RADIATION RESEARCH 194, 665–677 (2020)

0033-7587/20 $15.00
Ó2020 by Radiation Research Society.
All rights of reproduction in any form reserved.
DOI: 10.1667/RADE-20-00047.1

Photon GRID Radiation Therapy: A Physics and Dosimetry White Paper

from the Radiosurgery Society (RSS) GRID/LATTICE, Microbeam and
FLASH Radiotherapy Working Group

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Hualin Zhang,a,1 Xiaodong Wu,b Xin Zhang,c Sha X. Chang,d Ali Megooni,e Eric D. Donnelly,a
Mansoor M. Ahmed,f,2 Robert J. Griffin,g James S. Welsh,h Charles B. Simone, IIi and Nina A. Mayrj
a
Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; b Excecutive Medical Physics
Associates and Biophysics Research Institute of America, Miami, Florida 33179; c Department of Radiation Oncology, Boston Medical Center, Boston,
Massachusetts 02118; d Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516;
e
Department of Radiation Therapy, Comprehensive Cancer Center of Nevada, Las Vegas, Nevada 86169; f Division of Cancer Treatment and Diagnosis,
Rockville, Maryland 20892; g University of Arkansas for Medical Sciences, Department of Radiation Oncology, Little Rock, Arkansas; h Loyola University
Chicago, Edward Hines Jr. VA Hospital, Stritch School of Medicine, Department of Radiation Oncology, Maywood, Illinois 60153; i New York Proton
Center, Department of Radiation Oncology, New York, New York 10035; and j Department of Radiation Oncology, University of Washington Medical
Center, Seattle, Washington 98195

ning, the Physics Working Group of the Radiosurgery

Zhang, H., Wu, X., Zhang, X., Chang, S. X., Megooni, A., Society (RSS) GRID/Lattice, Microbeam and Flash Radio-
Donnelly, E. D., Ahmed, M. M., Griffin, R. J., Welsh, J. S., therapy Working Groups, was established after an RSS-NCI
Simone, C. B. II and Mayr, N. A. Photon GRID Radiation Workshop. One of the goals of the Physics Working Group
Therapy: A Physics and Dosimetry White Paper from the was to develop consensus recommendations to standardize
Radiosurgery Society (RSS) GRID/LATTICE, Microbeam dose prescription, treatment planning approach, response
and FLASH Radiotherapy Working Group. Radiat. Res. 194, modeling and dose reporting in GRID therapy. The
objective of this report is to present the results of the
665–677 (2020).
Physics Working Group’s consensus that includes recom-
The limits of radiation tolerance, which often deter the mendations on GRID therapy as an SFRT technology, field
use of large doses, have been a major challenge to the dosimetric properties, techniques for generating GRID
treatment of bulky primary and metastatic cancers. A novel fields, the GRID therapy planning methods, documentation
technique using spatial modulation of megavoltage therapy metrics and clinical practice recommendations. Such un-
beams, commonly referred to as spatially fractionated derstanding is essential for clinical patient care, effective
radiation therapy (SFRT) (e.g., GRID radiation therapy), comparisons of outcome results, and for the design of
which purposefully maintains a high degree of dose rigorous clinical trials in the area of SFRT. The results of
heterogeneity across the treated tumor volume, has shown well-conducted GRID radiation therapy studies have the
promise in clinical studies as a method to improve treatment potential to advance the clinical management of bulky and
response of advanced, bulky tumors. Compared to conven- advanced tumors by providing improved treatment re-
tional uniform-dose radiotherapy, the complexities of sponse, and to further develop our current radiobiology
megavoltage GRID therapy include its highly heterogeneous models and parameters of radiation therapy design. Ó 2020
dose distribution, very high prescription doses, and the by Radiation Research Society

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 INTRODUCTION
well understood. To advance SFRT technology and plan-
Megavoltage X-ray GRID therapy is a form of spatially
1 Address for correspondence: Department of Radiation Oncology,
fractionated radiation therapy (SFRT) that has been used
Northwestern University Feinberg School of Medicine, Northwestern successfully to manage patients with bulky tumors, which
Memorial Hospital, Chicago, IL 60611; email: [email protected]. are often refractory to conventional radiation therapy and
2 This article reflects the scientific opinion for the RSS Working
other cancer therapies (1, 2). GRID therapy employs an X-
Group established after an RSS-NCI Workshop, August 2018.
Members of the National Cancer Institute (NCI) participate in this ray fluence in a spatially-fractionated irradiation pattern in
group. This is the personal professional judgment of the member, the shape of a grid (grid pattern). This grid pattern is
Mansoor M. Ahmed and does not represent opinion, guidance, created by the use of a physical GRID block (3) or GRID
position statement or policy of the Radiation Research Program,
Division of Cancer Treatment and Diagnosis, NCI, Department of collimator that contain arrays of apertures within a
Health and Human Services or U.S. government. Cerrobend or brass block. Newer technologies also
665
666 ZHANG ET AL.

distribution illustrated by the light field pattern on a

patient’s skin. 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 symptom-

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atic 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,
6–16). 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, 10–16). The mechanisms hypothesized to
underpin the observed responses in GRID therapy, such
as immunological, bystander and microvascular effects,
continue to be an area of active research (17–19). The
purpose of this article is to provide a clinical physics
consensus and guidelines for technology selection,
commissioning, quality assurance (QA), dose prescription,
treatment planning and reporting for GRID therapy, and
staff training. Based on the consensus, recommendations
are made to standardize these physics and dosimetry
processes for all GRID therapy plans to improve clinical
treatments, facilitate the interpretation of clinical trial
results and further aid the elucidation of translational
biological parameters underpinning the effects of SFRT,
based on a consistent and standardized approach to dosing,
delivery and dose reporting of this unique and complex
treatment approach.

