Dosimetric comparison of volumetric modulated arc therapy and proton pencil beam scanning with or without deep inspiration breath-hold in left-sided breast cancer irradiation including internal mammary nodes

Introduction

Breast cancer is the most prevalent malignancy among women globally, accounting for approximately 30% of all new cancer diagnoses in females and remaining the leading cause of cancer-related mortality in this population (1). Adjuvant radiotherapy following breast-conserving surgery or mastectomy plays an indispensable role in reducing locoregional recurrence rates and improving long-term survival, as demonstrated by large-scale meta-analyses (2). Despite these therapeutic benefits, the delivery of radiation to the breast or chest wall inevitably involves exposure of adjacent normal tissues, leading to a spectrum of acute and chronic toxicities that can compromise patient quality of life.

For patients with left-sided breast cancer, the proximity of the heart and lungs to the radiation field presents a unique challenge. Numerous studies have established a dose-dependent relationship between cardiac irradiation and an increased risk of cardiovascular morbidity and mortality, with even low doses contributing to ischemic heart disease and other coronary events over decades (3). The left anterior descending coronary artery (LAD), a critical substructure of the heart responsible for myocardial perfusion, is particularly vulnerable due to its anatomical position near the chest wall. Similarly, radiation exposure to the lungs can result in pneumonitis or fibrosis, further complicating the therapeutic balance between tumor control and normal tissue preservation.

Furthermore, regional nodal irradiation, particularly involving the internal mammary nodes (IMNs), magnifies these challenges substantially. IMNs are clinically indicated in patients with node-positive disease, medial/central tumors, or other high-risk features. However, due to their parasternal anatomical location, IMN coverage necessarily requires medial beam angles that traverse the heart and coronary vasculature, resulting in substantially elevated cardiac doses compared to breast-alone irradiation.

Efforts to mitigate these risks have driven the development of advanced radiotherapy techniques. Deep inspiration breath-hold (DIBH) is one such strategy that has gained widespread adoption in recent years. By instructing patients to take a deep breath and hold it during radiation delivery, DIBH increases the physical distance between the heart and the chest wall through thoracic cavity expansion (4). This separation has been shown to reduce cardiac doses significantly, particularly when irradiating the left breast or regional lymph nodes, including IMNs (5). However, DIBH also alters lung geometry, potentially increasing the volume of lung tissue exposed to low-dose radiation, a phenomenon that warrants careful consideration.

Parallel to these advancements in delivery techniques, the advent of proton therapy has revolutionized radiation oncology. Unlike photon-based modalities—such as three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), or volumetric modulated arc therapy (VMAT)—protons exhibit a distinct dose deposition profile characterized by the Bragg peak. This physical property allows protons to deliver their maximum energy at a specified depth, followed by a rapid dose fall-off, minimizing exit dose to surrounding tissues (6). Proton pencil beam scanning (PBS), a refined form of proton therapy, further enhances precision by modulating beam intensity and direction, making it an attractive option for left-sided breast cancer where organ at risk (OAR) sparing is paramount.

While the individual benefits of DIBH and proton therapy have been well-documented, their combined efficacy remains an area of active research. Previous studies have primarily compared proton therapy with older photon techniques like 3DCRT or IMRT, with fewer investigations focusing on VMAT, a highly conformal and widely utilized modern photon modality (7). Moreover, it is unclear whether the inherent dosimetric advantages of proton therapy render DIBH redundant or if DIBH provides additional value in this context. This study aims to address these gaps by conducting a comprehensive dosimetric comparison of VMAT and proton PBS under both free breathing (FB) and DIBH conditions in a cohort of left-sided breast cancer patients. By analyzing doses to critical OARs and target volumes, we seek to elucidate the optimal radiotherapy approach for this patient population, with particular attention to cases requiring IMN coverage and the necessity of DIBH with proton therapy. We present this article in accordance with the STROBE reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-25-20/rc).

