Treatment Planning and Delivery Overview of Biology-guided

Radiotherapy

Angela Da Silva, Ph.D.1, Sam Mazin, Ph.D.2

BACKGROUND

Despite growing clinical evidence suggesting that combination therapy improves survival for patients
with multiple tumors3, clinicians are not able to efficiently treat multiple tumors extracranially, in
parallel, during a single session with conventional radiotherapy. As such, approximately 90% of the
more than 320,000 patients diagnosed with metastatic disease annually in the United States are not
eligible for radiotherapy (RT) due to its limitations, which includes motion management of the tumor
and toxicity to healthy tissue. While recent clinical studies demonstrate the benefit of treating many
tumors in a single session, today the average is closer to one or two tumors per fraction4.

Biology-guided radiotherapy or BgRT aims to overcome these limitations by reducing the volume
of tissue treated with radiation, and therefore cumulative toxicity, to enable the treatment of
oligometastatic and polymetastatic disease, in parallel, in a single session. This paper provides a
discussion of BgRT fundamentals, the treatment workflow and its potential in these treatment areas.

PURPOSE AND SCOPE

BgRT Defined

BgRT is a method of radiotherapy that relies The combination of positron emission

on the emissions generated by an injected tomography (PET) and radiotherapy, in a
radiotracer to guide the radiotherapy beam single machine, brings a paradigm change to
during each fraction. As a result, BgRT allows conventional image-guided radiotherapies.
for real-time, tracked dose delivery to tumors,
even in those subject to motion.

The purpose of this white paper is to describe

BgRT including the workflow, treatment
planning and considerations for clinical
implementation.

1
Principal Clinical Scientist, RefleXion Medical, Inc.
2
Chief Technology Officer and Founder, RefleXion Medical, Inc.
3
Palma, David A, et al. “Stereotactic Ablative Radiotherapy versus Standard of Care Palliative Treatment in Patients with Oligometastatic Cancers (SABR-
COMET): a Randomised, Phase 2, Open-Label Trial.” The Lancet393, no. 10185 (May 18, 2019): 2051–58. https://doi.org/10.1016/s0140-6736(18)32487-5.
4
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624708/

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INTRODUCTION TO BGRT CLINICAL WORKFLOW

Figure 1. Schematic of BgRT Clinical Workflow

DELIVERY
IMAGING-ONLY
• PET injections &
• PET injections & uptake
uptake • Patient set-up on
• Patient set-up machine
SIMULATION on machine • kVCT scan
• kVCT scan • Localization
• Dx PET/CT
• Localization • PET pre-scan & PET
• CT simulation
• Obtain planning evaluation
• Contouring PET image • BgRT delivery

1 2 3 4 5

All simulation
PLAN SET-UP OPTIMIZATION
completed on an
external system. • Import Patient
• Set Optimization
Data
constraints
• Enter Physician
• Optimize plan
Intent (Rx)
• Evaluate plan
• Start BgRT plan
• Patient-specific
• Approve for
QA
imaging-only
• Approve for
delivery

Figure 1 depicts an overview of the BgRT treatment planning and delivery processes, with steps unique to BgRT highlighted in orange.

CT Simulation the imaging-only session on the RefleXion

machine to acquire both a planning PET image
Similar to conventional RT clinical workflow, for BgRT treatment planning and a CT scan for
BgRT begins with a CT simulation scan for target localization.
treatment planning followed by contouring the
target volumes and organs at risk. These steps With BgRT, the patient receives an injection
are performed on systems separate from the of the commonly available radiotracer
RefleXion platform. fluorodeoxyglucose (FDG). As FDG distributes
throughout the body, the tracer accumulates
Once completed, the CT simulation scan and in the tumor(s) just as it does for a diagnostic
treatment planning contours are imported into PET scan. (In the future, BgRT aims to
the RefleXion treatment planning system and take advantage of a wide array of disease-
the initial physician intent is created. specific tracers as they become available and
validated.)
Imaging-only Session
The imaging-only session is much like a
The next step in the BgRT clinical workflow is treatment fraction, but without actual

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radiotherapy delivery. When the patient arrives that the BgRT plan can be safely delivered
at the clinic, they receive an injection of FDG as prescribed. Once this is confirmed, the
and undergo the standard uptake period. machine proceeds with treatment.

