Imaging Dose, Cancer Risk and Cost Analysis in Image-guided Radiotherapy of Cancers
SCientifiC REPORTS |
Imaging Dose, Cancer Risk and Cost Analysis in Image-guided Radiotherapy of Cancers
OPEN The purpose of this retrospective study is to evaluate the cumulative imaging doses, the associated cancer risk and the cost related to the various radiological imaging procedures in image-guided radiotherapy of cancers. Correlations between patients' size and Monte Carlo simulated organ doses were established and validated for various imaging procedures, and then used for patient-specific organ dose estimation of 4,832 cancer patients. The associated cancer risk was estimated with published models and the cost was calculated based on the standard billing codes. The average (range) cumulative imaging doses to the brain, lungs and red bone marrow were 38.0 (0.5-177.3), 18.8 (0.4-246.5), and 49.1 (0.4-274.4) cGy, respectively. The associated average (range) lifetime attributable risk of cancer incidence per 100,000 persons was 78 (0-2798), 271 (1-8948), and 510 (0-4487) for brain cancer, lung cancer and leukemia, respectively. The median (range) imaging cost was $5256 (4268-15896) for the head scans, $5180 (4268-16274) for the thorax scans, and $7080 (4268-15288) for the pelvic scans, respectively. The image-guidance procedures and the accumulated imaging doses should be incorporated into clinical decision-making to personalize radiotherapy for individual patients.
Age (years) at initial treatment
??Mean for Males
??Range for Males
??Mean for Females
??Range for Females
Year of initial treatment
Organs irradiated by imaging
??Red bone marrow only
??Brain and lungs (no red bone marrow)
??Brain and red bone marrow (no lungs)
??Lungs and red bone marrow (no brain)
??Brain, lungs and red bone marrow
Services (CMS) of US government were used to calculate the cost related to various imaging procedures. In this
work, all the patients undergoing radiotherapy received one or few of the 4 imaging procedures available in our
institution including CT, kVCBCT, kVPI and MVPI. As there have been no MV-CT or Tomotherapy installed in
our institution, we did not include the analysis of the cumulative imaging dose, second cancer risk and imaging
cost from MV-CT scans or Tomotherapy in this paper.
Patient characteristics and data collection. All the cancer patients treated with radiotherapy at
YaleNew Haven Hospital from September 1, 2009 to April 30, 2014 were reviewed with institutional review board
(IRB) approval by Yale University Human Investigation Committee (HIC#1403013576). By the time when this
retrospective study was initiated, all the reviewed patients who underwent radiotherapy at our institution have
signed informed consent, finished their radiation treatments, and left our clinic already. Hence no separate
informed consent was necessary. Patients treated without any image-guidance or computed tomography (CT)
scans, and patients treated with total body irradiation or with large blocks protecting the brain, lungs or RBM,
were excluded from this study. A total of 4,832 patients whose brain, lungs or RBM were irradiated by at least one
of the three image-guidance modalities (i.e., kVCBCT, kVPI, MVPI) were included and all data were anonymized
in this retrospective study. The characteristics of 4,832 patients were summarized in Table?1.
The gender, age, numbers and types of image-guidance procedures performed on these 4,832 patients were
obtained directly from ARIA record & verify system (Varian Medical Systems, Palo Alto, CA). One axial CT slice
at the eyebrows, nipples, or hip level was exported from Eclipse treatment planning system via DICOM, based on
which the circumference of the head, thorax or pelvis was computed using the DICOMan software17. The patients?
circumferences (surrogates of patients? size) ranged from 39 to 66 cm, 42 to 160 cm, and 37 to 168 cm in the head,
thorax and pelvis regions, respectively.
Monte Carlo simulations of CT, kVCBCT, kVPI and MVPI. An EGSnrc/BEAMnrc code was used to
simulate the photon beams emanated from the X-ray sources of CT, kVPI, MVPI and kVCBCT systems,
respectively18,19. Particularly, the default settings such as kVp, mAs, blades and bowtie filter specific to individual scan
protocol were used. The phase space data were first scored below the last beam-shaping device (e.g., bowtie filter
in kVCBCT) and then used to derive the multiple source model for the corresponding scan protocol20,21.