MATERIALS AND METHODS

In view of the unique characteristics of SFRT, and the lack of
widespread familiarity among medical physicists with the principles
and intricacies of GRID therapy, the RSS GRID/Lattice, Microbeam
and Flash Radiotherapy set of Working Groups established the
Physics Working Group after an RSS-NCI Workshop in August 2018,
to develop and provide recommendations, guidelines and procedures
for GRID therapy as a special treatment modality that can be applied
for clinical management and clinical trials. The recommendations
were developed based on a comprehensive review of the physics and
clinical literature. The consensus was specifically focused on the
GRID component of treatment because ample guidelines exist for the
conventional radiation therapy component that is often combined with
GRID. Lattice therapy, a variant and a 3-dimensional (3D)
configuration of SFRT with an array of high-dose regions generated
FIG. 1. The GRID block (High Dose Radiation GRID; Radiation by converging intensity-modulated beams or volumetric modulated
Products Design) and field. arc therapy (VMAT), was felt to be beyond the scope of this article.
Based on this review the Physics Working Group determined that
include grid pattern generation by a treatment planning there is an urgent need to provide an up-to-date review of GRID
system through a virtual block and entirely by multileaf therapy and to develop and propose guidelines for GRID therapy
technology selection, commissioning, dose calibration, dosimetric
collimator (MLC) modulation (4). A typical GRID approaches, treatment planning and evaluation, treatment dose
collimator is shown in Fig. 1 and the resulting dose prescription and reporting, QA and staff training. The guidelines
 GRID THERAPY GUIDELINES RECOMMENDED BY RSS WORKING GROUP 667

development process included close collaboration with dosimetrists,

radiobiology experts and radiation oncologists to ensure that basic
science as well as the clinical perspective were brought into this
clinical physics consensus work.

CLINICAL RESULTS REVIEW

Based on a phone survey with physicians and physicists
in five radiation therapy centers in the U.S. that have used
GRID therapy, at least 2,000 patients have been treated with

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this technique nationwide. While no data are available on
the exact total number of patients who have received GRID
therapy, the actual number of patients treated with GRID
therapy could be significantly higher than the survey data
above. Currently, at least one clinical trial of GRID therapy
is ongoing on in the U.S. (20).
Several studies have evaluated the clinical efficacy of
GRID therapy in a variety of settings. Mohiuddin et al.
(10) reported that among 87 patients with bulky and
therapy-refractory tumors of various histologies (sarcoma,
squamous cancer, adenoma, melanoma and others) treated
palliatively with GRID therapy, an overall palliative
symptom response rate of 94% was achieved with doses
greater than 15 Gy prescribed to the dmax depth in one
fraction at 3–42 months of follow-up. With doses less
than 15 Gy, the response was decreased to 62%. Response
was higher when GRID therapy was followed by
conventionally fractionated open-field uniform external-
beam therapy (92%), compared to GRID therapy alone
(86%). Furthermore, open-field external-beam radiation
doses of 40 Gy or greater resulted in higher response than
lower doses. Mohiuddin et al.’s study thereby provided
foundational dose-response relationship data for GRID
therapy and for the combination open-field uniform
external beam radiation. It also demonstrated the need to
combine GRID therapy with open-field uniform external
beam radiation to improve the probability of clinical
symptom response in advanced bulky palliatively treated
tumors.
While the original GRID therapies were delivered using
Cerrobend GRID blocks on non-digital accelerators (Fig. 1),
MLCs on digital accelerators have enabled GRID fields
FIG. 2. The MLC-created GRID radiation field (4). MLCs also
with the added ability to shape the field to conform to the could be used to generate grid-like field. In this example, five separate
tumor volume and spare organs at risk (OARs). Several MLC-shaped beams were used, and each defined two columns of the
investigators have studied advanced treatment planning grid openings. The composite of the five beams gave rise to an
effective ‘‘GRID’’ with the openings arranged in an alternating
systems (TPS) to design virtual GRID blocks (21–23), checkerboard pattern and open-to-close areal ratio of 1:3 (4).
where the function of the physical GRID block is achieved
by software and multileaf collimators (Fig. 2), as well as the
use of multiple beams and arc 3D treatment approaches.
Lattice therapy, a variant of SFRT, employs non-coplanar While there is increasing interest among clinicians in
focused beams or VMAT to generate an array of individual the use of SFRT techniques to treat patients, there is no
high-dose spherical vertices within the tumor while established clinical guidance to assist them in treatment
reducing the peripheral tumor dose (24). Furthermore, planning and evaluation. In addition, as more GRID
proton therapy centers have begun exploring proton beams therapy techniques and planning methods become avail-
in GRID therapy beam configurations employing pencil able, their complexity and variation increases signifi-
beam scanning (25, 26). cantly, making meaningful evaluation and comparison of
668 ZHANG ET AL.

