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The UK HeartSpare Study (Stage IB): Randomised comparison of a voluntary breath-hold technique and prone radiotherapy after breast conserving surgery

Published:November 26, 2014DOI:https://doi.org/10.1016/j.radonc.2014.11.018

      Abstract

      Purpose

      To compare mean heart and left anterior descending coronary artery (LAD) doses (NTDmean) and positional reproducibility in larger-breasted women receiving left breast radiotherapy using supine voluntary deep-inspiratory breath-hold (VBH) and free-breathing prone techniques.

      Materials and methods

      Following surgery for early breast cancer, patients with estimated breast volumes >750 cm3 underwent planning-CT scans in supine VBH and free-breathing prone positions. Radiotherapy treatment plans were prepared, and mean heart and LAD doses were calculated. Patients were randomised to receive one technique for fractions 1–7, before switching techniques for fractions 8–15 (40 Gy/15 fractions total). Daily electronic portal imaging and alternate-day cone-beam CT (CBCT) imaging were performed. The primary endpoint was the difference in mean LAD NTDmean between techniques. Population systematic (Σ) and random errors (σ) were estimated. Within-patient comparisons between techniques used Wilcoxon signed-rank tests.

      Results

      34 patients were recruited, with complete dosimetric data available for 28. Mean heart and LAD NTDmean doses for VBH and prone treatments respectively were 0.4 and 0.7 (p< 0.001) and 2.9 and 7.8 (p< 0.001). Clip-based CBCT errors for VBH and prone respectively were ⩽3.0 mm and ⩽6.5 mm (Σ) and ⩽3.5 mm and ⩽5.4 mm (σ).

      Conclusions

      In larger-breasted women, supine VBH provided superior cardiac sparing and reproducibility than a free-breathing prone position.

