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Original Article

Progress in Medical Physics 2018; 29(2): 73-80

Published online June 30, 2018 https://doi.org/10.14316/pmp.2018.29.2.73

Copyright © Korean Society of Medical Physics.

Dosimetric Plan Comparison of Accelerated Partial Breast Irradiation (APBI) Using CyberKnife

Chang Yeol Lee*, Woo Chul Kim*, Hun Jeong Kim*, Jeongshim Lee*, Seungwoo Park, Hyun Do Huh*

*Department of Radiation Oncology, College of Medicine, Inha University, Incheon, Research Institute of Radiological and Medical Sciences, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

Correspondence to:Hyun Do Huh (hyundohuh@gmail.com) Tel: 82-32-890-3073 Fax: 82-32-890-3082

Received: June 14, 2018; Revised: June 23, 2018; Accepted: June 23, 2018

Accelerated partial breast irradiation (APBI) is a new treatment delivery technique that decreases overall treatment time by using higher fractional doses than conventional fractionation. Here, a quantitative analysis study of CyberKnife-based APBI was performed on 10 patients with left-sided breast cancer who had already finished conventional treatment at the Inha University Hospital. Dosimetric parameters for four kinds of treatment plans (3D-CRT, IMRT, VMAT, and CyberKnife) were analyzed and compared with constraints in the NSABP B39/RTOG 0413 protocol and a published CyberKnife-based APBI study. For the 10 patients recruited in this study, all the dosimetric parameters, including target coverage and doses to normal structures, met the NSABP B39/RTOG 0413 protocol. Compared with other treatment plans, a more conformal dose to the target and better dose sparing of critical structures were observed in CyberKnife plans. Accelerated partial breast irradiation via CyberKnife is a suitable treatment delivery technique for partial breast irradiation and offers improvements over external beam APBI techniques.

KeywordsAPBI, Cyberknife, Treatment planning

Breast-conserving therapy (BCT) is the preferred treatment for early-stage breast cancer, and numerous published studies have shown that equivalent overall survival between patients who received breast-conserving surgery with whole breast irradiation (WBI) and patients treated by mastectomy alone. These studies demonstrate a 70% reduction in local recurrence, with the addition of adjuvant radiation after breast-conserving surgery.1,2) However, researchers have estimated that up to 25% of patients have not received adjuvant radiation therapy after breast conservation surgery.3) Prolonged treatment time, cost, distance to treatment facilities, and patient inconvenience have been implicated as possible deterrents to BCT.4,5)

Accelerated partial breast irradiation (APBI) is a new treatment delivery technique that decreased overall treatment time by using higher fractional doses than conventional fractionation. As opposed to whole breast irradiation, the dose is only given to the resection volume. Various techniques have been tried and complete reviews of APBI techniques can be found in the literature.6,7)

Applying to three-dimensional conformal radiation therapy (3D-CRT) and the NASBP B-39/RTOG0413 dose guidelines, Hepel et al.8) found a severe late toxicity in six of 60 patients who were treated with APBI. Recht et al.9) observed a higher risk of pneumonitis in patients with APBI who were treated with 3D-CRT. In other to reduce the dose to organs at risk (OAR), other treatment modalities have been used for APBI, including intensity modulated radiation therapy (IMRT), tomotherapy, and proton therapy. IMRT showed improved ipsilateral breast and other normal tissue dose sparing compared with 3D-CRT, with very low acute toxicity.10) Tomotherapy also reduced the dose to ipsilateral breast tissue, but at the cost of considerable increases in lung and heart doses. Protons have proven dosimetrically superior to all these techniques, but their availability is limited to a few centers globally.11)

A frameless robotic stereotactic radiosurgery system, the CyberKnife (Accuray Incorporated, Sunnyvale, CA, USA) provides image-guidance for the continuous tracking of target motion during respiration and patient movement. In the context of APBI, the Cyberknife could spare non-target breast tissue volume (NTBTV) more efficiently and potentially, which allows more agreeable cosmetic outcomes due to the combination of non-coplanar fields with tracking of the target volume. Indeed, researchers at the University of Texas Southwestern Medical found that APBI treatment plans achieved highly conformal target coverage with sparing doses to OAR, relative to 3D-CRT plans.12) Fox Chase’s treatment planning study has come to a similar conclusion as improving the boost dose distribution produced by CyberKnife.13) Here, a quantitative analysis study of CyberKnife-based APBI was performed on 10 patients with left-sided breast cancer who had already finished conventional treatment at the Inha University Hospital.

1. Patient selection

After Institutional Review Board (IRB) approval was obtained, 10 previously treated patients with left-sided breast cancer were selected for our retrospective study. Patients for CyberKnife-based APBI were selected over 50 years of age with stage I and II histologically-confirmed invasive non-lobular carcinoma or ductal carcinoma in situ (DCIS). All patients were treated with 50.4 Gy in 28 fractions, in a conventional fractionation. Further patient details are listed in Table 1.

2. Acquisition and definition of treatment volumes

A radiotherapy treatment planning CT scan was acquired for each patient. Patients underwent standard CT simulation at 2.5 mm slice spacing, in the supine position, not using a breast board. The gross tumor volume (GTV) was identified on the planning CT based on clear visualization and/or with the help of surgical clips. The clinical target volume (CTV) was obtained by a uniform 10 mm expansion of the GTV. The planning target volume (PTV) was delineated as the CTV expanded by a margin of 2 mm, to account for setup uncertainties. All plans were calculated for each patient using same PTV margin for technique comparison purposes. This comparison allowed us to evaluate the dosimetric characteristics of both planning systems at the same target volume. The CTV and PTV were limited to 3 mm from the skin surface and the chest wall, and lungs were not included in the PTV and CTV volumes. The OAR considered in this study were ipsilateral, contralateral breast, ipsilateral, contralateral lung, heart, thyroid, chest wall, and skin.