MCSIM, an EGS4/BEAM user code, was used to calculate the three-dimensional dose distributions in patient
anatomy with multiple source model as beam input for each imaging procedure22,23. To convert Monte Carlo
simulations into absolute dose, the absorbed dose was first measured at the isocenter of an acrylic ball phantom of
5 cm in diameter with a calibrated EXRADIN A12 ionization chamber (Standard Imaging, Middleton, WI) for the
specific scan protocol24. The EXRADIN A12 ionization chamber was calibrated every two years by an Accredited
Dosimetry Calibration Laboratory (ADCL) traceable to the National Institute of Standards and Technology
(NIST). In performing the in-phantom ion chamber measurement, the ratio of mass energy-absorption
coefficient for water to air and other beam-quality and chamber-related correction factors were applied per TG-61
protocol24. Monte Carlo simulation was then performed to a chamber volume inside the ball phantom with the
same beam setup using multiple source model. The ratio of the measured dose to the Monte Carlo simulation
yielded a conversion factor, which was unique to the clinical setup and beam configuration. We repeated the
process for all the imaging devices and protocols used in our clinic and obtained corresponding conversion factors.
With all those conversion factors, all the Monte Carlo simulations in patient CT anatomy can be converted into
absolute doses to water.
The following imaging devices and protocols were routinely used in our clinic and modeled with Monte Carlo
) A GE LightSpeed 16-slice CT scanner: head protocol (helical scan, 120 kV, 304 mAs, pitch 0.938); chest
protocol (axial scan, 140 kV, 250 mAs); and pelvis protocol (axial scan, 140 kV, 250 mAs).
) OBI kVCBCT systems mounted on Varian accelerators: high-quality head protocol (100 kV, 720 mAs, 204?
arc, full bowtie); low-dose thorax protocol (110 kV, 262 mAs, 364? arc, half bowtie); and pelvis protocol
(125 kV, 680 mAs, 364? arc, half bowtie).
) Paired kVPI on Varian OBI systems: 180? and 270? gantry, 120 kV, 126 mAs, no bowtie filter, average field
X1 = X2 = 13.3 cm, Y1 = Y2 = 10.0 cm.
) Paired MVPI on Varian accelerators: 6-MV, 2 MU, 180? and 270? gantry, average field = 20 cm ? 20 cm for
the head, 22.8 cm ? 20.1 cm for the chest, and 21.5 cm ? 20.1 cm for the pelvis respectively.
In all the Monte Carlo simulations, the energy cutoff for electrons (ECUT) = the threshold for ?-ray
(AE) = 521 keV, and the energy cutoff for photons (PCUT) = the threshold for bremsstrahlung (AP) = 10 keV. A
statistical uncertainty (1?) of 2% has been achieved for all the Monte Carlo simulations in this study.
Organ dose and lifetime attributable risk estimation. Using SigmaPlot suite, Monte Carlo-simulated
doses to the brain, lungs and RBM deposited by CT, kVPI, MVPI and kVCBCT scans were regressed as
empirical functions of the corresponding circumference, respectively. Using the established empirical functions, mean
organ doses of 4,832 patients from 142,824 imaging procedures were estimated and accumulated. The lifetime
attributable risk (LAR) of cancer incidence based on BEIR VII models16 was calculated to quantify the probability
of cancer incidence associated with the cumulative imaging doses in IGRT.
The LAR for a person exposed to dose D (Sv) at age e (years) was defined as
LAR(D, e) = ?M(D, e, a) ?
where a denotes attained age (years), M(D, e, a) is the excess absolute risk (EAR), S(a) denotes the probability of
surviving until age a, and S(a)/S(e) denotes the probability of surviving to age a conditional on survival to age e.
For brain and lung cancer,
ERR or EAR(D, s, e, a) = ?sD exp(?e?)???? 6a0 ?????
where ERR stands for the excess relative risk.
ERR or EAR(D, s, e, t) = ?sD(1 + ?D)exp?????e? + ? log???? 2t5 ????? + ?e? log???? 2t5 ?????????
All the parameters in the equations such as e*, ?, ?, ?, ?, and ? were extracted from BEIR VII report. An in-house
MATLAB code was developed for site-sp ecific LAR estimates.
Imaging cost analysis. CMS standard billing codes (applicable to USA only) were used in this study to
calculate the imaging cost associated with the various imaging procedures performed on the 4,832 patients.
Specifically, $3,828 was charged for each CT scan. $76, $76 and $118 were charged to each MVPI, kVPI and
kVCBCT procedure, respectively, on top of a one-time fee of $440. The proportions of kVCBCT, MVPI and kVPI
used in each lesion site for all the 4,832 patients were calculated and the summation of all the cost related to
various procedures yielded the total imaging cost for each patient.