      Keywords

      The number of breast cancer (BC) survivors is increasing due to improvements in detection and more effective treatments [
      • Autier P.
      • Boniol M.
      • La Vecchia C.
      • et al.
      Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database.
      ]. However, improvements in survival mean more women will live to see the late effects of their cancer treatments. Breast radiotherapy is associated with a 1–2% excess of non-BC mortality at 15 years, the majority of which is attributable to cardiac disease [
      • Clarke M.
      • Collins R.
      • Darby S.
      • et al.
      Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.
      ], and recent work has demonstrated a linear, no-threshold relationship between mean heart dose and the risk of subsequent major coronary events (MCE) [
      • Darby S.C.
      • Ewertz M.
      • McGale P.
      • et al.
      Risk of ischemic heart disease in women after radiotherapy for breast cancer.
      ]. It remains unclear which cardiac substructures contribute to the development of MCE, although evidence from myocardial perfusion [
      • Lind P.A.
      • Pagnanelli R.
      • Marks L.B.
      • et al.
      Myocardial perfusion changes in patients irradiated for left-sided breast cancer and correlation with coronary artery distribution.
      ] and coronary angiography [
      • Correa C.R.
      • Litt H.I.
      • Hwang W.T.
      • Ferrari V.A.
      • Solin L.J.
      • Harris E.E.
      Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer.
      ,
      • Nilsson G.
      • Holmberg L.
      • Garmo H.
      • et al.
      Distribution of coronary artery stenosis after radiation for breast cancer.
      ] studies implicates the left anterior descending coronary artery (LAD).
      The development and implementation of heart-sparing breast radiotherapy techniques remains an international priority. Breath-holding techniques reduce heart doses [
      • Pedersen A.N.
      • Korreman S.
      • Nyström H.
      • Specht L.
      Breathing adapted radiotherapy of breast cancer: reduction of cardiac and pulmonary doses using voluntary inspiration breath-hold.
      ,
      • Borst G.R.
      • Sonke J.J.
      • den Hollander S.
      • et al.
      Clinical results of image-guided deep inspiration breath hold breast irradiation.
      ,
      • Hayden A.J.
      • Rains M.
      • Tiver K.
      Deep inspiration breath hold technique reduces heart dose from radiotherapy for left-sided breast cancer.
      ,
      • Vikstrom J.
      • Hjelstuen M.H.
      • Mjaaland I.
      • Dybvik K.I.
      Cardiac and pulmonary dose reduction for tangentially irradiated breast cancer, utilizing deep inspiration breath-hold with audio-visual guidance, without compromising target coverage.
      ] but have not yet been widely implemented in the UK [2012 Royal College of Radiologists audit] due to resource costs and staff training. A recent UK study (HeartSpare IA) demonstrated a voluntary breath-hold technique to be as effective at heart-sparing and as reproducible as breath-holding treatment with the active breathing coordinator™ (ABC) (Elekta, Crawley, UK) [
      • Bartlett F.R.
      • Colgan R.M.
      • Carr K.
      • et al.
      The UK HeartSpare Study: randomised evaluation of voluntary deep-inspiratory breath-hold in women undergoing breast radiotherapy.
      ]. Additional benefits, including shorter treatment setup times and lower implementation costs, are likely to establish this technique as the standard of care for many left-sided women in the UK. However, there remains a group of larger-breasted women in whom the relative benefits of breath-hold vs. prone positioning are unknown. Previous work has shown that, although the prone position moves the heart closer to the chest wall under gravity, larger breasts fall further forward, allowing for shallower tangential radiotherapy beam placement [
      • Buijsen J.
      • Jager J.J.
      • Bovendeerd J.
      • et al.
      Prone breast irradiation for pendulous breasts.
      ,
      • Patel R.R.
      • Becker S.J.
      • Das R.K.
      • Mackie T.R.
      A dosimetric comparison of accelerated partial breast irradiation techniques: multicatheter interstitial brachytherapy, three-dimensional conformal radiotherapy, and supine versus prone helical tomotherapy.
      ] and reduced cardiac doses in larger-breasted women [
      • Kirby A.M.
      • Evans P.M.
      • Donovan E.M.
      • Convery H.M.
      • Haviland J.S.
      • Yarnold J.R.
      Prone versus supine positioning for whole and partial-breast radiotherapy: a comparison of non-target tissue dosimetry.
      ].
      This single centre randomised non-blinded crossover study compares cardiac dosimetry for the supine voluntary breath-hold (VBH) technique with free-breathing prone positioning in larger-breasted women using a within-patient comparison.

      Materials and methods

      This study was approved by the Research and Development and Research Ethics Committees (ISRCTN 53485935). Women with left BC who had undergone breast-conserving surgery for invasive ductal or lobular carcinoma (pT1-3b,N0-1,M0), who required radiotherapy to the breast alone (± tumour bed boost) without nodal irradiation, and who had an estimated breast volume of >750 cm3 were approached. All patients were treated at one institution. Randomisation procedures followed those reported previously [
      • Bartlett F.R.
      • Colgan R.M.
      • Carr K.
      • et al.
      The UK HeartSpare Study: randomised evaluation of voluntary deep-inspiratory breath-hold in women undergoing breast radiotherapy.
      ].