techniques challenging for both clinical care and for the performed using a water scanning system. The water
development, analysis and reporting of clinical trials. scanning system usually consists of a 48 3 48 3 48 cm3
or similar size water tank, an electrometer, an ionization
chamber and data acquisition/processing software. The
UNIQUE CONSIDERATIONS FOR
GRID collimator is placed in the blocking tray slot of the
PHOTON GRID THERAPY AND DOSIMETRY
linear accelerator. Data are acquired for 6-MV and 10-MV
The key technical, dosimetric and workflow parameters of photon beams at 100 cm source-to-surface distance (SSD).
GRID therapy include treatment prescription, non-uniform Beam energies above 10 MV are not used to avoid neutron
dose planning and evaluation (such as peak and valley dose production. Depth ionization scans are obtained along the

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ratio and equivalent uniform dose), delivery technique beam central axis under the central aperture of the grid for 5
selection [3D-CRT, conformal arc, intensity-modulated 3 5, 10 3 10, 15 3 15 and 20 3 20 cm2 collimator jaw
radiation therapy (IMRT), TomoTherapy, VMAT and settings. GRID output factors are measured at 1.5, 2 and 5
proton therapy], selection of energy corresponding to cm depth for 10 3 10 cm2 jaw setting. The scanning system
patient-specific GRID therapy target (shallow or deep- is carefully aligned to maintain the ion chamber at the center
seated, size and shape of target volume, sparing or of the beam profile at all depths. Depth doses are assumed
disregarding of the critical OARs, considering or disregard- to be directly obtainable from the normalized depth
ing the neutron and electron contamination, etc.), and ionization profiles without any further consideration for
treatment delivery time consideration with practical treat- loss of electronic equilibrium or energy spectrum changes.
ment times (as longer treatment times may cause patient Cross-beam ionization profiles at 5 3 5, 10 3 10, 15 3 15
motion and discomfort as well as slow workflow through- and 20 3 20 cm2 collimator jaw settings are respectively
put). obtained in both the transverse and radial planes at a depth
Although some investigators have proposed methods to of 1.5 cm for 6-MV beam and at 2 cm for 10-MV beam.
standardize the dose documentation (27), a consensus has Cross-beam ionization profiles at the depth of 3, 5 and 10
not been established. In addition, GRID therapy has been cm are also measured. Because the grid apertures of
used under diverse clinical regimens, ranging from one to commercially available GRID collimators are arranged in a
several fractions of GRID therapy, followed by a standard hexagonal close-packed form, as further discussed in
several-week course of uniform radiation. Furthermore, Commercially available GRID collimators in the section,
these variable regimens have also been used in variable Treatment Planning for Spatially Fractionated (GRID)
combinations with chemotherapy. Major ongoing questions Radiation Therapy, the transverse profiles cut the grid along
focus on the dose criteria of GRID therapy, and whether and a line joining opposite apertures of the central hexagon,
how the dose from GRID radiation should be added in the whereas the radial profiles cut the grid along a line bisecting
patients’ conventionally fractionated radiation course, so as opposite sides of the central hexagon. Therefore, the
to establish consistency when treatment response end points spacing between the peaks and the heights of the peaks
are evaluated. It is anticipated that the more precise and and valleys in the profiles are different for the two
standardized the implementation and reporting of the orthogonal scan directions. The transverse and radial dose
physical treatment parameters are in clinical GRID therapy profiles can be obtained directly from the normalized
trials, the more robust will be the resulting dose parameters ionization profiles without any further consideration for loss
and clinical outcome correlations. of electronic equilibrium or energy spectrum changes. A
detailed example of the water phantom measurements is
given in the subsection, Example of a Physical GRID
EQUIPMENT, COMMISSIONING
Collimator Commissioning and Table 1.
AND QUALITY ASSURANCE
Attention to technology implementation, commissioning Film Dosimetry
and robust quality assurance processes is of critical
EBT film (Eastman Kodak, Rochester, NY) has been
importance for the establishing and maintaining a SFRT
widely used in radiotherapy applications, including IMRT
program, and should be tailored to the individual facility’s
quality assurance, and it has been shown to have a better
capabilities and needs. The following procedures for
dose-response range and improved linearity (28). In the
commissioning the GRID collimator and treatment QA are
past, EDR2 films (by the same company) were also used to
recommended.
measure GRID dose distribution at depths of interest (29).
As a convenient tool, films can be utilized to obtain the dose
Water Phantom Measurements
output factor and dosimetric distributions at the tumor
Before the GRID collimator is used in clinic, a water depth. Calibration curves should be obtained for each batch
phantom dosimetric study must be performed, since of film. With the film, beam profiles of the GRID field will
different linear accelerators may have different beam be obtained in both the radial and transverse directions, as
properties. All water phantom measurements can be well as in a full 2D representation.
 GRID THERAPY GUIDELINES RECOMMENDED BY RSS WORKING GROUP 669