Statistical analysis. Descriptive Statistics and Mann-Whitney Rank Sum Test were conducted using
SigmaPlot suite (Version 12.0, Systat Software, San Jose, CA). A P-value less than or equal to 0.05 indicates a
Validation of Monte Carlo simulations. As shown in Fig.?1, Monte Carlo simulations of 4 imaging
devices/protocols were compared with the ion chamber measurements in a 32-cm diameter CTDI phantom for
(a) CT, (b) kVCBCT, (c) kVPI and (d) MVPI. The measured and simulated absolute doses (in cGy) were indicated
with red and blue values for a variety of points located at the center, 3, 6, 9 and 12 o?clock positions, respectively.
For clarity, only isodose lines of 20%, 40%, 60%, 80% and 100% of 4.5 cGy, 5.0 cGy, 2.0 cGy and 5.0 cGy were
shown on (a) to (d), respectively. The relative differences of absolute dose between the Monte Carlo simulations
and the ion chamber measurements ranged from 0.8% to 5.0% for CT, from 1.0% to 5.3% for kVCBCT, from 1.0%
Red bone marrow
Red bone marrow
Red bone marrow
Imaging Dose (cGy) = Fitting Parameters
y0 ? exp(?a ? C)
y0 + a ? C
y0 + a ? C
y0 + a ? C + b ? C2
y0 + a ? C
to 5.0% for kVPI, and from 0.3% to 2.9% for MVPI, respectively. Overall, the ion chamber measurements have
confirmed the dose calculation accuracy of our Monte Carlo simulations of the imaging procedures to within
5.3%. Hence, these validated Monte Carlo models were employed in the subsequent population-based dose study
in patient anatomy. Empirical functions were used to describe correlations between patient size and structural
mean dose, whose parameters are listed in Table?2, where the empirical functions of kVCBCT for lungs and RBM
were published in our previous work4,8.
Patterns of image-guidance procedures. Figure?2 shows the statistics of various imaging procedures
and the new patients receiving IGRT during the past four-and-half years at our institution. Overall, there has been
a steady rise in the numbers of new patients and imaging procedures each year from 2009 to 2013, followed by
a decrease in 2014. Compared to the previous year, the total number of imaging procedures increased by 52.1%,
26.6%, 14.7%, and 6.8%, respectively from 2010 to 2013. The decrease of imaging procedures in 2014 was
primarily due to the decrease of new patients treated in the first months of 2014. KVCBCT, MVPI and kVPI accounted
for 14.1%, 24.1 and 58.1% of all the 142,824 imaging procedures performed on 4,832 patients, respectively. The
average CT, kVCBCT, MVPI and kVPI scans per patient were 1.1, 4.2, 7.1 and 17.2, respectively.
Cumulative imaging doses to the brain, lungs and RBM. As shown in Fig.?3, since different
image-guidance procedures were used in the head, thorax and pelvis regions, the dose depositions to the regional
OARs were quite different. The majority of our patients received 15cGy or less imaging doses to the lungs, yet
the imaging doses to the brain and RBM ranged from 5 to 75 cGy for most patients. Among 5,384 organs being
irradiated, the average (range) cumulative imaging doses to the brain, lungs and RBM were 38.0 (0.5?177.3),
18.8 (0.4?246.5), and 49.1 (0.4?274.4) cGy, respectively. Out of 4,832 patients, 63.8%, 88.7% and 61.9% of them
received 50 cGy or less doses to the brain, lungs and RBM, respectively. Yet, 272 organs (19 brain, 19 lungs and
234 RBM volumes), which accounted for 5% of patients in this study, received 100 cGy or more doses with the
maximum doses of 177.3, 246.5 and 274.4 cGy, respectively. Among these 272 organs with high doses, 6 brain
and 5 lung volumes were from the patients younger than 20 years old. These high doses were found to be largely
caused by the repetitive imaging procedures and non-personalized scan settings.
The LAR of cancer incidence. Figure?4 depicts for both males and females, the correlations between the
exposed age and averaged LAR of cancer incidence as a result of cumulative imaging doses to the brain, lungs and
RBM, respectively. For both genders, the averaged LAR of incidence for brain and lung cancers decreased
monotonically with age. However, the LAR of leukemia incidence displayed an unusual trend with a regular decrease in
young groups followed by a ?hump? in senior groups. The hump peaks around 65 years old for males due largely
to the frequent kVCBCT scans in prostate IGRT, whereas it peaks around 45 years old for females due to the
increased image-guidance in radiation treatments of pelvic lesions. Regardless of age, a statistically significant
difference was observed for the LAR of both lung cancer and leukemia incidence between the males and females
(p < 0.001), but was not present in the LAR of brain cancer incidence (p = 0.063). The difference between females
and males for lung cancer LAR was largely due to the larger ?S factor for the females in the BEIR VII model.
