10.5.

2 Internal Dosimetry
Radiation dosimetry is the method used to convert the amount of ionizing radiation deposited
in tissue to its effect in tissue, which is influenced by the “damage potential” of the radiation
type (e.g., energy, size, charge, half-life, etc.), the administered dose, and the dose rate [69–
71]. The quantities obtained from dosimetry calculations are fundamental to estimating
radiation protection, risk assessment, diagnostic dose estimates, and treatment planning [72].
Internal dosimetry in drug development is primarily used from two perspectives [72]. For
early-phase I or phase I clinical trials, dosimetry is performed
after radiopharmaceutical administration to provide standard diagnostic procedural dose
estimates and define dose-limiting organs in a limited number of healthy volunteers. A
second type of dosimetry is used to guide treatment and thus performed prior to the
therapeutic drug administration for all patients undergoing treatment. Organ-specific (target
and source organs) and total effective dose equivalent dosimetry estimates are calculated in
diagnostic studies, whereas in treatment planning, dosimetry estimates are focused regionally
that correspond to the treatment area [69,71,72].
Since radiation dose calculations include many factors [73,74] and are lengthy, tedious, and
error-prone when performed manually, the FDA strongly recommends using dosimetry code
software when submitting dosimetry estimates for new radiopharmaceuticals that are or will
be administered to humans for experimental or clinical use (Table 10.1) [59]. Dosimetry
software such as Medical Internal Radiation Dose (MIRDose) [75] or Organ Level Internal
Dose Assessment Exponential Modeling (OLINDA/EXM, successor to MIRDose, FDA
510(k)-approved device) [71] offer users a variety of phantoms that permit calculating
radiation doses for individuals at various ages and sizes, and for women at different stages of
pregnancy.
Table 10.1 . Advantages to Using Dosimetry Code Software [71]

1.
Provides a standardized framework and methodology for automated dosimetry
calculations in the user community
2.
Minimal user input data required to generate radiation dose estimates
3.
Most standard and up-to-date models for internal dosimetry are incorporated
(i.e., software already includes quantities effective dose equivalent and
effective dose derived from the most recent tissue weighting factors and quality
factors recommended by the International Commission on Radiological
Protection (ICRP) and the MIRD of the Society of Nuclear Medicine and
Molecular Imaging (SNMMI))
4.
Greatly facilitates difficult dose calculations that can be tedious to complete
manually
5.
The same output quantities are reproduced by all users when inputting the
same data
6.
Can be used to make theoretical calculations for existing radiopharmaceuticals,
 teaching, and other purposes
7.
FDA readily accepts the dosimetry calculations when reviewing new IND
applications, thereby speeding up the approval process
To create radiation dose estimates for the reference population (Table 10.2), the user inputs
the radionuclide, chooses the anthropomorphic model, and inputs the integral values (that
demonstrate cumulated percent activity) derived from the PK time–activity curve data from
the patient’s images [59].
Table 10.2 . Radiation Dosimetry Calculated Using OLINDA Code

Adult Female Total Dose Adult Male Total Dose

Organ (rem/mCi) (rem/mCi)
Adrenals 8.84E−02 6.94E−02
Brain 2.57E−02 2.10E−02
Breasts 7.17E−02 5.70E−02
Gallbladder wall 8.63E−02 7.16E−02
LLI wall 8.81E−02 6.90E−02
Small intestine 8.37E−02 7.32E−02
Stomach wall 8.55E−02 6.86E−02
ULI wall 9.00E−02 7.19E−02
Heart wall 1.33E−01 1.03E−01
Kidneys 3.03E−01 2.76E−01
Liver 1.13E−01 8.52E−02
Lungs 5.39E−02 4.28E−02
Muscle 4.03E−02 3.01E−02
Ovaries 8.67E−02 NR
