NRG Medical Physics Subcommittee Radium-223 Dichloride Template

Template for Radium-223 Dosimetry

Authors: George Sgouros, Department of Radiology, Johns Hopkins University; Emilie Roncali,
Departments of Biomedical Engineering and Radiology, University of California Davis;
Robert F. Hobbs, Radiation Oncology, Johns Hopkins University

Co-Authors: Bryan Bednarz, University of Wisconsin; Stanley H Benedict, University of California

at Davis Cancer Center; Vikram Bhadrasain, National Cancer Institute, National Institutes of Health;
Jeffrey C. Buchsbaum, National Cancer Institute; Jacek Capala, National Cancer Institute; Yuni
Dewaraja, University of Michigan; Sara St. James, University of California

NRG Radiation Oncology Committee Reviewers:

Daniel Pryma, University of Pennsylvania
Evan Wuthrick, Moffitt Cancer Center

Maintained By: NRG Oncology Medical Physics Subcommittee

Original Date: 08-12-2020

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 NRG Medical Physics Subcommittee Radium-223 Dichloride Template

BACKGROUND

Radium-223 Dichloride

Radium-223 dichloride (BAY 88-8223, formerly known as Alpharadin) is a bone-targeted alpha particle
emitting radiopharmaceutical that represents a new generation of natural bone-seeking radionuclides
(Radium-223 Investigator’s Brochure, 2018). Radium-223 dichloride solution for injection was brought
into clinical development in 2001 in Europe and was approved by the United States Food and Drug
Administration (FDA) under the trademark Xofigo® in 2013 for the treatment of patients with castration-
resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic
disease. As of May 14, 2018, approximately 6,400 patients have been enrolled in company-sponsored
interventional clinical trials, including patients with bone metastases from prostate cancer, breast cancer,
other solid tumors, or multiple myeloma, and non-interventional studies.

The methodology to estimate dosimetry for alpha emitters is still at a very early stage, and the available
software developed for beta and gamma emitters does not apply (Radium-223 Investigator’s Brochure,
2018). In reviewing these dosimetry results, it is essential to understand that they only represent the best
possible approximation of average absorbed organ doses given the current state of knowledge. In
patients treated with the standard-of-care 55 kBq/kg body weight (b.w.) of Radium-223 dichloride, the
highest absorbed doses were seen in bone (osteogenic cells) and red marrow; the calculated absorbed
doses in the bone (osteogenic cells) and red marrow were 1.15 Gy/MBq (4260 rad/mCi) and 0.14
Gy/MBq (514 rad/mCi), respectively. The calculated absorbed doses to the intestines (using the MIRD
schema), which is the dominating excretory organ, were low (small intestine wall 0.00726 Gy/MBq,
upper large intestine wall 0.0323 Gy/MBq, and lower large intestine wall 0.0465 Gy/MBq,
corresponding to 26.9, 120, and 172 rad/mCi, respectively). However, the safety data from clinical
phase 1 and 2 trials with Radium-223 dichloride are not consistent with such high absorbed doses to
these organs. Approximately 4 hours after dosing, no specific uptake was visible on scintillation camera
images in other organs such as the heart, liver, gallbladder, kidneys, urinary bladder, stomach, and
spleen. The calculated absorbed doses to these organs were low, and well below dose levels associated
with toxicity.

Special Studies

Radium-223 Radionuclide Dosimetry

Dosimetry will be performed using quantitative single photon emission computed tomography
(SPECT)/computed tomography (CT) imaging after administration of Radium-223 dichloride. As there
can be inter-lesion and inter-patient variability of Radium-223 dichloride uptake and retention, image-
based dosimetry will help to measure the Radium-223 dichloride bio-distribution and absorbed dose in
each bone lesion and elsewhere in the body as well. Imaging will also measure bio-distribution
especially in critical organs for toxicity. The SPECT/CT imaging will be performed at three time points
during Cycle 1 (4, 24, and 72 hours after the Radium-223 dichloride dose). Imaging for diagnostic or for
dosimetry purpose should be obtained (if possible) prior to any biopsy of a suspect or known lesion.

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 NRG Medical Physics Subcommittee Radium-223 Dichloride Template

BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES

Special Studies

Imaging and Dosimetry to Assess the Impact of Radium-223 dichloride Dosimetry and
Pharmacokinetics

Sites planning to perform single-photon emission computed tomography (SPECT) scans for Radium-
223 dichloride dosimetry and pharmacokinetics on this trial must have access to commercial SPECT
systems in clinical use.

