Comparison of Heart and Lung Doses According to Tumor Bed Boost Techniques in Early-Stage Left-Sided Breast Cancer: Simultaneous Integrated Boost versus Sequential Boost

Background and Objectives: The boost dose to the tumor bed after whole breast irradiation (WBI) can be divided into sequential boost (SEQ) and simultaneous integrated boost (SIB). SIB using modern radiation therapy (RT) techniques, such as volumetric modulated arc therapy, allow the delivery of a highly conformal dose to the target volume and has a salient ability to spare at-risk organs. This study aimed to compare the radiation dose delivered to the heart and lungs according to boost technique and tumor bed location. Materials and Methods: RT planning data of 20 patients with early-stage left-sided breast cancer were used in this study. All patients were treated with volumetric modulated arc therapy after breast-conserving surgery with a sentinel lymph node biopsy. For each patient, two different plans, whole breast irradiation with simultaneous integrated boost (WBI-SIB) and sequential boost after WBI (WBI-SEQ), were generated. To compare the dose received by each organ at risk (OAR), dose-volume histogram data were analyzed. The mean dose (Dmean) and volume of each organ that received x Gy (Vx) were calculated and compared. Results: For the heart, the V10 was lower for the WBI-SIB plan than for the WBI-SEQ plan (5.223 ± 1.947% vs. 6.409 ± 2.545%, p = 0.008). For the left lung, the V5 was lower in the WBI-SIB plan than for the WBI-SEQ plan (27.385 ± 3.871% vs. 32.092 ± 3.545%, p < 0.001). The Dmean for the heart and left lung was lower for the WBI-SIB plan than for the WBI-SEQ plan (heart: 339.745 ± 46.889 cGy vs. 413.030 ± 52.456 cGy, p < 0.001; left lung: 550.445 ± 65.094 cGy vs. 602.270 ± 55.775 cGy, p < 0.001). Conclusions: The WBI-SIB plan delivered lower radiation doses to the heart and left lung than the WBI-SEQ plan in terms of Dmean and low-dose volume in hypofractionated RT of early-stage left-sided breast cancer patients. Furthermore, a large radiation dose per day may be advantageous, considering the radiobiologic aspects of breast cancer. Long-term follow-up data are needed to determine whether the dosimetric advantages of the WBI-SIB plan can lead to clinically improved patient outcomes and reduced late side effects.


Introduction
Whole breast irradiation (WBI) following breast-conserving surgery (BCS) is the current standard treatment for early-stage breast cancer, and a patient's risk for recurrence is evaluated to determine whether to administer a boost dose to the tumor bed [1]. Tumor bed boost timing can be divided into sequential boost (SEQ), which is applied after WBI (WBI-SEQ), and simultaneous integrated boost (SIB), which is applied simultaneously (WBI-SIB).
Strict dose constraints are required in modern radiation therapy (RT) planning [2][3][4] due to the association between radiation dose to the heart and late heart disease. The heart 2 of 11 is anatomically located closer to the target volume in cases of left-sided breast cancer than in cases of right-sided breast cancer, which requires strategies to minimize the radiation dose delivered to the heart. Modern RT techniques, such as volumetric modulated arc therapy (VMAT), allow the delivery of a highly conformal dose to the target volume and have a salient ability to spare organs at risk (OAR) compared to two-dimensional RT or three-dimensional conformal RT techniques [5]. The advantages of SIB in RT planning for breast cancer have already been demonstrated in several studies [6][7][8][9]; however, to date, few studies conducted have dosimetrically compared SEQ and SIB [10][11][12].
We compared doses delivered to the heart and lungs via the two boost techniques and analyzed which boost techniques were superior according to the target volume location of the tumor bed boost (inner versus outer quadrant) in terms of the dose delivered to the heart and lungs.

Patients
This single-center study was performed at Incheon St. Mary's Hospital. RT planning data of 20 patients with early-stage left-sided breast cancer were used in this study. All patients underwent VMAT between January 2021 and March 2022 after BCS with a sentinel lymph node biopsy. The eligibility criteria for the study included pT1-2 and N0 disease. Age at diagnosis and histologic subtype were not restricted. Patients treated with any neoadjuvant chemotherapy before BCS and those with a previous history of breast augmentation were excluded. This study was approved by the Institutional Review Board of the Catholic University of Korea at Incheon St. Mary's Hospital (approval number: OC22EIDI0043), which waived the requirement for informed consent owing to the study's retrospective nature.