Pancreas 8.96E−02 7.19E−02
Red marrow 6.66E−02 5.46E−02
Osteogenic cells 1.65E−01 1.25E−01
Skin 6.62E−02 5.23E−02
Spleen 8.55E−02 6.83E−02
Testes NR 6.00E−02
Thymus 7.97E−02 6.17E−02
Thyroid 7.46E−02 6.05E−02
Urinary bladder wall 7.48E−02 6.75E−02
 Adult Female Total Dose Adult Male Total Dose
Organ (rem/mCi) (rem/mCi)
Uterus 8.62E−02 NR
Total body 8.47E−02 6.60E−02
Effective dose
8.09E−02 6.57E−02
(rem/mCi)
Dosimetry in 5 Healthy Human Volunteers Imaged at Stanford University. Dosimetry values were based on the
average percent injected activity (%IA) in the kidney, stomach, small intestine, bladder, pancreas, liver, lung,
heart, muscle and whole body remainder. The average area under the curve (AUC) of the %IA was determined
by ROI analysis of static 18F-FP-R0 1-MG-F2 PET scans acquired immediately upon tracer injection, 1 hour and
2 hours after injection. These values were entered into OLINDA to determine the radiation dosimetry to each of
the organs listed in the table. The kidneys were determined to be the dose limiting organ at 0.0490 mSV/MBq in
an adult male. (manuscript entitled “A First-in-Human Study of Integrin avb6 Cystine Knot Positron Emission
Tomography (PET) Tracers “submitted for review by Kimura, R, Wang, L, Shen, B, Huo, L, Tummers, W,
Filipp, F, Abou-Elkacem, L, Baratto, L, Habte, F, Devulapally, R, Witney, T, Cheng, Y, Haywood, T, Tikole, S,
Chakraborti, S, Nix, J, Bonagura, C, Hatami, N, Visser, B, Poultsides, G, Norton, J, Natarajan, A, Ilovich, O,
Srinivas, S, Srinivasan, A, Paulmurugan, R, Willmann, J, Chin, F, Cheng, Z, Iagaru, A, Li, F, Gambhir, S)”.

Currently, dosimetry estimates assume uniform distributions of absorbed radiation energy

across the entire organ and do not provide dosing gradients at tissue boundaries or direct
tumor dose correlations [59,71]. While standardized dose estimates using these phantoms are
sufficient for diagnostic imaging because the dose/exposures are relatively low and
justifiable, dose estimates prior to radiolabeled therapy (e.g., dosimetry-guided radiotherapy
using 177Lu) [76–79] must be more precise so as to better predict toxicity in dose-limiting
organs, namely bone marrow (most radiosensitive organ) and kidneys (most common method
of radionuclide excretion) [72,76,77,79–83]. One method to address these limitations
includes incorporating an organ-specific tomographic activity distribution data map from the
patient’s SPECT/CT or PET/CT scan [76,78,80,84–87]. Access to 3D voxel data would
maximize tumor dose while minimizing toxicity to surrounding tissues [76]. Additionally,
blood collections (timing and quantity of samples) must match the PK properties of the
radiotracer and be precisely recorded by the research team during imaging [80].
View chapter Purchase book
Relative Dosimetry for MV Beams
Sonja Dieterich PhD, DABR, ... Jing Zeng MD, DABR, in Practical Radiation Oncology
Physics, 2016
(1) Accurate Technical Functionality
Relative dosimetry is very sensitive to technical changes in the accelerator itself. For
example, changes in the steering coils or ion chamber can cause the beam symmetry to
deviate above the limits specified by acceptance testing and American Association of
Physicists in Medicine (AAPM) recommendations. Relative dosimetry is used during
installation and acceptance testing to fine-tune accelerator technical parameters.
Subsequently, relative dosimetry measurements are used as part of periodic accelerator QA to
verify accurate and consistent functioning of the accelerator. AAPM Task Groups (TG)-
401 and TG-1422 provide detailed tables of the relative dosimetry measurements, frequencies,
and tolerances recommended for clinical practice in standard linear accelerators. AAPM TG-
1353 and TG-1484 provide additional information for CyberKnife and TomoTherapy,
respectively.