3. Delineation and treatment planning

The CT images were exported to Eclipse treatment planning system (Version 8.6) and MultiPlan treatment planning system (Version 2.2.0). The Phase III NSABP B39/RTOG 0413 partial breast protocol was followed for structure delineation and planning. The structures contoured for planning were the lumpectomy cavity or GTV, CTV, PTV, ipsilateral, contralateral breast, ipsilateral, contralateral lung, and heart. The eclipse-planned technique were 3DCRT, IMRT, and volumetric modulated arc therapy (VMAT). The 3D-CRT and IMRT plans were generated using a 5-field and 4-field coplanar technique, respectively. The VMAT plans were generated using RapidArc with anisotropic analytical algorithm (AAA). A double partial arc of 180° to 200° around the treated breast was used. The CyberKnife plans were generated using the iterative optimization mode to achieve the optimal dose to the target and normal structures. We used the fiducial marker tracking method. Prior to treatment, four 2-mm gold fiducials were implanted around the lumpectomy site under ultrasound guidance by a single board-certified radiologist. Depending on the size of the tumor, 1–2 fixed collimator ranging from 10 to 15 mm were chosen. Approximately, 95% of the PTV was to receive 100% of the prescription dose. All plans were generated to deliver 30 Gy in five fractions to the PTV over consecutive days.

4. Dosimetric parameters for plan comparison

For all treatment plans, dosimetric parameters calculated for the OARs are listed in Table 2. Here V30Gy, V15Gy, V9Gy, and V1.5Gy represent the percentage volumes of the normal organs receiving 30 Gy, 15 Gy, 9 Gy, and 1.5 Gy doses, respectively. Dmax is the maximum dose received by 1% of the evaluated OAR volumes. The dose conformity index (CI) for each plan was also calculated based on the Radiation Therapy Oncology Group (RTOG) definition14): CIRTOG=VRI/TV

where VRI=100% reference isodose volume (the volume receiving 100% prescription dose) and TV=target volume.

For the purpose of this study, cumulative dose-volume histograms of the normal structures were used for observation. Dosimetric parameters during these four treatment plans (3D-CRT, IMRT, VMAT, and CyberKnife) were analyzed and compared to constraints in the NSABP B39/RTOG 0413 protocol and a published CyberKnife-based APBI study. The total MUs for all plans were calculated and analyzed.

For the 10 patients recruited in this study, all the dosimetric parameters, including target coverage and doses to normal structures, met the NSABP B39/RTOG 0413 protocol, except for the contralateral breast maximum dose constraint as shown in Table 3. The PTV coverage requirement in the protocol is V90%>90%, which means that the percentage volume receiving 90% of the prescription dose should be greater than 90%. In our study, the mean percentage volume covering 100% of the prescription dose was 96.5±0.7%, which was more conformal than the target dose required in the protocol. The average CI for all the plans was 1.2±0.1%. The mean V15 Gy and mean V30 Gy to the ipsilatearal breast were 24.0±12.9% and 10.0±6.6%, which were well below 60% and 35% of the total volume, as required in the protocol. The maximum dose to the contralateral breast was relatively difficult to meet, depending on the distance between the tumor and the contralateral breast. The maximum doses to the contralateral breast for all 10 patients varied from 1.0 Gy to 8.0 Gy. The mean V1.5 Gy and mean V9 Gy to the contralateral and ipsilateral lungs were 9.0±5.7% and 3.0±2.6%, respectively. The means of V1.5 Gy to the heart was 23.0±10.6%. The CyberKnife plan was designed to deliver a multiple, non-isocentric, noncoplanar beam set. For this reason, the CyberKnife plan is more likely to pass through the contralateral breast than other plan techniques. The CyberKnife has the function of arbitrarily limiting the beam intersection to the tumor or OAR. If this function is used well without reducing target coverage, it may be possible to control maximum doses of contralateral breast.

We also compared our planning results to the published data from the studies of Olusola et al. and Sndra et al., which followed a similar protocol. We extracted all the corresponding dosimetric parameters for our 10 patients and compared these parameters to the data of Olusola et al. and Sndra et al. as shown in Table 4. Dosimetric data from CyberKnife studies were very close for the ipsilateral and contralateral breast and the ipsilateral and contralateral lungs. However, in our planning study, the mean V1.5 Gy doses to the heart were lower than those of the published data.

Our quantitative analysis study results is superior to the previously published work from Xu et al.,15) who showed the feasibility of using the CyberKnife for APBI. Their work proposed the dosimetric comparison of treatment plans that were calculated for 14 patients to previously published results obtained using 3D-CRT and IMRT. However, the results were somewhat limited because the authors compared their planning results to published data that was based on IMRT and 3D-CRT. Using different plans calculated for the same patients, we were able to compare mean DVHs for a better evaluation of the differences between techniques.

Table 5 shows mean dosimetric data computed for each treatment technique, and the corresponding mean DVHs are displayed in Fig. 1 for all treatment techniques. Dosimetric data for the contralateral breast and contralateral lung between techniques are very similar. In contrast, as shown in Fig. 1a, 1c, 1e, and 1f, DVHs of theses OARs show significant differences between techniques. These differences could relate to the more conformal beam arrangement in CyberKnife treatment, since the beams could enter the patient body from many angles. Significant differences were found between CyberKnife and all other techniques for the volumes receiving 15 Gy (V15 Gy) and 25 Gy (V25 Gy) of the ipsilateral breast and chest wall. Also, significant differences in the volume of the heart and ipsilateral lung receiving less than 5 Gy were observed.

The mean total MUs and standard deviations are 12138±3121 for CyberKnife plans, 749.3±32.7 for 3D-CRT plans, 1284.6±181.8 for IMRT plans, and 2432.5±1580.8 VMAT plans. The total MU with 3D-CRT plans was significantly lower than that of IMRT (mean total MU reduction ratio of 41.7%), VMAT (mean total MU reduction ratio of 69.2%), and CyberKnife (mean total MU reduction ratio of 93.8%) plans. Using the CyberKnife system with fixed collimator, treatment time including patient set-up on treatment couch was approximately 60 min, with a range from ~ 40 min to ~ 90 min. The longer time (90 min) was limited to the initial treatments and was a consequence of the inexperience of the team, especially in the patient setup and fiducial alignment phase. In general, larger breasts were associated with increased mobility, requiring longer patient set-up time. Time is important for the efficiency of treatment, but it is more meaningful when accuracy is involved. Although the treatment time of the CyberKnife is longer than other plan techniques, the PTV margin is unnecessary because the CyberKnife is tracked target volume considering the respiration of the patient. Therefore, the CyberKnife plan can save NTBTV and improve the accuracy of treatment over other plan techniques.

