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Radiation dose and contralateral breast cancer risk associated with megavoltage cone-beam computed tomographic image verification in breast radiation therapy
Practical Radiation Oncology (2013) 3, 93–100
www.practicalradonc.org
Original Report
Radiation dose and contralateral breast cancer risk associated with megavoltage cone-beam computed tomographic image verification in breast radiation therapy Alexandra Quinn BMedRadPhysAdv a,b,⁎, Lois Holloway PhD a,b,c , Eng-Siew Koh MBBS, FRANZCR b,d,e , Geoff Delaney MD, FRANZCR b,d,e,f , Sankar Arumugam PhD b , Gary Goozee MAppSc, MACPSEM b , Peter Metcalfe FACPSEM, FinstP a,b a
Centre for Medical Radiation Physics, University of Wollongong, Wollongong, NSW, Australia Liverpool and Macarthur Cancer Therapy Centres, NSW, Australia c School of Physics, University of Sydney, Sydney, NSW, Australia d Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia e Collaboration for Cancer Outcomes Research and Evaluation, Liverpool Hospital, Liverpool, NSW, Australia f School of Medicine, University of Western Sydney, Sydney, NSW, Australia b
Received 23 January 2012; revised 6 May 2012; accepted 8 May 2012
Abstract Purpose: To measure and compare organ doses from a standard tangential breast radiation therapy treatment (50 Gy delivered in 25 fractions) and a megavoltage cone-beam computed tomography (MV-CBCT), taken for weekly image verification, and assess the risk of radiation-induced contralateral breast cancer. Methods and Materials: Organ doses were measured with thermoluminescent dosimeters placed strategically within a female anthropomorphic phantom. The risk of radiation-induced secondary cancer of the contralateral breast was estimated from these values using excess absolute risk and excess relative risk models. Results: The effective dose from a MV-CBCT (8-monitor units) was 35.9 ± 0.2 mSv. Weekly MV-CBCT imaging verification contributes 0.5% and 17% to the total ipsilateral and contralateral breast dose, respectively. For a woman irradiated at age 50 years, the 10-year postirradiation excess relative risk was estimated to be 0.8 and 0.9 for treatment alone and treatment plus weekly MV-CBCT imaging, respectively. The 10-year postirradiation excess absolute risk was estimated to be 4.7 and 5.6 per 10,000 women-years.
Conflicts of interest: None. ⁎ Corresponding author. University of Wollongong, Centre for Medical Radiation Physics, Northfields Ave, Wollongong, NSW 2522, Australia. E-mail address: [email protected] (A. Quinn). 1879-8500/$ – see front matter © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2012.05.003
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Conclusions: The increased dose and consequent radiation-induced second cancer risk as calculated by this study introduced by the imaging verification protocols utilizing MV-CBCT in breast radiation therapy must be weighed against the benefits of more accurate treatment. As additional image verification becomes more common, it is important that data be collected in regard to long-term malignancy risk. © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction There are increasing numbers of breast cancer survivors1 due to significant increases in diagnosis and more effective treatment.2,3 Radiation therapy is a primary treatment for breast cancer; 83% of breast cancer patients will receive at least 1 course of radiation therapy during their cancer management.4 Long-term risks, such as radiation-induced secondary malignancies, while relatively uncommon, are a concern for this large population of long-surviving patients.2 Based on current data, the benefits of radiation therapy as adjuvant therapy outweigh the risks of radiation-induced secondary malignancies.5 However, any additional radiation, such as that from verification imaging dose, should be accurately quantified and examined as to the cost-benefit to the patient, especially when other imaging modalities such as electronic portal imaging devices exist that have lower radiation doses.6 The AAPM (American Association of Physicists in Medicine) Task Group 757 has addressed some of these issues by providing radiation dose data for various imaging modalities typically used in radiation therapy, as well as recommendations on how to estimate and reduce additional radiation dose to the patient. One image modality mentioned in this report, but for which there is limited patient organ dose information, is megavoltage cone-beam computed tomography (MV-CBCT). MV-CBCT utilizes the treatment beam to acquire a 3-dimensional image set of the patient, providing soft tissue information. For complex breast radiation therapy techniques, such as intensity modulated radiation therapy (IMRT), patient position verification based on soft tissue information has been found to reduce setup uncertainty in comparison with bony anatomy alignment with electronic portal imaging.8 Since the AAPM Task Group 75 report was published, a small number of studies providing dose values for various organs from MV-CBCT have been reported. One Monte Carlo study estimated the dose to patients from head and neck and pelvic MV-CBCT scans.9 The surface dose from a female chest MV-CBCT has been measured with thermoluminescent dosimeters (TLDs) and metal-oxide-semiconductor field-effect-transistor detectors.10 Two treatment-planning studies investigated the dose to limited organs from a simulated MV-CBCT on a treatment-planning CT.11,12 These treatment-planning studies were limited to organs within
the field-of-view of the treatment-planning CT and hence the effective dose and whole body stochastic effect could not be evaluated. The purpose of this study was to measure and compare organ doses from a standard tangential breast radiation therapy treatment and a MV-CBCT taken for image verification. The risk of radiation-induced secondary malignancies of the contralateral breast was estimated from these with an excess absolute risk and excess relative risk13 model.
Methods and materials Thermoluminescent dosimeter calibration Standard 3 × 3 × 0.9 mm3 lithium-fluoride TLD chips (TLD-100; Erlangen, Germany) were used. Individual chip calibration factors were established and used to correct for inter-chip variability within a batch. TLD chip sensitivity was established by irradiating batches of TLD chips to known doses within the expected range of MVCBCT and breast radiation therapy energies and doses. Only TLD chips with sensitivity ranging within ± 5% were selected for measurements. TLD chips were read with a Rialto NE TLD reader (NE Technology Ltd, Cambridge, UK) within 24 hours of irradiation.
