Immobilization-assisted abdominal deep inspiration breath-hold in post-mastectomy radiotherapy of left-sided breast cancer with internal mammary chain coverage

Introduction

Breast cancer ranks first in female cancer incidence worldwide (1). Adjuvant radiotherapy reduces recurrence and prolonged survival, especially in patients with lymph node involvement (2,3). Post-mastectomy radiotherapy (PMRT) usually encompasses the chest wall and regional lymph nodes, but whether to prophylactically irradiate the ipsilateral internal mammary chain (IMC) remains controversial because of conflicting data about the gains and losses of this treatment strategy (4-6). It is especially true of left-sided breast cancer where the heart is an organ at risk (OAR). Numerous reports have demonstrated increased cardiac morbidity and mortality years after adjuvant radiotherapy (RT) to the left-sided breast (7-11), which negated RT’s benefits.

Although the threshold cardiac dose is poorly understood, it is believed that each increased dose unit (Gy) translates into a proportional rise in the likelihood of heart damage and ischemic heart disease (8,12). Unlike those early breast cancer patients undergoing postoperative whole breast irradiation, almost all patients undergoing PMRT with IMC coverage will have been administered chemotherapy or even anti-HER2 therapies, which together can lead to additional toxicities (13). Over the past decades, several measures have been introduced to minimize doses to the heart during PMRT for left-sided breast cancer (5), including technical improvements of the Linac which is a linear accelerator equipment, respiratory gating to reduce the internal target volume (ITV), and deep inspiration breath-hold (DIBH) during RT (14,15). Since the first report in a small cohort of patients in 2001 by Sixel et al. (16), DIBH has been extensively studied in patients undergoing PMRT. Overall, considerable dose reduction of the heart and lungs was observed using DIBH regardless of the RT technique.

Nevertheless, there remain drawbacks to the currently practiced DIBH technique. Thoracic respiration is multi-muscular action that includes the intercostal muscles and the diaphragm. It is two-dimensional, thoracic respiration, if mostly using the intercostal muscles or abdominal respiration if mostly using the diaphragm. Accordingly, DIBH is not unidimensional but has thoracic (tDIBH) and abdominal DIBH (aDIBH) components. Changes in the proportion of these lead to target shifts. Understandably, one study reported significant movement of the lymph node areas due to DIBH, which implies a larger internal target volume (ITV) is needed to compensate for the movement (17). Our previous study found that by reducing the thoracic proportion as much as possible, aDIBH could further decrease the cardiac dose (18) because the significantly lowered heart position keeps it further away from the clinical target volume (CTV).

The IMC usually runs from the first to the fifth intercostal spaces adjacent to the sternum. During aDIBH, the sternum and the IMC remain almost motionless while the heart moves caudally together with the diaphragm. Given this geometrical advantage of aDIBH, we conducted a comparative dosimetric study of aDIBH and FB to maximally reduce the cardiac doses in the clinical setting of PMRT with IMC coverage.

Methods

Ethics

This study was approved by the hospital’s Institutional Review Board and complied with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for trials involving humans. Informed consent was given by all patients, who were carefully screened to rule out any contraindications to aDIBH.

Participants and preparations

From March 2018 to June 2019, 19 left-sided breast cancer patients (median age 52 years, range 31–69 years) with ≥4 axillary lymph nodes metastasis were included in the study. Before CT simulation, all patients were coached by a specialty nurse to familiarize them with the procedure of aDIBH. They were instructed to keep practicing for at least 1 week at home with video guidance. Key points of the practice were to use the diaphragm to displace the abdominal contents downwards during deep inspiration, keep the chest wall relatively motionless, and hold the breath for at least 10–15 s at the end of each maximal inhalation. This procedure was repeated 5–7 times, corresponding to the beam-on times during each treatment session.

CT simulation

The patients were placed on a dedicated breast board with a specially designed thermoplastic mesh (Orfit Industries NV, Wijnegem, Belgium), which served as the immobilization device for both setup reproducibility and suppression of thoracic movement. Part of the mesh covering the anterior abdominal wall was hollowed out to allow the abdomen’s inflation during aDIBH and facilitation of a Realtime Positioning Management (RPM, Varian Medical System, Palo Alto, CA, USA) system. A tissue equivalent compensator (bolus) of 5 mm thickness was put on the left chest wall beneath the mesh. All patients underwent plain CT simulation with a 3-mm slice thickness. CT image acquisition under FB was done first and once, and then two scans under aDIBH for a consistency check. The procedure of CT simulation took about 10 s. Additionally, the patient’s head was turned to the right and fixed with a smaller mesh for supraclavicular irradiation (See Figure S1 and Video 1).