For a fairer comparison, it would have been interesting to compute doses using the same algorithm for each of the two modalities. However, we believe that the results obtained on NTBTV are too important to be a result of the dose calculation algorithm. It would also be interesting to calculate dose distributions on four-dimensional computed tomography (4DCT), to further investigate the benefit of tracking. Unfortunately, 4DCTs were not available for the selected patients.

Using Synchrony to track respiratory motions could reduce PTV margins and thus reduce the dose delivered to the NTBTV. However, the fiducial markers must follow the target volume shift inside the patient. Titanium surgical clips are used for delineating the excision volume after surgery. Surgical clip tracking has the advantage of not requiring additional implantation of fiducial markers. Implantation of fiducial markers is an additional invasive act for a patient. If these clips are visible in CyberKnife’s tracking system, the implantation of fiducial markers is no longer necessary. On the other hand, there may be no surgical clip depending on the surgery protocol of institution.

The CyberKnife does not require the extra margin to compensate for treatment set-up and breathing motion. As such, we believe that the steep dose gradients that are characteristic of CyberKnife APBI will allow more than acceptable cosmetic results and low toxicity over the long-term.

For the 10 patients who were recruited in this study, all the dosimetric parameters, including target coverage, and doses to normal structures, met the NSABP B39/RTOG 0413 protocol. Compared to other treatment plans, a more conformal dose to the target and better dose sparing of critical structures were observed in CyberKnife plans. Accelerated partial breast irradiation via CyberKnife is a suitable tretment delivery technique for partial breast irradiation and offers improvements over external beam APBI techniques.

Patient and tumor characteristics for the ten patients with ten treated tumors.

Characteristic Value
Age (years)
 Mean 60
 Range 50~78
Tumor type
 DCIS 0
 IDC 10
Tumor stage
 Tis 0
 T1a 1
 T1b 2
 T1c 3
 T2 4
GTV (cm3)
 Mean 6.4
 Range 3.5~11.2
PTV (cm3)
 Mean 37.7
 Range 21.3~65.1
Tumor laterality
 Right 0
 Left 10
Quadrant
 UOQ 6
 UIQ 3
 Central 1
 LOQ 0
 LIQ 0

IDC, invasive ductal carcinoma; DCIS, ductal carcinoma in situ; UOQ, upper outer quadrant; UIQ, upper inner quadrant; LIQ, lower inner quadrant.

Constraints given by the NSABP B39/RTOG 0413 protocol for patients treated with CyberKnife SAPBI.

Structure Constraint
Ipsilateral breast V30 Gy<35%
V15 Gy<60%
Contralateral breast Dmax<1 Gy
Ipsilateral lung V9 Gy<15%
Contralateral lung V1.5 Gy<15%
Heart (left breast) V1.5 Gy<40%
Heart (right breast) V1.5 Gy<5%
Thyroid Dmax<1 Gy
Skin Dmax<36 Gy
Chest wall Dmax<36 Gy

SAPBI, stereotactic accelerated partial breast irradiation; NSABP, National Surgical Adjuvant Breast and Bowel Project; RTOG, Radiation Therapy Oncology Group.

Dosimetric parmeters from plans based on the NSABP B39/RTOG 0413 protocol.

Structure and dosimetric parameters NSABP B39/RTOG 0413 Protocol Min (%) Max (%) Mean (%) Std (%)
Ipsilateral breast V30 Gy<35% 2 22 10 6.6
V15 Gy<60% 5 48 24 12.9
Contralateral breast Dmax<1 Gy 1 Gy 8 Gy 3 Gy 3.1 Gy
Ipsilateral lung V9 Gy<15% 0 9 3 2.6
Contralateral lung V1.5 Gy<15% 0 20 9 5.7
Heart (left breast) V1.5 Gy<40% 4 36 23 10.6
Thyroid Dmax<1 Gy 0 Gy 1.5 Gy 1 Gy 0.2 Gy
Skin Dmax<36 Gy 29 Gy 34 Gy 31 Gy 1.5 Gy
Chest wall Dmax<36 Gy 23 Gy 35 Gy 31 Gy 3.2 Gy
Coverage of PTV >90% 95 97.6 96.5 0.7
CI 1.1 1.35 1.2 0.1

Comparison of our dosimetric parameters to other CyberKnife studies.

Structure and dosimetric parameters CyberKnife (mean, range) Olusola et al (mean, range) Sndra et al (mean, range)
Ipsilateral breast 10%, 2–22% 14%, 3–26% 11%, 8–13%
24%, 5–48% 31%, 8–58% 23%, 16–30%
Contralateral breast 3 Gy, 1–8 Gy 3 Gy, 0–11 Gy 1 Gy, 1–2 Gy
Ipsilateral lung 3%, 0–9% 3%, 0–17% 5%, 0–10%
Contralateral lung 9%, 0–20% 8%, 0–21% 6%, 2–10%
Heart (left breast) 23%, 4–36% 31%, 7–43% 40%, 25–54%
Heart (right breast) NA 18%, 0–37% NA
Thyroid <1 Gy, 0–1.5 Gy <1 Gy, 0–1.4 Gy <1 Gy, 0–1 Gy
Skin 31 Gy, 29–34 Gy 32 Gy, 28–36 Gy 33 Gy
Chest wall 31 Gy, 23–35 Gy 26 Gy, 13–33 Gy 30 Gy

Comparison of our dosimetric parameters to 3D-CRT, IMRT, and VMAT plan.

