Clinical and Translational Radiation Oncology 29 (2021) 1–7

Contents lists available at ScienceDirect

Clinical and Translational Radiation Oncology

journal homepage: www.elsevier.com/locate/ctro

Original Research Article

The technical design and concept of a PET/CT linac for biology-guided

radiotherapy
Oluwaseyi M. Oderinde ⇑, Shervin M. Shirvani, Peter D. Olcott, Gopinath Kuduvalli, Samuel Mazin,
David Larkin
RefleXion Medical, Inc, Hayward, CA, USA

a r t i c l e i n f o a b s t r a c t

Article history: This is a summary of the design and concept of the RefleXion X1, a system for biology-guided radiother-
Received 15 December 2020 apy (BgRT). This system is a multi-modal tomography (PET, fan-beam kVCT, and MVD) treatment
Revised 30 March 2021 machine that utilizes imaging and therapy planes for optimized beam delivery of IMRT, SBRT, SRS, and
Accepted 7 April 2021
BgRT radiotherapy regimens. For BgRT delivery specifically, annihilation photons emanating outward
Available online 17 April 2021
from a PET-avid tumor are used to guide the delivery of beamlets of radiation to the tumor at sub-
second latency. With the integration of PET detectors, rapid beam-station delivery, real-time tracking,
Keywords:
and high-frequency multi-leaf collimation, the BgRT system has the potential to deliver a highly confor-
BgRT
Real-time tracking
mal treatment to malignant lesions while minimizing dose to surrounding healthy tissues. Furthermore,
Biological signature the potential use of a single radiotracer injection to guide radiotherapy to multiple targets opens avenues
Positron emission tomography for debulking in advanced and metastatic disease states.
Sub-second latency Ó 2021 RefleXion Medical. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and
Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

1. Introduction enabling a tumor to communicate its present position directly to a

linear accelerator. This technology combines dual imaging tech-
Optimized radiation treatment aims to accurately irradiate nologies (CT and PET) with a slice therapy linear accelerator [8].
tumoral tissues while sparing the surrounding normal tissue Fundamentally, the system functions by utilizing kVCT imaging
[1,2]. This goal must address and overcome the challenges of for initial patient setup and then PET detection of outgoing tumor
intra-fractional and inter-fractional changes in tumor location emissions to detect the location of a tumor and respond with
[3]. With the advent of hypo-fractionated treatment, image- beamlets of radiotherapy with sub-second latency. This direct
guided radiotherapy (IGRT) has become standard for enabling feedback loop between the lesion itself and treatment machine
more accurate and repeatable treatments in several indications allows the system to accurately guide and conform radiation
[4]. Nonetheless, conventional IGRT typically relies on an image beamlets to the tumor as the tumor is moving during ongoing
of a tumor that precedes radiotherapy delivery and does not adjust treatment, resulting in a tracked dose distribution characterized
to changes in tumor position that may occur as treatment is ongo- by high dose falloff and less dose to normal tissues than conven-
ing. Several modalities such as ultrasound, stereoscopic X-ray, tional radiotherapeutic approaches.
implanted radiofrequency-emitting fiducials, and on-board mag- This improvement in the therapeutic ratio stems from two fea-
netic resonance imaging (MRI) have been considered for providing tures. Firstly, the tumor’s emitted PET profile or biological signa-
more ‘‘real-time” tumor tracking during radiation delivery [5–7]. ture acts as a fiducial, which increases the confidence in lesion
However, each of these methods is limited by complex workflows localization during treatment [9,10]. Therefore, the clinical team
or uncertainties in tumor position that require additional compen- can reduce the positional margins in the treatment plan that
sation, such as gating delivery to a single phase of respiration. account for setup errors and patient drifts. Secondly, the BgRT
The RefleXionTM X1 biology-guided radiotherapy system (RefleX- tomographic delivery algorithm does not require surrogate motion
ion Medical Inc, Hayward, CA) seeks to overcome these hurdles by sensors, predictive motion models, or breath-hold coaching tech-
niques. This simplification of workflow in combination with a
sub-second (350–400 ms) latency means that the BgRT system
⇑ Corresponding author at: RefleXion Medical, Inc, 25841 Industrial Blvd, #275 can manage motion in a wide range of indications throughout
Hayward, CA 94545, USA.
the body. In turn, the clinician can avoid approaches in which
E-mail address: [email protected] (O.M. Oderinde).