Following the uptake period, the patient is setup

on the RefleXion machine for a pretreatment FDG Considerations
kVCT localization scan that confirms target
location. Once completed, the machine acquires Because BgRT utilizes positron emissions to
the planning PET image. Since the patient has guide radiation delivery, the logistics of using
been setup according to the simulation CT FDG during radiotherapy must be considered
used for planning, the planning PET image when integrating this technology into clinical
automatically registers to the simulation CT practice. If PET imaging is not already used
and serves as a key input for BgRT treatment in the radiation oncology department,
planning. Note that the imaging-only session coordination and scheduling with the nuclear
requires a full treatment time period. medicine department is paramount, as is
appropriately planning the treatment schedule
in the radiation oncology department.
Treatment Planning
Additionally, since BgRT requires an FDG
The workflow for the rest of the treatment injection prior to each treatment fraction, it
planning process is similar to that for is best suited for hypofractionated therapy.
conventional radiotherapy. After the BgRT In certain instances, FDG uptake may not be
treatment plan has been satisfactorily sufficient for tumor localization on the day of
optimized, evaluated and approved, it is ready treatment, thus necessitating delivery of CT
to guide treatment delivery. The planning image-guided stereotactic body radiotherapy
volumes specific to BgRT along with other (SBRT).
unique aspects of the BgRT treatment planning
process are described below.
PET IMAGING FOR BGRT VS.
DIAGNOSTIC IMAGING
Treatment Delivery
Emission Detection
As with the imaging-only session, the patient
receives an FDG injection and after the standard With BgRT, emissions generated by PET tracer
uptake period, is moved to the RefleXion accumulation in the cancer cells are detected
machine, setup in the treatment position and a by two 90-degree PET arcs on the machine.
pre-treatment CT scan is performed to confirm These emissions continuously broadcast the
target location. location of the tumor – even while in motion.

After CT localization, a quick PET pre-scan

image is acquired, and evaluated to verify

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Limited Time Sampled PET Images with an internal margin (IM) as well as a setup
margin (SM) to account for tumor motion and
The PET image that guides BgRT delivery is setup uncertainties, respectively.
very different than a diagnostic PET image.
Instead of waiting for the generation of a The construction of the PTV for BgRT is
full diagnostic image, the PET arcs on the similar, but the margins used to arrive at the
RefleXion machine continuously acquire limited treatment volume vary from that of SBRT.
time sampled (LTS) PET images throughout BgRT delivers a tracked dose of radiation to
treatment delivery which reveal the tumor’s a moving tumor target so the entire motion
biological signature. path of the target and the conventional setup
margin are not part of the PTV expansion.
Using algorithms capable of processing Instead, a unique biological guidance margin
large and complex amounts of data within (BgM) that accounts for tracking uncertainties
milliseconds, these LTS PET images are rapidly and registration uncertainties between the
processed into machine instructions that control simulation CT and the planning PET constitutes
the radiation treatment beam to deliver the the PTV expansion.
dose specified by the treatment plan.
In contrast to the conventional SBRT PTV,
which is fixed relative to the patient anatomy,
THE CONTINUOUS LIVE FEEDBACK the BgRT PTV moves within the biology-
FROM THE TUMOR ITSELF IS A KEY tracking zone (BTZ), an area unique to BgRT
DIFFERENTIATOR BETWEEN IMAGE-GUIDED defined by the radiation oncologist at the time
AND BIOLOGY-GUIDED RADIOTHERAPY. of treatment planning.

BGRT vs. CONVENTIONAL

TREATMENT PLANNING

Treatment Volumes

While many aspects of BgRT treatment planning

are similar to conventional radiotherapy, there
are unique differences. In conventional SBRT
Figure 2 is an animation describing the treatment planning
an internal margin is added to the clinical volumes for BgRT.
target volume (CTV) to compensate for internal
physiological movements and variation in size, The BTZ encompasses the full range of motion
shape, and position of the CTV during therapy. of the GTV plus a margin that includes the BgM
and the SM. The RefleXion machine uses the
To account for uncertainties in patient BTZ as a limiting factor or safe zone for the
positioning during treatment planning and delivery of the prescription dose; PET signals
through all SBRT treatment sessions, a setup arising outside of the BTZ are disregarded by
margin (SM) is required. The planning target the machine and do not influence the dose
volume (PTV), therefore, includes the CTV delivery.

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It’s important to note that while radiation CONCLUSION
delivery can occur anywhere within the BTZ,
dose delivery is only prescribed to the moving BgRT is designed to overcome the current
PTV. logistical, toxicity and motion management
challenges that today limit the use of
radiotherapy for metastatic patients.
WHILE DOSE CAN OCCUR ANYWHERE
WITHIN THE BTZ, RADIATION IS ONLY Through the use of PET emissions for
PRESCRIBED TO THE SMALLER, MOVING PTV. tracking and treating cancer in real time,
reducing the treatment volume to allow more
dose to treat other tumors, BgRT aims to one
day treat multiple tumors in parallel during a
THE BGRT TREATMENT PLAN single session.

Another unique aspect of BgRT is the output

from the treatment planning system. As
mentioned previously, the planning PET image
acquired on the RefleXion machine is a required
input to the treatment planning system.

The BgRT planning process consists of first,

defining the desired dose distribution, and
subsequently, calculating a mapping from
the planning PET image to this desired dose
distribution. This mapping is a set of firing
filters. The desired dose distribution uses the
same types of planning goals and optimization
constraints as in conventional radiotherapy.

The BgRT plan is optimized, refined and re-

optimized as necessary and the calculated set
of firing filters is the output of the treatment
planning process. This is fundamentally different
from conventional radiotherapy where the
treatment plan consists of a set of machine
instructions. During BgRT delivery, the firing
filters are used in conjunction with the rapidly
acquired LTS PET images to control the
treatment beam.

*The RefleXion® X1 is cleared for SBRT/SRS/IMRT. BgRT is pending regulatory review and is not commercially available.

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