Non-coplanar volumetric modulated arc therapy for locoregional radiotherapy of left-sided breast cancer including internal mammary nodes

Adjuvant radiotherapy after breast-conserving surgery has been proven to be effective in reducing the risk of recurrence and death from breast cancer.1, 2 In radiotherapy for breast cancer, internal mammary nodes (IMN) and supraclavicular nodes (SCN) are often included in planning target volume (PTV) to improve local control.3, 4, 5, 6 However, irradiation of IMN inevitably increases the dose delivered to heart and lungs, raising the risk of radiation pneumonitis and cardiac mortality.7 Indeed, approximately 1%–5% of patients with breast cancer develop radiation pneumonitis after radiotherapy as predicted by the normal tissue complication probability model.8 In a study of 61 patients with early breast cancer who received radiotherapy, approximately 12.5% developed > grade 1 radiation pneumonitis at 12 months.9 Additionally, cardiac diseases, such as ischemic heart disease is another major concern associated with radiotherapy in breast cancer10, 11, 12 and controversies remain concerning IMN irradiation.7, 8, 9, 10, 11, 12, 13 Therefore, reducing the dose to organs at risk during irradiation of nodal regions is crucial for improving the benefits of treatment while reducing associated toxicity.

Several techniques are used for locoregional breast irradiation. While modified wide tangential beam with forward planning used to be the most common technique14, intensity-modulated radiotherapy (IMRT) was introduced for radiotherapy of left-sided breast cancer with IMN with the development of technology.15 Conformity and homogeneity were improved and the proportion of volume receiving 30 Gy (V₃₀) for the heart and the proportion of volume receiving 20 Gy (V₂₀) for the left lung was reduced with IMRT using inverse optimization compared to conventional planning. The recently implemented volumetric modulated arc therapy (VMAT) technology for left-sided breast cancer with IMN can achieve similar PTV coverage and organ-at-risk (OAR) sparing compared to IMRT.16, 17, 18 Helical tomotherapy (HT) is another potential solution; however, beam delivery is time consuming compared with conventional linear accelerator.19 Furthermore, HT does not provide significant improvement to the mean dose delivered to heart compared with VMAT.20 However, new technologies such as IMRT, VMAT, and HT can reduce the dose to OARs compared with wide tangential beams and it remains important to explore approaches that can improve OAR sparing.

Non-coplanar VMAT (ncVMAT) c an extend beam angle arrangements and is therefore potentially better in sparing OARs.21 With non-coplanar techniques, different fixed fields or arcs do not employ the same geometric plane, which significantly increases the space of solution for optimizing. This can be realized with a C-arm linear accelerator by rotating the treatment couch around the isocenter. The implementation of ncVMAT has already been studied in partial-breast, complicated whole-breast radiotherapy, and postmastectomy radiotherapy.22, 23, 24 However, no studies to date have reported the utility of non-coplanar technique in the treatment of left-sided breast cancer after breast-conserving surgery including the internal mammary and supraclavicular nodal regions. In the present study, ncVMAT plans using four arcs were designed to explore the feasibility of ncVMAT for locoregional radiotherapy of left-sided breast cancer. Additionally, dosimetric parameters, such as target coverage, conformity index, homogeneity index, and OAR sparing ability, were compared between ncVMAT and coplanar VMAT (coVMAT).

Figure 2 shows an example of dose distribution by ncVMAT and coVMAT, demonstrating that the dose lines from 500 cGy to 4000 cGy with ncV-MAT provided better conformity for PTVbreast and PTVimn. A similar difference could also be observed in the dose- volume histogram of PTV and selected OARs (Figure 3). In this particular patient, ncVMAT provided better sparing of the LAD, heart, bilateral lungs, and right breast and better homogeneity for PTVimn.

Figure 2

Figure 3

In the present study, ncVMAT was designed for locoregional radiotherapy of left-sided breast cancer including irradiation of IMN. For coVMAT, the heart was inevitably irradiated to cover the PTVimn which was deeply located and anatomically adjacent to the heart. This was observed in Figure 2 A (left) as several sharp peak dose lines across the heart. As the dose constraints were very strict for lungs and the contralateral breast, the beam only irradiated the internal mammary chains, primarily via the vertical direction. By rotating the treatment couch to 90°, the beam irradiated internal mammary chains, more through the ipsilateral breast, the prethoracic muscles and bones, and also through the superior and inferior direction of PTVimn. Hence, the conformity of doselines from 500 cGy to 2000 cGy around PTVimn was improved with ncVMAT. We clarify this in the revised manuscript. (Figure 2 A, right). This observation was characteristic of the non-coplanar technique in delivering a higher dose from the superior and inferior direction of the target volume to increase conformity of the target. For the same reason, an improved sparing of the lungs and the contralateral breast was generated with ncVMAT as the beam irradiated more through the middle line. Another possible explanation for an increased sparing of OARs with ncVMAT was that the non-coplanar technique provided more freedom for plan optimization.

Encompassing the IMN is challenging in breast cancer radiotherapy, as it introduces extra irradiation to the heart and lungs. Approaches to reduce toxicity in adjacent OARs compromise the coverage of PTVimn, and 85%29 to 90%30 of the prescribed dose is acceptable in clinical practice. However, the present study investigating the potential utility of ncVMAT in sparing OARs without impacting local control revealed that the coverage of PTVimn was around 95% with both coVMAT and ncVMAT. A tradeoff between target coverage and possible harmful effects is inevitable, and lower coverage of the PTVimn can also be utilized during planning to further reduce the dose to heart and lungs. With ncVMAT, the hot spots V₅₅ for PTVimn were improved, which might provide a potential advantage in protecting anatomically adjacent vessels and nerves from high-dose irradiation.31 Moreover, the conformity and homogeneity of PTVall were similar between ncVMAT and coVMAT plans.