RAPID, Inc. has established a service operation for this technology, including imaging protocol
development, associated phantom study and dosimetry support. RAPID, Inc. will utilize
IROC’s infrastructure and make the service operation support available to participating
institutions. The approach enables centralized quality assurance, centralized reconstruction,
independent validation and the application of standardized image analysis and dosimetry
methodologies.

Patient preparation?

SPECT Acquisition Parameters

Image length: 20-30 min/FOV
FOVs: covering lesions and organs at risk
Imaging Time points: 4 +/- 1.5h, 24 +/- 3h, 72 +/- 5 h
SPECT acquisition parameters for SPECT/CT
Time interval between tracer N/A
injection & imaging
Collimator MEGP
Patient position Supine
Energy Window Setting (keV) 67.5 101.5 (40% at 84)
138.5 168.5 (20% at 154)
243.0 297.0 (20% at 270)
300 350 (15% at 325)
Matrix 128 x 128
Time /View 30 seconds/view
# of projection views 120
Angle range 360
Images taken Chest & Abdomen
Screen caps to make N/A

CT acquisition Parameters for SPECT/CT

The CT portion of the first SPECT/CT scan for each patient should be in high resolution (i.e.,
diagnostic mode); attenuation mode (low-dose) may be used for subsequent scans. Standard vendor

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 NRG Medical Physics Subcommittee Radium-223 Dichloride Template

settings for high resolution/diagnostic vs low-dose or attenuation acquisition may be applied.

Quality control required

Standard camera quality control (QC) as specified by the vendor should be up to date on all
cameras that will be used for this study. Typical QCs include uniformity, linearity/spatial resolution, and
center of rotation alignment. Dose calibrator QCs should also be routinely performed and documented
(accuracy, consistency, linearity, and geometry) and the 223Ra calibration setting determined with a
NIST-traceable (or other national laboratory equivalent) standard.
The credentialing process with phantoms will be coordinated between RAPID and IROC. We
will evaluate the optimal process for the efficiency and accuracy, e.g., the NEMA phantom, for multiple
vendors such as Siemens, GE, and Philips. The data from phantom experiments will be evaluated at
IROC’s central location and will be used to determine the sensitivity/calibration factor of the cameras.
Planar acquisition of a known 223Ra activity will be acquired for camera stability purposes for
every data set collected, both for phantom and patient data.
There is a recommended phantom calibration scan with either a NEMA PET IEC Body
Phantom or an ACR Phantom to be collected for each camera that may be used for patient imaging.

Additional requirement
Sensitivity needs to be measured prior to or immediately after the patient scan.

A step by step imaging procedure is included in a separate document.

Digital SPECT Data Submission to IROC Philadelphia and RAPID Inc. Using TRIAD

The preferred image transfer method is via TRIAD, a software application that IROC provides for
installation on a site’s computer. TRIAD installation documentation can be found on the IROC website
https://www.irocqa.org/Resources/TRIAD.

For more information, contact: TRIAD-support@phila.acr.org or call 215-940-8820.

TRIAD is the image exchange application used by ETCTN and by NCTN sites. TRIAD provides sites
participating in clinical trials a secure method to transmit DICOM images and other objects. TRIAD
anonymizes and validates the images as they are transferred. SPECT images received by IROC
Philadelphia will be forwarded electronically to RAPID Inc. (Bin He PhD, Michael Ghaly PhD, Eric
Frey PhD, or George Sgouros PhD). Radionuclide dosimetry will be done to measure Radium-223
dichloride bio-distribution and absorbed dose in each bone metastatic lesions, as well as elsewhere in the
body, including critical organs.

TRIAD Access Requirements:

Site physics staff who will submit images through TRIAD will need to be registered with The Cancer
Therapy Evaluation Program (CTEP) and have a valid and active CTEP Identity and Access
Management (IAM) account. Please refer to Section 4.1 of the protocol for instructions on how to
request a CTEP-IAM account.

To submit images, the site physics user must have been assigned the ‘TRIAD site user’ role on the

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 NRG Medical Physics Subcommittee Radium-223 Dichloride Template

relevant Group or CTSU roster. ETCTN users should contact your site Lead RA to be added to your site
roster. Users from other ETCTN/NCTN sites should follow their procedures for assignment of roster
roles. Research Associates are able to submit standard of care imaging through the same method.