Contouring and planning

Contouring of both the CTV and OARs [i.e., heart, left anterior descending coronary artery (LAD), lungs, and contralateral breast] was done by a senior radiation oncologist specializing in breast cancer radiotherapy, per guidelines recommended by Radiation Therapy Oncology Group (RTOG) Breast Contouring Atlas (19). The CTV included the left chest wall, supra- and infraclavicular regions, and the IMC from the first to the third intercostal spaces. A 5 mm expansion was added to CTV to form the planning target volume (PTV). The heart was defined as the volume from the lower part of the left pulmonary artery to the apex. The LAD was contoured with a diameter of 5 mm. The left main coronary artery (LMCA) was also contoured. The ipsilateral lung was contoured to exclude the major airways. The longitudinal distance from the sternal notch to the aortic valve (LDNV) in the Z-axis was calculated and compared under both FB and aDIBH during CT simulation. An Eclipse treatment planning system (Version 11, Varian Medical System, Palo Alto, CA, USA) was applied for dose calculations using the same constraints. The prescribed dose was 5,000 cGy in 25 fractions, requiring 95% of the PTV receiving at least 95% of the prescribed dosage. Six plans were generated for each patient, namely FB Three-dimensional conformal radiation therapy (3D-CRT), FB inverse planning intensity-modulated radiation therapy (IMRT), FB volumetric modulated arc therapy (VMAT), aDIBH _3D-CRT, aDIBH _IMRT, and aDIBH _VMAT. Table 1 illustrates the optimization objectives of IMRT and VAMT plans.

Table 1 Planning objectives for IMRT and VMAT optimization
Full table

The following parameters derived from the dose-volume histogram (DVH) were recorded for statistical analysis: the mean dose (D_mean) of PTV, the maximum dose of the 2% volume (D2%), the minimum dose of the 98% volume (D98%). Homogeneity Index (HI) was calculated with HI=(D2%-98%)/50. As for OARs, the volumes receiving 5 Gy (V5), 20 Gy (V20) and 30 Gy (V30) were recorded and compared between FB and aDIBH, as well as the mean doses.

Results

Geometric comparison of FB and aDIBH

As shown in Figure 1, the relationship between the IMC-inclusive PTV and OARs was demonstrated under both FB and aDIBH. With aDIBH, the heart and LAD moved downwards and further away from the PTV. Using the seventh thoracic vertebra as an internal reference, the degree of downward movement of the heart and LAD was easily observed. Compared with FB, the overlapping area was much smaller in the tangential view under aDIBH.

Figure 1 Spatial relationship between IMC-inclusive PTV (pink) and OARs in the tangential view. (A) Free breathing (FB); (B) abdominal deep inspiration breath-hold (aDIBH). The left lung (blue), heart (red), left anterior descending coronary artery (LAD: green), 1–4 anterior ribs (white), IMC (light blue), and the diaphragm (green) are shown as OARS. The seventh vertebral body (T7) is contoured as an internal reference. During aDIBH, the heart and LAD move caudally as compared with FB. OARs, organs at risk.

The heart’s positional difference between FB and aDIBH was calculated using LDNV, which was 1.44±0.48 cm (10.33±0.48 and 8.88±1.12 cm during aDIBH and FB, respectively) (Figure 2). Explicitly, the heart and LAD moved away from the internal mammary chain (IMC) in CT simulation during aDIBH.

Figure 2 Double-headed arrows (dark-blue) show the longitudinal distance between the sternal notch (red) and aortic valve (green), which is significantly increased with abdominal deep inspiration breath-hold (aDIBH). Also, note the heart (red) and left anterior descending coronary artery (LAD: dark-green) move away from the internal mammary chain (IMC: light-blue) during aDIBH.