      Patient positioning and image acquisition

      Before CT-planning, radio-opaque wire was used to delineate clinically palpable breast tissue with the patient in a supine position. The supine VBH CT-planning procedure has been described previously [
      • Bartlett F.R.
      • Colgan R.M.
      • Donovan E.M.
      • et al.
      Voluntary Breath-hold Technique for Reducing Heart Dose in Left Breast Radiotherapy.
      ]. For free-breathing prone CT-planning, patients were positioned on an Orfit AIO Solution® prone breast board (ORFIT Industries, Wijnegem, Belgium) (see Fig. 1). A marker (tattoo) was placed ipsilaterally in the posterior axillary line and aligned axially with a posterior midline marker using lateral lasers. A second posterior marker was placed 15 cm inferiorly to the primary posterior marker, in line with sagittal lasers. CT data (Philips Medical Systems, UK) were acquired without contrast for both scans (2 mm slices, C6 to below diaphragm). Both scans were performed in one CT-planning session, with patients dismounting the couch between scans. Photographs of patient positioning were taken for both techniques to aid treatment setup. The time taken to complete each CT was recorded, from the time the patient mounted the CT couch to the time at which they dismounted the couch. After completing both scans, patients and radiographers completed validated questionnaires to assess comfort and satisfaction respectively (see Figs. S1 and S2) [
      • Nutting C.M.
      • Khoo V.S.
      • Walker V.
      • et al.
      A randomised study of the use of a customised immobilisation system in the treatment of prostate cancer with conformal radiotherapy.
      ].
      Figure thumbnail gr1
      Fig. 1Patient positioned on Orfit AIO Solution® prone breast board (ORFIT Industries, Wijnegem, Belgium).

      Target and organ-at-risk delineation

      Target and organ-at-risk (OAR) volumes were delineated on both CT scans. The whole breast clinical target volume (WBCTV) was defined using the radio-opaque wire and any additional breast tissue visualised on CT (limited by pectoral fascia and 5 mm from skin). The tumour bed was defined using tumour bed clips (inserted at surgery), and included any associated seroma or distortion of breast architecture. A 15 mm margin was added (limited by WBCTV) to form the partial breast CTV (PBCTV). The method for outlining the heart, LAD and lungs has been described previously [
      • Bartlett F.R.
      • Colgan R.M.
      • Carr K.
      • et al.
      The UK HeartSpare Study: randomised evaluation of voluntary deep-inspiratory breath-hold in women undergoing breast radiotherapy.
      ]. The contralateral breast (CB) was also outlined, encompassing CB tissue visualised on CT.

      Radiotherapy planning

      Tangential fields were applied to encompass WBCTV. Philips Pinnacle 9.2 (Philips Medical Systems, Palo Alto, US) and the collapsed-cone algorithm (0.25 × 0.25 × 0.25 cm resolution) were used to produce plans such that the 95% isodose covered ⩾90% of the WBCTV and ⩾95% of the PBCTV [
      • Kirby A.M.
      • Evans P.M.
      • Donovan E.M.
      • Convery H.M.
      • Haviland J.S.
      • Yarnold J.R.
      Prone versus supine positioning for whole and partial-breast radiotherapy: a comparison of non-target tissue dosimetry.
      ]. Where required, multileaf collimation (MLC) was used to shield cardiac tissue. Segments were used to improve dose homogeneity and all plans fulfilled ICRU 62 criteria (dose variation ⩽ +7% and −5%, hotspots ⩽ 107%) [

      International Commission on Radiation Units and Measurements. ICRU Report 62. Prescribing, recording and reporting photon beam therapy (Supplement to ICRU Report 50). Bethesda, MD: ICRU, 1999.

      ]. Patients were prescribed 40 Gy in 15 fractions over 3 weeks using 6 and/or 10 MV photons.
      Dose-volume histogram (DVH) data were used to derive NTDmean (a biologically weighted mean of total dose to tissue normalised to 2 Gy fractions using a standard linear quadratic model [
      • Scrimger R.A.
      • Tome W.A.
      • Olivera G.H.
      • Reckwerdt P.J.
      • Mehta M.P.
      • Fowler J.F.
      Reduction in radiation dose to lung and other normal tissues using helical tomotherapy to treat lung cancer, in comparison to conventional field arrangements.
      ], α/β = 3 Gy) for LAD, heart, ipsilateral and whole lungs and CB. In addition, the maximum LAD dose (LADmax) was calculated. Conformity and homogeneity indices were calculated for both techniques using established formulae [

      International Commission on Radiation Units and Measurements. ICRU Report 62. Prescribing, recording and reporting photon beam therapy (Supplement to ICRU Report 50). Bethesda, MD: ICRU, 1999.