Anthropomorphic phantom and thermoluminescent dosimeter placement A female anthropomorphic phantom (Radiology Support Devices, Long Beach, CA) with size B breast attachments was used. The phantom consists of 34 axial slices with slice thickness 2.5 cm and is composed of human tissue and bone equivalent material. Each slice contains a matrix of holes for TLD placement. Organs specified by the International Commission on Radiological Protection (ICRP) 10314 were selected for dose measurements. Organ locations within the phantom were determined with a full body CT scan of the phantom, the guidance of a previous study,15 and an experienced radiation oncologist. Two TLD chips were placed at each point location to reduce statistical error in the TLD measurements; TLD distribution is specified in Table 1. The same TLD positioning was utilized for both the breast
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Table 1 Tissue weighting factors and number of utilized thermoluminescent dosimeters in considered organs; organ and tissue doses for a megavoltage cone-beam computed tomography and a tangential breast radiation therapy treatment Organ or tissue
Bone marrow (red) Colon Lung Stomach Breasts Contralateral breast Ipsilateral breast Gonads (ovaries) Bladder Esophagus Liver Thyroid Bone surface Brain Salivary glands Skin Remainder Oral mucosa Thymus Heart Muscle Spleen Gallbladder Adrenals Kidneys Pancreas Small intestine Uterus
Tissue weighting factor 0.12 0.12 0.12 0.12 0.12
0.08 0.04 0.04 0.04 0.04 0.01 0.01 0.01 0.01 0.12 a
No. of TLDs
Absorbed dose (cGy) Single MV cone beam CT
Treatment
cGy/MU
8 MU
0.30 ± 0.005 0.04 ± 0.001 0.68 ± 0.005 0.92 ± 0.009
2.38 ± 0.036 0.30 ± 0.008 5.44 ± 0.038 7.34 ± 0.069
224.2 ± 6.90 16.5 ± 0.32 363.4 ± 7.15 327.2 ± 10.5
2 1 4 4 2 13 6 2 23
0.68 ± 0.012 0.68 ± 0.031 0.02 ± 0.001 0.02 ± 0.002 0.74 ± 0.015 0.84 ± 0.019 0.05 ± 0.002 0.30 ± 0.005 0.01 ± 0.001 0.02 ± 0.001 0.19 ± 0.003
5.47 ± 0.096 5.44 ± 0.248 0.17 ± 0.010 0.13 ± 0.017 5.88 ± 0.124 6.72 ± 0.156 0.38 ± 0.014 2.38 ± 0.036 0.08 ± 0.005 0.14 ± 0.005 1.53 ± 0.023
136.3 ± 7.91 5070.0 ± 142 8.8 ± 0.25 8.4 ± 0.11 81.1 ± 3.70 66.7 ± 1.36 28.3 ± 1.08 224.2 ± 6.90 8.7 ± 0.14 16.0 ± 0.62 583.0 ± 10.2
1 2 13 6 2 1 2 2 2 2 1
0.02 ± 0.002 0.59 ± 0.030 0.79 ± 0.014 0.36 ± 0.011 0.82 ± 0.033 0.89 ± 0.022 0.68 ± 0.014 0.72 ± 0.022 0.78 ± 0.022 0.05 ± 0.002 0.02 ± 0.001
0.17 ± 0.015 4.73 ± 0.240 6.35 ± 0.113 2.90 ± 0.087 6.58 ± 0.265 7.08 ± 0.175 5.45 ± 0.116 5.78 ± 0.178 6.26 ± 0.174 0.39 ± 0.012 0.15 ± 0.008
24.6 ± 0.59 72.7 ± 1.54 169.5 ± 2.42 811.1 ± 24.5 215.3 ± 8.27 51.1 ± 2.35 33.3 ± 1.09 36.3 ± 1.17 53.7 ± 1.64 17.9 ± 0.51 8.2 ± 0.34
13 4 36 4 10
CT, computed tomography; MU, monitor unit; MV, megavoltage; TLD, thermoluminescent dosimeters. a Applied to the dose average of the adrenals, gallbladder, heart, kidneys, muscle, oral mucosa, pancreas, small intestines, spleen, thymus, and uterus13
radiation therapy treatment and MV-CBCT dose measurements. Dose measurements were repeated twice.
Breast radiation therapy treatment A treatment plan for the left breast was developed according to department protocol. The breast radiation therapy treatment was planned with the XiO treatmentplanning system (Elekta CMS Software Inc, Stockholm, Sweden) to deliver 50 Gy to the target volume in 25 fractions. The plan consisted of opposed tangential 6 MV fields with 15-degree virtual wedges. A Siemens ONCOR linear accelerator (Siemens Medical Solutions, Erlangen, Germany) was used to deliver the radiation therapy treatment. Five fractions were delivered to the phantom per measurement. This ensured TLDs far from the treatment field received an adequate dose. The measured dose resulting from 5 fractions was then multiplied by 5 to calculate the entire treatment dose of 25 fractions.
Megavoltage cone-beam CT The MV-CBCT image acquisition parameters included 6-MV photons, 27.4 × 27.4 cm2 field-of-view, 256 × 256 reconstruction matrix, and 0.1 cm slice thickness. The phantom was scanned using a 60-monitor unit (MU) protocol to ensure distant organs received a measureable dose. Measured dose values were then scaled to Gy/MU and from this the dose for an 8-MU protocol, the lowest MU setting available, was calculated.
Effective dose calculations Effective dose as defined by the ICRP 103 was calculated as follows: E = ∑ wT ∑ WR DT;R T
R
ð1Þ
where wT is the tissue weighting factor for an individual organ (specified by ICRP 103,14; Table 1), wR is the
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Weekly Imaging
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Treatment
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where β is the ERR/Gy and γ is an exponent of attained age. The ERR/Gy model was applied to the Massachusetts tuberculosis fluoroscopy cohort, its extension cohort, and the New York acute postpartum mastitis cohort; parameters β and γ were then determined to be 0.68 and −1, respectively.13 The Massachusetts and New York cohorts received similar dose values (mean dose 0.7-3.8 Gy) to those investigated in this study. A 10-year latency period for radiation-induced secondary malignancy was utilized13; this is within the time period (5-14 years), where Clarke et al2 found an excess of contralateral breast cancers after breast radiation therapy.