Heart and LAD

As compared with FB, all dose parameters of the heart and LAD under aDIBH were statistically significantly improved (Tables 2-4). With aDIBH, the D_mean of the heart and LAD were respectively reduced by 3.5 Gy (P<0.003) and 8.9 Gy (P<0.001) in 3D-CRT, 2.6 Gy (P<0.001) and 7.8 Gy (P=0.001) in IMRT, and 1.5 Gy (P<0.001) and 4.5 Gy (P=0.001) in VMAT plans (Figure 3A,B). Among all these plans, the D_mean of the heart was lowest in aDIBH _IMRT (Figure 3A), 1.3 Gy lower than aDIBH _VMAT (P=0.002). As compared with FB, a reduction of 3 Gy in the D_mean of the heart (P=0.001) and 19.5 Gy for the LAD (P<0.001) were observed using aDIBH _IMRT (Table 3). The D_mean, V20, V30, and D2% of the LAD showed a dosimetric advantage tendency with no statistical significance. Notably, the LAD’s V5 was higher in the VMAT plans than with IMRT and 3D-CRT (Table 5).

Table 2 Dosimetric comparison for 3D-CRT plans based on abdominal deep inspiration breath-hold (aDIBH) and free-breathing (FB)
Full table

Table 3 Dosimetric comparison for IMRT plans based on abdominal deep inspiration breath-hold (aDIBH) and free-breathing (FB)
Full table

Table 4 Dosimetric comparison for VMAT plans based on abdominal deep inspiration breath-hold (aDIBH) and free-breathing (FB)
Full table

Figure 3 Mean dose of the heart (a), LAD (b), left lung (c), and right lung (d) following three-dimensional conformal radiation therapy (3D-CRT), inverse planning intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT), plans during FB and aDIBH. Note: P values *<0.05, **<0.01, ***<0.001. ^#<0.05, ^##<0.01, ^###<0.001, ns: no significance. aDIBH, abdominal deep inspiration breath-hold; FB, free-breathing; LAD, left anterior descending coronary artery.

Table 5 Dosimetric comparison for IMRT and VMAT plans based on abdominal deep inspiration breath-hold (aDIBH)
Full table

Lungs

There was a significant difference in the lung volumes between FB and aDIBH, with an increase of 437.3 and 486.3 mL for the left and right lungs, respectively, under aDIBH (Table 2). Dosimetrically, the D_mean, V5, V10, V20, and V30 of the left lung decreased in both the aDIBH _3D-CRT and aDIBH _IMRT plans compared with their counterparts of FB _3D-CRT and FB _IMRT (Tables 2,3, Figure 3C). Consistently, VMAT plans resulted in higher D_mean, V5, and V10 of the left lung than IMRT plans. Also, an increase of 4.2 Gy (P<0.001), 33.2% (P<0.001), 11.7% (P<0.001), and 0.8% (P<0.001) of the D_mean, V5, V10, and V20, respectively, were observed using aDIBH _VMAT compared with aDIBH _IMRT. Overall, the respiratory mode had no effect on the right lung doses, whichever plan was applied (Table 5, Figure 3D).

Contralateral breast dose analysis

As compared with aDIBH _IMRT, aDIBH _VMAT showed an increase of 2.4 Gy (P<0.001) in the D_mean and 21.5% (P<0.001) in the V5 of the contralateral breast. Similarly, an increase of 3.5 Gy (P<0.001), 27% (P<0.001), and 8% (P<0.001) in the D_mean, V5, and V10 were observed using aDIBH _VMAT versus aDIBH _IMRT (Table 5).

PTV

The Homogeneity Index (HI) of the PTV was 0.17±0.2, 0.14±0.03, and 0.13±0.01 in aDIBH _3D-CRT, aDIBH _IMRT, and aDIBH _VMAT, respectively (Tables 2,5). Among the three techniques, aDIBH _3D-CRT resulted in the highest HI, and there was no difference in HI between aDIBH _IMRT and aDIBH _VMAT (Table 5).

Discussion

IMC’s prophylactic irradiation has been recommended for a subset of breast cancer patients with high metastatic potential (20). However, it brings additional risk because of the considerable increase in doses to the OARs when the IMC is included in the CTV (5,6). This study compared the dosimetric results obtained from six treatment plans (FB _3D-CRT, FB _IMRT, FB _VMAT, aDIBH _3D-CRT, aDIBH _IMRT, and aDIBH _VMAT) for left-sided breast cancer patients undergoing IMC-inclusive PMRT. We found that with aDIBH, the doses to the heart and LAD were substantially decreased regardless of the treatment plan (3D-CRT, IMRT, and VMAT), which is consistent with our previous study we first proposed using aDIBH to reduce the cardiac dose further (18).

