This observational study enrolled patients who were treated at West China Hospital, Sichuan University from October 2019 to July 2021. The inclusion criteria were as follows: 1) pathologically confirmed with invasive breast cancer; 2) treated with mastectomy and post-mastectomy breast reconstruction; 3) patients with primary tumor > 5cm, or ≥ 4 positive axillary nodes, or 1-3 positive axillary nodes with multiple high- risk factors, such as younger age, poor-differentiated or undifferentiated, HER-2 positive disease, triple negative disease, and high ki-67 index; 4) having willing to receiving PMRT. Male patients, patients aged ≤ 18 years, and patients with distant metastasis at diagnosis were excluded. This study was approved by the Biomedical Ethics Committee of West China hospital, Sichuan University (Approval number: 2021-900). All included patients signed written informed consent at initial diagnosis.

The images of the chest contour were obtained using the computed tomography (CT) scan, and were stored in digital imaging and communications in medicine (DICOM) format, and then converted into a format namely the stereolithography file. The 3D- printing software (Mimics 10.01) was used to create an individualized bolus based on CT images of the patients. The present study employed silicone material to fabricate the individualized bolus. With a physical density similar to human chest wall skin, silicone efficiently mitigates the interference caused by dose build-up effects in PMRT, ensuring precise radiation. Compared to other commercial materials, silicone exhibits characteristics such as resistance to deformation, high flexibility, long-term bendability, and resilience to deterioration during extended use. Overall, the 3D-printed bolus utilized in this study proves to be cost-effective and environmentally friendly. The positioning fixator was used to fix the bolus to reduce the positioning error. The conformability of the 3D-printed bolus was daily verified by cone beam computed tomography (CBCT).

The treatment planning was designed in the Raystation treatment planning system (TPS) (version 4.7.5; Ray Search Laboratories AB, Stockholm, Sweden) ( Figure 1 ). The clinical target volume (CTV) included the chest wall and supra and infraclavicular region with a planned dose of 50 gray/25 fractions, and the planning target volume (PTV) was defined as clinical target volume (CTV) with a certain 5mm margin. The PTV for the chest wall was denoted as PTV1, while the PTV for lymph drainage area was labeled as PTV2. In PTV2, the skin was cropped by 3mm from the body. As the chest wall was covered by the 3D-printed bolus, the skin was not cropped from the body in PTV1. The intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) radiotherapy techniques were used for radiation treatment planning. The dosimetric evaluation of PTV used the following parameters: D99%, D98%, D95%, Dmean, D50%, D2%, homogeneity index (HI = (D2%-D98%)/D50%), and absolute percentage differences (|%diff|=|100* (Dfact- Dtheory)/Dtheory|). The dose limit of OARs was evaluated as follows: ipsilateral lung (Dmean, V5, V20, V30), heart (Dmean, V30, V40), and spinal cord PRV Dmax) (19). Software Film QA Pro 2016 was used to analyze the dose distribution of the target volume and OARs.

A 3D-printed bolus was applied to the entire chest wall for in vivo dosimetry measurements following radiation. GafChromic EBT3 (International Specialty Products, Wayne, NJ, USA) was used to measure the absorbed skin dose in radiotherapy (20). The method of skin dose assessment was described in detail in our previous study (21). In our study, skin dose was measured by creating a volume in the TPS. Eight GafChromic EBT3 films, each sized 3 x 2 cm², were placed between the 3D-printed bolus and the chest wall. Within each EBT3 film, we identified a central 1 x 1 cm² region of interest (ROI). Each ROI were delineated in the center of each sub-region, with a size of 1 × 0.1 cm, between the 3D-printed bolus and the patient’s skin across three-slice CT images. The conformability of the 3D-printed bolus was assessed by measuring the air gaps between bolus and chest wall in 5 quadrants: center, upper outer, upper inner, lower outer, lower inner, in chest CT images. The max, mix, and mean gap values in above-mentioned quadrants were used to assess the conformability of the 3D printed bolus.