This study illustrates the increase in dose to critical organs and target volumes when MV-CBCT is utilized for
e
where β is the EAR associated with age at exposure, θ and γ are constants obtained from fitting the model to specific cohorts, agex is the age at exposure, and age is the attained age. Preston et al13 provide values of 10, −0.05, and 1 for parameters β, θ, and γ, respectively, after fitting the model to the female atomic bomb life span study cohort, the Massachusetts tuberculosis fluoroscopy cohort, its extension cohort, and the Rochester infant thymic irradiation cohort. agey ERR = Gy = β × ; ð3Þ 50
Discussion
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EAR per 10;000 women−years−Gy = β × eθðage x−25Þ agey ; ð 2Þ 50
Organ dose measurements for a normalized MV-CBCT in units cGy/MU, a single 8-MU MV-CBCT, and standard tangential breast radiation therapy treatment measurements are shown in Table 1. The effective dose for the 8-MU and 60-MU MV-CBCT was 35.9 ± 0.2 mSv, and 269.1 ± 1.6 mSv, respectively. The cumulative dose to various organs from treatment with nil image verification, treatment plus weekly MVCBCT verification, and treatment plus daily MV-CBCT verification is illustrated in Figs 1 and 2. The cumulative dose to the contralateral breast from treatment with no image verification, treatment plus weekly MV-CBCT imaging, and treatment plus daily MV-CBCT imaging is 1.36 ± 0.08 Gy, 1.64 ± 0.08 Gy, and 2.73 ± 0.08 Gy, respectively. For women treated at age 50 years, the EAR per 10,000 women-years and the ERR are illustrated in Figs 3 and 4, respectively; risk uncertainty is of the order of 40%.13
Bo n
The risk of radiation-induced secondary malignancy in the contralateral breast was estimated using 2 models; excess absolute risk (EAR) and excess relative risk (ERR).13 These models were developed from work that examined breast cancer incidence associated with imaging and low therapeutic doses (mean dose 0.3-5.8 Gy).13
Results
St
Contralateral breast cancer risk estimation
The above risks were estimated for the following image verification schedules: standard tangential breast radiation therapy with no verification imaging and standard tangential breast radiation therapy plus weekly 8-MU MV-CBCT imaging (5 scans).
Lu ng
radiation weighting factor (wR = 1 for photons), and DT,R is the individual organ mean absorbed dose for radiation type R. For nonuniform irradiations such as CT scans, effective dose provides an estimate of the corresponding uniform whole-body dose that would result in equivalent stochastic detriment. The fractional distribution of active marrow proposed by a previous study16 was used to calculate the red bone marrow dose. Due to the limited number of places to position the TLDs, the dose to the red bone marrow was used to estimate the bone surface dose. To measure the radiation dose to the skin, TLDs were placed on the surface at the front and sides of the phantom in the head, chest, and pelvic regions. This quantity was calculated for the imaging component of the radiation therapy treatment only, as several issues have been raised questioning the validity of calculating effective dose for radiation therapy.7,17
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Total organ dose (Gy)
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Figure 1 Total organ dose from treatment with nil image verification (left column), treatment with weekly image verification (middle column), and treatment with daily image verification (right column). The contribution of the treatment, weekly and daily imaging to the total dose, is illustrated in gray, black, and white, respectively.
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MV-CBCT dose and breast cancer risk
0.40
1
Daily Imaging 0.9
Weekly Imaging
0.30
Excess relative risk
Total organ dose (Gy)
0.35
Treatment 0.25 0.20 0.15 0.10 0.05
0.8
0.7
0.6
Treatment plus no imaging
0.5
Treatment plus weekly imaging r
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Figure 2 Total organ dose from treatment with nil image verification (left column), treatment with weekly image verification (middle column), and treatment with daily image verification (right column). The contribution of the treatment, weekly and daily imaging, to the total dose is illustrated in gray, black, and white, respectively.
image verification. This is attributable to the CBCT distributing imaging dose over the entire image field-of-view. The dose to critical organs surrounding the treatment field from the radiation therapy treatment is attributable to scatter from beam modifiers and from within the phantom, and linear accelerator head leakage. The measured contralateral breast dose from a standard tangential breast radiation therapy treatment is comparable with that reported in other studies with similar treatment setups or protocols, ranging from 0.6 to 4 Gy.18,19 Two
9 8 7 6 5 4 3 2
Treatment plus no imaging
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Treatment plus weekly imaging
0 50
60
60
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Attained age (years)
ar
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G on
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Excess absolute risk per 10 000 Women - Years
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70
80
90
Attained age (years)
Figure 3 Excess absolute risk per 10,000 women-years of developing a radiation-induced secondary malignancy in the contralateral breast post breast radiation therapy treatment.
Figure 4 The excess relative risk of developing a radiationinduced secondary malignancy in the contralateral breast post breast radiation therapy treatment.
previous studies measured limited organ doses with a treatment-planning system simulation of a chest MVCBCT, but the current study is the first study to assess a variety of organ doses. The measured contralateral breast, lung, and heart dose values from this study for an 8 MU chest MV-CBCT were comparable with values obtained from the patient treatment-planning simulation studies, 0.03 Gy,11 0.066 Gy, and 0.069 Gy,12 respectively. Differences are attributable to this being a phantom study, whereas other studies were completed on patient treatment planning CTs. For comparison with other imaging modalities, the breast, lungs, and heart receive a dose of 1.07 cGy, 1.14 cGy, and 1.12 cGy from a MV fan-beam CT,20 and 2.5-5.1 cGy, 1.2-3.9 cGy, and 1.7-2.7 cGy from a kilovoltage (kV) CBCT acquired for breast radiation therapy setup.21 Effective dose for a chest MV-CBCT has not been published previously. For comparison, a chest kV-CBCT has an effective dose of 23.6 mSv22 and a breast kVCBCT has an effective dose of 19.4 mSv.23 This highlights the higher stochastic risk associated with this 8-MU MV-CBCT protocol. Effective dose and image quality are both dependent on the number of monitor units. It may be that other image modalities are more appropriate for image guidance protocols in breast radiation therapy than MV-CBCT, depending on the imaging detail required for this site. The MV-CBCT dose, as a fraction of total organ dose, is small for the ipsilateral breast; 0.5% for weekly image verification. However, MV-CBCT imaging significantly increases dose to organs in the immediate surrounding region of the target volume when compared with no imaging. For treatment plus weekly MV-CBCT imaging, MV-CBCT contributes 17% of the total dose received by the contralateral breast and 7% of the total dose received by the lungs.