Treatment Planning and Target Volume Delineation
Hypofractionated (HF) RT was planned using the Eclipse TM treatment planning system and was administered using Halcyon TM (Varian Medical Systems, Palo Alto, CA, USA), which offers a 6 MV flattening-filter-free photon beam. For WBI, the clinical target volume (CTV) and planning target volume (PTV WB ) were delineated by a single radiation oncologist according to the European Society for Radiotherapy and Oncology consensus guidelines [13]. PTV WB was cropped to 3 mm from the body contour. For the tumor bed boost, surgical clips were delineated using computed tomography to define the lumpectomy cavity, and CTV Boost was defined by adding 1 cm around the clips and seroma. PTV Boost was defined by adding a 0.5 cm margin to CTV Boost . Two different plans, WBI-SIB and WBI-SEQ, were generated for each patient. The prescription doses and biologically effective doses (BED 3 ) for each plan are summarized in Table 1. A schematic of each treatment plan is shown in Figure 1. The prescription dose was administered at the isodose line to encompass at least 95% of the PTV, while limiting maximum doses to less than 107%. Two partial arcs with single-isocenter VMAT plans were generated for the WBI. When performing SEQ, the collimator angle was adjusted according to the PTV Boost location. The VMAT plans were optimized using the Eclipse photon optimization algorithm, and Acuros XB (version 16.1) was used for dose calculation. Dose constraints were prescribed based on institutional guidelines (Table 2).

Assessment of Plan Quality
Three plan quality metrics proposed by the Radiation Therapy Oncology G (RTOG) were used in this study: homogeneity index (HI), conformity index (CI), and ity of coverage (QOC) ( Table 3) [14,15]. HI measures the uniformity of dose distrib in the target volume; an HI ≤ 2 indicates that the plan does not deviate from the pro CI explains how well the dose distribution conforms to the shape of the target volum has an ideal value of 1. If CI > 1, then the irradiated volume is greater than TV, i.e. treatment; if CI < 1, then the irradiated volume is smaller than TV, i.e., undertreatm QOC > 0.9 indicates that over 90% of the isodose covers the target volume and th does not deviate from the protocol [16]. To compare the doses delivered to the O dose-volume histogram data were analyzed. The mean doses (Dmean) and volume o organ that received x Gy (Vx) were calculated and compared.

Assessment of Plan Quality
Three plan quality metrics proposed by the Radiation Therapy Oncology Group (RTOG) were used in this study: homogeneity index (HI), conformity index (CI), and quality of coverage (QOC) ( Table 3) [14,15]. HI measures the uniformity of dose distribution in the target volume; an HI ≤ 2 indicates that the plan does not deviate from the protocol. CI explains how well the dose distribution conforms to the shape of the target volume and has an ideal value of 1. If CI > 1, then the irradiated volume is greater than TV, i.e., overtreatment; if CI < 1, then the irradiated volume is smaller than TV, i.e., undertreatment. A QOC > 0.9 indicates that over 90% of the isodose covers the target volume and the plan does not deviate from the protocol [16]. To compare the doses delivered to the OARs, dose-volume histogram data were analyzed. The mean doses (D mean ) and volume of each organ that received x Gy (Vx) were calculated and compared. Table 3. Volume-based indices for plan quality assessment.

Index for PTV Formula Reference Value
Homogeneity index I max /RI ≤2: per protocol >2.0 and ≤2.5: minor deviation >2.5: major deviation

Statistical Analysis
Wilcoxon signed-rank tests were used to compare non-parametric data. IBM SPSS Statistics for Windows (version 27.0; IBM Corp., Armonk, NY, USA) was used for the statistical analyses, and all statistical tests were considered statistically significant at p values < 0.05.

Results
Patient and tumor characteristics are summarized in Table 4. In total, 20 women had pathologically confirmed early-stage left-sided breast cancer. All patients presented with clinically node-negative disease and had negative sentinel lymph node biopsies. Among the 20 patients, 14 (70.0%) received hormone suppression therapy. The mean PTV WB and PTV boost were 664.8 cm 3 (range, 196.3-1158.5 cm 3 ) and 70.5 cm 3 (range, 33.8-142.2 cm 3 ), respectively. The dose distribution and three-dimensional view of a typical patient receiving the WBI-SEQ and WBI-SIB plans are shown in Figure 2.