      ,
      • Gong Y.
      • Wang J.
      • Bai S.
      • Jiang X.
      • Xu F.
      Conventionally-fractionated image-guided intensity modulated radiotherapy (IG-IMRT): a safe and effective treatment for cancer spinal metastasis.
      ].

      Radiotherapy delivery

      Patients were randomised to receive one or other technique for fractions 1–7, before switching techniques for fractions 8–15. Patient setup for VBH has been described previously [
      • Bartlett F.R.
      • Colgan R.M.
      • Donovan E.M.
      • et al.
      Voluntary Breath-hold Technique for Reducing Heart Dose in Left Breast Radiotherapy.
      ]. Prone positioning was reproduced at treatment by aligning tattoos to lasers and using CT-planning photographs to check consistency. The left posterior oblique (LPO) field borders were checked using treatment plan measurements and CT skin-rendered views. Visualisation of the right anterior oblique (RAO) field borders was impeded by the prone board structure. Electronic portal images (EPI) were acquired daily and matched on-line to digitally reconstructed radiographs on fractions 1–3 and 8–10 using iView software (Elekta, Crawley, UK). Systematic shifts were applied if errors were >5 mm in the (u,v)-plane on at least three consecutive days. For study purposes setup errors were measured off-line for every fraction. The LPO was treated first and the RAO treated second.
      On-board kV-CT (CBCT) images of the chest were acquired immediately after setup on alternate days using the Elekta Synergy X-ray Volume Imaging System (Elekta, Crawley, UK). CBCT procedures for supine [
      • Donovan E.M.
      • Castellano I.
      • Eagle S.
      • Harris E.
      Clinical implementation of kilovoltage cone beam CT for the verification of sequential and integrated photon boost treatments for breast cancer patients.
      ] and prone [
      • Kirby A.M.
      • Evans P.M.
      • Donovan E.M.
      • Convery H.M.
      • Haviland J.S.
      • Yarnold J.R.
      Prone versus supine positioning for whole and partial-breast radiotherapy: a comparison of non-target tissue dosimetry.
      ] techniques have been described previously. CBCT data were acquired primarily for study purposes, although were used to make systematic shifts where errors were >10 mm in any plane or >5 mm on three consecutive days and/or insufficient chest wall was visible on EPI to make such shifts. Daily CBCT imaging for prone treatment was used where errors were >5 mm in opposite directions. Clip-based matches were performed by manually registering CBCT volumes to the reference planning-CT.
      Times at which patients mounted and dismounted the couch and the ‘beam on’ time were recorded for every fraction. Patients and radiographers completed questionnaires on fractions 1, 7, 8 and 15.