Cost of imaging procedures in IGRT. Figure?5 shows the total cost of imaging procedures per patient for
all the 4,832 patients from 2009 to 2014 with the 90th, 75th, median, 25th, and 10th percentiles indicated in the box
plots and the outliers shown as solid symbols. Generally speaking, the median imaging cost experienced a gradual
rise followed by a gentle decrease for each lesion site from 2009 to 2014. Specifically, the median imaging cost
from 2009 to 2014 was $5028, $5028, $5256, $5636, $6548, $5788 in the head, $5028, $4976, $5180, $5180, $5370
and $5104 in the chest, and $6396, $6510, $7840, $8220, $6890 and $5636 in the pelvis, respectively. In any given
year, the differences in the medians among the three sites are statistically significant (p= 0.016 for 2009, p < 0.001
from 2010 to 2013, and p = 0.025 for 2014). The median of the total imaging cost per patient in IGRT from 2009
to 2014 was $5180, $5180, $5256, $5465, $5484 and $5330, respectively.
In this study, organ-specific correlations between imaging dose and patient size were first established for various
imaging procedures based on Monte Carlo simulations in patient anatomy. Subsequently, the established
empirical functions (Table?2) coded with MATLAB were used to estimate organ doses when the OARs were irradiated
by various imaging procedures in IGRT. In general, 64.4% of our 4,832 patients received dose of more than 10 cGy
(equivalent to 100 mSv) from imaging procedures, 85.2%, 49.3% and 74.4% of which are in the brain, lungs and
RBM groups, respectively. In addition, our results indicated that the cumulative imaging doses may not be
considered negligible for a certain group of patients undergoing IGRT. For example, for children younger than 15
years, 5?10 abdominal CT scans or 2?3 head CT scans will result in a cumulative imaging dose of 5 cGy to the
RBM or 6 cGy to the brain, respectively5. In our study, among the 59 children younger than 15 years, the average
cumulative imaging doses to the brains and the RBMs were 64.4 cGy and 46.0 cGy, respectively, with the
associated LAR 10 and 8 times higher than that from the CT scans5.
The cumulative imaging dose depended on the frequency of imaging acquisitions and the radiation dose of
each procedure: the latter was directly related to the patient size and the scan settings. For example, using the
default settings of CT, kVCBCT, kVPI and MVPI, the mean doses to the lungs were 0.5, 1.1, 0.7 and 2.9 cGy for
an adult with a chest circumference of 120 cm, but were 0.8, 2.3, 1.4 and 3.7 cGy for a child with a chest
circumference of 60 cm, respectively. The excessive dose to the child from the default settings was clinically unjustifiable
and could be largely avoided by personalized imaging protocols25.
In the image-guided radiotherapy of cancers, there are the therapeutic doses used to kill the cancerous tissues
as well as the imaging doses used for tumor localization. The ratio of the imaging dose to the therapeutic dose
depends on the patient size, the prescription dose, the imaging modality, the frequency and the settings of the
applied image-guidance procedures. In the studied patients, it was found that the average ratio (range) of the
imaging dose to the therapeutic dose was 0.65% (0.01?7.59%), with about 0.2% of patients having a ratio larger
than 5%. The benefit/risk of image-guidance should be carefully evaluated for this small group of patients.
Recently there have been a series of studies on the scatter and leakage doses from linear accelerators and
the associated secondary cancer risk26?31. Vu Bezin et al. reported that the leakage doses from 6 MV photons
were similar to those delivered during CT scans (0.2?6 cGy for a 70 Gy delivery at isocenter), and the low doses
should not be neglected while estimating the secondary cancer risk30. In our study, 36.2%, 11.3% and 38.1% of
patients received cumulative imaging doses of 50 cGy or more to the brains, lungs and RBM, respectively. The
secondary cancer risk from the imaging doses may be comparable to that from the leakage dose in conformal and
intensity-modulated radiation therapy26,27. Besides this preliminary study, long-term follow-up and prospective
clinical trials will be much needed to confirm what kind of effect the cumulative doses from various radiological
imaging procedures may have on the patients undergoing IGRT particularly children.