View chapter Purchase book
Targeted Radionuclide Therapy
Joseph Gerard Jurcic, ... Ruby F. Meredith, in Clinical Radiation Oncology (Fourth Edition),
2016
Dosimetry
Dosimetry is the process of relating the administered amount of radioactivity to the absorbed
radiation dose in tumors, organs, or the whole body. Dosimetry is important for dose
correlation with clinical results, and in some instances, for treatment planning to avoid excess
toxicity. In general the doses calculated for TaRT are less accurate than for external beam
radiation therapy for a variety of reasons. These include limited radiation dose input data
(e.g., few sample points for a therapy using continuous exponentially decreasing irradiation),
inhomogeneous dose distributions, and the assumptions/calculation methodology used to
estimate TaRT absorbed doses.591 Dose calculation is also more complicated for internally
distributed radionuclides than for external beam irradiation. Alpha particle dosimetry adds the
complication of decay scheme cascade and daughter products that may have a different
distribution than the parent radionuclide.77,592,593 Additionally, the higher relative biologic
effectiveness (RBE) delivered by alpha- compared to beta-radionuclide therapy needs to be
considered.594 Data required for TaRT dose estimate calculations include the mass of tumors
and normal organs, the cumulative radioactivity taken up by organs and tumors, and
the pharmacokinetics of the administered radioactivity.595 Data is usually acquired by
serial gamma camera imaging. Bone marrow dose estimates are based on imaging studies of
bony regions of active marrow such as the spine or blood pharmacokinetics.596-598
Bremsstrahlung images from radionuclides that do not have gamma emissions are generally
of suboptimal quality, making accurate quantitation difficult. However, progress with
sophisticated methods has provided good images that have been useful for dose
estimates.599 As an alternative appropriate for many circumstances, estimates are often made
for nongamma-emitters from tracer studies using a gamma-emitter that has a similar
chemistry to that of the therapeutic radionuclide. Because animal studies have shown that
the biodistribution is similar, although not usually identical, for 111In and 90Y, tracer/dosimetry
studies with 111In-labeled antibody have frequently been performed in conjunction with 90Y-
labeled antibody therapy to estimate the subsequent biodistribution/dosimetry of the 90Y-
immunoconjugate.83,600,601 Quantitative immuno-PET with 89Zr-labeled antibody has shown
good correlation with 111In-labeled antibody biodistribution and may be useful as a positron-
emitting surrogate for 90Y-labeled antibody therapy.602 Position emission tomography (PET)
scanning with 124I-labeled conjugates can be useful for radionuclide dosimetry.603,604 PET
images from 89Zr-cG250 antibody have been superior to those of 111In-cG250 antibody in an
animal model and compare favorably with 124I.605,606 Other examples include use of 99mTc-
antibody for imaging/dosimetry studies in conjunction with 186Re-antibody
therapy.607 Another variable in estimating the expected dose from therapeutic TaRT using a
preliminary biodistribution/dosimetry is that even when a small amount of a therapeutic agent
is used, the correlation between doses predicted and later delivered has ranged up to ~30%
between estimated absorbed doses for the two procedures in the same patient.162,436,551,608 With
continued progress in refinement of methodology, improved correlation is anticipated. For
instance, quantitative SPECT reports accuracy within 5% to 15% for diagnostic or
therapeutic levels of radionuclide.
For many dose estimates, conjugate views of the whole body and regions of interest (ROI)
(e.g., tumors and normal organs such as liver) are obtained.596 The activity for each ROI is
measured from the counts in that region at multiple time points. The counts in each ROI are
corrected for background. Attenuation correction factors are calculated for each patient and a
sample of the administered radionuclide is used for calibration so that counts per minute can
be converted to units of radioactivity (mCi or MBq). Scatter correction may also be applied.
SPECT for ROIs can provide superior definition and quantitation.609 Despite expansion of this
technology, SPECT has not yet become the standard for most quantitation as it is more time
consuming than planar conjugate view methodology.610,611 Absorbed radiation doses can be
calculated from radioactivity quantitation and the specific absorbed fraction for the target.
The specific absorbed fraction takes into account the type and energy of radiation emissions,
the fraction of energy from the source absorbed by the target and mass of the target.612 The
mass of each ROI is usually determined by estimating volumes from computed tomography,
MRI, or other methods such as 99mTc-sulphur colloid liver scans, and converting volume to
mass by assuming a unit density of 1 g/mm3 for most soft tissues. Accounting for excretory
routes is needed in quantitating changes in radioactivity distribution over time. For
radionuclides such as 131I where the major route of excretion is renal, urinary activity
measurements can provide an estimate of total body clearance if it is not feasible to obtain
whole-body counts.