      Statistical methods

      The primary endpoint was the difference in mean LAD NTDmean between VBH and prone techniques. Assuming a 2-sided significance level of 0.05 and standard deviation (SD) of the difference in measurements of 6.7%, a sample size of 50 patients (allowing for a 10% drop-out rate) was estimated to provide 83% power to detect an absolute difference of 3 Gy between mean LAD NTDmean using the two techniques (assuming 0.1 correlation between techniques and SD of 5 Gy for each). During the study clinicians noted VBH was consistently better than prone at sparing heart tissue. An unplanned interim analysis was conducted and reviewed by an independent group (two clinicians and a statistician) after primary endpoint data was available for 27 patients. Following this review, the decision was made to close trial recruitment early following randomisation of 34 patients. The observed SD for the two techniques were lower than had been estimated in the original sample size calculation. Therefore, the power of the study remained 83% to detect a 3 Gy difference in mean LAD NTDmean despite stopping recruitment early (assuming 4 Gy SD for each technique and a 0.1 correlation gave a SD of differences of 5.37).
      Since Q–Q plots and Kolmogorov–Smirnov tests demonstrated that normal tissue dose data were not normally distributed, Wilcoxon signed-rank tests were used to compare doses between VBH and prone treatments, using each patient as their own control. Wilcoxon signed-rank tests were also used to compare timing data, target tissue and OAR volumes and numbers of segments used for each technique. McNemar’s test was used to compare frequency of MLC use for cardiac shielding, beam energies and frequency of systematic moves. Translational and rotational CBCT registration results were analysed in 3-dimensions for each patient. Population mean displacement (M), systematic (Σ) and random (σ) errors were estimated [
      • van Herk M.
      Errors and margins in radiotherapy.
      ]. EPI displacements were analysed for each beam in the (u,v)-plane for every patient [
      • Penninkhof J.
      • Quint S.
      • Baaijens M.
      • Heijmen B.
      • Dirkx M.
      Practical use of the extended no action level (eNAL) correction protocol for breast cancer patients with implanted surgical clips.
      ]; population M, Σ and σ were estimated. Paired t-tests were used to compare M between VBH and prone techniques. Patient comfort and radiographer satisfaction questionnaires were scored 0–9 (0 least comfortable, 9 most comfortable and 0 most satisfactory, 9 least satisfactory). Median comfort and satisfaction scores were calculated for each technique at each timepoint (CT, first and last fractions) and Wilcoxon signed-rank tests used to compare scores. Statistical analyses were performed using SPSS Statistics Version 21 (IBM, Portsmouth, UK).