Cardiac mortality associated with radiotherapy is a major concern in patients with left-sided breast cancer32,33, who are at higher risk of radiation-induced ischemic heart disease and cardiovascular disease compared to patients with right-sided breast cancer. The rate of major coronary events has been reported to increase by 7.4% with every 1-Gy increase in the dose to the heart.34 Therefore, it is crucial to reduce the dose delivered to heart to the greatest possible extent. In the present study, a reduction of 1.94 Gy in mean heart dose was achieved with ncVMAT; the heart V₃₀, V₂₀, V₁₀, and V₅ were significantly reduced as well. The D_mean of the heart with non-coplanar arcs was 9.22 ± 2.98 Gy, which was higher than data reported by Tyran et al.16 and Pham et al.35; our data suggested that the dose constraints for bilateral lungs and contralateral breast used in this study were much stricter than the aforementioned studies. Equally, coverage of nodal regions by the prescription dose was reduced in their studies, when compared to a 95% coverage of 50 Gy in this study. Further, ncVMAT was compared with coVMAT with similar optimization parameters without decreasing the coverage of nodal regions, while limiting the dose to lungs and contralateral breast strictly to reduce the risk of harmful effects. Obviously, the dose to the heart could be further reduced if reducing the dose constraints for lungs and contralateral breast while compromising the coverage of nodes. Some studies recommend that certain sensitive areas in heart, injury to which might cause functional damage, should be evaluated separately.36 Marks et al. reported that the probability of cardiac perfusion defects increased significantly with the increasing volume of irradiated left ventricle using single-photon emission CT.37 In a retrospective study of patients with breast cancer undergoing radiotherapy from the 1950s to 1990s, Taylor et al. found that the irradiation of anterior heart and LAD might have increased the risk of death from cardiac disease.38 Interestingly, improved sparing of V₅, V₁₀ delivered to the anterior heart, left ventricle, and LAD was possible with ncVMAT in the present study, as illustrated in Figures 2 and 3. With ncV-MAT, the maximum and mean doses of LAD were also lower comparing with coVMAT (p < 0.001). Although further evidence is necessary to demonstrate radiation-induced dysfunction in different parts of the heart, protection of these related areas still presents potential benefits.

Radiation pneumonitis is a well-known risk of thoracic tumor radiotherapy.39 For breast radiotherapy, moderate symptomatic radiation pneumonitis was not observed if the V₂₀ of the ipsilateral lung was <30%, as reported by Lind et al.40 Furthermore, a high V₁₃ indicated a worse recovery after chemotherapy for patients undergoing breast cancer radiotherapy.25 For the ipsilateral lung, Wen et al. recommended a V₂₀ < 39.8% and a V₃₀ < 25.7% for patients receiving local-regional irradiation.41 Thus far, the relationship between V₅ in both the ipsilateral and the contralateral lung, and the risk of radiation pneumonitis for patients after breast cancer radiotherapy is unclear. But according to the experiences in thoracic irradiation treatment, in the present study V₅ was strictly limited to as low as possible.42

In addition to pulmonary and cardiac toxicities induced by radiotherapy, a second primary breast cancer in the long term is another critical concern in young patients with breast cancer.43 Stovall et al. reported that the risk of a second primary breast cancer in patients younger than 40 years of age increased with treatment with more than 1 Gy in the contralateral breast.43 Boice et al. also illustrated that the risk of a second cancer was associated with age and that patients younger than 45 years of age had a higher risk of a second cancer after irradiation of the contralateral breast.44 Popescu et al.45 and Xu et al.20 demonstrated that VMAT had the ability to reduce irradiation of the contralateral breast compared to IMRT. In the present study, the dose delivered to contralateral breast can be reduced further with ncVMAT. Thus, ncVMAT might be preferred to reduce the risk of a second cancer in young patients.

In the present study, the doses delivered to other OARs were clinically acceptable. Clinicians always face a conflict between effective coverage of the target volume and sparing of the OARs. It remains possible to further reduce the dose delivered to specific OARs with ncVMAT by sacrificing either other OARs or coverage of the target volume, which requires further evaluation on a case-by-case basis. The treatment delivery time, including couch rotation, which was approximately 2.5 min longer with ncVMAT than with coVMAT, was still more efficient than HT (around 1000 s).20 The decline in treatment efficiency with ncVMAT is acceptable to an extent with improving plan quality. Deep inspiration breath-hold (DIBH) is another effective method in reducing dose delivery to the heart.35 The concept was not discussed here because free-breathing is still used in clinical practice, and DIBH was only suitable for patients capable of holding their breath to 70%–80% of the maximum inspiration capacity for a minimum 20–30 s.46 For patients incapable of DIBH, ncVMAT is an alternative technique, which better spares the heart and other OARs.

The present retrospective study comparing ncV-MAT with normal coVMAT for locoregional radiotherapy of left-sided breast cancer, including IMN revealed that the V₅₅, conformity, and homogeneity for PTVall were improved with similar coverage by introducing of two additional non-coplanar arcs. Regarding the OARs, ncVMAT provided better dose sparing in the heart, bilateral lungs, LAD, and right breast, with no significant differences for most other OARs. In conclusion, ncVMAT is potentially beneficial in reducing the risk of toxicity in left-sided breast cancer.