The MIRD Committee is one entity that provides guidance for methods to calculate radiation
absorbed dose estimates for the whole body and organs.613 This methodology has been
adapted for TaRT, with continuing effort by this committee and others to further improve the
models and methods available.564,595,598,609,613-624 A Java applet was created, in collaboration with
the MIRD Committee to provide worldwide access (http://mirdcell.njms.rutgers.edu/) to new
software that facilitates multicellular dosimetry and biological-response modeling. In addition
to MIRD publications and information posted through the SNM.org website, other
informational publications, websites, and computer programs have been developed to assist
with dosimetry calculations.624-627 Among websites available, www.doseinfo-radar.com was
developed to provide information in a number of areas including standardized dose estimates,
decay data, and absorbed fractions. With fusion of anatomic and physiologic images, dose
estimates can be calculated in three dimensions at the voxel level, taking into account
heterogeneity of radioactivity distribution within an organ.628-633
Biopsy results are infrequently used for as a sole measure for dosimetry. Although biopsy
provides a direct measurement and can be used for autoradiography, it is invasive, and not
practical for most tumor or organ dosimetry. Biopsy data is of interest to correlate with other
methods of dosimetry, but it is often of limited value alone because of the small sample size,
which may not be representative, and is usually only done once. Thus biopsy dosimetry
usually does not allow a time-activity curve to be generated. However, the development of
alpha cameras now allows activity over time to be measured.628,630,634-
636
 Implanted thermoluminescent dosimeters (TLD) and other devises have also been used for
quantitation in experimental preclinical studies and in limited clinical trials.637 When used in
patients with ovarian cancer treated with intraperitoneal TaRT, TDL-obtained dose
measurements were in the range of those estimated with other methods.607 As with biopsy,
TLDs provide a direct measurement of absorbed dose but also usually require an invasive
procedure for placement that has the disadvantage of potentially introducing a sampling error.
Like most other dosimetry methods, TLDs do not account for dose rate, which may be an
important determinant of dose response relationships. Another implantable dosimeter has
been developed and applied to external beam radiation that can give real-time wireless
feedback to a computer. This technology should be applicable to radionuclides but, similar to
TLDs, will only provide data from a small area.638
The relationship between outcome and radiation dose-related factors has been variable, with
some studies showing a strong correlation, whereas others show no correlation.639-642 Some of
the factors making it more difficult to establish a dose response relationship for TaRT, as
compared to external beam radiation therapy, may include relative uncertainty associated
with TaRT dose calculations, the heterogeneity of dose deposition that occurs with TaRT,
dose rate effects, and agent/patient variation in excretion/clearance. Whereas most normal
organ tolerance levels for external beam radiation have been established using high dose rate
radiation, and vary as a function of fraction size, the dose rate is often low and variable with
TaRT, limiting the validity of extrapolating from high dose rate tolerance levels to those
expected with TaRT. Fractionation of TaRT, as with external beam, can increase the total
radionuclide dose tolerated.53,210 Several studies have demonstrated how biologic factors
affect tolerance but are not accounted for in standard dose/toxicity reporting. Many of these
have been summarized in a review.539 Improved dose/toxicity correlations for marrow
suppression has included adjustment of calculated absorbed marrow dose for levels of a
biomarker involved in hematopoiesis, as well as cellularity and patient specific marrow
mass.542,643,644 Although data suggests the presence of a relationship between TaRT radiation
dose and tumor response, early analyses with relatively small numbers of patients receiving a
limited dose range fail to show strong correlation between these two factors.611,645 As
dosimetry accuracy has improved and nondosimetry factors (that affect biologic response)
have been considered, better correlation has been observed between dose delivered and tumor
control.639,646 Despite the progress toward improving accuracy of dosimetry and need for
individualized dose administration,603,611,647-651 most studies are still being done without
required organ or tumor dosimetry in the nontransplant setting. Activity is usually given per
kg or per square meter as is common with chemotherapy. For one of the FDA-approved
agents (131I-tositumomab), whole body effective half time is used to individualize
administered activity, but no organ or tumor dosimetry is required.647 As better correlation is
achieved between dosimetry results and clinical outcome, additional tumor dosimetry may be
required, as has usually been needed for high-dose therapy followed by stem cell rescue.652-
654
 Individualized kidney dosimetry has been important in predicting toxicity of PRRT.655 Like
marrow dose versus toxicity studies, adjustment for diseases, conditions, and factors that
influence kidney function such as hypertension have resulted in better correlation of
calculated kidney dose and renal toxicity in peptide TaRT therapy.648
As experience grows and dosimetry techniques improve, insight may be provided for
tolerance of new agents that become available. An example is the marrow studies pertinent to
alpha-emitter 223Ra.630
View chapter Purchase book
Targeted Radionuclide Therapy—Expanded Content
Ruby F. Meredith, ... Susan J. Knox, in Clinical Radiation Oncology (Third Edition), 2012
Dosimetry
Dosimetry is the process of relating the administered amount of radioactivity to the absorbed
radiation dose in tumors, organs, or the whole body. Dosimetry is important for dose
correlation with clinical results and, in some instances, for treatment planning to avoid excess
toxicity. In general, the doses calculated for TaRT are less accurate than those for external
beam radiation therapy for a variety of reasons. These include limited radiation dose input
data (e.g., few sample points for a therapy using continuous exponentially decreasing
irradiation), inhomogeneous dose distributions, and the assumptions/calculation methodology
used to estimate TaRT absorbed doses.555 Dose calculation is also more complicated for
internally distributed radionuclides than for external beam irradiation. Alpha particle
dosimetry adds the complication of decay and daughter products that may have a different
distribution than the parent radionuclide.69,556,557
Data required for TaRT dose estimate calculations include the mass of tumors and normal
organs, the cumulative radioactivity taken up by organs and tumors, and
the pharmacokinetics of the administered radioactivity.558 Data are usually acquired by
serial gamma camera imaging. Bone marrow dose estimates are based upon imaging studies
of bony regions of active marrow such as the spine and/or blood
pharmacokinetics.559,560 Although there have been attempts to provide dosimetry based on
Bremsstrahlung images from radionuclides that do not have gamma emissions, this is not
commonly done. The images are of suboptimal quality, making accurate quantitation
difficult. Instead, estimates are made for non–gamma emitters from tracer studies using a
gamma emitter that has a chemical makeup similar to that of the therapeutic radionuclide.