      Results

      Thirty-four patients were randomised between January 2013 and April 2014. Twenty-two (65%) patients completed the study as per protocol, and complete dosimetric data was available for 28 (82%) (see Fig. 2 and Supplementary material). 170/229 (74%) planned prone fractions and 221/221 (100%) of planned VBH fractions were completed. The median age of patients recruited was 57 years (range 25–79) and median BMI was 31.2 (range 24.5–38.3). Table S1 shows median target and OAR volumes and radiotherapy treatment plan characteristics for both techniques. Median WBCTV was similar for both techniques: 1064 cm3 (prone) vs. 1029 cm3 (VBH) and the difference between WBCTV for prone and VBH radiotherapy plans in all patients was <10%. Median target tissue coverage was ⩾95% for both techniques. Ipsilateral and whole lung volumes were significantly smaller in the prone position (all p< 0.001), but there was no significant difference between techniques for other OAR volumes.
      Figure thumbnail gr2
      Fig. 2CONSORT 2010 flow diagram for The HeartSpare Study (Stage IB). More detail on patient protocol breaches is given in the Supplementary material.
      All cardiac dose parameters (Gy) were statistically significantly lower with VBH than prone treatment [95% confidence intervals]: heart NTDmean 0.44 [0.38–0.51] vs. 0.66 [0.61–0.71] (p< 0.001), LAD NTDmean 2.9 [1.8–3.9] vs. 7.8 [6.4–9.2] (p< 0.001), and LADmax 21.0 [15.8–26.2] vs. 36.8 [35.2–38.4] (p< 0.001). Heart NTDmean was lower using VBH than prone treatment in 26/28 (93%) patients, as was LAD NTDmean (27/28, 96%) and LADmax (24/28, 86%). Within-patient comparisons of heart NTDmean and an example of the relationship between breast and cardiac tissue dosimetry for VBH and prone treatments are shown in Fig. 3, Fig. 4 respectively. Ipsilateral and whole lung NTDmean were significantly lower using the prone technique than using VBH: 3.73 [3.42–4.04] vs. 0.34 [0.27–0.42] (p< 0.001) and 1.81 [1.65–1.97] vs. 0.20 [0.16–0.24] (p< 0.001) respectively. Mean CB dose was significantly lower with VBH than prone treatment: 0.10 [0.08–0.11] vs. 0.33 [0.23–0.43] (p< 0.001).
      Figure thumbnail gr3
      Fig. 3Hi–Lo chart showing within-patient comparisons of heart NTDmean (Gy) for voluntary breath-hold (VBH) and prone techniques (* indicates no data available).
      Figure thumbnail gr4
      Fig. 4Axial CT slices of (a) prone and (b) supine voluntary breath-hold (VBH) treatment plan from the same patient, demonstrating the anatomical and dosimetric relationship between breast tissue, heart (yellow outline), and LAD (green colour wash with orange bullseye).
      Population M, Σ and σ for CBCT clip-based matches and EPI-based matches are shown in Tables 1 and S2 respectively. Displacement errors for prone treatment were consistently greater than for VBH irrespective of imaging technique. Systematic moves were performed in 11/23 prone treatments and 2/23 VBH treatments (p= 0.01).
      Table 1Population mean displacement (M), systematic (Σ) and random (σ) translational (mm) and rotational (°) errors in 3-dimensions for clip-based cone-beam CT versus planning CT matches for voluntary breath-hold (VBH) and prone techniques.
      TranslationalRotational
      VBHPronepVBHPronep
      Right–left (R–L)M−0.11.50.481.30.00.06
      Σ1.85.91.21.9
      σ1.95.41.51.5
      Superior–inferior (S–I)M2.05.20.10−0.5−1.00.15
      Σ3.06.51.42.7
      σ2.64.51.12.1
      Anterior–posterior (A–P)M0.0−3.10.04−0.2−1.40.02
      Σ1.85.21.73.5
      σ3.54.61.32.3
      Total number of CBCTs: 174 (88 VBH, 86 prone).
      Patients found VBH more comfortable than prone treatment at all timepoints (all p⩽ 0.013). No significant difference in radiographer satisfaction was found at CT (p= 0.06) or last fraction (p= 0.05), although for the first fraction VBH was more satisfactory (p= 0.01) (see Table S3).
      Median radiotherapy CT-planning and treatment times are shown in Table 2. There was no significant difference between techniques for planning-CT session times (p= 0.24). Treatment setup and total treatment session times were significantly less with VBH (p= 0.01, p= 0.002 respectively), although ‘beam on’ time was less with prone treatment (p= 0.004).
      Table 2Median of mean radiotherapy CT-planning session and treatment times for voluntary breath-hold (VBH) and prone techniques with ranges in brackets (min).
      VBHPronep
      CT-planning session23 (15–62)22 (14–48)0.240
      Treatment setup8 (4–12)9 (6–20)0.010
      ‘Beam on’ time5 (4–7)3 (2–13)0.004
      Leaving treatment room2 (1–3)2 (1–4)0.689
      Total treatment time17 (13–22)20 (13–49)0.002
      Data for 61 CTs (31 VBH, 30 prone) and 188 treatment fractions (138 VBH, 150 prone).