Structure and dosimetric parameters Constraint CyberKnife (mean, range)
Ipsilateral breast V30 Gy<35% 10%, 2–22%
V15 Gy<60% 24%, 5–48%
Contralateral breast Dmax<1 Gy 3 Gy, 1–8 Gy
Ipsilateral lung V9 Gy<15% 3%, 0–9%
Contralateral lung V1.5 Gy<15% 9%, 0–20%
Heart (left breast) V1.5 Gy<40% 23%, 4–36%
Thyroid Dmax<1 Gy <1 Gy, 0–1.5 Gy
Skin Dmax<36 Gy 31 Gy, 29–34 Gy
Chest wall Dmax<36 Gy 31 Gy, 23–35 Gy
CI 1.2
MU 12138

Structure and dosimetric parameters 3DCRT (mean, range) IMRT (mean, range) VMAT (mean, range)

Ipsilateral breast 16%, 4–33% 12%, 5–24% 12%, 2–25%
33%, 9–67% 33%, 8–59% 25%, 5–57%
Contralateral breast 3 Gy, 0–12 Gy 5 Gy, 3–13 Gy 2 Gy, 2–5 Gy
Ipsilateral lung 8%, 1–12% 2%, 0–9% 6%, 0–14%
Contralateral lung 26%, 17–36% 10%, 0–23% 13%, 1–41%
Heart (left breast) 58%, 32–94% 29%, 11–65% 43%, 28–59%
Thyroid <1 Gy, 0–0.1 Gy <1 Gy, 0–0.1 Gy <1 Gy, 0–0.1 Gy
Skin 30 Gy, 27–32 Gy 31 Gy, 29–33 Gy 31 Gy, 26–36 Gy
Chest wall 31 Gy, 21–36 Gy 30 Gy, 10–33 Gy 32 Gy, 19–38 Gy
CI 1.8 1.3 1.3
MU 749 1285 2433
  1. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, and Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-41.
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  2. Van Dongen JA, Voogd AC, Fentiman IS, Legrand C, Sylvester RJ, and Tong D, et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 2000;92:1143-50.
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  3. Nattinger AB, et al. Relation between appropriateness of primary therapy for earlystage breast carcinoma and increased use of breast-conserving surgery. Lancet 2000;356:1148-1153.
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  4. Legorreta AP, Liu X, and Parker RG. Examining the use of breast-conserving treatment for women with breast cancer in a managed care environment. Am J Clin Oncol 2000;23:438-41.
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  5. Arthur DW, and Vicini FA. Accelerated partial breast irradiation as a part of breast conservation therapy. J Clin Oncol 2005;23:1726-35.
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  6. Vicini FA et al. A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer. Philadelphia, PA: Radiation Therapy Oncology Group 2005. protocol #0413.
  7. Arthur DW, and Vicini FA. Accelerated partial breast irradiation as a part of breast conservation therapy. J Clin Oncol 2005;23:1726-1735.
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  8. Hepel JT, Tokita M, and MacAusland SG, et al. Toxicity of three-dimensional conformal radiotherapy for accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2009;75:1290-96.
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  9. Recht A, Ancukiewicz M, and Alm El-Din MA, et al. Lung dose-volume parameters and the risk of pneumonitis for patients treated with accelerated partial-breast irradiation using three-dimensional conformal radiotherapy. J Clin Oncol 2009;27:3887-93.
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  10. Livi L, Buonamici FB, and Simontacchi G, et al. Accelerated partial breast irradiation with IMRT: New technical approach and interim analysis of acute toxicity in a phase III randomized clinical trial. Int J Radiat Oncol Biol Phys 2010;77:509-15.
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  11. Moon SH, Shin KH, and Kim TH, et al. Dosimetric comparison of four different external beam partial breast irradiation techniques: three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, helical tomotherapy, and proton beam therapy. Radiother Oncol 2009;90:66-73.
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  12. Heinzerling JH, Ding C, Ramirez E, Chang K, Anderson JF, Edwards CM, Boike T, Rule W, Sol-berg T, and Timmerman RD. Comparative dose-volume analysis for CyberKnife and 3D conformal partial breast irradiation treatment of early stage breast cancer. Int J Radiat Oncol Biol Phys 2010;78:S3390.
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  13. Fan J, Hayes S, Freedman G, Anderson P, Li J, Wang L, Jin L, Price R, and Ma C. Planning the breast boost: dosimetric comparison of CyberKnife, photo mini tangents, IMRT, and electron techniques. Int J Radiat Oncol Biol Phys 2010;78:S3306.
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  14. Feuvret L, Noel G, and Mazeron J, et al. Conformity index:areview. Int J Radiat Oncol Biol Phys 2006;64:333-42.
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  15. Xu Q, Chen Y, Grimm J, Fan J, An L, Xue J, Pahlajani N, and Lacouture T. Dosimetric investigation of accelerated partial breast irradiation (APBI) using CyberKnife. Med Phys 2012;39:6621-8.
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Article

Original Article

Progress in Medical Physics 2018; 29(2): 73-80

Published online June 30, 2018 https://doi.org/10.14316/pmp.2018.29.2.73

Copyright © Korean Society of Medical Physics.

Dosimetric Plan Comparison of Accelerated Partial Breast Irradiation (APBI) Using CyberKnife

Chang Yeol Lee*, Woo Chul Kim*, Hun Jeong Kim*, Jeongshim Lee*, Seungwoo Park, Hyun Do Huh*

*Department of Radiation Oncology, College of Medicine, Inha University, Incheon, Research Institute of Radiological and Medical Sciences, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

Correspondence to:Hyun Do Huh (hyundohuh@gmail.com) Tel: 82-32-890-3073 Fax: 82-32-890-3082

Received: June 14, 2018; Revised: June 23, 2018; Accepted: June 23, 2018

Abstract

Accelerated partial breast irradiation (APBI) is a new treatment delivery technique that decreases overall treatment time by using higher fractional doses than conventional fractionation. Here, a quantitative analysis study of CyberKnife-based APBI was performed on 10 patients with left-sided breast cancer who had already finished conventional treatment at the Inha University Hospital. Dosimetric parameters for four kinds of treatment plans (3D-CRT, IMRT, VMAT, and CyberKnife) were analyzed and compared with constraints in the NSABP B39/RTOG 0413 protocol and a published CyberKnife-based APBI study. For the 10 patients recruited in this study, all the dosimetric parameters, including target coverage and doses to normal structures, met the NSABP B39/RTOG 0413 protocol. Compared with other treatment plans, a more conformal dose to the target and better dose sparing of critical structures were observed in CyberKnife plans. Accelerated partial breast irradiation via CyberKnife is a suitable treatment delivery technique for partial breast irradiation and offers improvements over external beam APBI techniques.