TABLE 1
Percentage Depth Doses for a 6-MV 10 3 10 cm2 GRID Field and an Open Field (29)
GRID field GRID field Open field Open field
Distance from 10 3 10 CM2 10 3 10 CM2 10 3 10 CM2 10 3 10 cm2
water surface D (cm) (WATER TANK) (MONTE CARLO) (WATER TANK) (Monte Carlo)
0.0 45.5 45.0 45.0 44.3
0.5 70.1 83.6 75.1 74.8
1.0 96.2 94.9 95.7 96.4
1.5 100.0 100.0 100.0 100.0
2.0 98.3 98.6 99.4 99.1

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2.5 95.7 94.7 97.6 97.0
3.0 93.4 94.8 95.7 95.1
3.5 90.5 90.8 93.6 92.9
4.0 88.3 89.3 91.4 90.8
4.5 85.4 84.7 89.4 88.6
5.0 83.5 83.5 87.3 86.7
5.5 80.9 80.4 85.2 84.5
6.0 77.7 77.2 83.1 82.4
6.5 76.7 73.9 81.1 80.4
7.0 74.7 74.7 79.3 78.2
7.5 72.4 72.8 77.2 76.2
8.0 70.0 70.5 75.2 74.2
8.5 68.0 69.1 73.3 72.5
9.0 66.2 66.2 71.5 70.6
9.5 64.4 63.8 69.6 68.8
10.0 62.8 62.2 67.8 66.9
10.5 60.7 59.4 66.1 65.1
11.0 59.3 58.2 64.3 63.4
11.5 57.1 55.2 62.6 61.7
12.0 54.9 55.7 60.9 60.0
12.5 54.1 51.4 59.4 58.2
13.0 52.3 51.5 57.8 56.7
13.5 50.8 51.1 56.2 55.3
14.0 48.5 47.8 54.6 53.8
14.5 47.9 45.8 53.3 52.1
15.0 46.4 44.8 51.8 50.7
15.5 44.9 42.5 50.5 49.4
16.0 43.5 41.2 49.2 48.2
16.5 41.7 41.2 47.9 46.9
17.0 39.9 40.5 46.6 45.5
17.5 39.4 38.0 45.3 44.3
18.0 38.8 36.8 44.0 43.0
18.5 37.7 36.6 42.8 41.9
19.0 35.6 36.2 41.6 40.7
19.5 36.1 33.7 40.5 39.7
20.0 34.1 33.3 39.4 38.5
Note. Gantry is at zero degree, distance is from the top water surface located at 100 cm source-to-surface
distance (SSD) to downstream.

Monte Carlo Simulation at the University of Kentucky prior to implementation of the

first systematic GRID therapy program, and in its concept
If possible, a Monte Carlo simulation can be performed to
has been published elsewhere (29).
obtain dosimetric characteristics of the GRID field at
Water phantom scanning work. The water phantom
different jaw settings and different tumor depths to
measurements were performed according to the standard
complement experimental data, but the results must be
procedure described above in Water Phantom Measure-
experimentally validated. The next section provides a
ments section, using the 48 3 48 3 48 cm3 water tank,
detailed example of Monte Carlo dosimetric characteriza-
electrometer and two scanning ion-chambers set-up. A
tion of a GRID collimator in detail.
Wellhoeffer CC01 microionization chamber was used for all
in-field measurements. The results are shown in Table 1.
Example of a Physical GRID Collimator Commissioning
Measurements were performed using a commercial GRID
This section describes the typical process of GRID collimator (High Dose Radiation GRID; Radiation Products
collimator commissioning and serves as an example for Design, Albertville, MN). The 6-MV photon beam was set
clinical practice. This commissioning work was carried out at 100 cm SSD of a Clinac 2100 EX linear accelerator
670 ZHANG ET AL.

(Varian Oncology Systems, Palo Alto, CA). As per EGS4 code (36). The grid collimator was simulated as a 2D
procedures, the depth ionization scans were acquired along array of 19 conical apertures having with hole diameters of
the central axis under the central aperture of the grid for 5 3 0.60 cm on the top side and 0.85 cm on the lower side and a
5, 10 3 10, 15 3 15 and 20 3 20 cm2 collimator jaw settings, 7.5-cm length arranged within a Cerrobend block in the
and cross-beam ionization profiles were acquired in both the hexagonal pattern. All holes in the grid were divergent and
transverse and radial planes at a depth of 1.5 cm. The depth roughly concordant with the beam tilt. The measurements
doses were assumed to be directly obtainable from the have shown that this design produced the same output from
normalized depth ionization profiles without any further all of the holes. The SSD for the phantom was set at 100 cm.
consideration for loss of electronic equilibrium or energy An array of spherical, 1-mm-diameter tally cells, spaced at 2