Assessment of Plan Quality
Plan quality was evaluated based on the criteria described in Table 3. The opt tion algorithm was balanced for PTV coverage and the values for the WBI-SIB and SEQ plans were found to be acceptable. The HI values for the WBI-SIB and WBI-SEQ were 1.323 ± 0.027 and 1.446 ± 0.020, respectively. According to the RTOG protoco plans were considered to comply with the protocol. CI values for the WBI-SIB and SEQ plans were 0.958 ± 0.158 and 0.980 ± 0.008, respectively. Plans with a CI of 1 w ideal value, and values between 0.9 and 1.0 were considered within minor deviatio acceptable. The QOC values for the WBI-SIB and WBI-SEQ plans were 0.986 ± 0.01 1.001 ± 0.115, respectively; both plans complied with the protocol. Our institutional g lines for dose constraints were satisfied for all patients. Figure 3 compares the heart and left lung doses received via the WBI-SIB and SEQ plans. For the heart, the V10 was lower for the WBI-SIB plan than for the WB plan (5.223 ± 1.947% vs. 6.409 ± 2.545%, p = 0.008), whereas the V20 values did not significantly between the WBI-SIB and WBI-SEQ plans (1.191 ± 0.672% vs. 1.057 ± 0 p = 0.161). As the dose increased, the difference in the irradiated volumes between th treatment plans remained small. For the ipsilateral lung, the V5 was lower for the SIB plan than for the WBI-SEQ plan (27.385 ± 3.871% vs. 32.092 ± 3.545%, p < 0.001 V20 values did not differ significantly between the WBI-SIB and WBI-SEQ plans (7 1.898% vs. 7.124 ± 2.027%, p = 0.588).

Assessment of Plan Quality
Plan quality was evaluated based on the criteria described in Table 3. The optimization algorithm was balanced for PTV coverage and the values for the WBI-SIB and WBI-SEQ plans were found to be acceptable. The HI values for the WBI-SIB and WBI-SEQ plans were 1.323 ± 0.027 and 1.446 ± 0.020, respectively. According to the RTOG protocol, both plans were considered to comply with the protocol. CI values for the WBI-SIB and WBI-SEQ plans were 0.958 ± 0.158 and 0.980 ± 0.008, respectively. Plans with a CI of 1 was the ideal value, and values between 0.9 and 1.0 were considered within minor deviation, but acceptable. The QOC values for the WBI-SIB and WBI-SEQ plans were 0.986 ± 0.015 and 1.001 ± 0.115, respectively; both plans complied with the protocol. Our institutional guidelines for dose constraints were satisfied for all patients. Figure 3 compares the heart and left lung doses received via the WBI-SIB and WBI-SEQ plans. For the heart, the V10 was lower for the WBI-SIB plan than for the WBI-SEQ plan (5.223 ± 1.947% vs. 6.409 ± 2.545%, p = 0.008), whereas the V20 values did not differ significantly between the WBI-SIB and WBI-SEQ plans (1.191 ± 0.672% vs. 1.057 ± 0.848%, p = 0.161). As the dose increased, the difference in the irradiated volumes between the two treatment plans remained small. For the ipsilateral lung, the V5 was lower for the WBI-SIB plan than for the WBI-SEQ plan (27.385 ± 3.871% vs. 32.092 ± 3.545%, p < 0.001). The V20 values did not differ significantly between the WBI-SIB and WBI-SEQ plans (7.277 ± 1.898% vs. 7.124 ± 2.027%, p = 0.588). Figure 4 compares the D mean for all OARs between the WBI-SIB and WBI-SEQ plans. The D mean for all OARs was lower for the WBI-SIB plan than for the WBI-SEQ plan

Subgroup Analysis: Inner Quadrant
For the heart dose, the WBI-SIB plan was slightly but non-significantly better than the WBI-SEQ plan for V10 (6.309 ± 1.391 vs. 7.314 ± 2.849, p = 0.074); for V20, there was no statistically significant difference between the WBI-SIB and WBI-SEQ plans (1.508 ± 0.715 vs. 1.428 ± 0.921, p = 0.575). For the left lung dose, the WBI-SIB plan was better than the

Subgroup Analysis: Inner Quadrant
For the heart dose, the WBI-SIB plan was slightly but non-significantly better the WBI-SEQ plan for V10 (6.309 ± 1.391 vs. 7.314 ± 2.849, p = 0.074); for V20, there wa statistically significant difference between the WBI-SIB and WBI-SEQ plans (1.508 ± 0 vs. 1.428 ± 0.921, p = 0.575). For the left lung dose, the WBI-SIB plan was better than