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This additional low dose may increase the risk of secondary cancer to the contralateral breast. Concerns about the additional risk from low doses have previously been raised in regard to IMRT.24,25 IMRT has been established to improve target dose homogeneity and sparing of normal tissues in comparison with 3dimensional CRT; however, it increases the volume of tissue receiving low doses.26 These low-dose regions (less than 6 Gy) near the target volume have been found to have an increased risk of second malignancy.27 While we are not aware of any follow-up or cohort studies to date that have found an increase in radiation-induced second malignancies due to IMRT, numerous studies have estimated using models an increased risk.24,25 Nor are we aware of any studies to date with sufficiently long follow-up to assess whether increasing imaging dose leads to greater radiation-induced secondary malignancy risk. For women irradiated at age 50 years, weekly MVCBCT imaging was determined to increase the 10-year postirradiation ERR from 0.8 for treatment alone to 0.9. The 10-year postirradiation EAR increased from 4.7 to 5.6 per 10,000 women-years. A previous study determined the EAR per 10,000 women-years for women treated with surgery and breast radiation therapy and who survived 5 or more years was 5 (2-7; 95% confidence interval).18 For comparison, 5-10 year postirradiation EARs, estimated from the current study for women treated at age 50 years with breast radiation therapy and no MV-CBCT imaging, was determined to range from 4 to 5 (40% uncertainty), which agrees with the previous study. Furthermore, the risk estimates calculated above are for breast cancer treatments involving radiation therapy only; treatments involving concurrent hormone therapy or chemotherapy have been associated with a decreased risk of contralateral breast cancer.3,28 A limitation of this study was that the measurements were performed on a single size and shape anthropomorphic phantom, and hence the inter-patient variation seen in practice is not represented by these measurements. These differences may be minimal as only a weak relationship between dose and body-mass-index has been found.12 As the phantom is immobile the possible dosimetric variation in the treatment volume and surrounding organs due to respiratory motion29 will not be evident. Furthermore, the phantom's breasts sit upright on the chest wall and do not fall laterally with gravity, as a patient's breasts might; this may result in a higher contralateral measured dose in comparison with a typical patient due to the phantom's contralateral breast remaining closer to the edge of the treatment beam. The largest field-of-view was utilized for these measurements. In practice, the length of the CBCT could be reduced if verification of the breast position within the treatment field only is utilized. This in turn would reduce the additional dose delivered to various organs such as the liver, stomach, and thyroid, superior and inferior to the
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ipsilateral breast. The dose to organs superior and inferior to the ipsilateral breast measured in this study represent the highest dose and “worst case” risk estimates in relation to the field-of-view. Other approaches to reduce MV-CBCT dose, which were not available for this study, include reducing the MU,30 reducing the gantry arc or number of projection images (also known as cone-beam digital tomosynthesis),31 lowering the imaging beam energy,32 and utilizing improved detector technology33 and image reconstruction algorithms.34 Currently the benefits of image guided radiation therapy are unclear as no prospective randomized trials have been performed. There are several sources of uncertainty in the risk estimates utilized in this study due to inherent limitations in the epidemiologic data on which the EAR and ERR/Gy values are based.13 Radiation-induced cancer risk is dependent on several factors, including age at exposure, attained age, and gender35; these factors were included in the risk estimation models used. For the absorbed dose range investigated, radiation exposure is currently understood to increase the risk of cancer as a linear function of dose.35,36 This is based on atomic bomb survivor data, which is considered the best quantitative human data in the radiation exposure range of approximately 0.1-2.5 Gy. Previous studies have determined systematic setup errors of up to 1.7 mm with kV-CBCT,8,37 3.3 mm with EPI,8 and 2.9 mm for skin mark alignment37 for breast radiation therapy. This increase in accuracy should be weighed against the extra dose. For breast radiation therapy, MV-CBCT may not be the most optimal method to improve patient setup reproducibility due to the additional dose accrued by the patient, as illustrated in this study, as well as the extra time and resources to acquire and process the images. Furthermore, the isocenter for most breast patients is located within the ipsilateral breast, and for couch and gantry clearance the couch may need to be moved centrally, potentially introducing additional errors. The use of alternate or additional patient immobilization devices or imaging devices such as optical surface imaging,38 that acquire patient setup information before and during treatment, may be more effective for breast radiation therapy.
Conclusions This study provides total organ doses for a tangential breast radiation therapy treatment and a chest MV-CBCT. MV-CBCT imaging verification contributes 17% of the total contralateral breast dose for a treatment plus weekly imaging protocol, with a single 8-MU MV-CBCT delivering 0.5 Gy to the contralateral breast. For a woman irradiated at age 50 years, the 10-year postirradiation ERR was estimated to be 0.8 and 0.9 for treatment alone and treatment plus weekly MV-CBCT imaging, respectively.
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The 10-year postirradiation EAR was estimated to be 4.7 and 5.6 per 10,000 women-years. The relative difference in the risk between treatment with and without CBCT imaging presented in this study should be carefully considered even though the risk uncertainty is large. The dose and postirradiation risk increases, introduced by imaging verification protocols utilizing MV-CBCT in breast radiation therapy, must be taken into account when considering an image guidance protocol for breast radiation therapy.
Acknowledgments The authors wish to thank the Illawarra Cancer Therapy Centre for lending their anthropomorphic phantom. The author A.Q. wishes to acknowledge National Health and Medical Research Council grant 553012 for funding assistance and the Liverpool and Macarthur Cancer Therapy Centres’ trust funds for scholarship. The author P.M. wishes to acknowledge financial assistance from the NSW (New South Wales) Cancer Institute Clinical Leaders program. The authors gratefully thank Vikneswary Batumalai for planning help and Lee Collins for discussion and comments on secondary cancer risk calculations.
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31. Pang G, Bani-Hashemi A, Au P, et al. Megavoltage cone beam digital tomosynthesis (MV-CBDT) for image-guided radiotherapy: a clinical investigational system. Phys Med Biol. 2008;53:999-1013. 32. Faddegon BA, Wu V, Pouliot J, Gangadharan B, Bani-Hashemi A. Low dose megavoltage cone beam computed tomography with an unflattened 4 MV beam from a carbon target. Med Phys. 2008;35:5777-5786. 33. El-Mohri Y, Antonuk LE, Zhao Q, Choroszucha RB, Jiang H, Liu L. Low-dose megavoltage cone-beam CT imaging using thick, segmented scintillators. Phys Med Biol. 2011;56:1509-1527. 34. Li L, Xing Y, Chen Z, Zhang L, Kang K. A curve-filtered FDK (C-FDK) reconstruction algorithm for circular cone-beam CT. J Xray Sci Technol. 2011;19:355-371.