https://doi.org/10.1016/j.ctro.2021.04.003
2405-6308/Ó 2021 RefleXion Medical. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
O.M. Oderinde, S.M. Shirvani, P.D. Olcott et al. Clinical and Translational Radiation Oncology 29 (2021) 1–7

the entire motion envelope (also termed the internal target vol- sitions, facilitates the rapid movement of collimator leaves such
ume) and all normal tissues within it must be ablated to ensure that the collimator is capable of switching leaves between open
target coverage. and closed states in about 7 ms. The binary MLC is sandwiched
Notably, implied in BgRT is the potential to use a single radio- between a split-jaw, the upper jaw having a thickness of 55 mm
tracer injection to efficiently manage motion across multiple tar- and the lower jaw having a thickness of 60 mm along the IEC Z-
gets in a single patient. This application may open avenues for axis. The aperture of the split-jaws can be adjusted to define a slice
investigating the role of radiotherapy for debulking disease in having a width of 1 or 2 cm. Furthermore, the split-jaw design
patients with metastatic cancer who are currently not candidates improves the penumbra in the IEC-Y slice direction. The nominal
for radiotherapy in light of the logistical limitations of present- beam treatment area is 40
1 cm2 or 40
2 cm2. However, the
day technology. This work presents the design and concept of a reference calibration field size area is set at 10
2 cm2.
BgRT system.
2.2. Positron emission tomography imaging system
2. Technical design and chief hardware components
The PET detector arcs are integral to BgRT, which uses PET emis-
The X1 is currently FDA-cleared for delivering intensity- sions from the tumor to rapidly deliver tracked beamlets of radia-
modulated radiotherapy (IMRT), stereotactic radiosurgery (SRS), tion. These arcs are comprised of 64 scintillation multi-pixel
and stereotactic body radiotherapy (SBRT). It is designed to eventu- counter (MPPC) modules. The PET scintillators have side shieldings,
ally support biology-guided radiotherapy (BgRT). Fig. 1 shows which consist of lead septa ~2 cm thick for reducing the patient
some of the main subcomponents of the X1. The system is a fast- scattered radiation that can cause an afterglow effect in the scintil-
rotating slip-ring gantry system with a bore diameter of 85 cm that lator crystal. The BgRT workflow uses these PET detectors at three
consists of two planes on the same 60 RPM gantry. These two different timepoints: (1) An imaging-only session to collect PET
planes are dedicated to kVCT imaging and PET-guided therapy, data from the patient for use in treatment planning (acquisition
respectively. The kVCT imaging axial plane is parallel and anterior time ~40 s per 2.1 mm of treatment extent), (2) a PET pre-scan ses-
to the PET-guided therapy central plane with a separation of sion immediately prior to radiation delivery to evaluate whether
38.6 cm axially (IEC-Y axis). In the PET-guided therapy plane, a lin- the PET radiotracer avidity of the tumor(s) in the treatment plan
ear accelerator (linac) head is placed between two 90° PET detector are sufficiently consistent with the prior imaging-only session to
arcs. A mega-voltage detector (MVD) array is fixed directly oppo- proceed with delivery (acquisition time ~10 s per 2.1 mm of treat-
site the linac head. These components are described in more detail ment extent), and (3) during BgRT delivery to actively guide the
below. therapeutic beam. Of note, scattered radiation from the 6MV linac
pulse may interact with the scintillation crystals of the PET detec-
2.1. Compact linear accelerator tor arcs. These scintillation events can generate false coincidence
events within 300 ls of the linac pulse. To avoid the false detection
The linac produces a flattening filter free (FFF) photon beam of 6 of a coincidence event, the PET scanner is gated with a blanking
MV with a nominal dose-rate of 850 cGy/min. It is equipped with a interval lasting approximately 300 ls immediately after the linac
tungsten alloy target, fixed primary collimator, and an adjustable pulse, as shown in Fig. 2.
binary multi-leaf collimator (MLC) of 64 leaves for beamlet defini-
tion at a source-to-axis distance of 85 cm. The low-leakage tung- 2.3. Kilovoltage computed tomography imaging system
sten MLC with a leaf thickness of 11 cm has an ultra-fast
transition time to reduce the latency between PET data acquisition The 16-slice kVCT imaging system is mounted at the gantry
and radiation beam delivery. This design, which required develop- entrance of the BgRT system. It acquires 3D CT fan-beam images
ment of a novel pneumatic spring-based mechanism for leaf tran- for localizing and aligning the patient for treatment delivery, just

Fig. 1. An overview of the BgRT system showing some of the major subcomponents.

