Left breast radiotherapy with multi fields hybrid intensity modulated radiotherapy (IMRT) versus volumetric modulated arc therapy (VMAT) : balance between left anterior descending artery sparing and secondary cancer induction risk

To explore the feasibility of using Volumetric-Modulated Arc Therapy (VMAT) to protect left anterior descending branch (LAD) after breast-conserving surgery for left breast cancer. 15 left breast cancer patients after breast-conserving surgery were selected. 7F-IMRT and 2A-VMAT treatment plans were designed with Varian Eclipse TPS (13.6version). The prescriptions of PTV and PTV Boost were 43.5Gy and 49.5Gy in 15 fractions. The dosimetric parameters, OARs dose sparing and second cancer risk (SCR) were compared between the two plans using a paired t-test. The VMAT plans obtain better PTV conformity and higher mean dose. VMAT plans show a better dose distribution in high dose areas and better sparing of OARs, including left lung, heart, and LAD. The Dmax and Dmean of LAD decreased significantly in VMAT plans. The SCRs of the contralateral lung and breast significantly increased with a higher mean dose. We recommend that contouring and evaluating the dose of LAD and LAD helping structures in left breast cancer radiotherapy. SCR should be evaluated for younger patients. To evaluate the heart and LAD sparing of Hybrid IMRT and VMAT techniques, 15 left-sided whole-breast cancer patients underwent simultaneously integrated boost (SIB) radiotherapy with were selected. Both Hybrid IMRT and VMAT plans were generated. The PTVs dose distribution, OAR sparing and SCR values were evaluated to explore the feasibility of VMAT for whole-breast radiotherapy.


Introduction
Breast cancer was the most frequently diagnosed cancer and the most frequent cause of death from cancer in women. Adjuvant whole-breast radiadiaton therapy following breast-conserving surgery became the main treatment of early invasive breast cancer, for obtaining the same local and regional control rate and long-term survival rate comparing to modified radical mastectomy [1][2][3][4]. Hypofractionated dose regimens described equivalent local control, survival, and toxicity to conventional fractionation in published articles [5][6][7][8]. Moreover, a simultaneous integrated boost (SIB) of tumor bed has been shown to be more advantageous than sequential boost delivery [9][10][11].
Non-cancer-related complications may significantly affect the overall survival of breast cancer patients. The study by Colzani et al. [12,13] assessed the general causes of death in patients with breast cancer in European countries, with the top complications being heart, circulatory, lung, and gastrointestinal diseases, respectively. Many retrospective research had demonstrated a relationship between heart dose and major coronary events. Sarah C et al [14] conducted a population-based case-control study of coronary events in 2168 women who underwent radiotherapy for breast cancer. The rate of major coronary events increased by 7.4% for each increase of 1 Gy in the mean radiation dose delivered to the heart (95% CI, 2.9 to 14.5; P<0.001).
The LAD often located deep into the target area in spatial terms ( Figure 1A). The risk of a major coronary event increased linearly with the mean dose to the heart [15,16]. The risk depends on the local radiation dose, which indicated the possibility of reducing the risk by optimizing the dose distribution in the heart and left anterior descending artery (LAD).
The hybrid intensity modulation technique (Hybrid IMRT) [17], which consists of two tangential conformal radiotherapy (CRT) fields and 3-5 IMRT fields, is widespread because of the homogeneous dose distribution and better target coverage comparing to tangential CRT. The volumetric arc modulation radiotherapy (VMAT) technique has been widely used because of its high dose deliver efficiency and OAR sparing. However, the VMAT techniques may increase second cancer risk (SCR) as they involve more beams and a larger exposed normal tissue volume [18,19].
To evaluate the heart and LAD sparing of Hybrid IMRT and VMAT techniques, 15 left-sided whole-breast cancer patients underwent simultaneously integrated boost (SIB) radiotherapy with were selected. Both Hybrid IMRT and VMAT plans were generated. The PTVs dose distribution, OAR sparing and SCR values were evaluated to explore the feasibility of VMAT for whole-breast radiotherapy.

Ethics approval and consent to participate
The study was approved by the institutional review board of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital. We confirm that all methods were carried out in accordance with relevant guidelines and regulations.

