Free breathing VMAT versus deep inspiration breath‐hold 3D conformal radiation therapy for early stage left‐sided breast cancer

Abstract The purpose of the in silico study was to compare free breathing volumetric modulated arc therapy (VMAT) to standard deep inspiration breath‐hold (DIBH) three‐dimensional conformal radiotherapy (3DCRT) and determine whether the former is a viable option for elderly patients with left‐sided early stage breast cancer. Data from 22 patients with early‐stage left breast carcinoma requiring breast‐only radiation therapy were used for this planning study. The robustness of VMAT plans when using the free breathing method was compared to that of standard 3DCRT plans using the DIBH method. The endpoints for evaluation were the target dose coverage as well as doses to the organs‐at‐risk. The free breathing VMAT plans produced a significantly higher mean dose to the heart and right breast than the DIBH‐3DCRT plans. Free breathing VMAT plans resulted in significantly better target coverage than did 3DCRT using DIBH. The external volume that received more than 40 Gy was significantly smaller in the VMAT plans. Free breathing VMAT is a viable alternative to DIBH 3DCRT in elderly patients with a limited life expectancy and in subjects who are unable to perform DIBH. The choice of treatment should be individualized, and all relevant risks ought to be considered.

respect to clinical goals, quick treatment delivery, more homogenous target doses, more conformal dose distributions, and tailored doses to the organs-at-risk (OARs). VMAT may therefore improve target coverage and robustness compared to 3DCRT when treating LSBC while lowering doses to the OARs. 11,12,14,15 Hence, VMAT has increasingly been used to treat patients with breast cancer. In a previous study, it was shown that a VMAT treatment plan could be produced in only a few hours and that the beam-on time for locoregional breast cancer was three minutes with two arcs. 15 Radiotherapy is associated with late cardiovascular complications when used to treat LSBC, and cardiovascular-related mortality in these patients has been found to be significantly higher after 15 yr of followup than it is for patients with right-sided breast cancer. 3 One study found that the 10-year cumulative incidences of major coronary events (such as myocardial infarction, coronary revascularization, and death from ischemic heart disease) in patients with left versus right-sided tumors were 5.5% and 4.5%, respectively. 4 Radiotherapy has also been shown to cause secondary malignancies (SM) 16 ; the risk of developing a secondary primary cancer of the breast or of another organ after treatment is reported to be higher for women with breast cancer. 16,17 Of note, elderly patients with short life expectancies might not require RT regimens that use DIBH owing to the small 10-year cumulative risk of major coronary events, as data show that 10-20 yr generally pass before any heart damage manifests. 18 Moreover, their risk of developing secondary malignancies during their remaining lifespans is low. 18 Patients also sometimes find it difficult to perform the DIBH technique, and in-house experience shows that some patients tend to flex their muscles in the shoulder region or arch their spine to reach the gating amplitude. Additionally, some older patients may struggle to hold their breaths for 20-30 s, which appears to be the general requirement in many clinics. In-house data have also shown that patients have very different breathing curves throughout their treatment sessions, which may be due to anxiety or illness during some treatment sessions. 19 These patients receive FB-3DCRT, which increases the risk of a higher dose to the heart or of exceeding dose guidelines to other OARs. In-house data show that minimizing the mean dose to the heart is usually preferred, especially in the presence of additional risk factors.
The aim of the study was to compare in silico FB-VMAT planning to DIBH-3DCRT planning in patients with early-stage LSBC with respect to target dose coverage and doses to the OARs. It was evaluated whether FB-VMAT was a suitable technique for elderly patients with breast cancer who had a limited life expectancy. To our knowledge, this is the first study comparing FB-VMAT with DIBH-3DCRT.

2.A | Patient selection and training
The patient population was previously described in detail, all patients were asked for written consent to participate in the Regional Ethics Committee approved protocol. 20

2.C | DIBH-3DCRT treatment planning
The radiation therapists produced a DIBH-3DCRT treatment plan in accordance with national guidelines based on an in-house protocol.
6 MV opposing mono-isocentric tangential conformal photon beams with low-weight 6 or 15 MV segments were used to achieve dose homogeneity. The clinical goal for target coverage was a minimum of 95% of the prescribed dose to the CTV. The national guidelines at the time of inclusion stated that the mean dose to the heart should be under 2 Gy, that less than 15% of the left lung should receive more than 20 Gy, and that the mean dose to the CTV should be 50 Gy in 25 fractions. No national guidelines regarding doses to the LAD, LV, spinal canal, or right lung or breast were available at the time of the study, so these were planned according to an in-house protocol based on the "as low as reasonably achievable" principle.
The treatment machine used for modeling was an Elekta Synergy with a 10 mm multi leaf collimator (MLC). The treatment plans were calculated with the "Collapsed Cone" algorithm in Oncentra.

2.D | FB-VMAT treatment planning
The FB-VMAT treatment plans were generated in RayStation using an Elekta VersaHD treatment machine with a 5 mm MLC for modeling. A set of optimization objectives were established for each VMAT plan to achieve approximately the same target coverage (PTV D 98% [Gy]) and heart sparing (mean heart dose) as the original 3D conformal plan (Table 1). To achieve the prescribed dose, two partial 6 MV photon arcs with arc lengths of 240°were used, where the start/stop angles were 179°/280°and the collimator angles were 355°/5°. The maximum delivery time was set to 90 s for each arc.
The robust optimization feature in RayStation uses a minmax optimization, where a plan is optimized in multiple geometries; the worst (maximum) objective value is used in the objective function. The VMAT optimization was set to be robust with respect to the distal tangent field edge due to breast movement and possible volume changes. The plan was optimized with isocenter offsets applied (in the specified directions mentioned above) to the PTV, which defined the volume for which the plan would be most robust. 22,23 The optimization objective using the robustness feature had a 10 mm margin in the left and anterior directions. It was assumed that coverage in the other directions would be achieved using the standard PTV margins. The optimized plan was calculated in five different scenarios. Figure 1 shows the typical isodose distributions for each method for the same patient.