Because animal studies have shown that the biodistribution is similar, although not usually
identical, for 111In and 90Y, tracer/dosimetry studies with 111In-labeled antibody have
frequently been performed in conjunction with 90Y-labeled antibody therapy to estimate the
subsequent biodistribution/dosimetry of the 90Y immunoconjugate.73,561 Quantitative immuno-
positron emission tomography (PET) with 89Zr-labeled antibody has shown good correlation
with 111In-labeled antibody biodistribution and may be useful as a positron-emitting surrogate
for 90Y-labeled antibody therapy.562 PET scanning with 124I-labeled antibody or other agents
may prove to be useful.563 Thus far, PET images from 89Zr-cG250 antibody have been
superior to those of 111In-cG250 antibody in an animal model.564 Other examples include use
of 99mTc antibody for imaging/dosimetry studies in conjunction with 186Re antibody
therapy.565 Another variable in estimating the expected dose from therapeutic RIT using a
preliminary biodistribution/dosimetry is that even when a small amount of a therapeutic agent
is used (trace-labeled study using the same antibody and radionuclide that will be used for
therapy), there can be either very good correlation between doses predicted and later
delivered or a significant discrepancy in the range of approximately 30% between estimated
absorbed doses for the two procedures in the same patient.436,512,566,567
To estimate the dose, conjugate views of the whole body and regions of interest (ROI) (e.g.,
tumors and normal organs such as liver) are obtained. The activity for each ROI is measured
from the counts in that region at multiple time points. The counts in each ROI are corrected
for background. Attenuation correction factors are calculated for each patient, and a sample
of the administered radionuclide is used for calibration so that counts per minute can be
converted to units of radioactivity (mCi or MBq). Scatter correction may also be
applied. SPECT (single-photon emission computed tomography) for ROIs may provide
superior definition and quantitation, but this has not yet become the standard for quantitation
and is more time-consuming than planar conjugate-view methodology.568,569 Absorbed
radiation doses can be calculated from radioactivity quantitation and the specific absorbed
fraction for the target. The specific absorbed fraction takes into account the type and energy
of radiation emissions, the fraction of energy from the source absorbed by the target, and the
mass of the target.570 The mass of each ROI is usually determined by estimating volumes
from CT, MRI, or other methods such as 99mTc-sulphur colloid liver scans and then
converting volume to mass by assuming a unit density of 1 g/mm3. Accounting for excretory
routes is needed in quantitating changes in radioactivity distribution over time. For
radionuclides such as 131I, where the major route of excretion is renal, urinary activity
measurements can provide an estimate of total body clearance if it is not feasible to obtain
whole body counts.
The MIRD Committee of the Society of Nuclear Medicine provides guidance for methods to
calculate radiation absorbed-dose estimates for the whole body and organs.571 This
methodology has been adapted for TaRT, with continuing effort by this committee and others
to further improve the models and methods available.528,529,570–574 MIRD 16, other
informational publications, web sites, and computer programs have been developed to assist
with these calculations.575,576 Among web sites available, www.doseinfo-radar.com was
developed to provide information in a number of areas, including standardized dose
estimates, decay data, and absorbed fractions. With fusion of anatomic and physiologic
images, dose estimates can be calculated in three dimensions at the voxel level, taking into
account heterogeneity of radioactivity distribution within an organ.577,578