The toxicity risk of breast cancer radiotherapy has been widely concerned by radiation oncologists. Darvby et al17 showed that the incidence of major coronary events after breast cancer radiotherapy was linearly increased with the mean cardiac dose. For every l00cGy increase in the mean dose to the heart, the corresponding probability of coronary adverse events hiked by 7.4%, and the risk of cardiotoxicity lasted for decades after treatment. Colossal amounts of studies have shown that amid left breast cancer radiotherapy, DIBH technology can separate the heart from mammary gland position, so as to significantly shrink the high dose volume and mean dose of the heart, and reduce heart disease risks associated18–20. Meanwhile, coupled with DIBH technology, it can also increase the lung volume, reduce the lung tissue density, which lowers the irradiation dose in the lung13, and slump the irradiation dose of the contralateral breast, stomach and liver to varying degrees21,22. Although DIBH technique is widely used in left-sided breast cancer, there are few reports on the clinical application of DIBH technique in right-sided breast cancer. According to several radiotherapy planning studies23–27, DIBH reduces lung dose compared with FB in patients with right-sided breast cancer and achieves liver protection during radiotherapy25.
A radiotherapy planning study by Conway JL et al13 showed that the mean lung dose was reduced by 340cGy and the mean cardiac dose was significantly slumped in patients undergoing DIBH irradiation coupled with internal mammary chain (IMC). A radiotherapy planning study conducted by Chloe et al23 showed that 8 patients with RNI-containing right breast cancer were treated with DIBH technique. Their mean dose of the ipsilateral lung was decreased from 1820 ± 320cGy to 1590 ± 230 cGy, and maximum dose of RCA was reduced from 1160 ± 720cGy to 560 ± 290cGy. Although DIBH technology has obvious dosimetric value in right-sided breast radiotherapy, especially in the right breast with RNI irradiation, due to the complexity of the technology and the cost investment of time and labor, no large number of cases have been reported for clinical application. Abiding by 'as low as reasonably achievable'(ALARA) principle, DIBH radiation therapy for breast cancer patients with RNI had been conducted in our department since May 2021 and a retrospective study on dosimetry and accuracy for 31 breast cancer patients with RNI was conducted.
In this study, the mean cardiac and RCA dose reduction rates by DIBH were 25.2% and 23.1%, respectively. However, the DIBH technique in left breast radiotherapy can reduce the mean dose of heart and LAD by 25–67% and 20–73%, respectively28, with an average reduction of 46% and 46.5%, respectively. In conclusion, in terms of the contribution of DIBH technology to the average decline rate for heart and RCA, the benefit of right breast cancer patients is significantly weaker than that of left breast cancer patients. It is speculated that, as the heart deviates from the right mammary gland, and the mean dose values of the heart and RCA are controlled at a low level under FB condition, although the distance between the heart and the chest wall is further increased by DIBH, its contribution to the mean reduction of the heart and its substructure is limited. With respect to maximum dose, DIBH technique significantly contracted the maximum dose of heart and RCA (decrease value: 740 ± 570cGy, 510 ± 460 cGy, P < 0.05), and the average decline rates were 44.3% and 46.7%, respectively. The results of this study were similar to those of Chloe et al23 reported. A study by Altinok et al29 showed that high doses of RCA in the heart, especially proximal part, increased the risk of coronary heart disease. During RNI irradiation, IMN is close to a small amount of heart volume, and DIBH technology can distance IMN from the heart, which significantly contributes to the reduction of the maximum dose of heart and RCA, and can reduce the risk of coronary heart disease in patients.