2.E | Statistics
A two-tailed Wilcoxon signed-rank test for the statistical analysis of each evaluated parameter was used, and the test was considered significant if the P-value was <0.05. 24 SPSS version 23 (IBM Corp., Armonk, NY, USA) was used to perform the calculations.

| RESULTS
Treatment planning statistics for all the included patients are shown in Table 2, whereas the mean doses to the selected OARs are shown in Figure 2.

3.A | Cardiac doses
FB-VMAT plans produced a significantly higher mean dose to the heart than did DIBH-3DCRT plans, although the absolute difference was small; the mean dose increased from 2.01 Gy with DIBH-3DCRT to 2.49 Gy with FB-VMAT. Notably, the FB-VMAT technique increased the dose to the heart when compared with DIBH-3DCRT in 21 of 22 plans. Differences in the remaining heart parameters were not statistically significant.

3.B | Target doses
FB-VMAT plans generally resulted in significantly improved target doses when compared to the DIBH plans, although the absolute differences were small. The largest difference in the PTV dose coverage was at V 47.5 Gy [%], where FB-VMAT plans were significantly better than DIBH-3DCRT plans.

3.C | General statistics
The FB-VMAT plans produced significantly lower mean doses to the lung union than did the DIBH-3DCRT plans; moreover, the volumes that received more than 20 Gy (V 20 Gy [%]) to the left lung were smaller when using the FB-VMAT plans. FB-VMAT plans generally produced a small increase in the low-dose lung bath (V 5 Gy [%]) and a larger increase in the mean dose to the right breast. The external volume that received more than 40 Gy was significantly larger in the DIBH-3DCRT plans; 21 of 22 plans were associated with larger volumes receiving a high radiation dose.
T A B L E 1 Median clinical objectives used for optimization using RayStation.

Structure
Goals Weight  The DIBH technique delivers lower doses to the OARs than do FB plans that use the same field configurations. 25 However, the study found that it was possible to produce comparable doses with FB-VMAT and DIBH-3DCRT. The FB-VMAT plans provided similar sparing of the lungs and LAD, but owing to the intrinsic low-dose bath of VMAT, the mean doses to the heart and right breast were significantly higher than those when using the DIBH-3DCRT technique.
Nevertheless, the absolute OAR differences were small, and the FB-VMAT plans were therefore clinically acceptable.
The study found a small but significant difference in the mean heart dose between the two techniques. Darby  Limited long-term follow-up data are available for patients who underwent modern RT techniques such as IMRT and VMAT.
Improvement in the conformity of treatment has been suggested to counteract the greater risks associated with large low-dose volumes. 32  results as indicating that a relatively small proportion of secondary cancers is related to RT in adults, whereas most are due to other factors such as lifestyle and genetics.
A low average dose to the right breast is a clinical objective when optimizing FB-VMAT plans; however, the overall mean dose is significantly higher with these plans. Pan et al. performed a systematic review and meta-analysis of the risk of secondary malignancies after partial versus whole-breast RT. 36 They found that partial breast RT, typically administered intraoperatively, produces a very limited dose to the organs surrounding the target compared to whole-breast external RT, although they found no significant difference in the incidences of secondary non-breast or right breast cancer between patients receiving partial versus whole-breast irradiation.
The good VMAT target coverage in the study was not at the expense of a high-dose bath to healthy tissue. Reidunsdatter et al.
found that the V 40 Gy was a significant predictor of increased fatigue during RT. 37 However, the VMAT plans in the study were more conformal than the 3DCRT plans were; the latter was associated with a 17.8% larger tissue volume receiving a high dose (i.e., above 40 Gy) inside the external contour compared to the former. Other groups also discovered significant correlations between the irradiated highdose volume (i.e., the tissue encompassed by the 50% isodose) and the intensity of fatigue after RT. [38][39][40] 43 Additionally, some older patients with dementia may struggle to hold their breath for 20 s and may therefore require more breath-holds; this can prolong treatment times and possibly increase intrafractional errors. 45 As the treatment time increases, baseline drift from the setup position has also been shown to increase. 46 On average, well-optimized VMAT plans are more robust than 3DCRT counterparts when localization errors during treatment are accounted for. 15  In recent years, VMAT has been increasingly used to treat patients with breast cancer; however, there are still no long-term data, and any cost-to-benefit relationship must therefore be modeled. A low-dose bath has been predicted to increase the risk of secondary cancers; however, no clinical studies to date have shown as high a risk as the theoretical models predicted. 32 The increased dose to surrounding tissue could possibly be counterbalanced by the improved target coverage, increased target homogeneity, and smaller volume receiving high doses in the VMAT plans.

| CONCLUSION S
This study shows that FB-VMAT is a feasible alternative to DIBH-

ACKNOWLEDG EMENTS
The work was supported by the Liaison Committee between the Central Norway Regional Health Authority (RHA) and the Norwegian University of Science and Technology (NTNU).