Comparison Between Deep Inspiration Breath Hold and Shallow Breathing for Prone Photon or Proton Irradiation of the Breast and Regional Lymph Nodes


 We report on a comparative dosimetrical study between deep inspiration breath hold (DIBH) and shallow breathing (SB) in prone crawl position for photon and proton radiotherapy of whole breast (WB) and locoregional lymph node regions, including the internal mammary chain (LN_IM). We investigate the dosimetrical effects of DIBH in prone crawl position on organs-at-risk for both photon and proton plans. For each modality, we further estimate the effects of lung and heart doses on the mortality risks of different risk profiles of patients. Thirty-one patients with invasive carcinoma of the left breast and pathologically confirmed positive lymph node status were included in this study. DIBH significantly decreased dose to heart for photon and proton radiotherapy. DIBH also decreased lung doses for photons, while increased lung doses were observed using protons because the retracting heart is displaced by low-density lung tissue. For other organs-at-risk, DIBH resulted in significant dose reductions using photons while minor differences in dose deposition between DIBH and SB were observed using protons. In high-risk patients for cardiac and lung cancer mortality, average thirty-year mortality rates from radiotherapy-related cardiac injury and lung cancer were estimated at 3.12% (photon DIBH), 4.03% (photon SB), 1.80% (proton DIBH) and 1.66% (proton SB). The radiation-related mortality risk could not outweigh the ~8% disease-specific survival benefit of WB + LN_IM radiotherapy in any of the assessed treatments. Trial registration: No trial registration was performed because there were no therapeutic interventions.


Introduction
Radiation therapy (RT) after breast-conserving surgery in locally advanced stage breast cancer improves locoregional control and survival. However, the bene t occurs at the expense of acute and late toxicity to the treated region, including but not limited to cardiac events, lung cancers and cancers in the contralateral breast [1][2][3][4][5][6] . Cardiac injury and cancer induction lead to excess mortality and are dose dependent. RT in prone position allows for dose reductions to lung and heart, hence lowering the risks of radiation-induced cardiac toxicity and lung cancer [7][8][9][10] .
Furthermore, prone positioning may be advantageous not only in whole breast (WB) irradiation, but also when combined with lymph node (LN) irradiation including the internal mammary (MI) chain 11,12 . However, patient support devices for prone radiotherapy share several drawbacks for locoregional radiotherapy 13 . To address these problems, we have studied a novel 'front crawl' prone position for patients requiring locoregional treatment at Ghent University [11][12][13] .
The dose to the heart can be further reduced by using deep inspiration breath hold (DIBH) in prone or supine position, rather than with shallow breathing (SB). Imaging studies in prone position con rm that DIBH retracts the MI chain away from the heart 14 . In a direct comparison of 4 techniques (prone or supine, SB or DIBH), prone DIBH achieved the lowest heart and lung doses for left-sided whole breast (WB) treatments 9 .
In this study, we investigate the dosimetrical effect of DIBH in prone crawl position on heart, lungs and other organs-at-risk (OARs) in both photon and proton plans, for the treatment of WB and LN (including the MI chain) as compared to SB. Afterwards, the mortality risk was compared, from radiation dose-related injury to heart and induction of lung cancer, to the expected survival bene t of WB + LN radiotherapy in this patient population.