      Discussion

      This randomised crossover study compared supine VBH with free-breathing prone treatment in terms of cardiac doses and setup reproducibility. Our results demonstrate that, for the majority of patients, VBH offers better cardiac sparing and a more favourable reproducibility profile than treatment in the prone position.
      There was a highly statistically significant difference between techniques in favour of VBH for all cardiac dose parameters measured, in keeping with published non-randomised data [
      • Verhoeven K.
      • Sweldens C.
      • Petillion S.
      • et al.
      Breathing adapted radiation therapy in comparison with prone position to reduce the doses to the heart, left anterior descending coronary artery, and contralateral breast in whole breast radiation therapy.
      ]. However, cardiac doses for both techniques were low. Prone mean heart dose was lower than seen in standard free-breathing left breast radiotherapy [
      • Bartlett F.R.
      • Yarnold J.R.
      • Donovan E.M.
      • Evans P.M.
      • Locke I.
      • Kirby A.M.
      Multileaf collimation cardiac shielding in breast radiotherapy: cardiac doses are reduced, but at what cost?.
      ] and lower than reported in other studies comparing prone and supine treatments [
      • Kirby A.M.
      • Evans P.M.
      • Donovan E.M.
      • Convery H.M.
      • Haviland J.S.
      • Yarnold J.R.
      Prone versus supine positioning for whole and partial-breast radiotherapy: a comparison of non-target tissue dosimetry.
      ,
      • Krengli M.
      • Masini L.
      • Caltavuturo T.
      • et al.
      Prone versus supine position for adjuvant breast radiotherapy: a prospective study in patients with pendulous breasts.
      ,
      • Mulliez T.
      • Veldeman L.
      • van Greveling A.
      • et al.
      Hypofractionated whole breast irradiation for patients with large breasts: a randomized trial comparing prone and supine positions.
      ]. Cardiac doses for VBH were lower than previously reported [
      • Bartlett F.R.
      • Colgan R.M.
      • Carr K.
      • et al.
      The UK HeartSpare Study: randomised evaluation of voluntary deep-inspiratory breath-hold in women undergoing breast radiotherapy.
      ], perhaps because MLC use and/or beam angle alterations to avoid cardiac tissue are likely to result in relatively less WBCTV coverage compromise in larger- vs. smaller-breasted women. Contrary to published reports [
      • Krengli M.
      • Masini L.
      • Caltavuturo T.
      • et al.
      Prone versus supine position for adjuvant breast radiotherapy: a prospective study in patients with pendulous breasts.
      ,
      • Merchant T.E.
      • McCormick B.
      Prone position breast irradiation.
      ,
      • Griem K.L.
      • Fetherston P.
      • Kuznetsova M.
      • Foster G.S.
      • Shott S.
      • Chu J.
      Three-dimensional photon dosimetry: a comparison of treatment of the intact breast in the supine and prone position.
      ], this study demonstrates that comparable dose homogeneity for prone and supine plans is achievable by the use of additional segments.
      Consistent with previous work [
      • Kirby A.M.
      • Evans P.M.
      • Helyer S.J.
      • Donovan E.M.
      • Convery H.M.
      • Yarnold J.R.
      A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.
      ] our results showed positional reproducibility for prone treatment to be inferior to supine treatment. Reproducibility for supine VBH [
      • Bartlett F.R.
      • Colgan R.M.
      • Carr K.
      • et al.
      The UK HeartSpare Study: randomised evaluation of voluntary deep-inspiratory breath-hold in women undergoing breast radiotherapy.
      ] and prone [
      • Kirby A.M.
      • Evans P.M.
      • Helyer S.J.
      • Donovan E.M.
      • Convery H.M.
      • Yarnold J.R.
      A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.
      ,
      • Morrow N.V.
      • Stepaniak C.
      • White J.
      • Wilson J.F.
      • Li X.A.
      Intra- and interfractional variations for prone breast irradiation: an indication for image-guided radiotherapy.
      ,
      • Veldeman L.
      • De Gersem W.
      • Speleers B.
      • et al.
      Alternated prone and supine whole-breast irradiation using IMRT: setup precision, respiratory movement and treatment time.
      ] treatments in this study was consistent with published reports. Reproducing the prone treatment position is difficult for several reasons, including the instability of breast and subcutaneous tissue, and the fact that target and OAR dosimetry is optimised by rotation of the patient towards the treated side. Reproducibility in this study was hindered by an inability to site a contralateral posterior axillary line tattoo due to excess soft tissue, something noted in previous work [
      • Kirby A.M.
      • Evans P.M.
      • Helyer S.J.
      • Donovan E.M.
      • Convery H.M.
      • Yarnold J.R.
      A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.
      ]. In line with recommendations from that study, a second midline posterior tattoo was introduced in order to improve reproducibility. However, rotational errors were greatest around the anterior-posterior axis, something which might be improved by increasing the distance between posterior tattoos. Additionally, we used a commercially available prone platform selected for its comfortable head position and improved arm positioning (no ‘T-bar’ [