Keywords: APBI, Cyberknife, Treatment planning

Introduction

Breast-conserving therapy (BCT) is the preferred treatment for early-stage breast cancer, and numerous published studies have shown that equivalent overall survival between patients who received breast-conserving surgery with whole breast irradiation (WBI) and patients treated by mastectomy alone. These studies demonstrate a 70% reduction in local recurrence, with the addition of adjuvant radiation after breast-conserving surgery.1,2) However, researchers have estimated that up to 25% of patients have not received adjuvant radiation therapy after breast conservation surgery.3) Prolonged treatment time, cost, distance to treatment facilities, and patient inconvenience have been implicated as possible deterrents to BCT.4,5)

Accelerated partial breast irradiation (APBI) is a new treatment delivery technique that decreased overall treatment time by using higher fractional doses than conventional fractionation. As opposed to whole breast irradiation, the dose is only given to the resection volume. Various techniques have been tried and complete reviews of APBI techniques can be found in the literature.6,7)

Applying to three-dimensional conformal radiation therapy (3D-CRT) and the NASBP B-39/RTOG0413 dose guidelines, Hepel et al.8) found a severe late toxicity in six of 60 patients who were treated with APBI. Recht et al.9) observed a higher risk of pneumonitis in patients with APBI who were treated with 3D-CRT. In other to reduce the dose to organs at risk (OAR), other treatment modalities have been used for APBI, including intensity modulated radiation therapy (IMRT), tomotherapy, and proton therapy. IMRT showed improved ipsilateral breast and other normal tissue dose sparing compared with 3D-CRT, with very low acute toxicity.10) Tomotherapy also reduced the dose to ipsilateral breast tissue, but at the cost of considerable increases in lung and heart doses. Protons have proven dosimetrically superior to all these techniques, but their availability is limited to a few centers globally.11)

A frameless robotic stereotactic radiosurgery system, the CyberKnife (Accuray Incorporated, Sunnyvale, CA, USA) provides image-guidance for the continuous tracking of target motion during respiration and patient movement. In the context of APBI, the Cyberknife could spare non-target breast tissue volume (NTBTV) more efficiently and potentially, which allows more agreeable cosmetic outcomes due to the combination of non-coplanar fields with tracking of the target volume. Indeed, researchers at the University of Texas Southwestern Medical found that APBI treatment plans achieved highly conformal target coverage with sparing doses to OAR, relative to 3D-CRT plans.12) Fox Chase’s treatment planning study has come to a similar conclusion as improving the boost dose distribution produced by CyberKnife.13) Here, a quantitative analysis study of CyberKnife-based APBI was performed on 10 patients with left-sided breast cancer who had already finished conventional treatment at the Inha University Hospital.

Materials and Methods

1. Patient selection

After Institutional Review Board (IRB) approval was obtained, 10 previously treated patients with left-sided breast cancer were selected for our retrospective study. Patients for CyberKnife-based APBI were selected over 50 years of age with stage I and II histologically-confirmed invasive non-lobular carcinoma or ductal carcinoma in situ (DCIS). All patients were treated with 50.4 Gy in 28 fractions, in a conventional fractionation. Further patient details are listed in Table 1.

2. Acquisition and definition of treatment volumes

A radiotherapy treatment planning CT scan was acquired for each patient. Patients underwent standard CT simulation at 2.5 mm slice spacing, in the supine position, not using a breast board. The gross tumor volume (GTV) was identified on the planning CT based on clear visualization and/or with the help of surgical clips. The clinical target volume (CTV) was obtained by a uniform 10 mm expansion of the GTV. The planning target volume (PTV) was delineated as the CTV expanded by a margin of 2 mm, to account for setup uncertainties. All plans were calculated for each patient using same PTV margin for technique comparison purposes. This comparison allowed us to evaluate the dosimetric characteristics of both planning systems at the same target volume. The CTV and PTV were limited to 3 mm from the skin surface and the chest wall, and lungs were not included in the PTV and CTV volumes. The OAR considered in this study were ipsilateral, contralateral breast, ipsilateral, contralateral lung, heart, thyroid, chest wall, and skin.

3. Delineation and treatment planning

The CT images were exported to Eclipse treatment planning system (Version 8.6) and MultiPlan treatment planning system (Version 2.2.0). The Phase III NSABP B39/RTOG 0413 partial breast protocol was followed for structure delineation and planning. The structures contoured for planning were the lumpectomy cavity or GTV, CTV, PTV, ipsilateral, contralateral breast, ipsilateral, contralateral lung, and heart. The eclipse-planned technique were 3DCRT, IMRT, and volumetric modulated arc therapy (VMAT). The 3D-CRT and IMRT plans were generated using a 5-field and 4-field coplanar technique, respectively. The VMAT plans were generated using RapidArc with anisotropic analytical algorithm (AAA). A double partial arc of 180° to 200° around the treated breast was used. The CyberKnife plans were generated using the iterative optimization mode to achieve the optimal dose to the target and normal structures. We used the fiducial marker tracking method. Prior to treatment, four 2-mm gold fiducials were implanted around the lumpectomy site under ultrasound guidance by a single board-certified radiologist. Depending on the size of the tumor, 1–2 fixed collimator ranging from 10 to 15 mm were chosen. Approximately, 95% of the PTV was to receive 100% of the prescription dose. All plans were generated to deliver 30 Gy in five fractions to the PTV over consecutive days.

4. Dosimetric parameters for plan comparison

For all treatment plans, dosimetric parameters calculated for the OARs are listed in Table 2. Here V30Gy, V15Gy, V9Gy, and V1.5Gy represent the percentage volumes of the normal organs receiving 30 Gy, 15 Gy, 9 Gy, and 1.5 Gy doses, respectively. Dmax is the maximum dose received by 1% of the evaluated OAR volumes. The dose conformity index (CI) for each plan was also calculated based on the Radiation Therapy Oncology Group (RTOG) definition14): CIRTOG=VRI/TV

where VRI=100% reference isodose volume (the volume receiving 100% prescription dose) and TV=target volume.