Patients, Materials And Methods
Thirty-one patients with invasive carcinoma of the left breast and pathologically con rmed positive lymph node status were included in this study, which was approved by the local ethics board of Ghent University Hospital. All research was performed in accordance with applicable guidelines and regulations and informed consent was obtained from all participants.
Patients were positioned on the Prone Crawl Breast Couch as described previously 12 . DIBH was monitored using Respisens magnetic sensors (Nomics, Angleur, Belgium) placed on the surface of the Breast Couch and lateral thoracic wall 15 . Patients underwent two computed tomography (CT) scans for radiotherapy planning, rst in a single short DIBH of around 15 seconds and later in SB, as described previously 15 . Patients were instructed to practice the DIBH maneuver in advance at home. CT-images of 5 mm slice thickness were acquired, starting at below the mandible, and caudally ending below the diaphragm. Neither patient positioning nor scan range were altered between DIBH and SB. This was to assure that the DICOM coordinate system, indicated by the frame of reference UID of the different scans, remained identical.
Target and OARs delineation and margin generation were performed on a Pinnacle 9.8 treatment planning system (Philips Healthcare, Fitchburg, Wisconsin, USA) as described previously 12 . In brief, the whole breast was delineated up to 5 mm from the skin surface as CTV_WBI. CTV_PC included axillary level II-IV lymph nodes, delineated using the PROCAB guidelines 16 . CTV_MI included the ipsilateral MI lymph nodes. Planning target volumes were obtained by performing a 3 mm isotropic expansion of CTV_PC and a 1 mm isotropic expansion of CTV_MI, thereby creating PTV_PC and PTV_MI, respectively. PTV_WBI was created using a 5 mm margin except towards the skin surface to minimize build-up effects. Photon plan optimization structures were created to reduce in uence of dose buildup underneath the skin on plan optimization and to account for breast swelling. The whole heart was delineated in accordance with guidelines proposed by Feng et al. 17 . The left anterior descending artery (LAD) and the apex were individually delineated. Left and right lungs were contoured separately using the automatic segmentation by Houns eld unit options provided in Pinnacle 9.8 with threshold 800-4096. Contralateral breast was delineated up to the skin. Thyroid was delineated where visible. The esophagus was delineated starting cranially from the inferior margin of the cricoid and ending inferiorly at the gastro-esophageal junction.
For photon plan optimization, a non-coplanar multiple overlying short arc VMAT technique was used, which exploits optimal beam directions and reduces low-dose spread to the OARs 13 . VMAT planning tools, developed at Ghent University Hospital as extensions of GRATIS™ treatment planning platform (Sherouse systems, Inc., Chapel Hill, NC, USA), are described elsewhere 18 . The nal dose calculation was performed using the convolution-superposition dose computation engine in Pinnacle 9.8.
For proton plan optimization, planning CT and structures acquired and contoured at Ghent University Hospital were imported in the Paul Scherrer Institut (PSI) treatment planning system in Switzerland. The pencil beam scanning (PBS) proton plans were computed using PSIplan, an in-house treatment planning system 19 . For each proton plan, three oblique anterior elds were used with about 30° of angular spread between them.
Combined target optimization of spot weights was done simultaneously for all elds using intensity modulated proton therapy (IMPT) 20,21 .
Detailed information for proton plan optimization has been described previously by Speleers et al. 12 .
Dose per fraction to the breast was 2.67Gy for photons or 2.67 GyRBE/fraction for protons, the level II-IV axillary and the ipsilateral MI lymph node regions. Results are reported for 15 fractions. The objective was a median dose of 40.05 Gy/GyRBE (prescribed dose) to the optimization structures related to PTV_WBI, PTV_PC and PTV_MI, with 95% of the volumes covered by ≥95% of the prescribed dose and no more than 5% receiving 105% of the prescribed dose. The dose homogeneity index was de ned as (D 02 -D 98 )/D mean Dose statistics are referred to as Dn (the minimal dose delivered to n % of the volume) or Vn (the volume percentage receiving ≥ n Gy/GyRBE). D 02 and D 98 were used as surrogates for maximum and minimum dose, respectively. Dose is reported for PTV_WBI, PTV_MI and PTV_PC. For statistical comparison, two-tailed paired t-tests were performed with an alpha level of 0.05.
Mean dose to heart, LAD, apex, lungs (both lungs together), ipsilateral and contralateral lung, thyroid, esophagus and skin overlaying the target volume are reported. The thirty-year mortality risk from radiation-induced cardiac injury and lung cancer for a reference patient, a 50-year old woman at the time of irradiation, was calculated from mean heart dose and mean dose to both lungs according to Taylor et al. 22 . Risk rates of 0.075%/Gy or 0.3%/Gy were used for patients without or with cardiac risk factors, respectively, to calculate cumulative 30-year risk of dying from radiation-induced heart disease 22 . Risk rates of 0.06%/Gy or 0.88%/Gy were used for non-smoking or smoking patients, respectively, to calculate cumulative 30-year risk of dying from radiation-induced lung cancer 22 . Cumulative risk of dying from heart disease and/or lung cancer was calculated as 1-(1-P h )(1-P l ) where P h and P l are the risks to die from radiation induced heart disease or lung cancer, respectively. We then made a risk-bene t classi cation for different risk categories of cardiac events and lung cancer. The line of regret 12 is calculated for the 8% diseasespeci c absolute 30-year survival bene t of radiotherapy, based on literature 23 . For each patient, mean heart and lung doses are plotted onto this graph, showing whether the bene ts of radiotherapy can (below the line of regret) or cannot (above the line of regret) outweigh the added risks of radiotherapy.