The respiratory movement executed by the intercostal muscles or the diaphragm corresponds to either thoracic or abdominal respiration. So, the deep inspiration maneuver consists of tDIBH and aDIBH, depending on the respective muscle groups’ work. During aDIBH, the heart descends maximally together with the diaphragm, whereas the IMC-inclusive PTV position stays unchanged due to suppressed sternal movement. It manifested as a difference (1.44±0.48 cm) in the LDNV between aDIBH and FB. As the LDNV increased, the overlapping area between the PTV and the heart in the tangential beam’s eye view became much smaller in aDIBH compared with FB.

If not properly trained, the patients will perform DIBH inconsistently, resulting in varying proportions of tDIBH and aDIBH. Pazos et al. reported an increased amplitude of the lymph node levels’ movement to be irradiated in breast cancer patients using DIBH compared with FB (21). We speculate that this phenomenon derives from unstable respiration modes during DIBH and will undoubtedly increase the ITVs, which offsets the benefit of DIBH. It is overcome by prior training for the patient and auxiliary devices to restrict the sternum’s anterior/superior movement that occurs with tDIBH. Our specially designed thermoplastic mesh served as an immobilization tool that both minimized the setup errors and eliminated the thoracic proportion of respiration.

As shown in Figure 4, a significant increase in lung volumes was observed during aDIBH. A positive relationship between lung expansion and cardiac sparing has been reported, and our results agree with those of previous studies (22). Besides, there was also a positive correlation between increased LDNV and cardiac dose reduction. Strikingly, in 3 of our 19 patients, the difference of LDNV between aDIBH and FB was small, resulting in insignificant cardiac sparing. Therefore, we speculate that compared with lung expansion, LDNV might better predict the advantage of aDIBH in reducing doses to the heart and LAD in patients receiving PMRT with IMC coverage. There is a need for further studies with more patient data to prove our speculation.

Figure 4 Correlational analyses of lung expansion and heart descent with cardiac dose. There is a positive correlation between the degree of lung expansion and cardiac dose reduction in all three treatment plans of three-dimensional conformal radiation therapy (3D-CRT), inverse planning intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT), most notably in 3D-CRT (A). Also, the more the heart descends, the less the radiation dose to the heart (B).

In this study, PTV coverage was the highest priority in multi-objective optimization in IMRT and VMAT plans. At least 95% of the PTV should be within 95% of the prescribed dose, with adequate IMC coverage in IMRT/VMAT plans under both aDIBH and FB. In contrast, the plan quality of 3D-CRT was relatively poor in this cohort of patients, as manifested by the higher HI (0.17) as compared with IMRT (0.14) and VMAT (0.13) plans. It is reported that using the field-in-field technique; HI can be significantly improved in 3D-CRT plans of the breast (23). Among all six plans, aDIBH _IMRT resulted in superior IMC dose coverage and the lowest cardiac irradiation.

PMRT can be associated with an increased risk of secondary cancers, especially of the lungs and the contralateral breast (24,25). Dosimetrically, although the percentage of high-dose regions of both lungs and the right breast decreased using VMAT, the low-dose volumes of these OARs increased considerably. This result was consistent with a report by Karpf et al. (26) and might increase the risk of developing secondary malignancies.

There are certain limitations to our study. Firstly, only 3D-CRT, inverse planning IMRT, and VMAT were utilized for dosimetric comparisons. It is reported that forward-planning IMRT might be better in dosimetric distributions, although it is more time-consuming and prone to bias because of its need for expertise (27). Secondly, our results can not be extrapolated to all women of different ethnicities and body shapes due to the relatively small sample size. aDIBH might not apply to women with excessive abdominal obesity because of the limited diaphragmatic movement due to high intra-abdominal pressure.

Conclusions

With aDIBH, doses to the heart, LAD, and the left lung can be substantially decreased in patients receiving IMC-inclusive PMRT as compared with FB. Our specially designed immobilization device can facilitate the maneuverability and reproducibility of aDIBH. This technique has excellent clinical potential that warrants robust study with larger sample sizes.

Acknowledgments

We thank all the patients participating in the study.

Funding: This study was supported by the Zhejiang Provincial Key Discipline of Traditional Chinese Medicine (2017-XK-A32), Chinese Medicine Research Program of Zhejiang Province (2018ZZ014), Zhejiang Provincial Natural Science Foundation & Zhejiang Society for Mathematical Medicine (LSY19H160002), and the Health Commission of Zhejiang Province (2020KY131, 2018KY063).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-831). The authors have no conflicts of interest to declare.

Ethical Statement: This study was approved by the hospital’s Institutional Review Board and complied with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for trials involving humans. Informed consent was given by all patients, who were carefully screened to rule out any contraindications to aDIBH.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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