 25,000 r and 120,000 r without a grid were found to be inhibitory and lethal respectively to the proliferation of normal tissue in vitro, the cancericidal dose in vivo being 24,000 r in air (3b). In the above case, the optimum dose without a grid enters the tumor-bearing area, while in the grid method only 40 per cent of the 24,000 r in air, or 9,600 r in air, enters the tum...
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