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spectrum changes. The transverse and radial dose profiles mm center-to-center, was defined at depths ranging from 0.25
were obtained directly from the normalized ionization to 7 cm at 0.25-cm increments for simulating 2D dose at each
profiles. layer. The dose distributions from all layers constituted a 3D
EDR2 film dosimetry. EDR2 film (Eastman Kodak) was dose distribution. The depth dose was obtained using 1-mm
irradiated in solid-water (Gammex RMI, Middleton, WI) voxels with a 2-mm spacing arranged along the beam central
slab phantoms to obtain cross-beam profiles. Films were axis. For each simulation, the low-energy cutoff was set at 10
irradiated at a depth of 1.5 cm using 6-MV photons from a keV and used a minimum of 5 3 108 histories. The statistical
Clinac 2100 EX linear accelerator (Varian Oncology error of each tallied dose was found to be less than 4%.
Systems). Calibration curves were obtained for each batch
of film. The film was processed at least 3 h postirradiation Treatment Planning Dose Calculation
to minimize known time-dependent film sensitivity (15). All
films were scanned using an Epson Expression 1680 flatbed Treatment planning dose calculation must be commis-
scanner (Epsont America Inc., Long Beach, CA) and sioned for GRID therapy using the commissioning mea-
analyzed with Procheck version 2.7 (NMPE, Lynnwood, surement data. The treatment planning system already
WA). Beam profiles of the GRID field were obtained in commissioned for conventional radiation therapy may not
both the radial and transverse directions, as well as in a full be adequate for GRID therapy and must be validated using
2D representation. the GRID therapy experimental data before clinical use.
Monte Carlo simulation. A Monte Carlo N-particle Many modern Monte Carlo codes are available for
Transport Code (MCNPX, version 2.5) (30) was used to radiotherapy beam simulation, and readers are encouraged
calculate the doses in water at a depth of 1.5 cm. Results of to explore this topic (29, 37, 38). Importantly, all dose
the Monte Carlo simulation are given in Table 1. The code is calculations, including the Monte Carlo simulation, must be
the extension for particle types and energy ranges of MCNP validated by GRID commissioning through experimental
(31). The photon interaction cross-section file used in this work before clinical use, as exemplified in detail in the
study was the DLC-200 library distributed by the Radiation subsection, Example of a Physical GRID Collimator
Shielding Information Computing Center (RSICC). The Commissioning.
MCNPX code considers photoelectric, coherent, Compton
and pair production interactions. There are several tally types GRID TREATMENT PRESCRIPTION
available in the MCNPX code for dose calculation. The *f8
tally calculates the difference between the energy carried into Although different GRID therapy prescription doses have
and out of the tally cell by particles. In this project, the *f8 been reported, most clinics use the prescription ranging
tally type was used to determine the dose-rate distribution in from 10 to 20 Gy to the open dose spot. If the tumor is
the flat water phantom at the depth of interest, 1.5 cm, as well shallowly seated (,3 cm deep), it is recommended that the
as the central axis percentage depth dose. A simplified source central hole maximum dose is set to be equal to the dose at
model (29), first described by DeMarco et al. (32) and Lewis depth of dmax and used as the prescription dose. If the
et al. (33), was used. Although this design ignores the true GRID aperture size is very small, the maximum dose from
photon phase space distribution, as pointed out by Siebers et the hole field may become sensitive to the size of the
al. (34), its effectiveness and accuracy have been demon- detector that is used experimentally or Monte Carlo
strated for flat phantoms when fine beam structure is not simulation. In this scenario, the peak is very sharp, and
emphasized. However, this simplified model ignores the one half of aperture physical size (half of aperture diameter)
existence of electron contamination in photon beam. The can be used to obtain average maximum dose at the depth of
cone-beam angle was chosen to allow a maximum field size dmax. This has been proven effective since the field is
of 40 3 40 cm2 on the phantom surface at 100 cm SSD by divergent, and the projected fields are magnified at the
collimators located 53 cm from the source. A spectrum treatment distance. This dose is also referred to as the
representative of photon energies that exit the monitor nominal dose.
ionization chamber was used. This spectrum was previously For deeply-seated tumors (.3 cm depth), it is recom-
determined for a Varian 21 EX 6-MV photon beams by Spezi mended that the dose at the tumor center depth be used as
et al. (35) and validated by comparison to that obtained from the prescription dose. When a commercially available GRID
 GRID THERAPY GUIDELINES RECOMMENDED BY RSS WORKING GROUP 671

shielded by the Cerrobend block. All holes in the GRID

were divergent and roughly concordant with the beam tilt.
For the commonly used, commercially available GRID
collimators, the MU needed for delivering the prescribed
nominal dose (i.e., 15 or 20 Gy) is calculated based on the
output factor of the central hole usually near, or passing
through, the beam’s central axis. The approach is the same
for the MLC-formed or jaw-formed GRID fields. Because
when the commercially available GRID collimator is