Methods

Patient selection

This retrospective study included ten female patients diagnosed with left-sided breast cancer who completed adjuvant radiotherapy at Chang Gung Memorial Hospital between January 2020 to December 2022. Patients were selected based on the availability of computed tomography (CT) simulation scans under both FB and DIBH conditions, completion of breast-conserving surgery with axillary lymph node dissection, and histologically confirmed negative surgical margins. Exclusion criteria included prior thoracic radiotherapy, bilateral breast cancer, or incomplete imaging data (without either FB or DIBH). Each patient served as her own control, minimizing inter-individual variability and strengthening the statistical power of the comparisons. Figure 1 presents a flowchart of the participant selection process.

Figure 1 Flowchart for patient inclusion. CT, computed tomography; DIBH, deep inspiration breath hold; FB, free breathing.

CT simulation and immobilization

Patients were positioned supine on a standard breast board with both arms raised above the head to optimize access to the breast and regional lymphatics. Immobilization was achieved using a custom thermoplastic mask or vacuum cushion to ensure reproducibility across simulation and treatment sessions. CT scans were acquired using a 16-slice scanner (GE Healthcare, Waukesha, WI, USA) with a 3-mm slice thickness, spanning from the mandible to the lung bases. For DIBH scans, respiratory motion was monitored using a real-time position management system (Varian Medical Systems, Palo Alto, CA, USA), with patients coached to maintain a consistent breath-hold depth. FB scans were obtained under natural respiration without gating.

Target and OAR delineation

Target volumes were contoured according to Radiation Therapy Oncology Group (RTOG) guidelines (8). The clinical target volume (CTV) encompassed the whole breast or chest wall, with regional lymphatics—including the supraclavicular, axillary, and IMN regions—included when clinically indicated based on staging or recurrence risk. A uniform 7-mm isotropic expansion was applied to the CTV to create the planning target volume (PTV), excluding the heart to avoid artificial dose constraints. For proton PBS plans, planning was based directly on the CTV, per American Society for Radiation Oncology (ASTRO) recommendations, due to the precision of proton beams and their sensitivity to range uncertainties (9). OARs delineated included the heart, LAD, bilateral lungs (left and right separately), and contralateral breast, with contours verified by two independent radiation oncologists to ensure consistency.

Treatment planning

Four treatment plans were developed for each patient: VMAT under FB, VMAT under DIBH, PBS under FB, and PBS under DIBH. All plans prescribed a total dose of 50.4 Gy delivered in 28 fractions, a standard regimen for adjuvant breast radiotherapy. VMAT plans were designed using the Eclipse treatment planning system (Varian Medical Systems), employing two partial arcs to optimize dose conformality and minimize OAR exposure. Proton PBS plans were generated using the Eclipse system (Varian), incorporating two to three beams (anterior and left anterior oblique orientations) tailored to the patient’s anatomy. A ±3% range uncertainty was applied to proton plans to account for potential variations in tissue density and beam penetration, simulating clinical robustness. Two medical physicists were involved in planning. Treatment planning parameters for VMAT and PBS are detailed in Tables 1,2.

Planning objectives were standardized across modalities: PTV V95% (volume receiving ≥95% of prescribed dose) ≥95%, V107% ≤2%, heart V22.5 ≤20%, left lung V20 ≤20%, and contralateral breast V2.4 Gy <5%. For proton plans, CTV V95% ≥90% was deemed acceptable due to the absence of a PTV margin. Optimization prioritized target coverage while minimizing OAR doses, with iterative adjustments to beam angles, weights, and constraints as needed.

Dosimetric analysis

Dose-volume histograms (DVHs) were extracted for all delineated structures. Primary endpoints included mean dose (Dmean), maximum dose (Dmax), and volume-based metrics (e.g., V5, V20, V22.5) for each OAR. Target coverage was assessed using V95% and V107%. Data were compiled in a centralized database and analyzed using statistical software (SPSS v25, IBM Corp., Armonk, NY, USA).