Practical Radiation Oncology: April-June 2013 35. National Research Council. BEIR, Health risks from exposure to low levels of ionizing radiation: BEIR VII Phase 2. Washington, DC: The National Academies Press. 2006. 36. Hall EJ, Henry S. Kaplan Distinguished Scientist Award 2003. The crooked shall be made straight; dose–response relationships for carcinogenesis. Int J Radiat Biol. 2004;80:327-337. 37. White EA, Cho J, Vallis KA, et al. Cone beam computed tomography guidance for setup of patients receiving accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2007;68: 547-554. 38. Djajaputra D, Li S. Real-time 3D surface-image-guided beam setup in radiotherapy of breast cancer. Med Phys. 2005;32:65-75.
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Original Report
Radiation dose and contralateral breast cancer risk associated with megavoltage cone-beam computed tomographic image verification in breast radiation therapy Alexandra Quinn BMedRadPhysAdv a,b,⁎, Lois Holloway PhD a,b,c , Eng-Siew Koh MBBS, FRANZCR b,d,e , Geoff Delaney MD, FRANZCR b,d,e,f , Sankar Arumugam PhD b , Gary Goozee MAppSc, MACPSEM b , Peter Metcalfe FACPSEM, FinstP a,b a
Centre for Medical Radiation Physics, University of Wollongong, Wollongong, NSW, Australia Liverpool and Macarthur Cancer Therapy Centres, NSW, Australia c School of Physics, University of Sydney, Sydney, NSW, Australia d Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia e Collaboration for Cancer Outcomes Research and Evaluation, Liverpool Hospital, Liverpool, NSW, Australia f School of Medicine, University of Western Sydney, Sydney, NSW, Australia b
Received 23 January 2012; revised 6 May 2012; accepted 8 May 2012
Abstract Purpose: To measure and compare organ doses from a standard tangential breast radiation therapy treatment (50 Gy delivered in 25 fractions) and a megavoltage cone-beam computed tomography (MV-CBCT), taken for weekly image verification, and assess the risk of radiation-induced contralateral breast cancer. Methods and Materials: Organ doses were measured with thermoluminescent dosimeters placed strategically within a female anthropomorphic phantom. The risk of radiation-induced secondary cancer of the contralateral breast was estimated from these values using excess absolute risk and excess relative risk models. Results: The effective dose from a MV-CBCT (8-monitor units) was 35.9 ± 0.2 mSv. Weekly MV-CBCT imaging verification contributes 0.5% and 17% to the total ipsilateral and contralateral breast dose, respectively. For a woman irradiated at age 50 years, the 10-year postirradiation excess relative risk was estimated to be 0.8 and 0.9 for treatment alone and treatment plus weekly MV-CBCT imaging, respectively. The 10-year postirradiation excess absolute risk was estimated to be 4.7 and 5.6 per 10,000 women-years.
Conflicts of interest: None. ⁎ Corresponding author. University of Wollongong, Centre for Medical Radiation Physics, Northfields Ave, Wollongong, NSW 2522, Australia. E-mail address: [email protected] (A. Quinn). 1879-8500/$ – see front matter © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2012.05.003
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Conclusions: The increased dose and consequent radiation-induced second cancer risk as calculated by this study introduced by the imaging verification protocols utilizing MV-CBCT in breast radiation therapy must be weighed against the benefits of more accurate treatment. As additional image verification becomes more common, it is important that data be collected in regard to long-term malignancy risk. © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction There are increasing numbers of breast cancer survivors1 due to significant increases in diagnosis and more effective treatment.2,3 Radiation therapy is a primary treatment for breast cancer; 83% of breast cancer patients will receive at least 1 course of radiation therapy during their cancer management.4 Long-term risks, such as radiation-induced secondary malignancies, while relatively uncommon, are a concern for this large population of long-surviving patients.2 Based on current data, the benefits of radiation therapy as adjuvant therapy outweigh the risks of radiation-induced secondary malignancies.5 However, any additional radiation, such as that from verification imaging dose, should be accurately quantified and examined as to the cost-benefit to the patient, especially when other imaging modalities such as electronic portal imaging devices exist that have lower radiation doses.6 The AAPM (American Association of Physicists in Medicine) Task Group 757 has addressed some of these issues by providing radiation dose data for various imaging modalities typically used in radiation therapy, as well as recommendations on how to estimate and reduce additional radiation dose to the patient. One image modality mentioned in this report, but for which there is limited patient organ dose information, is megavoltage cone-beam computed tomography (MV-CBCT). MV-CBCT utilizes the treatment beam to acquire a 3-dimensional image set of the patient, providing soft tissue information. For complex breast radiation therapy techniques, such as intensity modulated radiation therapy (IMRT), patient position verification based on soft tissue information has been found to reduce setup uncertainty in comparison with bony anatomy alignment with electronic portal imaging.8 Since the AAPM Task Group 75 report was published, a small number of studies providing dose values for various organs from MV-CBCT have been reported. One Monte Carlo study estimated the dose to patients from head and neck and pelvic MV-CBCT scans.9 The surface dose from a female chest MV-CBCT has been measured with thermoluminescent dosimeters (TLDs) and metal-oxide-semiconductor field-effect-transistor detectors.10 Two treatment-planning studies investigated the dose to limited organs from a simulated MV-CBCT on a treatment-planning CT.11,12 These treatment-planning studies were limited to organs within
the field-of-view of the treatment-planning CT and hence the effective dose and whole body stochastic effect could not be evaluated. The purpose of this study was to measure and compare organ doses from a standard tangential breast radiation therapy treatment and a MV-CBCT taken for image verification. The risk of radiation-induced secondary malignancies of the contralateral breast was estimated from these with an excess absolute risk and excess relative risk13 model.
Methods and materials Thermoluminescent dosimeter calibration Standard 3 × 3 × 0.9 mm3 lithium-fluoride TLD chips (TLD-100; Erlangen, Germany) were used. Individual chip calibration factors were established and used to correct for inter-chip variability within a batch. TLD chip sensitivity was established by irradiating batches of TLD chips to known doses within the expected range of MVCBCT and breast radiation therapy energies and doses. Only TLD chips with sensitivity ranging within ± 5% were selected for measurements. TLD chips were read with a Rialto NE TLD reader (NE Technology Ltd, Cambridge, UK) within 24 hours of irradiation.