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mounted, an MLC or jaw-pairs can be used to reduce the
field size to create a preliminary conformal field adapted to
the tumor size, the output factor (OUTdmax) of the GRID
field central hole at the depth of dmax will vary with the
field size and must be measured. The MU is calculated
according to:
DnominalðGyÞ
FIG. 3. Commercially available GRID collimator (High Dose MU ¼  Gy  : ð1Þ
Radiation Grid; Radiation Products Design). OUTdmax MU
For instance, if a GRID field has an output factor of 0.89
collimator is used, the dose at the prescription depth onto cGy/MU at the depth of dmax of GRID field central hole,
the central axis of the central hole is defined as the we can calculate and know that 2,247 MUs will be needed
prescription dose. The same definitions for dose prescrip- for giving 20 Gy at the dmax depth of the GRID field (2,000
tion apply to the MLC-based GRID therapy, and the cGy/0.89 cGy/MU). If the machine dose rate is 600 cGy/
prescription point is on or near the beam’s central axis, or min, the treatment will take 3.75 min.
near the field center. The water tank measurements indicate that, although the
percentage depth dose (PDD) curve has noticeably changed
compared to the open field, when the GRID aperture size is
TREATMENT PLANNING FOR SPATIALLY approximately 1 cm, the depth of dmax remains the same
FRACTIONATED (GRID) RADIATION THERAPY for 10 3 10 cm2 jaw size (3, 29). Thus, when we generate
Commercially Available GRID Collimators plans and perform the QAs, we can still use the dmax depths
measured from the open field (Fig. 4). Table 1 provides an
Most clinics use commercially available GRID collima- example of GRID field PDD that readers can use as a
tors, currently available from two companies (High Dose reference. While GRID beam data from various linacs are
Radiation GRID; Radiation Products Design; .decimalt, very similar if the energy and setting are kept constant,
Sanford, FL). Early GRID therapy was generated by GRID variations in the GRID collimator can alter the results. As
blocks with a hexagonal array of apertures within a we can see, the planning technique is very straightforward,
Cerrobend block. Preceding the development of MLCs, and we are simply calculating and delivering the nominal
this GRID block did not allow MLC-based field shaping.
prescription dose (e.g., 20 Gy) to the depth of dmax of the
The concept was then further developed into the currently
GRID beamlet field. Because each beamlet may be slightly
used GRID collimators that allow both a grid pattern of
different, we choose the central hole passing through the
irradiation and MLC-based field collimation. The original
beam’s central axis as the standard for MU calculation.
GRID collimator (manufactured by Radiation Products
However, the depth of the tumor center may be variable,
Design), consisted of a 7.5-cm thick Cerrobend block,
and the treating physician may decide to prescribe the dose
perforated by a hexagonal pattern (Fig. 3) of circular
to a depth (d) other than dmax. In addition, if two opposed
divergent holes, and was designed to be mounted in the
GRID fields are used (39), then the PDD curves would be
standard linear accelerator accessory mount 65.4 cm from
entirely different. If this is the case, then the physicist must
the source (Varian 21 EX, Varian Oncology Systems, Palo
measure or calculate the GRID field output factor at d.
Alto, CA). The GRID collimator configuration was
Again, the calculated output factor needs to be experimen-
subsequently advanced to a new design using brass as a
tally verified. If the output factor of the GRID field at the
construction material to reduce weight (.decimal). The
depth d is OUTd, then,
diameter of the holes is 0.60 cm on the top side and 0.85 cm
on the lower side, and the center-to-center separation of the DnominalðGyÞ
holes on the block is 1.15 cm on the lower surface. With the MU ¼  Gy  : ð2Þ
OUTd MU
original GRID collimator design, approximately one half of
the tissues in the collimated areas were irradiated by the Figure 5 shows the peaks and valleys of doses of the GRID
partially attenuated primary beam; the remainder were field. These peaks and valleys are spatially populated with
672 ZHANG ET AL.

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FIG. 4. Percentage depth-dose curves of a 10 3 10 cm2 open field and a 10 3 10 cm2 GRID field. The PDD of
the GRID field is measured by water tank and calculated using the Monte Carlo technique (29).

the designed pattern, which produces the SFRT. In GRID collimators with different aperture sizes and patterns might
therapy, another important dosimetric parameter is the provide different dosimetric and tissue effects. The role of
valley/peak (in some studies, presented as peak/valley) dose GRID collimators of different sizes, patterns and hole
ratio, VPDR or R, described as: center-to-center distance have not been systematically
explored. Future studies will be needed to provide more
Valley dose comprehensive characterization and a clearer understanding
R¼ : ð3Þ
Peak dose of the dosimetric and biological effects of GRID collimator
The VPDRs are variable (Fig. 6) and dependent on the design.
GRID collimator configuration, depth and energy. For
example, in one type of commercially available GRID (the Planning Approach for MLC-Generated GRID Dose
diameter of the holes was 0.60 cm on the top side and 0.85 Distributions
cm on the lower side, and the center-to-center separation on Using modern MLCs and advanced TPS software, a
the block was 1.15 cm on the lower surface), it was found GRID-like field and dose distribution can be created and
that when depth was increased from 1.5 cm to 5 cm, the delivered. Although the GRID apertures are made and
dose ratio between peak and valley decreased from 5.9 to adjusted in the TPS, because each beamlet (hole) is very
5.1 (40), or VPDR increased from 0.17 to 0.20. small and its diameter may only range from 0.5 to 1.5 cm,
It should be noted that, because block collimator-based the dose calculation from the TPS may not be accurate,
GRID therapy is largely performed with commercially mainly due to the fact that small-field dosimetry requires
available GRID collimators, most physics studies and special attention (41). Therefore, its calculation accuracy
clinical data are based on the hexagonal pattern, 1 cm must be commissioned beforehand, or the plan can be made
aperture diameter and 1.5 cm center-to-center distance through experimental measurement.
design of these collimators. Because different dose One approach recommended by the Physics Working
heterogeneities would be produced with different GRID Group for the planning is to place a Gafchromice film at
collimator designs, it is reasonable to consider that the depth of the tumor center in solid-water slabs with
 GRID THERAPY GUIDELINES RECOMMENDED BY RSS WORKING GROUP 673