      • Kirby A.M.
      • Evans P.M.
      • Helyer S.J.
      • Donovan E.M.
      • Convery H.M.
      • Yarnold J.R.
      A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.
      ]). However, radiographers found arm position difficult to reproduce since, without a T-bar, patients were able to use their elbows to support themselves. For prone treatment, systematic errors were consistently greater than random errors, suggesting that reproducibility could be improved by implementation of a CBCT-based correction protocol.
      Patients generally found prone treatment less comfortable than VBH, describing the headrest as uncomfortable, rib discomfort around the treated breast aperture and feeling unstable due to tilting. Radiographers found prone treatments less satisfactory at the first fraction, reflecting difficulties with prone setup and reproducibility.
      It was anticipated that CT session times would be shorter for prone CT-planning than VBH, given that VBH sessions included breath-hold training. The opposite was found, however, reflecting the additional care required to optimise prone position reproducibility at CT-planning (head comfort, patient rotation, CB position, avoiding elbow support). Reproducing these positions on treatment accounts for the difference in treatment setup and total treatment session times between the two techniques. Two to three breath-holds were required per treatment beam for VBH, meaning that VBH treatment delivery was longer than for prone treatment.
      The study was stopped early due to a significant difference in cardiac dosimetry between prone and VBH techniques. Although only 65% of patients completed the study as per protocol, primary endpoint data was available for 82% and the original power of the study remained despite stopping recruitment early. Reasons for failure to complete the study included failure to meet inclusion criteria, prone treatment plan issues, prone equipment shortcomings and prone setup difficulties (see Supplementary material). In addition, the crossover design of the study allowed clinicians to compare VBH and prone treatment plans prior to treatment. This study may be criticised for using mean LAD dose as its primary endpoint, as a recent study demonstrated considerable inter-observer variability in LAD outlining [
      • Lorenzen E.L.
      • Taylor C.W.
      • Maraldo M.
      • et al.
      Inter-observer variation in delineation of the heart and left anterior descending coronary artery in radiotherapy for breast cancer: a multi-centre study from Denmark and the UK.
      ]. However, this effect was minimised in our study by the same clinician outlining the LAD for all treatment plans. This was a single centre study at a centre where prone treatment is not in routine use, and this may affect the generalisability of our results, especially with regard to positional reproducibility.
      Despite demonstrating a statistically significant superiority for supine VBH over free-breathing prone treatment in terms of cardiac sparing and positional reproducibility, there is much to satisfy proponents of either technique in this study; cardiac doses were low for both techniques and reproducibility was, for the majority of women, within tolerance levels used for standard tangential field breast radiotherapy. In addition, continued improvements in prone breast board technology are likely to enhance both patient comfort and reproducibility. However, given the inferior reproducibility and paucity of visible chest wall on EPI, a CBCT-based correction protocol is indicated for prone treatment. It is hoped that the results of this study will inform the decisions of centres considering implementation of either of these heart-sparing techniques. However, it is expected that in the UK the focus of work will shift to developing the VBH technique further, especially as we anticipate it to be more compatible with complex breast radiotherapy techniques, such as simultaneous integrated boost, arc therapies, and regional nodal treatments.

      Conclusion

      Our data suggest that, in larger-breasted women, supine VBH treatment is better at sparing cardiac tissues and more reproducible than treatment using a free-breathing prone technique. Patients find VBH more comfortable than the prone position. Treatment setup and total treatment session times are shorter with VBH.

      Conflict of interest

      Orfit Industries (Wijnegem, Belgium) loaned the prone breast platforms used in this study.

      Acknowledgements

      This article presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-1010-23003 ). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The work was undertaken in The Royal Marsden NHS Foundation Trust which receives a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS executive. We acknowledge NHS funding to the NIHR Biomedical Research Centre and the support of the NIHR, through the South London Cancer Research Network. ED is funded by an NIHR Career Development Fellowship.

      Appendix A. Supplementary data

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