Statistical methods

Sample size was not prospectively determined based on power analysis due to the pilot nature of this dosimetric comparison. However, the paired design partially mitigates inter-individual variability and strengthens statistical inference for a feasibility study. With n=10 paired, power is ~80% for detecting 20% dose differences (alpha =0.05). Dosimetric parameters were compared across the four planning scenarios using the two-tailed Wilcoxon signed-rank test, a non-parametric method suitable for paired data and small sample sizes. Comparisons were made between modalities (VMAT vs. PBS) and breathing conditions (FB vs. DIBH) for each OAR and target volume. A p value <0.05 was considered statistically significant, with Bonferroni correction applied for multiple comparisons where appropriate.

Ethical considerations

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of the Chang Gung Medical Foundation (no. 202300768B0C5002) and individual consent for this retrospective analysis was waived.

Results

Patients and target coverage

There were 10 patients’ CT images included in this study. The patients’ characteristics were listed in Table 3. All four planning techniques achieved clinically acceptable target coverage. VMAT plans under FB and DIBH are with the mean values of 92.9% (range, 90.19–95.61%) and 92.79% (range, 90.33–95.25%), respectively. Proton PBS plans, evaluated against CTV V95% ≥90%, achieved mean coverages of 95.45% (range, 90.96–99.94%) under FB and 94.08% (range, 82.49–100%) under DIBH. Minor reductions in PBS-DIBH coverage were observed in three patients, likely due to anatomical shifts during breath-hold affecting proton range, though all remained within acceptable limits. Hot spots (V107%) were minimal across all plans, averaging <1% for VMAT and <0.5% for PBS, indicating excellent dose homogeneity. Color wash dose distribution by 4 techniques were shown in Figure 2.

Figure 2 Radiation dose distribution with color-wash display for four treatment techniques in sagittal and axial views. (A) VMAT-DIBH sagittal view; (B) VMAT-FB sagittal view; (C) VMAT-DIBH axial view; (D) VMAT-FB axial view; (E) Proton-DIBH sagittal view; (F) Proton-FB sagittal view; (G) Proton-DIBH axial view; (H) Proton-FB axial view. DIBH, deep inspiration breath-hold; FB, free breathing; VMAT, volumetric modulated arc therapy.

Heart dosimetry

DIBH significantly reduced heart doses compared to FB across both modalities (p<0.01). For VMAT, the mean heart dose decreased from 15.4 Gy (30.52% of prescription) under FB to 13.3 Gy (26.45%) under DIBH, a relative reduction of 13.6%. Proton PBS exhibited far lower baseline doses, with mean heart doses of 0.94 Gy (1.87%) under FB and 0.21 Gy (0.41%) under DIBH—a striking 77.7% reduction (p<0.01). The heart V22.5 followed a similar trend: VMAT-FB averaged 22.88%, dropping to 22.73% with DIBH, while PBS-FB averaged 1.64%, further reduced to 0.56% with DIBH. These reductions highlight the synergistic effect of PBS and DIBH in minimizing cardiac exposure.

LAD dosimetry

The LAD, a critical cardiac substructure, exhibited even more pronounced dose reductions. VMAT-FB plans delivered a mean LAD dose of 30.3 Gy (60.05%), which decreased to 22.8 Gy (45.32%) with DIBH (p<0.05). Proton PBS plans reduced this to 9.4 Gy (18.67%) under FB and 2.8 Gy (5.60%) under DIBH (p<0.01), with the V22.5 dropping from 15.85% (PBS-FB) to 6.75% (PBS-DIBH)—a greater than six-fold reduction. This dramatic sparing is clinically significant given the LAD’s role in long-term cardiovascular risk.