Second cancer risk
The risk of developing a second cancer is usually represented by excess absolute risk EAR (per 10,000 persons-years). Cancer incidence is assumed proportional to the organ equivalent dose (OED). The EAR can be caculated according to The EAR0 (per 10,000 person-years per Gy) for lung and breast cancer incidence at low dose is 7.5 (CI 95: 5.1-10) and 9.2 (CI 95: 6.8-12) cases per 10,000 persons per year per Gy at age of 70 years after exposure at age of 30 years (derived from the A-bomb survivor data) [20]. Thus, the OED is porportional to the second cancer incidence.
We calculated the OEDs of contralateral breast, ipsilateral and contralateral lung were calculated for the linear, linear-exponentia, and plateau dose-response models [21,22] based on the differential DVHs according to DVH(Di) is the volume received dose Di. VT is the volume of summation of all voxels for organ T.
The α and δ were estimated according to the Japanese A-bomb and Hodgkin cohorts [23].

Dose delivery
Total MUs and beam-on time (BOT) of both 7F-IMRT and 2A-VMAT plans were analyzed.

Statistical analysis
A paired t-test was performed for 7F-IMRT and 2A-VMAT plans comparison by using SPSS (22 Version).     In this study, we aim to compare the LAD sparing of hybrid IMRT and VMAT techniques. LAD and helping stuctures, including LAD PRV 5 and LAD PRV 10 were contoured. Table 4 summarized the dosimetirc comparison results. As to LAD, LAD PRV 5, and LAD PRV 10, the   The results indicated the VMAT plans obtained equal or lower heart mean dose than IMRT plans.

PTV dose distribution and evaluation
VMAT plans acquired significantly lower mean dose of LAD, LAD PRV 5, and LAD PRV 10.
VMAT plans had optimized sparing of heart and LAD. The LAD helping structures, such as LAD PRV5 or LAD PRV 10, could help to evaluate and LAD dose.  Figure 4 shows the range of OEDs as calculated by the linear (Fig 4A), linear-exponential ( Fig   4B), and plateau ( Fig 4C)  using linear, linear-exponential, and plateau models. C) plateau.

Discussion
Breast cancer is the most common malignant tumor in women, with more than 1 million new diagnosed each year [24]. Many survivors received adjuvant whole-breast radiation therapy following breast-conserving surgery [1][2][3]. For left breast cancer, the doses of the heart were usually higher, especially for these patients in whom the distance between the heart to the thoracic wall is small. The risk of a major coronary and other heart diseases increased with the mean dose to the heart. The volumetric arc modulation radiotherapy (VMAT) technique has been widely used because of its high dose deliver efficiency and OAR sparing. Comparing to traditional tangential CRT or hybrid IMRT plans, VMAT plans have a larger coverage volume of low dose, which may increase the second cancer risk (SCR).
In this study, we aim to evaluate the possibility of VMAT techniques for left breast cancer radiotherapy. 15 left breast cancer patients who underwent adjuvant whole-breast radiation were selected. Both hybrid IMRT and VMAT plans were generated for each patient. The PTVs dosimetric characteristics and OARs dose sparing, especially heart, LAD , and LAD helping structures (LAD PRV 5 and LAD PRV 10) were evaluated. Besides, the SCR of both hybrid IMRT and VMAT plans were evaluated.
As to PTV and PTV Boost, both 7F-IMRT and 2A-VMAT plans could reach clinical constraints.
VMAT plans showed better conformity but higher mean dose and larger low dose coverage. As to OARs, significantly better dose sparing of contralateral lung, heart, and LAD were observed in VMAT plans. Dmax, Dmean, V40, and V30 of LAD, LAD PRV5, and LAD PRV 10 were significantly decreased in VMAT plans. There is a correlation between heart mean dose and mean dose of LAD, LAD PRV5, and LAD PRV 10.
We evaluated the SCR of the Lungs, heart, and contralateral breast using linear, linear-exponential, and plateau dose-response models based on the differential DVHs. The SCRs of VMAT plans were significantly increased in VMAT plans for the increase of mean dose. Trine G et al found that radiotherapy for breast cancer is associated with an excess risk of second non-breast cancer. For irradiated patients, the incidence of second cancers including the lung, esophagus, thyroid, and connective tissues progressively increased over time.
In this study, hybrid IMRT and VMAT plans were evaluated to explore the possibility of using VMAT techniques in breast cancer radiotherapy. VMAT plans had better conformity and dose sparing of heart and LAD, but a larger volume of low dose coverage. We recommend that contouring the LAD and LAD helping structures in left breast cancer radiotherapy. SCR should be evaluated for younger patients. The choice of optimal treatment method should be chosen in every patient individually depending on the balance between the cardiac complications and second cancer risks.

Informed Consent for publication
The informed consents for publication of data have been obtained from patients.