Dose to target structures
The dose homogeneity index (HI) was 13.1% for photon DIBH, 12.8% for photon SB, 8.80% for proton DIBH and 9.38% for proton SB. HIdifferences between photon and proton plans are signi cant for SB (p=0.002) and DIBH (p=0.005). Average left breast volume was not signi cantly different at 398 cm³ (range: 45-921) and 393 cm³ (range: 53-902) in SB and DIBH, respectively. Dose objectives were met for all targets in all plans. Regarding the D 02 for PTV_WBI, there were no signi cant differences between photon DIBH and SB (p=0.11) and between proton DIBH and SB (p=0.37). For PTV_PC, the average D 02 was 0.36 Gy higher in photon DIBH than in photon SB (p=0.02) and 0.08 GyRBE higher in proton DIBH than in proton SB (p= 0.53). For the average maximum doses of PTV_MI, there was no signi cant difference between photon DIBH and SB (p=0.14), but the average maximum dose was 0.29 GyRBE higher in proton DIBH than in proton SB (p= 0.02).
Dose to organs at risk Dose indices of OARs are summarized in Table 1. The DIBH-technique, compared to SB, signi cantly decreased mean dose to heart in both photon and proton plans. Figure 2 provides an overview of the individual mean heart doses for photon (upper panel) and proton (lower panel) irradiation, ranked according to decreasing mean SB-dose. The mean heart dose reduction in DIBH, compared to SB, for photon and proton was on average 2.0 Gy (range: -1.0 -3.5) and 0.56 GyRBE (range: 0.1 -1.1), respectively.
As seen in Table 1, DIBH also resulted in a signi cantly lower mean dose for the esophagus for photons, but not for protons. On average in photon plans, left lung mean dose decreases about 13% by using DIBH, whereas in proton DIBH plans the average mean left lung dose increases by about 21%. No signi cant difference was observed both for proton and photon on the mean dose to the contralateral breast.
As for relevant maximum doses, we saw signi cantly higher doses in photon than in proton plans for brachial plexus and spinal cord. However, for the maximum dose on the esophagus and the mean thyroid dose, proton plans show signi cantly higher doses in both breathing settings.

Analysis of regret
Thirty-year risk estimations of dying from radiation induced heart disease or lung cancer (for a 50-year old reference patient) are given in Table 2.
Here, two different characteristics have been taken into account. The rst distinction is based on the presence of cardiac risk factors. The second distinction is based on the presence of lung cancer risk factors, in this case long-term smoking behaviour. These rates, multiplied with the average mean heart or lung dose in Gy or GyRBE, give an indication of the radiation-induced cardiac or lung cancer mortality risk, respectively, for the different groups. Figure 3 shows a risk-bene t classi cation of high-risk patients of both cardiac events and lung cancer. For none of the patients in this study, the 8% disease-speci c survival bene t 23 from radiotherapy would be outweighed by radiation-induced cardiac or lung cancer mortality. Data points on the line of regret show where the 8% disease-speci c survival bene t of radiotherapy is compensated by the survival loss from combined radiotherapy-related cardiac and lung cancer mortality.

