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Radiation Oncology Journal > Volume 41(2); 2023 > Article
Nangia, Burela, Noufal, Patro, Wakde, and Sharma: Proton therapy for reducing heart and cardiac substructure doses in Indian breast cancer patients

Abstract

Purpose

Indians have a higher incidence of cardiovascular diseases, often at a younger age, than other ethnic groups. This higher baseline risk requires consideration when assessing additional cardiac morbidity of breast cancer treatment. Superior cardiac sparing is a critical dosimetric advantage of proton therapy in breast cancer radiotherapy. We report here the heart and cardiac-substructure doses and early toxicities in breast cancer patients treated post-operatively with proton therapy in India’s first proton therapy center.

Materials and Methods

We treated twenty breast cancer patients with intensity-modulated proton therapy (IMPT) from October 2019 to September 2022, eleven after breast conservation, nine following mastectomy, and appropriate systemic therapy, when indicated. The most prescribed dose was 40 GyE to the whole breast/chest wall and 48 GyE by simultaneous integrated boost to the tumor bed and 37.5 GyE to appropriate nodal volumes, delivered in 15 fractions.

Results

Adequate coverage was achieved for clinical target volume (breast/chest wall), i.e., CTV40, and regional nodes, with 99% of the targets receiving 95% of the prescribed dose (V95% > 99%). The mean heart dose was 0.78 GyE and 0.87 GyE for all and left breast cancer patients, respectively. The mean left anterior descending artery (LAD) dose, LAD D0.02cc, and left ventricle dose were 2.76, 6.46, and 0.2 GyE, respectively. Mean ipsilateral lung dose, V20Gy, V5Gy, and contralateral breast dose (Dmean) were 6.87 GyE, 14.6%, 36.4%, and 0.38 GyE, respectively.

Conclusion

The dose to heart and cardiac substructures is lower with IMPT than published photon therapy data. Despite the limited access to proton therapy at present, given the higher cardiovascular risk and coronary artery disease prevalence in India, the cardiac sparing achieved using this technique merits consideration for wider adoption in breast cancer treatment.

Introduction

Cardiovascular disease has an earlier onset and a more lethal course in Indians and other South Asians than in other population groups; this propensity has been noted to persist even in the diaspora [1]. In addition, a significant number of Indians suffer from diabetes and hypertension, both of which increase the propensity for cardiovascular ailments [2].
Even as the incidence of breast cancer rises [3], mortality due to the disease has declined [4]. A recently published audit of more than 2,000 breast cancer patients treated in a single year, at one of India’s largest cancer centres, documented a 5-year disease-free survival of 85% for early and 68% for locally advanced breast cancer patients, respectively [5]. This makes the issues of survivorship relevant; one of these is treatment-related cardiac side-effects [4].
Cardiac ailments account for the highest number of non-cancer deaths in breast cancer patients. Deaths from cardiac causes constitute 10.1% of all deaths within one year and 19%, i.e., nearly a fifth of all deaths in patients surviving >10 years after breast cancer diagnosis [6].
Several systemic treatments, such as adriamycin, taxanes, trastuzumab, and letrozole are cardiotoxic [7-10]. Though the cardiotoxicity of radiotherapy has declined due to the development of better techniques [11] it remains relevant, with dose-volume parameters being better understood now.
Darby et al. [12] defined acute coronary events (ACEs) as the diagnosis of myocardial infarction, coronary revascularization, or death resulting from ischemic heart disease after completion of treatment. The authors noted a 7.4% increase in the relative risk of an ACE for every 1 Gy increase in mean heart dose with no lower threshold of radiation dose for these events. Prior ischemic heart disease (IHD) markedly increased the odds of an ACE 6.67 times; hypertension, diabetes, chronic obstructive pulmonary disease (COPD), obesity and smoking also nearly doubled the risk, even with no history of IHD.
Subsequent to Darby’s landmark study [12], there has been a further analysis on the dose-volume relationship of cardiac toxicity and the dose received by cardiac substructures; coronary arteries and the left ventricle have emerged as organs-at-risk (OARs) [13,14]. In a prospective study by Abraham et al. [14], 17% of left-sided breast cancer patients, with only a small fraction receiving adriamycin and trastuzumab, had some form of cardiac ailment.
A review of mean heart doses published after 2014 has noted a mean heart dose of 3.6 Gy for left-sided breast cancer patients and 4.8 Gy in left-sided patients receiving a boost with photon therapy [15]. In contrast, mean heart doses in both dosimetric and clinical studies of proton therapy for breast cancer, are <1.5 Gy and <1 Gy for left and right-sided lesions, respectively [16]. Proton therapy, delivered by enface beams, is an elegant method to treat the breast/chest wall while reducing the dose to the heart and cardiac substructures [17,18]. Mutter et al. [19] have published a consensus statement that comprehensively discusses the role, technique & impact of proton therapy across various clinical scenarios.
Proton therapy has recently become available in India. A prospective registry HYPRO-B has been initiated to document the impact of proton therapy in Indian breast cancer patients. We report the dosimetric and early clinical outcomes of 20 consecutive breast cancer patients treated using pencil beam-based proton therapy in the region’s first proton therapy center.

Materials and Methods

Proton therapy was initiated in January 2019 and the first breast patient was treated in October 2019. We reviewed the details of 20 consecutive patients treated for breast cancer with proton therapy. The latter 16 patients were included in the HYPRO-B registry (HYpofractionated PROton therapy in Breast cancer). This study was approved by the Institutional Ethics Committee-Biomedical Research, Apollo Hospitals, Chennai, India (IEC No. API-I-C-S-004110-20). All patients were treated after informed consent.