The imaging cost for a cancer patient consists of a fixed charge and a variable charge. While the fixed charge
has been standardized per CMS billing codes, the variable charge depends on both the frequency and the type of
image-guidance procedures. An optimized choice of the frequency and the procedure type could help reduce the
imaging cost while maintaining a high quality for radiation treatment. Based on this study, the average imaging
cost per patient was $6197, $6183, $6358, $6428, $6535 and $6092 from 2009 to 2014, respectively. An
optimized and personalized application of the image-guidance procedures for each patient would help deliver a
cost-effective health care in the radiotherapeutic management of cancers32,33. For example, we can personalize
scan range for the individual patient, restrict the use of fluoroscopy, or choose alternative imaging modalities such
as magnetic resonance imaging and ultrasound. Also, we should apply not only site-specific but also size-specific
protocols to minimize radiation doses while maintaining acceptable imaging quality34.
It is important to recognize the importance of image-guidance in cancer radiotherapy as well as its potential
risk1,35,36. On one hand, with image-guidance, the significant shrinkage of CTV-PTV margin will reduce not
only the volume of healthy tissues near target exposed to higher doses of radiation but also the volume of
normal tissues distal from target exposed to lower doses, hence resulting in a decrease in second cancers. On the
other hand, as a result of smaller margins and better positioning with IGRT, higher therapeutic doses are more
frequently delivered with modern advanced radiotherapy techniques such as SRS, SBRT and VMAT, which may
increase the risk for second cancers in those patients if the tumoricidal doses were not delivered as planned due
to intra-fraction organ motion or deformed target volume.
While the effects of high and acute doses of ionizing radiation are easily observed and understood in humans
such as Japanese Atomic Bomb survivors, the effects of low-level radiation are very difficult to observe and highly
controversial. This is because the baseline cancer rate is already very high and the risk of developing cancer fluctuates
significantly with individual life style and environmental factors, obscuring the subtle effects of low-level radiation.
This is especially true for the patients undergoing image-guided radiotherapy where a large lethal dose in the order
of tens of Gy is intended for the tumor killing while a small imaging dose in the order of cGy to tens of cGy is used for
tumor localization and alignment. However, besides the confirmed positive correlation between ionizing radiation
and cancer risk in both children and radiation-monitored workers5,6, Mathews et al. have reported a dose-response
relation in 680,000 children and adolescents with increased incidence of cancer due to exposure to low dose
diagnostic CT scans at 4.5 mSv per scan37. Rampinelli et al. have recently demonstrated that the median cumulative radiation
exposure from low dose CT screening over 10 years was 9.3 mSv for men and 13.0 mSv for women, respectively, with
an non-negligible but acceptable cancer risk38. All of these studies have taken many years to finish. Hence, we expect
that it would take a long-term investigation with collaborative efforts to determine the association of cancer with the
imaging doses for a large patient population who undergoes IGRT of cancers.
While most of procedures are clinically justified by the benefit outweighing the potential risk, we should be
prudent about the application of image-guidance in a small portion of patients who may receive dangerously high
doses to some critical organs as a result of non-personalized scan settings and over-imaging. One end product of
this retrospective study was the creation of an institutional ?Big Data? repository consisting of patient gender, age,
size, treatment history, imaging procedures, shifts as well as organ dose depositions. Moving forward, we plan to
track the organ doses for all the patients, particularly those with imaging doses higher than 100 cGy, considering
the imaging doses as well as the scatter and leakage doses from the mega-voltage radiation treatments. A
comprehensive understanding of organ doses would help the clinicians tailor radiotherapy for each of their patients.
In conclusion, our results suggest that it is essential to evaluate the cumulative imaging doses to
personalize image-guidance and radiation treatment for individual patient undergoing IGRT. Appropriate usage of
image-guidance procedures is highly desired to maintain a cost-effective health care.
Data availability. The corresponding author has full access to all the data in the study and final responsibility
for the decision to submit for publication. The data in this study will be available from the corresponding author
The authors thank H. Liu (Department of Therapeutic Radiology, Yale-New Haven Hospital) and Y. Yan
(Department of Radiation Oncology, University of Texas Southwestern Medical Center) for their assistance in
this work. L.Z. was awarded a scholarship under the Sichuan University Scholarship Fund to pursue this research
as a visiting scholar, working with J.D. at the Department of Therapeutic Radiology of Yale University from
December 2013 to June 2015.
Both L.Z. and J.D. contributed to literature search, study design, data collection, data analysis and manuscript
writing, and collaborated with other authors. All authors reviewed the manuscript and made the decision to
submit the manuscript for publication, and agreed to be accountable for the accuracy and integrity of the data
Competing Interests: The authors declare no competing interests.
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