Radiation therapy after conservative breast surgery is an integral part of the locoregional treatment of early breast cancer since first approved by the World Health Organization Committee of Investigators for Evaluation of Methods of Diagnosis and Treatment of Breast Cancer in 1969 . Such radiotherapy proved to reduce the local recurrence and the risk of death from breast cancer. But long-term trials had shown that radiotherapy can also augment the risk of ischemic heart disease through the incidental irradiation of the heart, especially in the left sided breast cancer, which is already known to be slightly more common than the right sided carcinoma  .
The dose-volume predictors for acute and late radiation-induced toxicities are established for the lung and heart as a whole structure. An estimated linear increase of 7.4% in major coronary events and 4.1% in cardiac mortality were found per every Gy of the mean heart dose (MHD)  . For lung toxicity, dose-volume values of the treatment plan e.g., mean dose to the whole lung and V20, are the risk factors for pneumonitis and lung fibrosis. Other factors like breast volume, nodal irradiation and boost were found to increase the MHD in a study done by Pierce et al. .
The aim of radiation planning is to achieve the best coverage of the Clinical Target Volume (CTV)/Planning Target Volume (PTV), while reducing the dose to the Organs at Risk (OAR). However, ideal plans are not always achievable with the conformal three dimensions plans (3DCRT). In the last decade, radiation oncologist started to use the Intensity Modulated Radiotherapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT) for irradiating the breast, as they believe that dose distribution and target dose of both the PTV and OAR could be better achieved .
The aim of the study is to compare 3DCRT, IMRT and VMAT for left breast cancer patients in terms of PTV coverage, OAR constrains, homogeneity index and conformity index. The study also revised the different dose distributions in 1) different breast volume categories, 2) nodal irradiation versus breast only, and 3) boost versus no boost.
2. Patients and Method
We revised the treatment plans of 19 female patients, who received radiotherapy after conservative surgery for left breast cancer in our department of radiation oncology at the International Medical Center (IMC) Cairo, Egypt, from March 2017 and March 2020. Treatment methods were variable upon physician choice, 6 received VMAT, 7 received 3DCRT and 6 received IMRT. We created two other plans for each patient, so we could physically compare the three types of plans (3DCRT, IMRT, VMAT) for each patient.
2.2.1. Positioning and CT Scanning
Patients have their both arms raised above their heads, fixed by breast board. CT scanning of 5 mm slicing, was performed (aperture of 64 spiral slices CT, GE Medical Systems). CT scans obtained from the mandible to the lower border of the thorax.
2.2.2. Clinical Target Volume (CTV) and Organ at Risk (OAR) Delineation
CTV included the left breast only or, with lymph node region, and/or boost to the tumor bed. Dedicated OAR included: ipsilateral lung, heart, the spinal cord, contralateral lung, contralateral breast, and the left anterior descending artery (LAD). All delineated by the radiation oncologist, using Varian eclipse 15.6 treatment planning system (TPS). Planning Target Volume (PTV)/CTV margin was decided to be 5 mm isotropically.
2.3. Plan Design
2.3.1. Plan Goals
PTV was prescribed to a total dose of 50 Gy, in 25 fractions. When a boost was indicated, an added 10 Gy to the tumor bed was planned, to be given sequentially. Plan goals were as follows: For the PTV, 99% of the PTV should receive at least 95% of prescription dose (47.5 Gy), maximum dose ≤ 107%, and the minimum dose ≥ 95%. For the ipsilateral lung, V20 < 30% and the mean dose (D mean) < 22 Gy. For the spinal cord, the Dmax should be < 45 Gy. For the heart, V25 < 10 Gy. For the contralateral lung V5 Gy < 26% and V15 Gy < 5%. The contralateral breast, the mean dose (D mean) < 5 Gy. The left anterior descending (LAD) artery should be less as possible.
2.3.2. Plan Arrangement
For each patient, we developed three plans using the same techniques as shown in (Table 1).
2.4. Plan Assessment
For each plan, we assessed the followings:
· For the PTV:
PTV Max %, PTV Min %, 107% volume, PTV 100% cc (the PTV volume receiving 100% of the dose), D2, D98, D50 (dose received by the 2%, 98% and 50% of the volume, respectively). CI (Conformity Index) was defined as: Body V100% (cc)/PTV (cc), HI (Homogeneity Index) was defined as: (D2%-D98%)/D50%.
· For the OARs:
For the ipsilateral lung: V10, V20, and D mean. For the contralateral lung: D
Table 1. 3DCRT, IMRT and VMAT beam arrangements.
mean, V5 and V10. For the contralateral breast D mean and D max. For the heart D mean and V5, V10 and V25. For the LAD, D mean, D max. For the body, V100% (the body volume receiving 100% of the dose).
3. Statistical Analysis
Data collected were analyzed using SPSS version 22. We used the paired-samples T-test to perform the comparison of dosimetry differences among 3 plans, which is based on as the statistical difference (P < 0.05).
4.1. Patient and Target Volume Criteria
In our cohort the mean age was 57.37 years. All the patients received radiotherapy to the left breast, with 7 patients (36.8%) received nodal irradiation and 13 patients (68.4%) received a boost to the tumor bed. According to breast volume, patients were categorized into three categories small, intermediate, large volume (Table 2).
4.2. PTV and OAR Dosimetrics
Table 3 shows the archived dose constrains in percentage dose format, for the PTV and the routinely reported OARs.
Regarding the PTV coverage, there was no difference in both PTV Max and PTV Min dose in the three techniques, only the 107% cc volume was significantly lower in IMRT plans compared with VMAT (p 0.045).
Table 2. Patient and target volume.