Discussion
DIBH and prone radiation techniques offer signi cant dose reductions to heart and lung for breast-only irradiation (Table 1). In a factorial design study prone versus supine and DIBH versus SB, the combination of prone positioning and DIBH was shown to achieve lower heart and lung doses than any other combination 9 . Patients requiring both breast and regional lymph node (locoregional) irradiation receive even higher lung and heart doses, but at present technical reasons hamper the combination of DIBH and prone radiotherapy and this combination cannot be delivered for routine care. Accordingly, we have also developed a prone support device (Prone Crawl Breast Couch) to facilitate patient positioning, CTsimulation and treatment. Using the Prone Crawl Breast Couch for the locoregional treatment, without or with inclusion of the MI chain, we showed that dose reductions to lung, heart and other OARs could be obtained beyond what is achievable using advanced supine photon irradiation techniques 11,12 .
We adapted our prone DIBH-technique for use on the Prone Crawl Breast Couch and showed the potential of the combination for heart and lung dose reductions. The relative dose reductions by prone DIBH shown in this study, on average 44% mean heart dose reduction by DIBH, are comparable with those previously obtained for local radiation by Mulliez (i.e. 45% mean heart dose reduction by DIBH in supine; 41% mean heart dose reduction in prone) 24 . Saini reported 48% mean heart dose reduction by DIBH in supine and 9% mean heart dose reduction in prone for local irradiation 9 . These relative reduction rates establish the role of DIBH in photon therapy and support the hypothesis that also for locoregional treatment, the combination of prone positioning and DIBH will allow for achieving substantially lower heart and lung doses than the 3 other techniques.
In the photon SB plans of this study, the mean heart dose was 4.55 Gy (range: 2.4-6.58). This is about double the mean heart dose of 2.54 Gy Looking at the individual mean heart doses for photon plans in this study, we nd lower heart doses in DIBH for all patients except one. This is due to the creation of a hotspot in the shoulder, cranial outside the lymph node regions. This hotspot derives from the para-sagittal beam direction, as a consequence of trying to spare the heart from dose by lateral beam directions, by which the optimizer was struggling during optimization. In trying to get rid of the hotspot during optimization, the dose to heart increased by enlarging the beam aperture of the lateral beam directions and their dose weights. The different steps of the optimization process are described in The dose spread difference between the photon and proton modality in this study is clari ed in Figure 5 and Figure 6. In the intra-thoracic and dorsal shoulder region, ratios of larger dose spread were found for photon (both DIBH and SB) than for proton plans, similar to our previous study 12 . The main difference in this study is the mutual ratio of dose spread in lung between DIBH and SB photon and proton modality, respectively. In the DIBH proton setting, we found higher mean lung doses whereby a larger dose spread is seen in low density cavities. This can be explained anatomically as the heart and tissues of higher density protect the lung and low density areas from unwanted dose spread in proton SB. Internal anatomical changes during the DIBH-maneuver retract the heart from the target region, which is replaced by lung or low density tissue that is exposed to a higher radiation dose. The lower mean lung dose in DIBH photon plans, compared to SB photon plans, can be explained by the use of non-coplanar VMAT beam directions and the gain of unexposed lung volume expansion in the posterior and caudal direction by DIBH .
The use of multiple short breath holds of 15-30 seconds represents the most common mode of implementation of DIBH. Clinical experience indicates that multiple short breath-holds are more challenging with the addition of regional irradiation. Whereas a local radiotherapy session is typically completed using 3-6 multiple short breath-holds each of 12-18 seconds and most patients can be trained to perform these easily, we nd that a locoregional radiotherapy session requires 10-14 multiple short breath-holds each of 15-30 seconds. This represents a substantial physical and mental effort for all but the most able patients. At the University and Queen Elizabeth Hospital (Birmingham, UK), a single prolonged breathhold technique was developed, using pre-oxygenation and asymptomatic hypocapnia induced by mechanical hyperventilation [27][28][29][30][31] . Volunteers and breast cancer patients were able to maintain safely and comfortably single prolonged breath-holds of 5 minutes and more. Another solution could be the use of percussive ventilation 32 . An entire locoregional radiotherapy session could therefore be delivered in theory in one single prolonged breath-hold. The prolonged breath-hold technique is presently being translated for use in the prone crawl position.
Using modern radiation techniques such as IMPT and PBS, proton therapy is able to decrease OAR-dose beyond what is possible with photon techniques 12 . However, breathing motion may jeopardize the accuracy of proton therapy because it may induce uncertainty in proton range and dose prediction. Motion of breast, shoulder and sternal regions by breathing is smaller in prone crawl than in supine position and dose prediction uncertainty is also expected to be smaller. We hypothesized that the relevance of studying DIBH in prone crawl proton therapy resided in its effects on dose to heart, lungs and other OARs. DIBH reduced mean heart, apex and LAD doses on average by 42%, 21% and 3% respectively, but increased left and right lung mean doses by 21% and 75%, respectively. The relative dose increase for both lungs combined was 46%. The use of couch rotation or novel techniques like proton arc therapy and real-time motion monitoring in respiratory-gated PBS proton therapy could mitigate this issue 33 . DIBH resulted further in small dose increases in esophagus, contralateral (right) breast and spinal cord. The cause of opposite dose changes on heart and lung is explained above. Using DIBH in prone locoregional breast proton therapy can be bene cial, neutral or detrimental depending on the clinical situation. In patients with cardiac but no lung cancer risk factors, overall risk reduction can be expected from DIBH. In patients with lung cancer but no cardiac risk factors, SB would be indicated, and end-expiratory breath hold might be worth investigating.

Conclusion
We further investigated the potential bene ts of prone crawl positioning in WB + LN (including MI) RT by evaluating the dosimetrical effects of DIBH and SB in photon and proton plans. DIBH signi cantly decreased doses to heart for proton and photon radiotherapy. For photons, the relative reduction rates establish the role of DIBH in photon RT. This supports the hypothesis that also for locoregional treatment, the combination of prone positioning and DIBH will allow for achieving substantially lower heart and lung doses than the 3 other techniques. To overcome the practical challenges of DIBH in locoregional RT, further development and evaluation is proposed. For DIBH in proton plans, an increase of lung dose should be taken into account. The radiation-related mortality risk could not outweigh the ~8% disease-speci c survival bene t of WB + LN_IM radiotherapy in any of the assessed treatments.