Feasibility study: Spot-scanning Proton Arc therapy (SPArc) for left-sided breast irradiation

This study investigated the feasibility and potential clinical benet of utilizing a new proton treatment technique: Spot-scanning Proton Arc (SPArc) therapy for left-sided breast cancer irradiation to further reduce radiation dose to healthy tissue and mitigate the probability of normal tissue complications compared to conventional Intensity Modulated Proton Therapy(IMPT). Eight patients diagnosed with left-sided breast cancer and treated with breast-preserving surgery followed by whole breast irradiation without regional nodal irradiation were included in this retrospective planning. Two proton treatment plans were generated for each patient: vertical intensity-modulated proton therapy used for clinical treatment (vIMPT, gantry angle 10°-30°) and SPArc for comparison purpose. Both SPArc and vIMPT plans were optimized using the robust optimization of ± 3.5% range and 5 mm setup uncertainties. Root-mean-square deviation dose (RMSD) volume histograms were used for plan robustness evaluation. All dosimetric results were evaluated based on dose-volume histograms (DVH), and the interplay effect was evaluated based on the accumulation of single-fraction 4D dynamic dose on CT50. The treatment beam delivery time was simulated based on a gantry rotation with energy-layer-switching-time (ELST) from 0.2 to 5 s. ranging from 0.61 to 0.86 depending on the clinical endpoint. The RMSD Volume Histogram(RVH) analysis shows SPArc provided better plan robustness in OARs sparing, including the heart, LAD, ipsilateral lung, and skin. The average estimated treatment beam delivery times were comparable to vIMPT plans when the ELST is about 0.5 s. and 34.51% (3.07% vs 4.68%, p = 0.003) via SPArc. The skin3mm structure mean and maximum dose was reduced to 3999.38 cGy and 4395.63 cGy compared to vIMPT plans (4104.25 cGy (p = 0.039) and 4411.63 cGy (p = 0.043)) respectively. However, the study found that the mean dose of the contralateral breast was increased to 18.5 cGy in the SPArc plans compared to the vIMPT plans (12.13 cGy, p = 0.011).


Introduction
Breast cancer is one of the most common cancers among women globally [1]. Breast-conserving surgery with adjuvant whole breast irradiation has become an increasingly popular treatment option for early-stage breast cancer [2][3][4][5][6]. Currently, conventional photon Page 3/16 Compared to photon radiotherapy, proton beam therapy may provide a dosimetric advantage whentreating left-side breast cancer due to the sharp distal dose fall-off of the proton beam. Utilization of intensity modulated proton therapy (IMPT) for breast cancer treatment has increased over the last several years [14][15][16]. In IMPT, the positions and number of beam spots are optimized simultaneously to obtain the desired dose distribution, and robust optimization has been used to deal with uncertainties such as setup uncertainty, range uncertainty, and breathing motion uncertainty [17][18][19][20][21][22]. However, due to the low delivery e ciency with the current proton system, IMPT plans in breast cancer are still limited to a few beam angles. In addition, a large volume of the target may exceed the maximum eld size. As a result, some IMPT plans may require a second isocenter for eld matching [23], which further prolongs treatment time. These obstacles restrict the ability to further exploit the bene ts of IMPT, and motivates us to explore better planning techniques to overcome the current limitations in terms of plan quality and clinical work ow e ciency. Spot-scanning proton arc therapy (SPArc) is an emerging technique that is able to deliver the proton beam through a dynamic rotational gantry [24]. Preliminary results demonstrated the potential clinical bene ts for various disease sites, including prostate, head and neck, lung, and brain cancers [25][26][27][28]. This study is the rst to exploit the feasibility and potential bene ts of utilizing SPArc in the treatment of left-sided breast cancer patients compared to the conventional IMPT technique.