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O.M. Oderinde, S.M. Shirvani, P.D. Olcott et al. Clinical and Translational Radiation Oncology 29 (2021) 1–7

Fig. 2. The linac produces high energy photons over a concise 5-ls time interval.

as in conventional cone-beam CT (CBCT) [11,12]. It has a source-to- The purpose of the multi-pass couch motion technique is to
detector distance of 113.3 cm and source to isocenter distance of reduce dose artifacts caused by the interplay effect between MLC
64.3 cm for 2 cm axial coverage and 50 cm transverse field of view. and tumor motion. In BgRT delivery, the number of gantry rota-
The system has a bowtie filter and two-level collimators to atten- tions per beam station is precomputed during treatment planning
uate beam exposure to peripheral extents in the IEC-X axis, and the and identical across all beam stations. In sequential order, the
X-ray tube has flexible movement in the IEC-X and IEC-Y directions treatment couch automatically moves from one beam station to
for focal spot alignment. The system has scan modes for fast and another until the treatment plan is fully delivered.
slow helical CT with settings of up to140 kV and 300 mA and table
speeds of 4.5 mm/s to 28 mm/s.
3. Conceptual underpinning and treatment planning for
biology-guided radiotherapy
2.4. Megavoltage X-ray detector

3.1. Overview of BgRT treatment planning

The custom flat-panel MVD subsystem is designed to measure
radiotherapy exit dosimetry and facilitate quality assurance (QA)
BgRT delivers a radiotherapy beam based on PET data emanat-
in order to confirm proper operation of the MLC and the linac
ing outward from a tumor. Essentially, the radiotracer uptake con-
(for example: beam energy and output reproducibility). The MVD
verts the tumor itself into a biological fiducial for localization and
panel is made of a gadolinium oxysulfide (GOS) scintillation screen
delivery of a tracked dose. Understanding the features of active
with a thin film transistor (TFT) photodiode array with an active
delivery help frame the BgRT algorithm and the output of the treat-
area of 78.8 cm
11.8 cm, which is appropriate for the largest field
ment planning process.
size on the BgRT system at a source-to-detector distance (SDD) of
During active treatment, rapidly-acquired limited time sampled
136.7 cm.
(LTS) PET images guide beamlets of radiation according to prede-
fined coverage goals. Treatment is delivered across a sequence of
2.5. Treatment couch beam stations. For every beam station, delivery is further divided
across multiple firing positions (FPs)/couch angles subgroups. At
The BgRT system contains a robotic couch with 6 degrees of set the commencement of treatment, the first 20 FPs (25 ms/FP) are
up correction consisting of 5 physical degrees of freedom (adjust- used to collect the initial PET data as shown in Fig. 4. Afterward,
ments in x-, y-, z-axes, and also pitch and yaw rotations) in addi- there is a reconstruction and calculation of the MLC sequence over
tion to a slip-gantry (roll rotation) encoder offset for the 6th 100 ms in 10 ms interval, while the beam is continuously and
degree. Radiation can be delivered using single pass (for IMRT) or simultaneously delivered in parallel with the PET image acquisi-
multi-pass (for SBRT and BgRT) motions, with a ‘‘pass” defined as tion. The LTS image is refreshed every 100 ms using the last
the movement of the treatment couch in the IEC-Y direction during 500 ms of information, as shown in Fig. 4. This refreshed LTS is sub-
treatment delivery such that a target volume passes through the sequently used in a firing calculation to determine machine
treatment plane once. For multi-pass couch motions, the patient’s instructions for the partial fluences, which are delivered over the
treatment extent typically passes through the therapy plane four next 10 firing positions that the linac head passes through. This
times (back and forth process) in the IEC-Y direction. During each cycle is repeated in such a way that the aggregate of partial flu-
pass, the couch pauses at a set of discrete positions separated by ences delivers the intended dose to the tumor target and meets
2.1 mm called beam stations, as shown in Fig. 3. Of note, the use the specified limits for surrounding tissues. Furthermore, this pro-
of discrete beam stations is distinct from other gantry-based sys- cess must be robust to some degree of variation in PET signal or
tems which utilize constant couch motion through the treatment tumor motion that is expected to occur from fraction to fraction.
plane in the IEC-Y direction. This characteristic provides better In summary, the gantry is continuously rotating while the couch
beam modulation along IEC-Y and therefore more flexibility during is stopped at each beam station and the LTS image acquisition
treatment planning. and treatment delivery occur simultaneously.
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O.M. Oderinde, S.M. Shirvani, P.D. Olcott et al. Clinical and Translational Radiation Oncology 29 (2021) 1–7

Fig. 3. Depiction of the couch movement during delivery.