The routinely reported dose constrains for the ipsilateral lung (mean dose, V10 and V20), and for the heart (mean dose, V5, V10 and V25,) were not significantly different on comparing the three techniques. While for the contralateral lung, the difference in mean dose was statistically significant and generally in favor of 3DCRT: (p 0.001 3D vs IMRT vs VMAT), (p 0.002 3D vs IMRT in favor of 3D), (p 0.001 3D vs VMAT in favor of 3D). Regarding the Max dose, 3DCRT provided the lowest dose in comparison with VMAT (p < 0.041). Similarly, the contralateral breast mean dose constrains had a better profile in favor of 3DCRT: (p 0.002 3D vs VMAT in favor of 3D), (p 0.006 (3D vs IMRT in favor of 3D), (p 0.002 (3D vs VMAT in favor of 3D). Contrarily, in our cohort, IMRT provided lower LAD mean dose when compared with 3DCRT (p < 0.001).
4.2.3. The Effect of Breast Volume, Nodal Irradiation and Boost
The three techniques showed almost the same dose constrains (Table 4) except for:
1) In large breast volume, 3DCRT provided a lower Max dose to the contralateral lungand lowest mean dose to the contralateral breast when compared to IMRT (p < 0.046 3D vs IMRT).
2) In case of No nodal irradiation, the contralateral breast mean dose was lower in 3DCRT in comparison to IMRT and VMAT (p < 0.037 3DCRT vs IMRT vs VMAT). Also, Body Volume receiving 100% cc was lower in VMAT (p < 0.031 VMAT vs 3DCRT). And IMRT provided higher homogeneity index compared with VMAT (p < 0.046 IMRT vs VMAT).
3) When boost dose was given, 3DCRT plans had produced a lower Max dose to the contralateral lung (p < 0.017 3D vs IMRT) and lower mean dose to the contralateral breast (p < 0.006 3D vs IMRT).
Radiotherapy in breast cancer is challenging due to the geometric differences in the breast tissue structures which may have an impact on the dose distribution so the selection of the radiotherapy technique is crucial for safe treatment delivery . A number of studies have demonstrated the dosimetric benefit of IMRT
Table 3. Percentage dose constrains for PTV, OAR.
compared to 3DCRT; some of these trials have reported lower doses to the ipsilateral lung, heart, and left anterior descending artery . Meanwhile VMAT has a great advantage in reducing the treatment time and the number of MU without reducing dose distribution . In this study we had compared the dosimetric parameters of 3DCRT, IMRT and VMAT in order to select the best technique for post-operative radiotherapy delivery to left breast ± draining lymph nodes ± boost irradiation, after breast conservative surgery. Also, breast volume categories were challenged against the three techniques.
In our cohort, with three plans (3DCRT, IMRT and VMAT) generated for each patient, there was no significant difference neither in PTV Max nor in Min dose. Only the 107% volume in PTV was lower in IMRT plans. These results were comparable to Vasudevan et al. , who reported that the PTV volume
Table 4. Breast volume, nodal irradiation and boost dosimetrics.
received 107% of the prescribed dose was higher for VMAT and 3DCRT compared to IMRT. Conversely, Lancellotta et al. , reported that 3DCRT provided the poorest target coverage in comparison with IMRT.
As regards to the routinely used OARs, the heart and ipsilateral lung dose were the same among the three techniques but LAD mean dose was lower in IMRT. These findings are opposed to what Aras et al.  reported, that at lower doses, the dose to the left lung and the heart, were lower with the 3D-CRT technique. Differently, Vasudevan et al. , reported that the mean heart and lung doses were higher with VMAT and IMRT compared to 3DCRT.
In literature, the risk of second malignancy is related to the low dose regions rather than the high dose regions in the OARs . Unfortunately, the dose constrains of the contralateral lung and breast are not routinely reported. These constrains of the contralateral organs may be one of the areas of difference, and debate, between the three techniques. In our study, 3DCRT provided a lower mean and Max doses to the contralateral lung breast. On the other side Vasudevan et al. , documented that the mean dose to contra lateral breast and lung were similar for IMRT and 3DCRT, but higher with VMAT.
Regarding the definition of different breast volumes, some of the studies used the bra size , others used the distance between the edges of the lateral and medial fields i.e., separation. . But more conveniently to the modern radiation techniques, breast volume (in cc) is better used to categorize the clinical target volumes (CTV) volumes. One of the commonly used categorizations, suggested by Michalski A et al., is as follows: Large volume ≥ 1.600 cm3, Intermediate 975 - 1.600 cm3, and Small ≤ 500 - 975 cm3 . In large breast volume category, the 3DCRT showed an advantage over IMRT and VMAT, in terms of achieving a better constrains to the contralateral organs e.g., a lower Max dose to the contralateral lung and lower mean dose to the contralateral breast.
Also, the 3DCRT had been shown to be more protective to the contralateral breast in patients who received breast only irradiation, as it provided a lower mean dose. Conversely, in those patients with no nodal irradiation, IMRT provided higher HI. Additionally, 3DCRT provided lower Max dose to the contralateral lung and lower mean dose to the contralateral breast, when we added boost dose 10 Gy/5fx .
The choice of radiotherapy in breast cancer treatment is a very important factor in the protection of normal tissue and in providing proper coverage of the target. The three techniques (3DCRT, IMRT, and VMAT) can meet the clinical dosimetry demands of radiotherapy for left breast cancer after conservative surgery, as long as the routinely OARs only (heart and ipsilateral lung) are reported. Our study showed that 3CDRT can provide a lower dose to the contralateral organs (breast and lung), specially, in case of large breast volumes, no nodal irradiation and when a boost is given.
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