For the purpose of this study, cumulative dose-volume histograms of the normal structures were used for observation. Dosimetric parameters during these four treatment plans (3D-CRT, IMRT, VMAT, and CyberKnife) were analyzed and compared to constraints in the NSABP B39/RTOG 0413 protocol and a published CyberKnife-based APBI study. The total MUs for all plans were calculated and analyzed.

Results and Discussion

For the 10 patients recruited in this study, all the dosimetric parameters, including target coverage and doses to normal structures, met the NSABP B39/RTOG 0413 protocol, except for the contralateral breast maximum dose constraint as shown in Table 3. The PTV coverage requirement in the protocol is V90%>90%, which means that the percentage volume receiving 90% of the prescription dose should be greater than 90%. In our study, the mean percentage volume covering 100% of the prescription dose was 96.5±0.7%, which was more conformal than the target dose required in the protocol. The average CI for all the plans was 1.2±0.1%. The mean V15 Gy and mean V30 Gy to the ipsilatearal breast were 24.0±12.9% and 10.0±6.6%, which were well below 60% and 35% of the total volume, as required in the protocol. The maximum dose to the contralateral breast was relatively difficult to meet, depending on the distance between the tumor and the contralateral breast. The maximum doses to the contralateral breast for all 10 patients varied from 1.0 Gy to 8.0 Gy. The mean V1.5 Gy and mean V9 Gy to the contralateral and ipsilateral lungs were 9.0±5.7% and 3.0±2.6%, respectively. The means of V1.5 Gy to the heart was 23.0±10.6%. The CyberKnife plan was designed to deliver a multiple, non-isocentric, noncoplanar beam set. For this reason, the CyberKnife plan is more likely to pass through the contralateral breast than other plan techniques. The CyberKnife has the function of arbitrarily limiting the beam intersection to the tumor or OAR. If this function is used well without reducing target coverage, it may be possible to control maximum doses of contralateral breast.

We also compared our planning results to the published data from the studies of Olusola et al. and Sndra et al., which followed a similar protocol. We extracted all the corresponding dosimetric parameters for our 10 patients and compared these parameters to the data of Olusola et al. and Sndra et al. as shown in Table 4. Dosimetric data from CyberKnife studies were very close for the ipsilateral and contralateral breast and the ipsilateral and contralateral lungs. However, in our planning study, the mean V1.5 Gy doses to the heart were lower than those of the published data.

Our quantitative analysis study results is superior to the previously published work from Xu et al.,15) who showed the feasibility of using the CyberKnife for APBI. Their work proposed the dosimetric comparison of treatment plans that were calculated for 14 patients to previously published results obtained using 3D-CRT and IMRT. However, the results were somewhat limited because the authors compared their planning results to published data that was based on IMRT and 3D-CRT. Using different plans calculated for the same patients, we were able to compare mean DVHs for a better evaluation of the differences between techniques.

Table 5 shows mean dosimetric data computed for each treatment technique, and the corresponding mean DVHs are displayed in Fig. 1 for all treatment techniques. Dosimetric data for the contralateral breast and contralateral lung between techniques are very similar. In contrast, as shown in Fig. 1a, 1c, 1e, and 1f, DVHs of theses OARs show significant differences between techniques. These differences could relate to the more conformal beam arrangement in CyberKnife treatment, since the beams could enter the patient body from many angles. Significant differences were found between CyberKnife and all other techniques for the volumes receiving 15 Gy (V15 Gy) and 25 Gy (V25 Gy) of the ipsilateral breast and chest wall. Also, significant differences in the volume of the heart and ipsilateral lung receiving less than 5 Gy were observed.

The mean total MUs and standard deviations are 12138±3121 for CyberKnife plans, 749.3±32.7 for 3D-CRT plans, 1284.6±181.8 for IMRT plans, and 2432.5±1580.8 VMAT plans. The total MU with 3D-CRT plans was significantly lower than that of IMRT (mean total MU reduction ratio of 41.7%), VMAT (mean total MU reduction ratio of 69.2%), and CyberKnife (mean total MU reduction ratio of 93.8%) plans. Using the CyberKnife system with fixed collimator, treatment time including patient set-up on treatment couch was approximately 60 min, with a range from ~ 40 min to ~ 90 min. The longer time (90 min) was limited to the initial treatments and was a consequence of the inexperience of the team, especially in the patient setup and fiducial alignment phase. In general, larger breasts were associated with increased mobility, requiring longer patient set-up time. Time is important for the efficiency of treatment, but it is more meaningful when accuracy is involved. Although the treatment time of the CyberKnife is longer than other plan techniques, the PTV margin is unnecessary because the CyberKnife is tracked target volume considering the respiration of the patient. Therefore, the CyberKnife plan can save NTBTV and improve the accuracy of treatment over other plan techniques.

For a fairer comparison, it would have been interesting to compute doses using the same algorithm for each of the two modalities. However, we believe that the results obtained on NTBTV are too important to be a result of the dose calculation algorithm. It would also be interesting to calculate dose distributions on four-dimensional computed tomography (4DCT), to further investigate the benefit of tracking. Unfortunately, 4DCTs were not available for the selected patients.

Using Synchrony to track respiratory motions could reduce PTV margins and thus reduce the dose delivered to the NTBTV. However, the fiducial markers must follow the target volume shift inside the patient. Titanium surgical clips are used for delineating the excision volume after surgery. Surgical clip tracking has the advantage of not requiring additional implantation of fiducial markers. Implantation of fiducial markers is an additional invasive act for a patient. If these clips are visible in CyberKnife’s tracking system, the implantation of fiducial markers is no longer necessary. On the other hand, there may be no surgical clip depending on the surgery protocol of institution.

The CyberKnife does not require the extra margin to compensate for treatment set-up and breathing motion. As such, we believe that the steep dose gradients that are characteristic of CyberKnife APBI will allow more than acceptable cosmetic results and low toxicity over the long-term.