Lung dosimetry

Left lung doses were substantially lower with PBS than VMAT. VMAT plans averaged a mean left lung dose of 15.1 Gy (30.06%) under both FB and DIBH, with no significant difference (p=0.72), reflecting the limitations of photon scatter. PBS plans reduced this to 4.3 Gy (8.44%) under FB and 4.8 Gy (9.53%) under DIBH (p<0.05), a slight increase attributed to lung expansion during breath-hold. The left lung V20 was 15.93% for VMAT-FB, 11.71% for VMAT-DIBH, 2.56% for PBS-FB, and 4.95% for PBS-DIBH, all within planning constraints. Right lung doses were negligible across all plans, averaging <1 Gy, due to its distance from the treatment field.

Contralateral breast dosimetry

Proton PBS virtually eliminated dose to the contralateral breast, with mean doses of 0.09 Gy (0.18%) under DIBH compared to 6.4 Gy (12.69%) for VMAT-DIBH (p<0.01). VMAT-FB data were not fully reported but showed similar trends. The contralateral breast V2.4 Gy was <1% for PBS plans versus 4.8% for VMAT-DIBH, underscoring PBS’s ability to spare non-target tissues. The radiation dose detail was shown in Table 4.

Discussion

Dosimetric superiority of proton PBS

The results unequivocally demonstrate that proton PBS outperforms VMAT in reducing OAR doses in left-sided breast cancer radiotherapy. The Bragg peak’s sharp dose fall-off enabled PBS to deliver therapeutic doses to the target while minimizing exposure to the heart, LAD, lungs, and contralateral breast—advantages consistent with prior proton therapy literature (10). Mean heart doses with PBS were an order of magnitude lower than VMAT (0.41% vs. 26.45% with DIBH), aligning with studies showing proton therapy’s potential to reduce cardiac risk (11). Similarly, the near-elimination of contralateral breast dose (<0.2 Gy) highlights a significant benefit for younger patients, where secondary malignancy risk is a concern (12).

Additive value of DIBH

The integration of DIBH further enhanced these outcomes, particularly for cardiac structures. While PBS already achieves low baseline doses, DIBH reduced mean heart and LAD doses by over 75% and 70%, respectively, compared to FB. This additive effect is likely due to increased physical separation between the heart and chest wall, a mechanism well-documented in photon-based studies (4). The synergy between PBS and DIBH suggests that even with advanced modalities, anatomical optimization remains a valuable tool for improving dosimetric profiles.

DIBH with proton therapy: necessary or excessive?

Given proton therapy’s inherent ability to spare OARs, a critical question arises: Is DIBH necessary with PBS, or does it represent an excessive measure in radiotherapy planning? Proton PBS’s sharp dose gradient already achieves mean heart doses as low as 0.94 Gy under FB, well below thresholds associated with significant cardiovascular risk (e.g., <4 Gy) (3). For the LAD, PBS-FB delivers 9.4 Gy, a notable reduction from VMAT’s 30.3 Gy, though still within a range where further sparing could be beneficial. The addition of DIBH reduces these doses to 0.21 and 2.8 Gy, respectively—improvements of 77.7% and 70.2%. While statistically significant, the clinical relevance of these reductions requires scrutiny.

In cases without IMN irradiation, where the target volume is confined to the breast or chest wall, PBS-FB may suffice for most patients. The heart’s baseline dose is already minimal, and the absolute risk reduction from DIBH (e.g., 0.73 Gy for the heart) may not translate to measurable long-term benefits, given the low starting point. Studies suggest a 7.4% increased risk of coronary events per Gy of mean heart dose (3), implying an additional risk reduction of −5% with DIBH in PBS plans—a small absolute gain for patients with otherwise favorable cardiac profiles. Moreover, DIBH introduces logistical challenges: it requires patient training, respiratory monitoring equipment, and extended treatment times, potentially increasing costs and reducing throughput in proton centers, which are already resource-intensive.

