This study evaluated the sufficiency of the 5 mm CTV-to-PTV margin and the dosimetric effects in the presence of setup uncertainties and tissue deformations in breast cancer RT. The 5 mm margin was sufficient to account for CTV deformations only in 85% of the treatment fractions using daily CBCT setup. In the cumulative dose distributions with CBCT setup, the goal for CTV dose coverage was fulfilled in 59% and 62% of patients with tVMAT and 3D-CRT, respectively. Therefore, reducing the margin below 5 mm is unadvisable. The results also argue for caution in patient positioning, as less accurate methods may further compromise the target dose coverage.

While the CTV-to-PTV margin can be reduced to 5 mm with modern IGRT techniques [1], this study showed that a 5 mm margin is not enough to enclose all anatomical and setup uncertainties of the CTV inside the body. CTV-to-PTV margins of 7 and 10 mm during treatment planning would have enclosed 95% and 100% of CTV shape changes, respectively (Fig. 5). An increase in margin would probably improve the delivered dose coverage, but the effect of increasing the enclosure percentage on local recurrence probability is not known.

The cumulative dose distributions demonstrated a median decline of 0.4 and 0.5 percentage points in CTVin coverage with tVMAT and 3D-CRT, respectively, while the median coverages remained above the planning goal with both techniques. Therefore, both techniques proved robust in this patient cohort. The dosimetric effects in the cumulative dose distributions were caused by both tissue deformation and setup uncertainties that were incorporated in the deformed CT images. The median CTV coverage values of cumulative dose distributions fulfilled the initial planning goal, even though the planning goal of V95% > 98% of prescribed dose was relatively strict. A larger impact was demonstrated in PTVin coverage, which was retained with 3D-CRT and slightly declined below the planning goal for tVMAT. This effect was to be expected as random position error mainly manifest as blurring on the edges of a homogeneous dose distribution [7]. The range of CTVin and PTVin coverages was larger for 3D-CRT compared to tVMAT, but the median values indicate that both techniques are robust towards positional and deformative uncertainties in this patient cohort.

Previous studies investigated dosimetric effects using more simplified methods. Van der Veen et al. utilized deformed CT images based on CBCT, demonstrating differences of -2% to + 0.5% in CTVin coverage [15]. Rossi et al. found a minor decline in PTVin coverage with CBCT-based tissue modifications [12]. Our study utilized a more comprehensive simulation method with CBCT images from each treatment fraction, as opposed to three to five CBCT images, and supports these findings [12, 15]. By contrast, Dekker et al. achieved CTVin V95% coverage above 98% in 90% of patients with tangential IMRT and hybrid IMRT techniques by calculating the dose on the CBCT images [16]. However, a higher proportion of their plans met initial planning goals compared to clinical tVMAT and 3D-CRT reference plans in this study. Similar to van der Veen et al. and Rossi et al., Dekker et al. included only three to four CBCT images.

Unlike this study, most of the dosimetric studies considering breast cancer treatment uncertainties have only incorporated one individual uncertainty without daily CBCT. Hennet et al. demonstrated a 4% decline in PTVin V95% coverage with 4 to 7 mm isotropic swelling by using a conventional VMAT technique without avoidance sectors [10]. Rossi et al. simulated worst-case scenarios with tVMAT and isotropic expansion of the breast of 4, 8 and 12 mm [11]. With a 20 mm Auto Flash setting, the initially acceptable chest wall CTV (commonly the CTVb/c) V95% coverage declined to 90% with 4 mm isotropic swelling [11]. However, the PTVin V95% coverage remained clinically acceptable. According to Rossi et al., swelling of the target breast up to 4 mm is to be expected roughly in 50% of the patients [12]. Likewise, Seppälä et al. reported breast expansion of less than 3 and 5 mm in 38% and 66% of patients during the radiotherapy course of the breast, respectively [29]. In this study, the dosimetric impact in the presence of anatomical deformations was small compared to the referred studies [10, 11].