Lung is an important OARs in breast cancer radiotherapy. In a meta-analysis of 742648 breast cancer patients, Grantzau and Overgaard30 found that compared with patients who did not receive radiotherapy, patients accepted radiotherapy had a higher secondary lung cancer morbidity 5 and 15 years after treatment, 39% and 66% respectively. Due to advances in technology, the incidence of radiation pneumonitis (RP) after modern breast radiotherapy is lower (1%-5%) and pulmonary function decline is more common, but lung dose is positively associated with the incidence and severity of RP31–33. Therefore, breast cancer patients who received extra RNI have a significantly higher rate of RP than those who received whole breast radiotherapy alone34,35. In this study, V500cGy (from 53.3 ± 3.0% to 48.3 ± 2.9%, p < 0.05), V2000cGy (from 25.7 ± 1.9% to 20.6 ± 3.2%, p < 0.05), V3000cGy (from18.3 ± 2.5% to 15.3 ± 2.3%, p < 0.05), and mean dose (from 1332.1 ± 128.7cGy to 1165.4 ± 148cGy, p < 0.05) were decreased to different degrees. The V3000cGy of the ipsilateral lung decreased to less than 20% in all patients. The results of this study further proves the feasibility and necessity of using DIBH to reduce pulmonary exposure during RNI-containing right breast radiotherapy.
Among the OARs involved in this study, liver changed the most in terms of mean dose (916.9 ± 318. 9cGy to 281.2 ± 150.3 cGy) and average dose reduction rate(69.4%). Although radiation-induced liver toxicity has been widely recognized, the related research in breast cancer radiotherapy is still insufficient. Only a few radiotherapy planning studies have shown that DIBH technique can achieve good liver protection effect in right breast cancer23,24,37. In the DIBH state, the increase of lung volume makes the liver deviate from the target volume to the human foot side, which is the direct reason for the significant reduction of liver dose. Although the evidence related to the clinical benefit of liver protection in breast cancer radiotherapy is still short, according to the ALARA principle, DIBH potential benefit value for liver protection of the right breast cancer radiotherapy patients is still positive.
With the development of DIBH radiotherapy technology, the repeatability and stability of interfractional and intrafractional breath holding have been widely concerned38–42. SGRT-based DIBH radiotherapy adopts optical image-guided positioning to improve the setup accuracy before treatment, and to monitor patients' position changes in real time during treatment, which enhances the repeatability and stability of patients' breath-holding and effectively guarantees treatment accuracy for patients40–43. Amid the implementation of SGRT-based DIBH radiotherapy, the position of the respiratory gating primary point can be manual placed. In most of the reported studies, the position of the gating primary point is not clear, and there is a lack of relevant comparative studies to guide the set up of the gating primary point14,15,43−45. AAPM Task Group Report 302 believes that a better respiratory curve can be obtained when the gating point is placed at the xiphoid process43. D.Reit Z et al44 analysed the breath-hold stability and repeatability of 6013 DIBH fractional treatment. In that study, all patients' gating primary points were placed at the edge of xiphoid process, and the breath-hold amplitude displayed by the SGRT system between patients' fractional treatment was used as an indicator to judge the breath-hold stability and repeatability. Schönecker et al45 reported that DIBH radiotherapy for left breast cancer has also been performed by setting gating primary points on the sternum. Among the 31 patients included in this study, the gating primary points of the patients undergoing breast-conserving surgery were placed on the edge of xiphoid process (11 cases) or the middle of sternum (12 cases), and 8 cases of the patients undergoing radical mastectomy surgery were set on the contralateral breast wall where the bolus was avoided. The research team compared and analysed the CBCT validation data collected from 187 fractions in 31 patients under DIBH after dividing them into three groups (EXP group, SM group, LBW group), and performed a retrospective evaluation study on the treatment accuracy.
The statistical results of the three sets of data showed that, in the SM group and LBW group, the overall setup errors in all directions were 2.4 ± 3.0mm and 2.5 ± 3.2mm, respectively. The incidence of absolute setup errors within 3mm was 64.1% and 59.8%, respectively and meanwhile, only one fraction showed setup error greater than 8mm in both groups, with an occurrence rate of less than 1%. This indicated that the SM group and LBW group had better breath-hold repeatability and stability, and in turn higher treatment accuracy. Whereas, in EXP group, the overall setup error in all directions was 3.2 ± 4.0mm, the incidence of the absolute value of setup error within 3mm was 52.6% and 6 fractions showed abnormal setup error greater than 8mm, five of them clustered in AP direction. Through the analysis of these abnormal data on CBCT images, it was found that inspiratory capacity seriously insufficient occured in 4 patients, and the positions of heart, lung and liver were significantly inconsistent with those of localization CT images, as shown in Fig. 3.This is an important finding, and although all patients were trained to perform thoracic breathing and were performed CBCT scans while holding their breath to a preset range of gating windows, abnormal breath-hold stability and repeatability persisted.