Subgroup Analysis: Inner Quadrant
For the heart dose, the WBI-SIB plan was slightly but non-significantly better than the WBI-SEQ plan for V10 (6.309 ± 1.391 vs. 7.314 ± 2.849, p = 0.074); for V20, there was no statistically significant difference between the WBI-SIB and WBI-SEQ plans (1.508 ± 0.715 vs. 1.428 ± 0.921, p = 0.575). For the left lung dose, the WBI-SIB plan was better than the WBI-SEQ plan for V5 (26.611 ± 3.550 vs. 31.139 ± 3.814, p = 0.007); for V20, there was no statistically significant difference between the WBI-SIB and WBI-SEQ plans (6.671 ± 1.946 vs. 6.170 ± 1.989, p = 0.153). Figure 5 compares the D mean for all OAR between the WBI-SIB and WBI-SEQ plans. The D mean values for the heart, left lung, right lung, and whole lung were lower for the WBI-SIB plan than for the WBI-SEQ plan WBI-SEQ plan for V5 (26.611 ± 3.550 vs. 31.139 ± 3.814, p = 0.007); for V20, there wa statistically significant difference between the WBI-SIB and WBI-SEQ plans (6.671 ± vs. 6.170 ± 1.989, p = 0.153). Figure 5 compares the Dmean for all OAR between the WBI-SIB and WBI-SEQ p The Dmean values for the heart, left lung, right lung, and whole lung were lower fo WBI-SIB plan than for the WBI-SEQ plan (heart: 360. 930

Subgroup Analysis: Outer Quadrant
In terms of heart dose, the WBI-SIB plan was superior to the WBI-SEQ plan for (4.137 ± 1.855 vs. 8.503 ± 1.930, p = 0.017); in contrast, for V20, there was no statisti significant difference between the two plans (0.873 ± 0.707 vs. 0.685 ± 0.601, p = 0.092) the left lung dose, the WBI-SIB plan was superior to the WBI-SEQ plan for V5 (28.1 4.207 vs. 33.046 ± 3.156, p = 0.009), while for V20, there was no statistically significan ference between the two plans (7.882 ± 1.732 vs. 8.078 ± 1.642, p = 0.445). Figure 6 compares the Dmean for all OARs between the two plans. The Dmean value the heart, left lung, right lung, and whole lung were lower for the WBI-SIB plan tha the WBI-SEQ plan (heart: 318. 560

Discussion
In this study, we focused on the importance of heart and lung radiation doses i treatment of early-stage left-sided breast cancer and analyzed how boost technique tumor bed location affected RT planning and its dosimetric effects on the heart an lung. Our results showed that the WBI-SIB plan resulted in a lower Dmean for all OAR the WBI-SEQ plan and particularly reduced the low-dose volume of the heart and lung.
Although RT is an integral part of breast cancer treatment, long-term attention t risk of late complications, such as heart disease, is required, particularly for left-s breast cancer patients [2][3][4]17]. Carlson et al. [17] reported the results of a WELC (Women's Environmental Cancer and Radiation Epidemiology) follow-up study of reported incident cardiovascular disease in women with left-sided breast cancer. The year cumulative incidence of coronary artery disease was 2.5-fold higher in women left-sided breast cancer than in those with right-sided breast cancer (95% confidenc terval, 1.3-4.7). Darby et al. conducted another large population-based case-control s of major coronary events, such as myocardial infarction, coronary revascularizatio death of ischemic heart disease [2], and reported that the major coronary events ra creased by 7.4% per Gy with increasing Dmean to the heart. Several studies using mo RT techniques such as VMAT have been conducted in an effort to reduce the dose d ered to the heart [18,19].
SIB allows the simultaneous delivery of a differential dose per fraction to diff target volumes and offers several advantages such as a higher biologically effective to PTVTB, shorter overall treatment time than SEQ, and highly homogeneous and co mal dose distributions compared with SEQ or field-in-field techniques [20,21]. Sever cent studies have examined intensity-modulated radiation therapy (IMRT) with SIB p and have shown dosimetric advantages [5,7]. Guerrero et al. [6]. compared the con tional treatment of WBI (45 Gy in 25 fractions) plus SEQ (20 Gy in 10 fractions) a biologically equivalent alternative plan of WBI (45 Gy in 25 fractions) with SIB (60 G 25 fractions) using IMRT and reported that the latter provided good coverage of the t volume and reduced the volume of excessively high doses to the breast, especiall patients with deep-seated tumors.