In order to retain all of these qualities during active delivery, the The second novel concept is the introduction of a new region,
BgRT treatment planning algorithm is necessarily different than termed the biology-tracking zone (BTZ). The BTZ encompasses
existing radiotherapy planning algorithms, while building upon the motion extent of the target with an additional margin to cap-
optimization principles of IMRT, SRS, and SBRT. Initially, CT simu- ture biology-guidance margin as well as patient set-up error, as
lation and CT-defined RT structures are imported into the BgRT shown in Fig. 5. Benchtop testing suggests that the total margin
treatment planning system (TPS) to initiate the planning process. required is 5 mm. Similar to an ITV, the motion extent for the
Next, a BgRT imaging-only session is performed to acquire PET BTZ is delineated from a 4D-CT image set that is acquired during
emission data from the region of the body containing the target the CT simulation, which shows the position of the target tumor
tumor. The BgRT TPS algorithm then generates a plan that calcu- at each phase of the respiratory cycle. However, unlike an ITV,
lates a fluence map using the planning PET images to achieve the the BTZ does not constitute a treatment volume. Instead, it acts
prescribed dose objectives. These steps are described in more to limit the region from which PET emissions are gathered to guide
detail below. radiotherapy; as such, it prevents emissions from non-target, PET-
avid structures from influencing treatment delivery.

3.2. Novel contouring elements: BgM and BTZ

3.3. BgRT plan optimization
The International Commission on Radiation Units and Measure-
Like other radiotherapy inverse-planning algorithms, the goal of
ments Reports 50, 62, 83 and 91 [13–16] described a schema for
the BgRT optimization algorithm is to minimize a cost function
radiotherapy treatment volumes that incorporate safety margins
whose inputs are physician-defined target coverage goals and
that account for uncertainties in tumor extent, tumor motion,
OAR constraints. A traditional IMRT algorithm uses a cost function
and patient setup. To that end, these reports defined a gross tumor
numerical score to identify a fluence map, F, that generates an opti-
volume (GTV), a clinical target volume (CTV) that accounts for
mal dose distribution in the patient’s anatomy that meets dosimet-
microscopic disease, and a planning target volume (PTV) that com-
ric objectives. BgRT likewise uses an inverse-planning optimization
pensates for uncertainties in planning or treatment delivery. An
algorithm to achieve a global minimum cost function through sev-
internal target volume (ITV) has also been defined to capture the
eral iterations with an automated stopping criterion. However, the
range of internal motion for a mobile tumor. The conventional
essential difference for BgRT is that the fluence map itself is
aim for treatment planning is to achieve an optimal treatment
defined by an operator (P) acting on a matrix of tumor PET projec-
delivery to the CTV by targeting the PTV (or ITV) while limiting
tions (X) circumferentially arranged around the patient:
exposure to nearby organs at risk (OAR).
The BgRT TPS adds two new concepts to this schema. First, a
F ¼PX
biology-guidance margin (BGM) is used to define an expansion
from a GTV/CTV to PTV that accounts for localization errors intrin- Data that informs the PET projection matrix, X, is obtained at a
sic to BgRT, such as the residual latency between PET emission col- PET imaging-only session on the X1. Because the tumor PET projec-
lection and beamlet delivery. Importantly, because BgRT results in tion is a fixed quantity, the optimization algorithm uses the cost
a tracked dose distribution, the PTV can be defined with an expan- function to find the optimal operator, P, which is termed the ‘‘firing
sion of the GTV/CTV at a single timepoint. This has potential dosi- filter”. This concept is schematized in Fig. 6: The simulation CT
metric advantages over an ITV approach that requires adding a images, RT structures, PET planning images, and dose objectives
margin to the aggregation of the tumor’s position across all phases are all inputs to generating the optimal firing matrix using the cost
of respiration in order to form the final treatment volume (Fig. 5). function optimization process.
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O.M. Oderinde, S.M. Shirvani, P.D. Olcott et al. Clinical and Translational Radiation Oncology 29 (2021) 1–7

Fig. 4. System latency in the BgRT radiotherapy system.

Fig. 5. Comparison of volumes used for ITV-based RT, such as SBRT (left) and BgRT (right). IM-internal margin, SM – setup margin, GTV – gross tumor volume, CTV – clinical
target volume, ITV – internal target volume, PTV – planning target volume, BgM – biology – guidance margin, and BTZ-biology tracking zone.