In the event that image transfer is not available by TRIAD, SPECT images should be recorded on CD as
DICOM images and mailed to the IROC. Image may be mailed to:

ACR CRI
ATTN: RTQA
1818 Market Street
Suite 1720
Philadelphia, PA 19103
Digital Data Submission Requirements

Summary of Dosimetry Digital Data and Report Submission

Submit digital data via TRIAD; see section 5.10.1.4 for TRIAD account access and installation
instructions.

The phantom (e.g., NEMA IEC PET IQ) data should include: 
 Planar calibration scan 
 raw projection data 
 CT scan 
 vendor-generated attenuation map 
 vendor-generated SPECT recon with AC 
 vendor-generated SPECT recon without AC 
 A form containing the activity in the phantom and other data 
 projection of point source 

Patient data sets include:

Item Due

DICOM Items The dosimetry SPECT Image Projection (4 hr) By 4 weeks after
will be performed at 4, 24 SPECT Image Projection (24 completion of cycle 1 of
and 72 hours after Radium-223 hr) radiopharmaceutical
dichloride administration during SPECT Image Projection (72 therapy.
Cycle 1. It is strongly encouraged hr)
to collect the complete image set CT images
(all three timepoints of 4, 24 CT images with contrast (if any)
and 72 hours) as collection of 2 or Attenuation Maps
fewer time points is not clinically
meaningful. The scan is voluntary
to both the participating institution
and study patients. A maximum of
10 patients with qualifying bone
metastases will undergo this scan.

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 NRG Medical Physics Subcommittee Radium-223 Dichloride Template

Rapid will undertake transmission of the dosimetry analysis results to the IROC QA team for further
evaluation and validation: DICOM CT; DICOM SPECT; DICOM dose; DICOM RT structure

STUDY CALENDAR

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6

Base-
line D D D D D D D D D D D D D D D D D D D D D D D
1 3 15 28 1 3 15 28 1 3 15 28 1 3 15 28 1 3 15 28 1 3 15
Radium-223
A A A A A A
dichloride
M3814 B--------------B B--------------B B--------------B B--------------B B--------------B B-------------
Avelumab C C C C C C C C C C C C
Informed
X
Consent
Demographics X
Medical
X
History
Concurrent
X X ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
meds
Physical exam X X X X X X X
Vital signs X X X X X X X
Height X
Weight X X X X X X X
Performance
X X X X X X X
statusE
CBC w/diff,
X X X X X X X
plts
ChemistryF X X X X X X X
Testosterone X X X X X X X
EKG (as
X
indicated)
Adverse event
X ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
evaluation
Total alkaline
phosphatase,
bone-specific
X X X X X X X
alkaline
phosphatase,
& PSA
Osteocalcin X X X X X X X
Blood
Collections
X
for TCR
repertoire
Blood
Collection for
X
WES / RNA-
seq
Archival
Specimen
collection for
Whole Exome
X
sequence/RN
A Seq, and
TCR
Repertoire
Radium-223
D
dosimetry
Skeletal lesion
response,
X X X X
99m-Tc
MDPG

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 NRG Medical Physics Subcommittee Radium-223 Dichloride Template

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6

Base-
line D D D D D D D D D D D D D D D D D D D D D D D
1 3 15 28 1 3 15 28 1 3 15 28 1 3 15 28 1 3 15 28 1 3 15
PRO-CTCAE
XI XI XI XI XI XI
collection

A: Radium-223 dichloride (1.49 microcuries/kg [55 kBq/kg] IV D1 q28 days x6 cycles). Each cycle is 28 days.
B: M3814 (50, 100, or 200 mg PO D3-28 BID x6 cycles [de-escalation 100 mg QD, 50 mg QD]). Each cycle is 28 days.
C: Avelumab 800 mg IV q14 days on Days 1 and 15 x12 doses . Each cycle is 28 days. For patients in the 2nd Lead-in phase only.
D: Timing: 4, 24 and 72 hours after cycle 1 223Ra administration represents a complete image set. Collection of 2 or less time points is not clinically
meaningful. Participation by participating institutions and study patients is voluntary. Maximum of 10 patients with qualifying bone metastases .