However, this perspective shifts when considering individual variability and specific clinical scenarios. Anatomical differences—such as a naturally smaller heart-to-chest wall distance—can elevate PBS-FB doses in some patients, as seen in one case where the mean heart dose reached 1.5 Gy without DIBH. Here, DIBH reduced it to 0.35 Gy, a more substantial relative benefit. Additionally, younger patients with decades of survivorship may benefit from any incremental reduction in cardiac dose, as cumulative risk accrues over time. The LAD’s sensitivity further supports DIBH’s role; reducing its mean dose from 9.4 to 2.8 Gy could lower the risk of late coronary stenosis, a concern not fully mitigated by PBS alone.

Thus, while DIBH with PBS may appear excessive for the average patient without IMN involvement, it is not universally redundant. Its necessity hinges on patient-specific factors (e.g., anatomy, age, comorbidities) and treatment goals. Routine use may be overkill, but selective application—guided by pre-treatment dosimetry or risk stratification—could optimize outcomes without overburdening resources. Prospective trials correlating dosimetric gains with clinical endpoints are needed to define thresholds where DIBH adds meaningful value in the proton context.

IMN irradiation: challenges and benefits

Irradiation of the IMNs poses a distinct challenge in left-sided breast cancer radiotherapy due to their anatomical location along the parasternal region, immediately adjacent to the heart and LAD. IMN treatment is clinically indicated in patients with high-risk features—such as node-positive disease or medial/central tumors—based on evidence suggesting improved disease-free survival with regional nodal irradiation (13). However, this comes at the cost of increased OAR exposure, particularly to cardiac structures, as the IMN field extends the radiation volume medially and inferiorly.

In this study, patients required IMN coverage, providing a valuable subgroup for analysis. With VMAT-FB, the mean heart dose in these patients was 17.8 Gy (35.3%), reflecting the difficulty of sparing the heart with photon beams in this scenario. VMAT-DIBH reduced this to 14.5 Gy (28.8%), an 18.5% improvement, consistent with DIBH’s ability to displace the heart caudally and posteriorly. However, these doses remain clinically concerning given the established link between heart dose and coronary events (3). In contrast, PBS-FB achieved a mean heart dose of 1.2 Gy (2.4%) in IMN-inclusive plans, a dramatic reduction attributable to the proton beam’s finite range. PBS-DIBH further lowered this to 0.3 Gy (0.6%), a 75% decrease from PBS-FB and a near-elimination of cardiac exposure.

The LAD followed a similar pattern in IMN cases. VMAT-FB delivered a mean LAD dose of 34.2 Gy (67.9%), reduced to 26.1 Gy (51.8%) with DIBH. PBS-FB achieved 11.3 Gy (22.4%), dropping to 3.4 Gy (6.7%) with DIBH—a greater than three-fold reduction. These findings underscore the limitations of VMAT in IMN irradiation, where photon scatter and penumbra inevitably increase cardiac doses, even with DIBH. Proton PBS, by contrast, leverages its steep dose gradient to conform tightly to the IMN target, sparing adjacent structures. The addition of DIBH enhances this precision by shifting the heart out of the beam path, particularly for anterior proton beams commonly used in breast radiotherapy.

For IMN irradiation, DIBH with PBS appears far from excessive is arguably essential. The baseline cardiac doses with PBS-FB (1.2 Gy heart, 11.3 Gy LAD) are low but not negligible, especially for the LAD, where doses >10 Gy correlate with increased stenosis risk (14). DIBH’s ability to reduce these to 0.3 and 3.4 Gy, respectively, offers a compelling safety margin, particularly for high-risk patients where IMN coverage is non-negotiable. The clinical implications are profound: PBS-DIBH could enable safer IMN irradiation, potentially broadening its use without the historical trade-off of cardiac toxicity seen in older photon-based studies (15).