Conclusion

For the 10 patients who were recruited in this study, all the dosimetric parameters, including target coverage, and doses to normal structures, met the NSABP B39/RTOG 0413 protocol. Compared to other treatment plans, a more conformal dose to the target and better dose sparing of critical structures were observed in CyberKnife plans. Accelerated partial breast irradiation via CyberKnife is a suitable tretment delivery technique for partial breast irradiation and offers improvements over external beam APBI techniques.

Acknowledgements

This work was supported by the General Researcher program (NRF-2016M2A2A6A03946592 and 2017R1D-1A1B03027854).

Conflicts of Interest

The authors have nothing to disclose.

Availability of Data and Materials

All relevant data are within the paper and its Supporting Information files.

Ethics Approval and Consent to Participate

The study was approved by the institutional review board (IRB approval number; 2017-11-002-003).

Tables

Patient and tumor characteristics for the ten patients with ten treated tumors.

Characteristic Value
Age (years)
 Mean 60
 Range 50~78
Tumor type
 DCIS 0
 IDC 10
Tumor stage
 Tis 0
 T1a 1
 T1b 2
 T1c 3
 T2 4
GTV (cm3)
 Mean 6.4
 Range 3.5~11.2
PTV (cm3)
 Mean 37.7
 Range 21.3~65.1
Tumor laterality
 Right 0
 Left 10
Quadrant
 UOQ 6
 UIQ 3
 Central 1
 LOQ 0
 LIQ 0

IDC, invasive ductal carcinoma; DCIS, ductal carcinoma in situ; UOQ, upper outer quadrant; UIQ, upper inner quadrant; LIQ, lower inner quadrant.

Constraints given by the NSABP B39/RTOG 0413 protocol for patients treated with CyberKnife SAPBI.

Structure Constraint
Ipsilateral breast V30 Gy<35%
V15 Gy<60%
Contralateral breast Dmax<1 Gy
Ipsilateral lung V9 Gy<15%
Contralateral lung V1.5 Gy<15%
Heart (left breast) V1.5 Gy<40%
Heart (right breast) V1.5 Gy<5%
Thyroid Dmax<1 Gy
Skin Dmax<36 Gy
Chest wall Dmax<36 Gy

SAPBI, stereotactic accelerated partial breast irradiation; NSABP, National Surgical Adjuvant Breast and Bowel Project; RTOG, Radiation Therapy Oncology Group.

Dosimetric parmeters from plans based on the NSABP B39/RTOG 0413 protocol.

Structure and dosimetric parameters NSABP B39/RTOG 0413 Protocol Min (%) Max (%) Mean (%) Std (%)
Ipsilateral breast V30 Gy<35% 2 22 10 6.6
V15 Gy<60% 5 48 24 12.9
Contralateral breast Dmax<1 Gy 1 Gy 8 Gy 3 Gy 3.1 Gy
Ipsilateral lung V9 Gy<15% 0 9 3 2.6
Contralateral lung V1.5 Gy<15% 0 20 9 5.7
Heart (left breast) V1.5 Gy<40% 4 36 23 10.6
Thyroid Dmax<1 Gy 0 Gy 1.5 Gy 1 Gy 0.2 Gy
Skin Dmax<36 Gy 29 Gy 34 Gy 31 Gy 1.5 Gy
Chest wall Dmax<36 Gy 23 Gy 35 Gy 31 Gy 3.2 Gy
Coverage of PTV >90% 95 97.6 96.5 0.7
CI 1.1 1.35 1.2 0.1

Comparison of our dosimetric parameters to other CyberKnife studies.

Structure and dosimetric parameters CyberKnife (mean, range) Olusola et al (mean, range) Sndra et al (mean, range)
Ipsilateral breast 10%, 2–22% 14%, 3–26% 11%, 8–13%
24%, 5–48% 31%, 8–58% 23%, 16–30%
Contralateral breast 3 Gy, 1–8 Gy 3 Gy, 0–11 Gy 1 Gy, 1–2 Gy
Ipsilateral lung 3%, 0–9% 3%, 0–17% 5%, 0–10%
Contralateral lung 9%, 0–20% 8%, 0–21% 6%, 2–10%
Heart (left breast) 23%, 4–36% 31%, 7–43% 40%, 25–54%
Heart (right breast) NA 18%, 0–37% NA
Thyroid <1 Gy, 0–1.5 Gy <1 Gy, 0–1.4 Gy <1 Gy, 0–1 Gy
Skin 31 Gy, 29–34 Gy 32 Gy, 28–36 Gy 33 Gy
Chest wall 31 Gy, 23–35 Gy 26 Gy, 13–33 Gy 30 Gy

Comparison of our dosimetric parameters to 3D-CRT, IMRT, and VMAT plan.

Structure and dosimetric parameters Constraint CyberKnife (mean, range)
Ipsilateral breast V30 Gy<35% 10%, 2–22%
V15 Gy<60% 24%, 5–48%
Contralateral breast Dmax<1 Gy 3 Gy, 1–8 Gy
Ipsilateral lung V9 Gy<15% 3%, 0–9%
Contralateral lung V1.5 Gy<15% 9%, 0–20%
Heart (left breast) V1.5 Gy<40% 23%, 4–36%
Thyroid Dmax<1 Gy <1 Gy, 0–1.5 Gy
Skin Dmax<36 Gy 31 Gy, 29–34 Gy
Chest wall Dmax<36 Gy 31 Gy, 23–35 Gy
CI 1.2
MU 12138

Structure and dosimetric parameters 3DCRT (mean, range) IMRT (mean, range) VMAT (mean, range)

Ipsilateral breast 16%, 4–33% 12%, 5–24% 12%, 2–25%
33%, 9–67% 33%, 8–59% 25%, 5–57%
Contralateral breast 3 Gy, 0–12 Gy 5 Gy, 3–13 Gy 2 Gy, 2–5 Gy
Ipsilateral lung 8%, 1–12% 2%, 0–9% 6%, 0–14%
Contralateral lung 26%, 17–36% 10%, 0–23% 13%, 1–41%
Heart (left breast) 58%, 32–94% 29%, 11–65% 43%, 28–59%
Thyroid <1 Gy, 0–0.1 Gy <1 Gy, 0–0.1 Gy <1 Gy, 0–0.1 Gy
Skin 30 Gy, 27–32 Gy 31 Gy, 29–33 Gy 31 Gy, 26–36 Gy
Chest wall 31 Gy, 21–36 Gy 30 Gy, 10–33 Gy 32 Gy, 19–38 Gy
CI 1.8 1.3 1.3
MU 749 1285 2433

Fig 1.