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FIG. 6. Radial and transverse dose profiles of GRID therapy in a
FIG. 5. The dose distribution at the dmax depth measured using flat water phantom at 0.5, 1.5, 3.0 and 6 cm depths for a 6-MV beam.
film dosimetry (29). The doses were normalized to a 10 3 10 cm2 open field at 1.5-cm
depth, and 100 cGy was applied to the open field as a standard. Panels
A and B: In plane and cross plane, respectively (40).
enough backscattering, measure the dose at the central
beamlet hot spot, then derive an output factor at that depth spatial distribution of dose in 1997, in which he introduced
for the central beamlet hot spot by comparison with the film an equation where the EUD is calculated by adjusting the
measurement result of the reference open field and film dose reference dose survival fraction in a given volume to the
calibration curve; then calculate the total MU needed for various local doses (42). The equation is as follows:
delivering the prescription dose by dividing the prescription 8 9
dose by the measured output factor. The output factors for <PN DV 3 q 3 ðSF ÞDDrefi =
i 2
other beamlet hot spot also must be verified, to ensure that ln i¼1
PN i
the variation of output factors of the GRID beamlet hot spot : i¼1
DVi 3 qi ;
across the target depth is within 5%. EUD ¼ Dref 3 : ð4Þ
lnðSF2 Þ

What are the Useful Dosage Parameters of GRID Therapy? Dref is a reference dose of 2 Gy, SF2 is a reference survival
fraction of the specific clonogen when treated with Dref, Di is
Because the dose delivered by GRID therapy is highly
the local dose and DVi is the local volume corresponding to
non-uniform, the nominal dose (i.e., the dose delivered at
the dose profile peak) likely does not fully represent the Di. qi is the local clonogen density.
dose-response relationship for tumor control and cell kill In addition, applying the modified-linear-quadratic
achieved by GRID therapy. The equivalent uniform dose (MLQ) model, we can calculate the average surviving
(EUD) can be employed to describe the GRID dose and fraction of GRID therapy, and then an EUD can also be
calculate dose–tumor control parameters achieved by GRID derived (40). The MLQ model instead of LQ model is
therapy for the tumor volume. preferable because the GRID therapy uses a nominal dose as
It should be noted that there are several different high as 20 Gy, and consequently a significant volume of the
approaches to estimate the EUDs of a non-uniform radiation tumor will receive doses of more than 10 Gy. In this high-
field. Niemierko explored the EUD in the non-uniform dose range the LQ model tends to underestimate the cell
674 ZHANG ET AL.

survival, as its radiosensitivities are obtained from the low-

dose range for estimating the survival fraction (43–45).
A study comparing the EUDs calculated by Niemierko’s
model with the MLQ model demonstrated that the MLQ-
based EUD is approximately 5% lower than that derived
from Niemierko’s equation (46). Because the MLQ model
corrects the overkilling predicted by the LQ model and
Niemierko’s equation, we suggest that the EUD formalism
proposed by Zhang et al. (40), described in detail below, be

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used to obtain the EUD of GRID therapy. Equation (5) is
the MLQ model:
 
SFi ¼ exp a 3 Di  bGðk 3 T þ d 3 Di Þ 3 D2i ; ð5Þ

where SFi is the survival fraction at the dose Di, a and b are
2ðkT þekT 1Þ
radiosensitivity parameters of the cell, GðkTÞ ¼ ðkTÞ2
,
k is the repair rate (T1=2 ¼ ln2
k ), T1/2 is cell doubling time and T
is the delivery time of the treatment.
The average survival fraction SF was calculated with Eq.
(6) using the MLQ parameters listed in Table 2 (46), breast
cancer, for example.
Pi¼N Xi¼N
SFi 3 fi
SF ¼ 1¼1 fi ¼ 100: ð6Þ
100 i¼1