Lung dose considerations

An unexpected finding was the slight increase in left lung dose with DIBH in PBS plans (4.3 to 4.8 Gy). This likely reflects lung expansion during deep inspiration, increasing the volume of lung tissue intersected by the proton beam’s entry path (16). In IMN-inclusive plans, this effect was slightly more pronounced (4.5 Gy FB vs. 5.1 Gy DIBH), as medial beam angles traverse more lung tissue. However, absolute doses remained well below toxicity thresholds (e.g., V20 <20%), and the trade-off is outweighed by cardiac benefits. VMAT showed no such increase, as photon scatter dominates lung dose rather than geometric changes, but its higher baseline doses (15 Gy) negate any relative advantage.

Clinical implications

These findings have significant implications for clinical practice. The linear relationship between heart dose and coronary events—estimated at a 7.4% increased risk per Gy (3)—underscores the importance of minimizing cardiac exposure. PBS-DIBH’s ability to reduce mean heart dose to 0.21 Gy and LAD dose to 2.8 Gy in the full cohort (and 0.3 and 3.4 Gy with IMNs) could translate to a near-elimination of excess cardiovascular risk, a benefit not achievable with VMAT. For IMN-inclusive treatments, where cardiac sparing is particularly challenging, this approach offers a robust solution. Additionally, the negligible contralateral breast dose with PBS-DIBH may reduce secondary cancer risk, particularly relevant for patients with long life expectancies.

Limitations and future directions

This study has several limitations. The sample size (n=10) limits generalizability, though the paired design enhances statistical power. The retrospective nature introduces potential selection bias, as patients were chosen based on available imaging rather than consecutive enrollment. Proton planning was performed by staff with limited experience, potentially underestimating PBS’s full potential; expert optimization might further improve outcomes. Future research should include prospective cohorts, long-term clinical outcomes (e.g., cardiac events), and cost-effectiveness analyses to guide implementation, given proton therapy’s higher cost. Specific to DIBH with PBS, trials assessing its incremental benefit—stratified by IMN status and patient anatomy—could clarify when it is truly necessary. In this study, we used the conventional fractionation of 50.4 Gy in 28 fractions to allow direct comparison with established dosimetric benchmarks. We did not perform the analysis with hypofractionated schemes, as our focus was on dosimetric comparison under standard conditions. However, hypofractionation is increasingly used for photon treatments, and emerging evidence supports its use in proton therapy as well, though less commonly due to limited long-term data. We expect the relative dosimetric advantages of PBS over VMAT to persist across fractionations, as the physical dose distribution properties remain similar, but absolute OAR doses would scale proportionally.

While proton therapy can indeed increase skin dose due to the entrance dose profile, in our PBS plans, we optimized beam angles and used range shifters to mitigate this. Skin doses were not explicitly reported as an OAR in this dosimetric study, but mean skin doses (defined as a 3-mm rind) were approximately 45 Gy for PBS vs. 40 Gy for VMAT, within acceptable limits for acute reactions. Clinical skin toxicity was not assessed, as this was a planning study.

Conclusions

Proton PBS with DIBH demonstrates the most favorable dosimetric profile for minimizing OAR doses in left-sided breast cancer radiotherapy, significantly outperforming VMAT. The combination reduces heart and LAD doses to unprecedented levels, even in challenging IMN-inclusive cases, while maintaining excellent target coverage. While DIBH may not be universally necessary with PBS for all patients, its value is indisputable in IMN irradiation and select cases with unfavorable anatomy, outweighing logistical drawbacks. Although lung dose slightly increases with DIBH in PBS plans, the overall dosimetric profile remains highly favorable. These findings advocate for the selective integration of DIBH into proton therapy protocols to potentially optimize therapeutic ratios and improve long-term patient outcomes in left-sided breast cancer radiotherapy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-25-20/rc

Data Sharing Statement: Available at https://tro.amegroups.com/article/view/10.21037/tro-25-20/dss

Peer Review File: Available at https://tro.amegroups.com/article/view/10.21037/tro-25-20/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-25-20/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of the Chang Gung Medical Foundation (no. 202300768B0C5002) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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