Methods
Retrospective patient data selection and treatment planning Eight patients treated with whole breast irradiation without regional nodal irradiation from our institution using IMPT were included in this study. All patients underwent 4D-CT simulation using a spiral CT scanner (Philips Brilliance Big Bore, Philips Healthcare System, Cleveland, OH), and an average CT image was reconstructed based on a pixel-by-pixel averaging of the 4D-CT scan. The CT datasets were then transferred to RayStation version 9A (RaySearch Laboratories AB, Stockholm, Sweden) for planning. Clinical target volume (CTV) was de ned as the volume irradiated based on the Radiation Therapy Oncology Group (RTOG) guidelines [29]. The internal target volume (ITV) was generated on the average CT scan, which was the union of the CTVs from all individual respiratory phase CT scans.
Two separate treatment plans were created for each case: vertical IMPT (vIMPT, 10°-30°) and SPArc (partial-arc) plans. Three of the patients with large tumors required two-isocenter IMPT plan due to the eld size limitation (20 cm x 24 cm maximum eld size). SPArc plans used a single isocenter with a partial arc. Both planning strategies used ITV plus robustness optimization to take into account setup (± 5 mm) and range (± 3.5%) uncertainties (total 21 scenarios). A standard deviation of 1.0% was used in Monte Carlo (MC) dose calculation with a dose grid of 3.0 mm. Organs at risk (OARs) include heart, LAD, ipsilateral lung, contralateral breast and skin3mm.
The skin3mm was de ned as a 3 mm deep layer starting from the external body contour and following the extension of the ITV. The prescribed dose for all patients was 4256 cGy in 16 fractions [30,31]. Plans aimed to achieve 100% of the prescribed dose in 98% of the ITV. SPArc and vIMPT plans were optimized in Raystation TPS in similar objectives and constraints for OARs. The objective and constrain functions were speci ed individually for each patient to obtain the best achievable treatment plan until there is no signi cant improvement.
Nominal dosimetric Plan quality evaluation and plan robustness analysis Target coverage and doses to OAR's were all evaluated and compared based on the DVH between SPArc and vIMPT. Also, the plan dose homogeneity was evaluated by homogeneity index (HI), which was de ned as D 5 /D 95 (where D5 and D95 are the minimum dose in 5% and 95% of the target volume). The ideal value of HI is 1. ITV coverage was evaluated by the conformality index (CI), which was de ned as CI= (TVDp/TV)*(TVDp/VDp), where the TV is target volume, and TVDp and VDp are the target volume covered by the prescribed dose, and the volume enclosed by the prescription isodose line, respectively [32]. The plan robustness was de ned by the ability of a proton plan to retain its objectives under the in uence of uncertainties. In the present study, all plans were evaluated using worst case scenario perturbed dose with setup uncertainties of ± 5 mm for x, y, z directions, and ± 3.5% range uncertainties. Besides, the root-meansquare deviation doses (RMSD) for each voxel of all the 21 scenarios were calculated. The RMSD volume histograms (RVH) and the area under the RVH curve (AUC), which introduced by Liu et al. were computed for relative comparison of IMPT and SPArc plan robustness [33]. The smaller the AUC value, the more robust the plan was for the speci c structure(s).

Evaluation of motion interplay effect
The interplay effect was evaluated by the single-fraction 4D dynamic dose calculation without considering re-scanning for different starting respiratory phases [34]. This 4D dynamic dose calculation used a method by relating the time sequence of each spot delivery to the corresponding 4D-CT phase from the patient breathing cycle. Then it accumulated each spot dose via the deformable image registration on the corresponding respiration phase to the reference 4D-CT phase (CT50) for evaluation, assuming the energy-layerswitching-time (ELST) of 1 s and a regular respiratory breathing cycle of 4.5 s.

Treatment beam delivery time calculation and statistics analysis
The treatment delivery e ciency of SPArc and vIMPT plans were evaluated based on assumptions of a gantry with 1 rotation per minute gantry speed, 2 ms spot switching time, and ELST from 0.2 to 5 s [24]. Statistical analysis was performed with non-parametric Wilcoxon signed rank test using SPSS 21.0 software (International Business Machines, Armonk, New York). The p-value < 0.05 was considered statistically signi cant.
Evaluation of Potential clinical bene t for OARs based on the NCTP model Potential clinical bene ts of each OAR such as heart, LAD, left lung, and skin were estimated using the normal tissue complication probability (NTCP) model from the literature (Table 1). Brie y, Lyman-Kutcher-Burman (LKB) and Possion LQ models were employed [35][36][37][38][39]. To compare risk values between SPArc and vIMPT plans, we de ned the ratio of NTCP (R NTCP ), as R NTCP = NTCP SPArc / NTCP vIMPT .

Results
Nominal Dosimetric plan quality comparisons Figure 1 shows an example (patient #5) of radiation treatment plans and DVHs for SPArc and vIMPT. With a similar target coverage (Table 2), the SPArc technique achieved signi cantly higher dose homogeneity compared with the vIMPT technique (p < 0.001).

Evaluation of dosimetric impact from the interplay Effect
The study found that SPArc could improve the plan robustness in both target and OARs (  Figure 3 shows a representative example of the 4D dynamic dose calculation of SPArc versus vIMPT plans. Beam delivery e ciency Table 3 lists the estimated beam delivery time per fraction for both SPArc and vIMPT plans for various ELST. When the proton system's ELST is 5 s, the average estimated delivery time ratios between SPArc and vIMPT plans was 1.40 (1059s vs. 758 s), which means it would take signi cantly longer to deliver a SPArc plan (p < 0.001). The difference became smaller as the ELST is faster. When the ELST was less than 0.5 s, the treatment delivery time of SPArc plan could be less than vIMPT (p = 0.005) (Fig. 4). However, the estimated treatment time didn't take into account the additional time to perform iso-shift and re-imaging. For the 2-isoenter vIMPT plan, additional couch movement for the next iso and IGRT veri cation procedures may be needed to ensure the treatment accuracy. For SPArc, only a single iso is needed, which would save signi cant additional treatment time as well as simplify the clinical treatment work ow.