Anthropomorphic phantom and thermoluminescent dosimeter placement A female anthropomorphic phantom (Radiology Support Devices, Long Beach, CA) with size B breast attachments was used. The phantom consists of 34 axial slices with slice thickness 2.5 cm and is composed of human tissue and bone equivalent material. Each slice contains a matrix of holes for TLD placement. Organs specified by the International Commission on Radiological Protection (ICRP) 10314 were selected for dose measurements. Organ locations within the phantom were determined with a full body CT scan of the phantom, the guidance of a previous study,15 and an experienced radiation oncologist. Two TLD chips were placed at each point location to reduce statistical error in the TLD measurements; TLD distribution is specified in Table 1. The same TLD positioning was utilized for both the breast
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Table 1 Tissue weighting factors and number of utilized thermoluminescent dosimeters in considered organs; organ and tissue doses for a megavoltage cone-beam computed tomography and a tangential breast radiation therapy treatment Organ or tissue
Bone marrow (red) Colon Lung Stomach Breasts Contralateral breast Ipsilateral breast Gonads (ovaries) Bladder Esophagus Liver Thyroid Bone surface Brain Salivary glands Skin Remainder Oral mucosa Thymus Heart Muscle Spleen Gallbladder Adrenals Kidneys Pancreas Small intestine Uterus
Tissue weighting factor 0.12 0.12 0.12 0.12 0.12
0.08 0.04 0.04 0.04 0.04 0.01 0.01 0.01 0.01 0.12 a
No. of TLDs
Absorbed dose (cGy) Single MV cone beam CT
Treatment
cGy/MU
8 MU
0.30 ± 0.005 0.04 ± 0.001 0.68 ± 0.005 0.92 ± 0.009
2.38 ± 0.036 0.30 ± 0.008 5.44 ± 0.038 7.34 ± 0.069
224.2 ± 6.90 16.5 ± 0.32 363.4 ± 7.15 327.2 ± 10.5
2 1 4 4 2 13 6 2 23
0.68 ± 0.012 0.68 ± 0.031 0.02 ± 0.001 0.02 ± 0.002 0.74 ± 0.015 0.84 ± 0.019 0.05 ± 0.002 0.30 ± 0.005 0.01 ± 0.001 0.02 ± 0.001 0.19 ± 0.003
5.47 ± 0.096 5.44 ± 0.248 0.17 ± 0.010 0.13 ± 0.017 5.88 ± 0.124 6.72 ± 0.156 0.38 ± 0.014 2.38 ± 0.036 0.08 ± 0.005 0.14 ± 0.005 1.53 ± 0.023
136.3 ± 7.91 5070.0 ± 142 8.8 ± 0.25 8.4 ± 0.11 81.1 ± 3.70 66.7 ± 1.36 28.3 ± 1.08 224.2 ± 6.90 8.7 ± 0.14 16.0 ± 0.62 583.0 ± 10.2
1 2 13 6 2 1 2 2 2 2 1
0.02 ± 0.002 0.59 ± 0.030 0.79 ± 0.014 0.36 ± 0.011 0.82 ± 0.033 0.89 ± 0.022 0.68 ± 0.014 0.72 ± 0.022 0.78 ± 0.022 0.05 ± 0.002 0.02 ± 0.001
0.17 ± 0.015 4.73 ± 0.240 6.35 ± 0.113 2.90 ± 0.087 6.58 ± 0.265 7.08 ± 0.175 5.45 ± 0.116 5.78 ± 0.178 6.26 ± 0.174 0.39 ± 0.012 0.15 ± 0.008
24.6 ± 0.59 72.7 ± 1.54 169.5 ± 2.42 811.1 ± 24.5 215.3 ± 8.27 51.1 ± 2.35 33.3 ± 1.09 36.3 ± 1.17 53.7 ± 1.64 17.9 ± 0.51 8.2 ± 0.34
13 4 36 4 10
CT, computed tomography; MU, monitor unit; MV, megavoltage; TLD, thermoluminescent dosimeters. a Applied to the dose average of the adrenals, gallbladder, heart, kidneys, muscle, oral mucosa, pancreas, small intestines, spleen, thymus, and uterus13
radiation therapy treatment and MV-CBCT dose measurements. Dose measurements were repeated twice.
Breast radiation therapy treatment A treatment plan for the left breast was developed according to department protocol. The breast radiation therapy treatment was planned with the XiO treatmentplanning system (Elekta CMS Software Inc, Stockholm, Sweden) to deliver 50 Gy to the target volume in 25 fractions. The plan consisted of opposed tangential 6 MV fields with 15-degree virtual wedges. A Siemens ONCOR linear accelerator (Siemens Medical Solutions, Erlangen, Germany) was used to deliver the radiation therapy treatment. Five fractions were delivered to the phantom per measurement. This ensured TLDs far from the treatment field received an adequate dose. The measured dose resulting from 5 fractions was then multiplied by 5 to calculate the entire treatment dose of 25 fractions.
Megavoltage cone-beam CT The MV-CBCT image acquisition parameters included 6-MV photons, 27.4 × 27.4 cm2 field-of-view, 256 × 256 reconstruction matrix, and 0.1 cm slice thickness. The phantom was scanned using a 60-monitor unit (MU) protocol to ensure distant organs received a measureable dose. Measured dose values were then scaled to Gy/MU and from this the dose for an 8-MU protocol, the lowest MU setting available, was calculated.
Effective dose calculations Effective dose as defined by the ICRP 103 was calculated as follows: E = ∑ wT ∑ WR DT;R T
R
ð1Þ
where wT is the tissue weighting factor for an individual organ (specified by ICRP 103,14; Table 1), wR is the
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where β is the ERR/Gy and γ is an exponent of attained age. The ERR/Gy model was applied to the Massachusetts tuberculosis fluoroscopy cohort, its extension cohort, and the New York acute postpartum mastitis cohort; parameters β and γ were then determined to be 0.68 and −1, respectively.13 The Massachusetts and New York cohorts received similar dose values (mean dose 0.7-3.8 Gy) to those investigated in this study. A 10-year latency period for radiation-induced secondary malignancy was utilized13; this is within the time period (5-14 years), where Clarke et al2 found an excess of contralateral breast cancers after breast radiation therapy.