Discussion
In this study, we focused on the importance of heart and lung radiation doses in the treatment of early-stage left-sided breast cancer and analyzed how boost techniques and tumor bed location affected RT planning and its dosimetric effects on the heart and left lung. Our results showed that the WBI-SIB plan resulted in a lower D mean for all OAR than the WBI-SEQ plan and particularly reduced the low-dose volume of the heart and left lung.
Although RT is an integral part of breast cancer treatment, long-term attention to the risk of late complications, such as heart disease, is required, particularly for left-sided breast cancer patients [2][3][4]17]. Carlson et al. [17] reported the results of a WELCARE (Women's Environmental Cancer and Radiation Epidemiology) follow-up study of selfreported incident cardiovascular disease in women with left-sided breast cancer. The 27.5-year cumulative incidence of coronary artery disease was 2.5-fold higher in women with left-sided breast cancer than in those with right-sided breast cancer (95% confidence interval, 1.3-4.7). Darby et al. conducted another large population-based case-control study of major coronary events, such as myocardial infarction, coronary revascularization, or death of ischemic heart disease [2], and reported that the major coronary events rate increased by 7.4% per Gy with increasing D mean to the heart. Several studies using modern RT techniques such as VMAT have been conducted in an effort to reduce the dose delivered to the heart [18,19].
SIB allows the simultaneous delivery of a differential dose per fraction to different target volumes and offers several advantages such as a higher biologically effective dose to PTV TB , shorter overall treatment time than SEQ, and highly homogeneous and conformal dose distributions compared with SEQ or field-in-field techniques [20,21]. Several recent studies have examined intensity-modulated radiation therapy (IMRT) with SIB plans and have shown dosimetric advantages [5,7]. Guerrero et al. [6]. compared the conventional treatment of WBI (45 Gy in 25 fractions) plus SEQ (20 Gy in 10 fractions) and a biologically equivalent alternative plan of WBI (45 Gy in 25 fractions) with SIB (60 Gy in 25 fractions) using IMRT and reported that the latter provided good coverage of the target volume and reduced the volume of excessively high doses to the breast, especially for patients with deep-seated tumors.
Based on four published randomized trials [22][23][24][25][26][27], the National Comprehensive Cancer Network guidelines recommend a HF dose of 40-42.5 Gy in 15-16 fractions for the WBI [1]. Few reports are available on the dosimetric feasibility of HF-SIB, which has not yet been widely adopted clinically for breast cancer. Yu T et al. [28] dosimetrically compared HF-WBI with SEQ versus SIB in the supine and prone positions using three-dimensional conformal RT with the field-in-field technique. The dose prescribed for WBI was 40.05 Gy in 15 fractions, while that of the tumor bed was 9.6 Gy in 3 fractions for SEQ and 48 Gy in 15 fractions for SIB. Regardless of the position, SIB-HF-WBI resulted in better target coverage and a lower dose to the OARs. Breast cancer is estimated to have a low α/β ratio, similar to that of late-reacting normal tissue [22][23][24]. The low estimated α/β ratio for breast cancer indicates that it is probably more sensitive to the effect of fraction size than most other tumors; therefore, hypofractionation for breast cancer may have a therapeutic advantage over conventional fractionation.
The heart is normally located behind and slightly to the left of the breastbone, and the left anterior descending coronary artery (LAD) runs along its surface. When the PTV TB is in the inner quadrant, the distance between the heart or LAD and the PTV TB is anatomically closer than that in the outer quadrant. Bouchardy et al. [29] compared breast cancer-specific and cardiovascular mortality between the inner and outer quadrants using data of 1245 women in the population-based Geneva Cancer Registry. In their study, patients with inner quadrant breast cancer had a 2.5-fold higher risk for cardiovascular mortality than those with outer quadrant breast cancer (95% confidence interval, 1.1-5.4). Since the heart dose can increase as the tumor bed becomes closer to the heart, we assessed which treatment plan has the potential benefit of either WBI-SIB or WBI-SEQ according to tumor bed location. It was not possible to determine which treatment plan was better for the heart dose depending on the tumor bed location, and it was confirmed that the WBI-SIB plan had potential advantages over the WBI-SEQ plan in the low-dose region, regardless of the tumor bed location.
This study had a number of limitations. We agree that the small sample size weakened the statistical power and the lack of the evaluation of acute and late complications limited this study, which is an inherent limitation of RT planning studies. Through a further randomized controlled study, we expect to compare late complications and cosmetic outcomes of the WBI-SIB versus WBI-SEQ plans.

Conclusions
In this study, we have confirmed that the WBI-SIB plan offered lower doses to OARs in terms of D mean and low-dose volume in HF RT of patients with left breast cancer. WBI-SIB offers a shortened overall treatment period and increases patient convenience. Furthermore, a large radiation dose per day may be advantageous, considering the radiobiologic aspects of breast cancer. Long-term follow-up data are needed to determine whether these dosimetric advantages of the WBI-SIB plan can lead to clinically improved patient outcomes and reduced late side effects.

Informed Consent Statement:
The need for informed consent was waived due to the study's retrospective nature.
Data Availability Statement: Data are available upon reasonable request.

Conflicts of Interest:
The authors declare no conflict of interest.