Potential clinical bene t for heart
The results show that there was a potential clinical bene t based on NTCP model calculation of using SPArc over vIMPT (Table 4).
More speci cally, heart, LAD, left-lung, and skin complications showed an overall reduction in the toxicity risk prediction for SPArc plans compared with the vIMPT plan, with R NTCP ranging from 0.61 to 0.86, depending on the clinical endpoint (Fig. 5). Discussion This is a rst and comprehensive dosimetric planning study to explore the feasibility and potential dosimetric and clinical bene ts in the management of patients with left-sided breast cancer receiving whole breast irradiation. This study also analyzed plan robustness in the presence of setup and range errors in addition to the breathing-induced interplay effect. Our results indicate that the SPArc technique with additional degree of freedom in optimization and delivery could not only improve dosimetric quality but also improve plan robustness compared to conventional vIMPT.
The results from this study agree with previous ndings that SPArc could shorten the total treatment delivery time based on the modern proton therapy machines where the average of ELST is less than 0.5 s [25][26][27][28]40]. In the presence of the larget target size, which requires multi-isoenter eld matching, SPArc technique could utilize a single-isoenter to simplify the clinical treatment work ow. For example, three out of eight cases included in this study required a second isocenter. As a result, therapists need to apply an isocenter shift, image validation, and second treatment eld in the vIMPT treatment. A review of treatment logs of these three cases found that it took 5.11 ± 0.05 min on average to perform these additional procedures for the 2nd isocenter shift. These additional couch isocenter shift and image acquisition times prolong the overall treatment time and also increase the chance of intrafraction motion [41][42][43].
Thus, SPArc has the potential to provide a more e cient clinical treatment work ow through one arc trajectory and further reduce the uncertainties from the intrafraction motion.
Cardiac toxicityremains a leading treatment related cause of morbidity and mortality among long-term breast cancer survivors after radiotherapy, especially in the patient population with left-sided breast cancer [44]. Previous studies have found several heart dosimetric metrics related to acute or late cardiotoxicity, although there are still debates in which dosimetric metric and substructures are more related to the acute or late cardiotoxicity [45][46][47][48].
Darby et al. found that the rate of the incidence of ischemic heart disease increased linearly with the mean heart dose by 7.4% per Gy [13]. In addition, the RADCOMP (Radiotherapy Comparative Effectiveness) trial has also pointed out that the mean heart dose as a critical indicator for cardiotoxicity [45,49]. The mean heart dose of the delivered vIMPT plans in our study was 6.38 cGy, which is higher than SPArc 4.5 cGy (p = 0.04). Moreover, there is increasing evidence that the dose of heart substructures needs to be considered. Some studies have focused on the LAD as important parts of the heart associated with radiation-induced heart disease [11,50]. Conventional proton beam therapy (IMPT or Passive-scattering) could reduce the dose of the heart and LAD in left-side breast cancer patients compared to the photon radiotherapy technique in the high cardiac doses sparing [10,15,51]. This study found that the new proton treatment technique, SPArc, could further reduce the D1 of heart and LAD which might mitigate the probability of heart acute and late toxicities. We recognize that the relevance of photon NTCP models to proton therapy has not been established and further proton study would be needed to correlate the proton dose with the cardiotoxicity. The study also found that the contralateral breast mean doses were slightly higher in SPArc planning group compared with vIMPT. It is important to consider and choose the optimal treatment technology for an individual patient considering the possible clinical bene ts as well as the limitation of using SPArc technique.
Another critical OAR that could bene t from SPArc is the healthy lung tissue. Reducing the radiation dose to the lung can result in reducing the risk of radiation pneumonitis in patients. Our feasibility study nds that the technology of SPArc can substantially improve not only the heart and LAD sparing but also the lung sparing in comparison with vIMPT. Previous studies have con rmed that proton therapy can signi cantly reduce the V500(cGy) and V2000(cGy) of the ipsilateral lung by nearly 50% compared to traditional 3DCRT and IMRT [10,52,53]. This study found that SPArc plans further reduced all dose-volume parameters while providing a reduced or similarly high-dose radiation volume with IMPT in left-sided breast cancer.

Conclusions
SPArc can achieve superior OARs sparing and robust plan quality in left breast irradiation compared to the traditional IMPT. With ELST less than 0.5 s in current modern proton systems, the total beam delivery time per fraction of SPArc would be faster than IMPT which would be desirable for future clinical implementation. Availability of data and materials

Abbreviations
All data generated or analyzed during this study are included in this published article. Additional information is available from the corresponding author on reasonable request.
Authors' contributions SC and GL contribute to the acquisition, analysis and interpretation of the result and draft and design the paper. PK WZ, SJ, PC, CS and JD provided clinical inputs; DY and LZ provide imaging acquisition and support and statistical analysis; XL provided technical support.
XD, contribute to the design of the study, revise the draft and lead the research direction. All authors read and approved the nal manuscript.
Ethics approval and consent to participate The patient data used in this study is approved by Beaumont institutional IRB.

Consent for publication
Not applicable.