Radiation Therapy Oncology Group (RTOG) radiation injury classification was used to evaluated the skin toxicities during and after PMRT (22). The grades of the skin toxicity were as follows: grade 1, mild erythema, dry desquamation or both; grade 2, moderate erythema or patchy moist desquamation; grade 3, confluent moist desquamation, pitting edema and tenderness; grade 4, necrosis, ulceration, or bleeding. The classification of the skin toxicity was assessed by 2 or 3 radiotherapists to guarantee the accuracy. All patients were visited once a week from initial radiotherapy to four weeks after PMRT. Patients were advised better to keep the irradiated chest wall dry, minimize the friction and use radioactive skin protectants during radiation. Not all patients utilized the 3D-printed bolus throughout radiotherapy. The decision to continue bolus usage was determined by assessing skin toxicities after 3-4 weeks of radiotherapy. Patients with grade 2 skin toxicities, thin chest wall skin, and a low risk of local recurrence, or those with grade 3 skin toxicities should discontinue bolus usage.

A total of 360 patients diagnosed between October 2019 and July 2021 in our institution were enrolled. At finally, only 41 patients received breast reconstruction and PMRT, while 30 of them were included for analysis. The median age of the patients was 40 years old (range: 24-57 years). The left and right sites of the tumor were 43.9% (n=18) and 56.10% (n=23), respectively. The majority of the patients were T2-3 stage (75.7%, n=31), and N1-2 stage (75.6%, n=31). According to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system of breast cancer, 9.8% (n=4), 31.7% (n=13), 39.0% (n=16), 4.9% (n=2), and 14.6% (n=6) of the patients had stage IIA, IIB, IIIA, IIIB, and IIIC diseases, respectively. The detailed information was showed in Table 1 .

The dosimetric characteristics of the target volume and OARs are presented in Table 2 . Among all the patients, the mean doses of D99%, D98%, D95%, D50%, D2%, Dmax and Dmean of PTV were 4606.29cGy (4026-4871cGy), 4797.04cGy (4504-4949cGy), 4943.32cGy (4006-5055cGy), 5216.07cGy (5155-5271cGy), 5236.10cGy (5169-5302cGy), 5440.28cGy (5303-5563cGy) and 5462.10cGy (5320-5605cGy), respectively. The mean, max, and mix of HI values were 0.12, 0.18, and 0.08, respectively. With regard to the limit dose of OARs, the mean doses of Dmean of ipsilateral lung and heart were 1198.68cGy (range: 201-1634cGy) and 395.40cGy (range: 339-442cGy), respectively. The mean values of V5, V20 and V30 of the ipsilateral lung were 46.10%, 21.66% and 16.31%, respectively, and the mean values of V30 and V40 of the heart were 1.02% and 0.22%, respectively. The mean dose of Dmax of Spinal cord PRV was 1634cGy.

In vivo skin surface doses were measured in 4 of 30 patients. The mean values of Dmean were 210.69cGy (209.14-211.59cGy) and 209.97cGy (205.04-214.42cGy) in theory and measurement, respectively. The average of the absolute difference percentage was 0.33% (0.06-1.96), which mean that the actual dose closely matched the theoretical dose. The detailed information was showed in Table 3 .

In addition, we evaluated the conformability of the 3D-printed bolus ( Table 4 ). The mean air gaps between the bolus and the chest wall in center, upper outer, upper inner, lower outer, and lower inner quadrants were 0.04 cm (range: 0-0.33), 0.18 cm (range: 0-0.68), 0.04 cm (range: 0-0.36), 0.04 cm (range: 0-0.26), and 0.07 cm (range: 0-0.47), respectively, which showed good conformability.

Among the 30 patients receiving breast reconstruction and PMRT, one patient lost follow-up. At finally, 29 patients were included for skin toxicities evaluation. During the radiation, 22 (76.0%) and 6 (21.0%) patients developed grade 1 and grade 2 skin toxicities. One patient experienced grade3dermal toxicities, resulting in an interruption of radiation. Furthermore, grade 1 (63.64%, n=14) and grade 2 (100%, n=6) skin toxicities were more likely to occur at fractions 22-25 during radiation. Within 4 weeks after PMRT, there were 11 (38.0%), 11 (38.0%), 5 (17.0%), and 2 (7.0%) patients suffering grade 1-4 skin toxicities ( Table 5 ).