fi is the fraction of target volume receiving dose Di. The

average survival fraction was then utilized to solve MLQ
Eq. (7) for deriving the equivalent uniform dose (EUD),
FIG. 7. The equivalent uniform doses (EUDs) of tumors of
namely by solving the following equation for EUD: different sizes in single-fraction GRID therapy calculated using the
MLQ model (40).
expðb 3 Gðk 3 T þ d 3ðEUDÞÞ 3 ðEUDÞ2  a 3ðEUDÞ
¼ SF: document dosimetric heterogeneity parameters in each
ð7Þ treatment plan in a standardized fashion, so that potential
correlations between the clinical outcomes and these
For a 3D tumor treated with the GRID therapy, an parameters can be studied. The Physics Working Group
approximation equation was given elsewhere (27), shown
recommends that dose covering 90%, 50%, 20%, 10% and
here as Eq. (8):
5% be documented along with other parameters, as outlined
EUD ¼ 2:47 þ 0:089 3 Dnominal ðDnominal  5GyÞ: ð8Þ in Table 3.
Figure 7 shows the relationship between the EUD and How Well are Normal Cells Spared by Commercially
nominal dose for 3D tumors.
Available GRID Collimators?
In addition, because the underlying reasons that GRID
therapy induces potential dose-heterogeneity-dependent Similar biological modeling considerations apply to
biological effects remain to be explored, it is essential to normal tissue effects of GRID therapy. The average

TABLE 2
MLQ Parameters of Breast Cancer Cell Lines (C1 and C2) and Normal Tissues (N1, N2
and N3)
Breast cancer cell Normal tissue
C1 C2 N1 N2 N3
a (Gy–1) 0.3 0.2 0.366 0.211 0.108
b (Gy–2) 0.03 0.052 0.118 0.068 0.035
a/b (Gy) 10 3.846 3.102 3.103 3.086
T1/2 (h) 1 1 1 1 1
k (h–1) 0.693 0.693 0.693 0.693 0.693
d (Gy–1) 0.15 0.15 0.15 0.15 0.15
 GRID THERAPY GUIDELINES RECOMMENDED BY RSS WORKING GROUP 675

TABLE 3 dosimetric parameters and planning strategy for GRID

collimator.
Summary of recommended GRID commissioning approaches, beam
data and GRID plan dosimetric metrics
1. GRID therapy dose should be documented not only by
the nominal dose at dmax, or at the prescription depth of
GRID commissioning
Water tank measurement
the central axis of the central hole, but also by the EUD.
Film dosimetry Because the EUD slightly depends on the a/b ratios, the
Monte Carlo simulation EUDs in treating all cancers can be approximated using
GRID field beam data Eq. (8) for hypofractionation (40).
Percentage depth dose (PDD) at the central hole for 10 3 10 cm2 2. The dose heterogeneity parameters describing VPDR,

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jaw setting
GRID output factor at 1.5 cm, 2 cm and 5 cm depth for 10 3 10 EUD and the dose D90, through D5 (Table 3) should all
cm2 jaw setting be documented.
Transverse and radial plane dose profiles at 1.5 cm, 2 cm, 3 cm, 3. The ratio of Dvalley/Dpeak, D90/D10 should be calculated
5 cm and 10 cm depth for 5 3 5, 10 3 10, 15 3 15 and 20 and documented. The single point peak dose and single
3 20 cm2 jaw settings
Dosimetric metrics of GRID plan point valley dose may misrepresent the spatial fraction-
Prescription dose (Dp, in Gy) ation in GRID therapy. Therefore, we suggest that a
Equivalent uniform doses (EUD, in Gy) for tumor and normal ratio of D90/D10 be used to replace the Dvalley/Dpeak ratio.
tissues 4. The specific GRID therapy dosing regimen should be
Output factor (OUTd) at prescription depth (d) (in Gy/MU)
tailored based on the clinical experience with its tumor-
Dose covering 90% of target (D90, in Gy)
Dose covering 50% of target (D50, in Gy) specific response and safety outcomes (1, 10, 13, 16, 27,
Dose covering 20% of target (D20, in Gy) 47).
Dose covering 10% of target (D10, in Gy) 5. GRID therapy should be followed by open-field external
Dose covering 5% of target (D5, in Gy) beam therapy to further control the disease in cases
Mean dose of target (Dmean)
Valley/peak dose ratio (VPDR)a when durable tumor control is the goal. This is
D90/D10 VPDR supported by both theoretical modeling and clinical
Peak width (defined at 50% of the max peak dose) outcomes indicating that SFRT can increase treatment
Peak-to-peak distance response; however, because the EUD is only a fraction
Peak dose
of the nominal dose, SFRT alone is not sufficient to
Valley dose
a
provide tumor control (27).
The term ‘‘peak/valley dose ratio (PVDR)’’ is also in use.
The Physics Working Group further notes that these
surviving fraction of normal tissue in a GRID field GRID therapy guidelines may have to be tailored based on
SFN ðGrid Þwas calculated using the same methodology as the presumed treatment goals, such as debulking large
was used for the cancer cell line, but with the normal cell tumors, sensitizing bulky tumors, changing tumor physiol-
MLQ parameters (Table 2). The ratio between the value ogy or microenvironment, and possibly improving tumor
SFN ðGrid Þand the surviving fraction of normal cells using immune response. In addition, further refinements of these
the EUD, i.e., SFN ðEUDÞ, will derive definitions with consensus guidelines will likely be needed in the future
respect to the therapeutic ratio (TR) of GRID therapy based on emerging information in the rapidly progressing
according to: field of SFRT.

SFN ðgrid Þ Received: February 20, 2020; accepted: September 18, 2020; published
TR ¼ : ð9Þ online: October 19, 2020
SFN ðEUDÞ
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