A common method for assessing the dosimetric effect of setup uncertainty is to apply rigid translations and recalculate the dose on the planning CT image. Based on this method, Jensen et al. applied clinical online match shifts to the planning CT image [4]. Similar to this study, they observed a 1 Gy decline in PTV D95% and only a 0.1 Gy decline in CTV D98% with VMAT robust optimization [4]. Ding et al. and Zhao et al. concluded that the effects of 3 mm shifts are rather negligible, but larger shifts demonstrated greater impact with VMAT compared to hybrid IMRT [13] and 3D-CRT [14] techniques. In the present study, the tVMAT technique proved robust in the presence of realistic uncertainties in the CTV edge position inside the body, that were less than 5 mm in 85% of fractions. It is noteworthy, that some studies [13, 14] did not report the use of skin flash technique, even though applying a skin flash is recommended in breast cancer treatment planning [29, 30].

This study only reported D1cc values for OAR structures as they were only partially visible in the CBCT field-of-view, thus rendering the DIR unreliable for the unseen parts of the OARs. No statistically significant increases were demonstrated in D1cc of any OAR, indicating that both tVMAT and 3D-CRT techniques are robust in terms of dose to normal tissue. Some increases in D1cc were found using CBCT setup, as the maximum increase in D1cc of the heart and LAD was larger for 3D-CRT. On the other hand, the maximum increase in D1cc of the contralateral breast was larger with tVMAT (Additional file 1: Tables S1–S6).

The residual error between initial SGRT setup and CBCT setup observed in this study (median 8.6 mm, 95% below 13.6 mm) was large compared to other studies. The largest reported average residual errors were 6–7 mm in magnitude [20, 21]. Much smaller component-wise values of < 2 mm have also been reported [19, 24]. Similar to this study, average lateral and longitudinal directions (0.2 and 0.5 mm) were observed by Cravo Sá et al. [22]. They also observed a pronounced vertical shift of 2.1 mm. A consistent bias in the median vertical shift was observed (6.2 mm vs. < 1 mm in other directions) at the authors’ clinic despite routine quality assurance of the SGRT system. A potential cause for the bias is that the live and reference FB surface for initial SGRT setup corresponded to different respiratory phases at the moment the automatic translations were applied. Other potential causes for the bias are intra-fraction movement and inter-operator variability in SGRT setup. In addition, breast surface deformation has been shown to cause uncertainty in SGRT positioning [31]. Based on these results, IGRT verification of the patient position is recommended to avoid systematic set up errors.

The recent ESTRO-ACROP guideline for SGRT [25] recommends the use of a defined protocol and verification of SGRT-only positioning by IGRT at least weekly, if SGRT is used without daily IGRT. However, IGRT offers greater accuracy of patient positioning when compared to SGRT [3, 18, 20,21,22,23, 25]. The results for CTVin and PTVin dose coverages of the present study demonstrate that no further uncertainty should be added on top of CBCT setup. This further reinforces the need of IGRT methods in conjunction with the initial SGRT setup. Particularly when using the VMAT technique, CBCT setup has been recommended over 2D kV setup [12].

Some limitations exist in this study. The pCT to dCT deformation based on the CBCT image is prone to exaggerating the expansion of the body tissue into air, if the air-tissue interfaces are blurred in the CBCT image. Moreover, the uncertainties in the DIR accuracy may have affected the shape of the dCT CTV structures to some degree. Finally, intra-fraction motion effects, such as variability in DIBH stability and reproducibility across multiple breath holds [32], were not incorporated in the dose accumulation process.

While CBCT setup combined with the 5 mm CTV-to-PTV margin could not account for all setup and deformation related uncertainties, good practice aims to minimize the setup and dosimetric errors. For this purpose, this study proved that there is little difference between tVMAT and conventional 3D-CRT techniques in terms of median CTV coverage and dose to OARs. Looking forward in breast cancer radiotherapy, the implementation of ultra-hypofractionation [33] might allow for even less uncertainty in patient setup thus highlighting the value of CBCT even when SGRT systems are used. However, the assessment of dosimetric uncertainty with only five fractions remain a subject for future investigations.