Importantly, once the firing filter is created, the principle of partial fluences is the intended total fluence. Mathematically, this
superposition allows for it to be applied to limited-time sample can be expressed as such:
PET images, xi, to generate partial fluences such that the sum of
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O.M. Oderinde, S.M. Shirvani, P.D. Olcott et al. Clinical and Translational Radiation Oncology 29 (2021) 1–7

Fig. 6. BgRT plan optimization (A) overview of BgRT TPS input and output. D = Dose Distribution, C = Cost function, A = Dose calculation matrix, P = Firing Matrix, the matrix-
vector product PX is assumed to be evaluated with 3D volume X linearized into a vector.

X
n X
n
radiotracer-avid. If the target lesion takes up the radiotracer, then
F ¼PX ¼P xi ¼ P  xi
the full workflow can be initiated. Standard radiotherapy workflow
i i
includes the steps of prescription, simulation, treatment planning,
This principle underpins the ‘‘real-time” nature of biology- and treatment delivery [19,20]. As illustrated in Fig. 7, the BgRT
guided radiotherapy because it allows radiotherapy beamlets to clinical workflow adds steps to the standard radiotherapy work-
be directed in response to rapidly collected packets of PET emis- flow so that dynamic PET targeting can be incorporated.
sions. This feature avoids the fundamental deficit of typical The additional steps are the BgRT imaging-only session and the
image-guided forms of radiotherapy where a full image has to be PET pre-scan. The imaging-only session serves to assess formal
formed prior to radiation delivery. Since it takes a longer time to candidacy for BgRT (i.e., sufficient radiotracer activity as observed
generating a full image, the information contained in the full image by the intrinsic RefleXion PET subsystem). As described above, this
is stale to some degree by the time the radiotherapy beam is step also provides the PET data that underpins the treatment plan-
activated. ning algorithm as described above.
After the BgRT plan is approved, the patient undergoes a PET
3.4. Bounded dose-volume histogram (bDVH) pre-scan immediately prior to actual delivery. This step generates
a predicted dose distribution from the tumor PET signal and
The dose distribution in the patient is calculated using the motion pattern that day. The system checks to ensure that the pre-
collapsed-cone convolution (CCCS) algorithm with recursive for- dicted DVH from the pre-scan data fits within the bounds of the
mulation [17]. The BgRT TPS accounts for the cumulative- bDVH approved at planning. The pre-scan image can be reviewed
cumulative kernel (tabulated kernel) approach and different voxel by the clinician to confirm that the target is within the BTZ on
size effects [18]. An additional feature is that the TPS models sce- the day of the treatment. Finally, if all criteria are satisfied, BgRT
narios where either the PET signal over background or tumor posi- delivery can commence. If the criteria are not satisfied, the clini-
tion changes between the PET imaging-only session and the day of cian can choose to abort and reschedule treatment or instead use
BgRT delivery. Plans that account for tumor-to-background signal a fall-back CT-guided plan generated in parallel with the BgRT
variations of ±25% relative to baseline and tumor shifts of 5 mm plan. These steps are schematized in Fig. 7. This process is repeated
in all 3 directions are calculated during treatment planning. The for each fraction until treatment is complete.
BgRT TPS simulates multiple dose-volume histograms (DVHs) Of note, a radiotracer injection can be used to ‘‘fiducialize” every
using these possible permutations and then collectively visualizes site of gross disease which takes up the radiotracer. Therefore, by
the possibilities in a bounded DVH (bDVH) where the DVH line for acting as a unified motion management solution across different
each volume and OAR is surrounded by confidence intervals repre- anatomic locations, the BgRT workflow holds promise as a platform
senting the different variations. As such, the bDVH shows the for efficiently ablating multiple malignant lesions in a metastatic
potential best case and worst case dosimetric outcomes for a given patient.
treatment plan and delivery so that the plan’s merits can be com-
prehensively evaluated. 5. Conclusion

4. Clinical workflow for the BgRT system Biology-guided radiotherapy has the potential to improve upon
current radiation methods by reducing treatment margins around
To select a patient for BgRT, an optional staging PET/CT may be targets and better compensating for motion. To translate this inno-
used to determine whether the target lesion is sufficiently vative concept into the real-world practice, unique and novel ele-
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O.M. Oderinde, S.M. Shirvani, P.D. Olcott et al. Clinical and Translational Radiation Oncology 29 (2021) 1–7

Fig. 7. Proposed clinical workflow of BgRT system.

ments for hardware, treatment planning, and workflow were [7] Ting L-L, Chuang H-C, Liao A-H, Kuo C-C, Yu H-W, Tsai H-C, et al. Tumor motion
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Declaration of Competing Interest multidimensional radiotherapy (MD-CRT): biological imaging and biological
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