Figure 1.Mean DVH data for ipsilateral breast (a), contralateral breast (b), ipsilateral lung (c), contralateral lung (d), heart (e), cheat wall (f ).
Progress in Medical Physics 2018; 29: 73-80https://doi.org/10.14316/pmp.2018.29.2.73

Table 1 Patient and tumor characteristics for the ten patients with ten treated tumors.

CharacteristicValue
Age (years)
 Mean60
 Range50~78
Tumor type
 DCIS0
 IDC10
Tumor stage
 Tis0
 T1a1
 T1b2
 T1c3
 T24
GTV (cm3)
 Mean6.4
 Range3.5~11.2
PTV (cm3)
 Mean37.7
 Range21.3~65.1
Tumor laterality
 Right0
 Left10
Quadrant
 UOQ6
 UIQ3
 Central1
 LOQ0
 LIQ0

IDC, invasive ductal carcinoma; DCIS, ductal carcinoma in situ; UOQ, upper outer quadrant; UIQ, upper inner quadrant; LIQ, lower inner quadrant.


Table 2 Constraints given by the NSABP B39/RTOG 0413 protocol for patients treated with CyberKnife SAPBI.

StructureConstraint
Ipsilateral breastV30 Gy<35%
V15 Gy<60%
Contralateral breastDmax<1 Gy
Ipsilateral lungV9 Gy<15%
Contralateral lungV1.5 Gy<15%
Heart (left breast)V1.5 Gy<40%
Heart (right breast)V1.5 Gy<5%
ThyroidDmax<1 Gy
SkinDmax<36 Gy
Chest wallDmax<36 Gy

SAPBI, stereotactic accelerated partial breast irradiation; NSABP, National Surgical Adjuvant Breast and Bowel Project; RTOG, Radiation Therapy Oncology Group.


Table 3 Dosimetric parmeters from plans based on the NSABP B39/RTOG 0413 protocol.

Structure and dosimetric parametersNSABP B39/RTOG 0413 ProtocolMin (%)Max (%)Mean (%)Std (%)
Ipsilateral breastV30 Gy<35%222106.6
V15 Gy<60%5482412.9
Contralateral breastDmax<1 Gy1 Gy8 Gy3 Gy3.1 Gy
Ipsilateral lungV9 Gy<15%0932.6
Contralateral lungV1.5 Gy<15%02095.7
Heart (left breast)V1.5 Gy<40%4362310.6
ThyroidDmax<1 Gy0 Gy1.5 Gy1 Gy0.2 Gy
SkinDmax<36 Gy29 Gy34 Gy31 Gy1.5 Gy
Chest wallDmax<36 Gy23 Gy35 Gy31 Gy3.2 Gy
Coverage of PTV>90%9597.696.50.7
CI1.11.351.20.1

Table 4 Comparison of our dosimetric parameters to other CyberKnife studies.

Structure and dosimetric parametersCyberKnife (mean, range)Olusola et al (mean, range)Sndra et al (mean, range)
Ipsilateral breast10%, 2–22%14%, 3–26%11%, 8–13%
24%, 5–48%31%, 8–58%23%, 16–30%
Contralateral breast3 Gy, 1–8 Gy3 Gy, 0–11 Gy1 Gy, 1–2 Gy
Ipsilateral lung3%, 0–9%3%, 0–17%5%, 0–10%
Contralateral lung9%, 0–20%8%, 0–21%6%, 2–10%
Heart (left breast)23%, 4–36%31%, 7–43%40%, 25–54%
Heart (right breast)NA18%, 0–37%NA
Thyroid<1 Gy, 0–1.5 Gy<1 Gy, 0–1.4 Gy<1 Gy, 0–1 Gy
Skin31 Gy, 29–34 Gy32 Gy, 28–36 Gy33 Gy
Chest wall31 Gy, 23–35 Gy26 Gy, 13–33 Gy30 Gy

Table 5 Comparison of our dosimetric parameters to 3D-CRT, IMRT, and VMAT plan.

Structure and dosimetric parametersConstraintCyberKnife (mean, range)
Ipsilateral breastV30 Gy<35%10%, 2–22%
V15 Gy<60%24%, 5–48%
Contralateral breastDmax<1 Gy3 Gy, 1–8 Gy
Ipsilateral lungV9 Gy<15%3%, 0–9%
Contralateral lungV1.5 Gy<15%9%, 0–20%
Heart (left breast)V1.5 Gy<40%23%, 4–36%
ThyroidDmax<1 Gy<1 Gy, 0–1.5 Gy
SkinDmax<36 Gy31 Gy, 29–34 Gy
Chest wallDmax<36 Gy31 Gy, 23–35 Gy
CI1.2
MU12138

Structure and dosimetric parameters3DCRT (mean, range)IMRT (mean, range)VMAT (mean, range)

Ipsilateral breast16%, 4–33%12%, 5–24%12%, 2–25%
33%, 9–67%33%, 8–59%25%, 5–57%
Contralateral breast3 Gy, 0–12 Gy5 Gy, 3–13 Gy2 Gy, 2–5 Gy
Ipsilateral lung8%, 1–12%2%, 0–9%6%, 0–14%
Contralateral lung26%, 17–36%10%, 0–23%13%, 1–41%
Heart (left breast)58%, 32–94%29%, 11–65%43%, 28–59%
Thyroid<1 Gy, 0–0.1 Gy<1 Gy, 0–0.1 Gy<1 Gy, 0–0.1 Gy
Skin30 Gy, 27–32 Gy31 Gy, 29–33 Gy31 Gy, 26–36 Gy
Chest wall31 Gy, 21–36 Gy30 Gy, 10–33 Gy32 Gy, 19–38 Gy
CI1.81.31.3
MU74912852433

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