This study illustrates the increase in dose to critical organs and target volumes when MV-CBCT is utilized for
e
where β is the EAR associated with age at exposure, θ and γ are constants obtained from fitting the model to specific cohorts, agex is the age at exposure, and age is the attained age. Preston et al13 provide values of 10, −0.05, and 1 for parameters β, θ, and γ, respectively, after fitting the model to the female atomic bomb life span study cohort, the Massachusetts tuberculosis fluoroscopy cohort, its extension cohort, and the Rochester infant thymic irradiation cohort. agey ERR = Gy = β × ; ð3Þ 50
Discussion
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EAR per 10;000 women−years−Gy = β × eθðage x−25Þ agey ; ð 2Þ 50
Organ dose measurements for a normalized MV-CBCT in units cGy/MU, a single 8-MU MV-CBCT, and standard tangential breast radiation therapy treatment measurements are shown in Table 1. The effective dose for the 8-MU and 60-MU MV-CBCT was 35.9 ± 0.2 mSv, and 269.1 ± 1.6 mSv, respectively. The cumulative dose to various organs from treatment with nil image verification, treatment plus weekly MVCBCT verification, and treatment plus daily MV-CBCT verification is illustrated in Figs 1 and 2. The cumulative dose to the contralateral breast from treatment with no image verification, treatment plus weekly MV-CBCT imaging, and treatment plus daily MV-CBCT imaging is 1.36 ± 0.08 Gy, 1.64 ± 0.08 Gy, and 2.73 ± 0.08 Gy, respectively. For women treated at age 50 years, the EAR per 10,000 women-years and the ERR are illustrated in Figs 3 and 4, respectively; risk uncertainty is of the order of 40%.13
Bo n
The risk of radiation-induced secondary malignancy in the contralateral breast was estimated using 2 models; excess absolute risk (EAR) and excess relative risk (ERR).13 These models were developed from work that examined breast cancer incidence associated with imaging and low therapeutic doses (mean dose 0.3-5.8 Gy).13
Results
St
Contralateral breast cancer risk estimation
The above risks were estimated for the following image verification schedules: standard tangential breast radiation therapy with no verification imaging and standard tangential breast radiation therapy plus weekly 8-MU MV-CBCT imaging (5 scans).
Lu ng
radiation weighting factor (wR = 1 for photons), and DT,R is the individual organ mean absorbed dose for radiation type R. For nonuniform irradiations such as CT scans, effective dose provides an estimate of the corresponding uniform whole-body dose that would result in equivalent stochastic detriment. The fractional distribution of active marrow proposed by a previous study16 was used to calculate the red bone marrow dose. Due to the limited number of places to position the TLDs, the dose to the red bone marrow was used to estimate the bone surface dose. To measure the radiation dose to the skin, TLDs were placed on the surface at the front and sides of the phantom in the head, chest, and pelvic regions. This quantity was calculated for the imaging component of the radiation therapy treatment only, as several issues have been raised questioning the validity of calculating effective dose for radiation therapy.7,17
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Figure 1 Total organ dose from treatment with nil image verification (left column), treatment with weekly image verification (middle column), and treatment with daily image verification (right column). The contribution of the treatment, weekly and daily imaging to the total dose, is illustrated in gray, black, and white, respectively.
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0.40
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Weekly Imaging
0.30
Excess relative risk
Total organ dose (Gy)
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Treatment 0.25 0.20 0.15 0.10 0.05
0.8
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0.6
Treatment plus no imaging
0.5
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ad
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Figure 2 Total organ dose from treatment with nil image verification (left column), treatment with weekly image verification (middle column), and treatment with daily image verification (right column). The contribution of the treatment, weekly and daily imaging, to the total dose is illustrated in gray, black, and white, respectively.
image verification. This is attributable to the CBCT distributing imaging dose over the entire image field-of-view. The dose to critical organs surrounding the treatment field from the radiation therapy treatment is attributable to scatter from beam modifiers and from within the phantom, and linear accelerator head leakage. The measured contralateral breast dose from a standard tangential breast radiation therapy treatment is comparable with that reported in other studies with similar treatment setups or protocols, ranging from 0.6 to 4 Gy.18,19 Two
9 8 7 6 5 4 3 2
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Figure 3 Excess absolute risk per 10,000 women-years of developing a radiation-induced secondary malignancy in the contralateral breast post breast radiation therapy treatment.
Figure 4 The excess relative risk of developing a radiationinduced secondary malignancy in the contralateral breast post breast radiation therapy treatment.
previous studies measured limited organ doses with a treatment-planning system simulation of a chest MVCBCT, but the current study is the first study to assess a variety of organ doses. The measured contralateral breast, lung, and heart dose values from this study for an 8 MU chest MV-CBCT were comparable with values obtained from the patient treatment-planning simulation studies, 0.03 Gy,11 0.066 Gy, and 0.069 Gy,12 respectively. Differences are attributable to this being a phantom study, whereas other studies were completed on patient treatment planning CTs. For comparison with other imaging modalities, the breast, lungs, and heart receive a dose of 1.07 cGy, 1.14 cGy, and 1.12 cGy from a MV fan-beam CT,20 and 2.5-5.1 cGy, 1.2-3.9 cGy, and 1.7-2.7 cGy from a kilovoltage (kV) CBCT acquired for breast radiation therapy setup.21 Effective dose for a chest MV-CBCT has not been published previously. For comparison, a chest kV-CBCT has an effective dose of 23.6 mSv22 and a breast kVCBCT has an effective dose of 19.4 mSv.23 This highlights the higher stochastic risk associated with this 8-MU MV-CBCT protocol. Effective dose and image quality are both dependent on the number of monitor units. It may be that other image modalities are more appropriate for image guidance protocols in breast radiation therapy than MV-CBCT, depending on the imaging detail required for this site. The MV-CBCT dose, as a fraction of total organ dose, is small for the ipsilateral breast; 0.5% for weekly image verification. However, MV-CBCT imaging significantly increases dose to organs in the immediate surrounding region of the target volume when compared with no imaging. For treatment plus weekly MV-CBCT imaging, MV-CBCT contributes 17% of the total dose received by the contralateral breast and 7% of the total dose received by the lungs.