After analysis, the research team believes that the rise in respiration at the edge of xiphoid process is affected by both the amplitude of thoracic and abdominal respiration, and during the course of treatment, patients involuntarily adopt abdominal or mixed breathing to make the breathing amplitude reach the preset range of the gating window, which leads to the relatively poor treatment accuracy of EXP group in this study. For patients with thoracic breathing, the gating point placed on the sternum or breast wall has better interfractions breath-holding repeatability and stability, and the EXP gating point needs to be carefully selected. DIBH radiotherapy for right breast cancer has high overall treatment accuracy under the premise of selecting appropriate gating point location. The analysis of regional anatomical location accuracy is not studied in this paper, which will be concerned in subsequent studies. Theoretically, the location selection of gating points is equally important to ensure the accuracy of DIBH radiotherapy for left and right breast cancer. If conditions permit, abdominal pressure technique can be used in thoracic breathing to control the occurrence of abdominal breathing.
In addition, we observed large differences in DIBH height when different gating points were placed. Statistics showed that the DIBH heights of the EXP, SM and LBM groups were 13.5 ± 3.7mm, 10.3 ± 2.4mm, and 9.6 ± 2.8mm, respectively and the difference was statistically significant (P < 0.05). The corresponding right lung volume increment was 71.3%, 69.9%, and 67.2%, respectively(P = 0.08), without statistically significant difference. Although the breath-hold height of EXP group was significantly higher than that of the other two groups, the lung volume increase rate was larger in all three groups without significant difference. Oonsiri et al47 studied the correlation between total lung volume (TLV), central lung distance (CLD), chest wall separation (CWS) and DIBH radiotherapy exclusion criteria for left breast cancer, and found that there was a deterministic relationship between TLV increment and cardiopulmonary dose decrease. The mean increase in lung volume in that study was 41.5%, which can be used as an exclusion criterion for DIBH radiotherapy. In traditional DIBH breathing training, the rise height of the gating point after breathing is generally considered as an important indicator for predicting lung volume increase. Schröde et al46 did not specify the position of the gating point during the clinical workflow of DIBH, but required that the rise height of the DIBH gating point be greater than 12m from the baseline. In this study, in the SM group and LBW group with better breath-holding repeatability and stability, a total of 11 patients did not reach 12mm in respiration height, the lowest of which was only 6.5mm, and the right lung volume increment of the patients was above 50%, which was higher than that in Oonsiri47 and other studies. Retrospective planning data in Table 1 also confirmed dosimetric benefits of varying degrees in these patients. We believes that the body surface rise of patients after DIBH varies greatly with different patients and different gating points. If breath-hold height is used as a reference index to evaluate lung volume increment and furthermore emerges as the exclusion criterion for DIBH radiotherapy, it is necessary to further study and clarify the specific reference values corresponding to different gating point locations. Until then, it is still recommended to observe the anatomical position changes and calculate the lung volume increment by scanning FB and DIBH CT images for accurate determination.
The results of previous radiotherapy planning studies suggested that patients receiving right breast radiotherapy with RNI had significant benefit in heart and lung dosimetry, while patients receiving right breast radiotherapy without RNI had less benefit22–26. To this end, DIBH radiotherapy was only applied to right breast cancer with RNI for this retrospective study. The results of this study confirmed the restricted effect of DIBH radiotherapy supported by optical surface images on OARs dose(especially liver) and proved that, DIBH technique had high therapeutic accuracy in right breast cancer. In the future, DIBH radiotherapy in right breast cancer without RNI will be studied, so as to explore its broader clinical application value.