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This additional low dose may increase the risk of secondary cancer to the contralateral breast. Concerns about the additional risk from low doses have previously been raised in regard to IMRT.24,25 IMRT has been established to improve target dose homogeneity and sparing of normal tissues in comparison with 3dimensional CRT; however, it increases the volume of tissue receiving low doses.26 These low-dose regions (less than 6 Gy) near the target volume have been found to have an increased risk of second malignancy.27 While we are not aware of any follow-up or cohort studies to date that have found an increase in radiation-induced second malignancies due to IMRT, numerous studies have estimated using models an increased risk.24,25 Nor are we aware of any studies to date with sufficiently long follow-up to assess whether increasing imaging dose leads to greater radiation-induced secondary malignancy risk. For women irradiated at age 50 years, weekly MVCBCT imaging was determined to increase the 10-year postirradiation ERR from 0.8 for treatment alone to 0.9. The 10-year postirradiation EAR increased from 4.7 to 5.6 per 10,000 women-years. A previous study determined the EAR per 10,000 women-years for women treated with surgery and breast radiation therapy and who survived 5 or more years was 5 (2-7; 95% confidence interval).18 For comparison, 5-10 year postirradiation EARs, estimated from the current study for women treated at age 50 years with breast radiation therapy and no MV-CBCT imaging, was determined to range from 4 to 5 (40% uncertainty), which agrees with the previous study. Furthermore, the risk estimates calculated above are for breast cancer treatments involving radiation therapy only; treatments involving concurrent hormone therapy or chemotherapy have been associated with a decreased risk of contralateral breast cancer.3,28 A limitation of this study was that the measurements were performed on a single size and shape anthropomorphic phantom, and hence the inter-patient variation seen in practice is not represented by these measurements. These differences may be minimal as only a weak relationship between dose and body-mass-index has been found.12 As the phantom is immobile the possible dosimetric variation in the treatment volume and surrounding organs due to respiratory motion29 will not be evident. Furthermore, the phantom's breasts sit upright on the chest wall and do not fall laterally with gravity, as a patient's breasts might; this may result in a higher contralateral measured dose in comparison with a typical patient due to the phantom's contralateral breast remaining closer to the edge of the treatment beam. The largest field-of-view was utilized for these measurements. In practice, the length of the CBCT could be reduced if verification of the breast position within the treatment field only is utilized. This in turn would reduce the additional dose delivered to various organs such as the liver, stomach, and thyroid, superior and inferior to the
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ipsilateral breast. The dose to organs superior and inferior to the ipsilateral breast measured in this study represent the highest dose and “worst case” risk estimates in relation to the field-of-view. Other approaches to reduce MV-CBCT dose, which were not available for this study, include reducing the MU,30 reducing the gantry arc or number of projection images (also known as cone-beam digital tomosynthesis),31 lowering the imaging beam energy,32 and utilizing improved detector technology33 and image reconstruction algorithms.34 Currently the benefits of image guided radiation therapy are unclear as no prospective randomized trials have been performed. There are several sources of uncertainty in the risk estimates utilized in this study due to inherent limitations in the epidemiologic data on which the EAR and ERR/Gy values are based.13 Radiation-induced cancer risk is dependent on several factors, including age at exposure, attained age, and gender35; these factors were included in the risk estimation models used. For the absorbed dose range investigated, radiation exposure is currently understood to increase the risk of cancer as a linear function of dose.35,36 This is based on atomic bomb survivor data, which is considered the best quantitative human data in the radiation exposure range of approximately 0.1-2.5 Gy. Previous studies have determined systematic setup errors of up to 1.7 mm with kV-CBCT,8,37 3.3 mm with EPI,8 and 2.9 mm for skin mark alignment37 for breast radiation therapy. This increase in accuracy should be weighed against the extra dose. For breast radiation therapy, MV-CBCT may not be the most optimal method to improve patient setup reproducibility due to the additional dose accrued by the patient, as illustrated in this study, as well as the extra time and resources to acquire and process the images. Furthermore, the isocenter for most breast patients is located within the ipsilateral breast, and for couch and gantry clearance the couch may need to be moved centrally, potentially introducing additional errors. The use of alternate or additional patient immobilization devices or imaging devices such as optical surface imaging,38 that acquire patient setup information before and during treatment, may be more effective for breast radiation therapy.
Conclusions This study provides total organ doses for a tangential breast radiation therapy treatment and a chest MV-CBCT. MV-CBCT imaging verification contributes 17% of the total contralateral breast dose for a treatment plus weekly imaging protocol, with a single 8-MU MV-CBCT delivering 0.5 Gy to the contralateral breast. For a woman irradiated at age 50 years, the 10-year postirradiation ERR was estimated to be 0.8 and 0.9 for treatment alone and treatment plus weekly MV-CBCT imaging, respectively.
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The 10-year postirradiation EAR was estimated to be 4.7 and 5.6 per 10,000 women-years. The relative difference in the risk between treatment with and without CBCT imaging presented in this study should be carefully considered even though the risk uncertainty is large. The dose and postirradiation risk increases, introduced by imaging verification protocols utilizing MV-CBCT in breast radiation therapy, must be taken into account when considering an image guidance protocol for breast radiation therapy.
Acknowledgments The authors wish to thank the Illawarra Cancer Therapy Centre for lending their anthropomorphic phantom. The author A.Q. wishes to acknowledge National Health and Medical Research Council grant 553012 for funding assistance and the Liverpool and Macarthur Cancer Therapy Centres’ trust funds for scholarship. The author P.M. wishes to acknowledge financial assistance from the NSW (New South Wales) Cancer Institute Clinical Leaders program. The authors gratefully thank Vikneswary Batumalai for planning help and Lee Collins for discussion and comments on secondary cancer risk calculations.
References 1. American Cancer Society. Breast Cancer Facts & Figures 2009– 2010. Atlanta, GA: American Cancer Society, Inc. 2009. 2. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366:2087-2106. 3. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687-1717. 4. Delaney G, Barton M, Jacob S. Estimation of an optimal radiotherapy utilization rate for breast carcinoma. Cancer. 2003;98:1977-1986. 5. Roychoudhuri R, Evans H, Robinson D, Møller H. Radiationinduced malignancies following radiotherapy for breast cancer. Br J Cancer. 2004;91:868-872. 6. Harrison RM, Wilkinson M, Rawlings DJ, Moore M. Doses to critical organs following radiotherapy and concomitant imaging of the larynx and breast. Br J Radiol. 2007;80:989-995. 7. Murphy MJ, Balter J, Balter S, et al. The management of imaging dose during image-guided radiotherapy: report of the AAPM Task Group 75. Med Phys. 2007;34:4041-4063. 8. Topolnjak R, Sonke JJ, Nijkamp J, et al. Breast patient setup error assessment: comparison of electronic portal image devices and conebeam computed tomography matching results. Int J Radiat Oncol Biol Phys. 2010;78:1235-1243. 9. Gu J, Bednarz B, Xu XG, Jiang SB. Assessment of patient organ doses and effective doses using the VIP-Man adult male phantom for selected cone-beam CT imaging procedures during image guided radiation therapy. Radiat Prot Dosimetry. 2008;131:431-443.
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