1. Proton therapy planning and delivery protocol

Patients were immobilized in the supine position, with arms above the head on a breast board (Access Supine Breast Device, Avondale, PA, USA), and a planning CT was performed with axial images of 2 mm thickness on Canon Aquilion LB CT scanner.
The clinical target volume (CTV) structures, including whole breast/chest wall and nodal volumes, were contoured as per the RTOG atlas [20]; these were clipped 5mm (for the whole breast) and 3 mm (for chest wall) from the skin, respectively. In one patient the chest wall volume was not clipped, because of the involvement of dermal lymphatics. The supraclavicular lymph node region extended to the midline medially, the cricoid superiorly, trapezius posteriorly and followed the medial edge of the clavicle laterally. OARs, including the heart, left lung, right lung, esophagus, and thyroid, were contoured. Fifteen cardiac segments (five left ventricular and 10 coronary arterial segments) were delineated as per the cardiac contouring atlas described by Duane et al. [21]. A 3-5 mm rib rind was contoured outward from the rib pleural interface to encompass the rib cage.
Proton therapy treatment was planned on a RayStation treatment planning system (version 9.0; RaySearch Laboratories AB, Stockholm, Sweden). The dose prescription was 40 GyE to whole breast/chest wall, 48 GyE simultaneous integrated boost (SIB) to tumour bed and 37.5 GyE to nodal volumes, supraclavicular region, axilla & internal mammary chain (IMC) in 20 fractions. The first four patients were treated with a more protracted 20-fraction regime. Standard fractionation of 50 Gy in 2 Gy per fraction was advised to patients with a rheumatoid disorder or a silicone implant in situ. Two en-face beams were used with a hinge angle of 20°–30° (Fig. 1). A water-equivalent 4 cm Lucite range shifter was used for each beam. The CTV was robustly optimized for a 3-mm setup and 3.5% range uncertainty. Both dose computation and optimization used a Monte Carlo algorithm. An average relative biological equivalent (RBE) of 1.1 was used and all patients were planned with single-field optimization (SFO) technique. The planning goal considered was ideal target coverage of CTV, i.e., 97% of the target to receive at least >95% of the prescribed dose.
Treatment was delivered using pencil beam scanning protons on Proteus Plus machine (IBA, Louvain-La-Neuve, Belgium), where in each energy layer is scanned (from –X to +X direction of every Y coordinate) as seen in the beam’s eye view (BEV) of particular beam geometry. For proton energies between 70.22 and 226.2 MeV, the in-air X (Y) spot sigma at the isocenter ranges from 2.96 (3.00) to 6.68 (6.52) mm.
Treatment was delivered 5 times a week, with daily CBCT based image guided repositioning and intra-treatment monitoring using AlignRT (version 5.1.2; VisionRT, London, UK) based surface guidance. AlignRT is integrated with beam delivery system of Proteus Plus using universal beam triggering interface (UBTI). It allows pausing of the beam when the breathing amplitude of the patient exceeds the set threshold (±3 mm).

2. Outcome assessment

1) Dosimetric

Coverage and OAR doses were documented as per dose prescription. Proton therapy plans were assessed for coverage of CTV 40 Gy, 37.5 Gy, 48 Gy by 95% of prescription dose, mean heart dose, mean and D0.02cc of left anterior descending artery (LAD) and right coronary artery (RCA), Dmax oesophagus, Dmax spinal cord, mean lung dose, mean ipsilateral and contralateral lung dose, V20Gy and V5Gy ipsilateral and contralateral lung and mean contralateral breast dose.

2) Clinical

All patients were reviewed weekly once during radiation therapy, 4 weeks after therapy and then at 3 monthly intervals.

Results

Eleven patients received proton therapy following breast-conserving surgery (BCS), one after a skin-sparing mastectomy and the remaining received radiation following a mastectomy (Table 1). One patient did not require regional nodal irradiation. Among the 19 patients requiring nodal irradiation, nine received composite irradiation to three nodal regions; axillary radiation was omitted in the remaining 11 patients. All patients undergoing proton therapy after BCS received a boost to the tumour bed.
Adjuvant/neoadjuvant systemic treatment included adriamycin in 13, taxanes in 16, and trastuzumab in five. The remaining patients received hormone therapy alone.
Cardiovascular risk factors were present in six patients, diabetes in two, hypertension in three, rheumatoid arthritis in two, obesity in one and previous heart ailment in one patient, respectively; four patients had multiple risk factors (>1).

1. Target

Proton therapy achieved adequate dose coverage of breast/chest wall, i.e., CTV40, with a mean 99% of the target receiving 95% of the prescribed dose (V95% > 99%). Similarly, 99% of the regional nodes (internal mammary, supraclavicular, and axilla) atleast 95% of the prescribed dose. The OAR doses and V95% of the target are shown in Fig. 2 and Tables 2, 3. The dosimetric outcomes of patients had internal mammary nodal irradiation are shown in Fig. 3.

2. OAR

The mean heart dose was 0.78 GyE, 0.41 GyE in patients with right-sided cancer and 0.88 GyE in patients with left-sided cancer. Among left-sided patients, the mean heart dose was 0.991 GyE for patients receiving chest wall proton therapy and 0.79 GyE for patients being irradiated following BCS; this was 0.475 GyE and 0.345 GyE, respectively, for right-sided patients. The mean ipsilateral lung dose was 6.84 GyE, V17 of 14.6%, and V4 of 36.4%.

3. Cardiac substructures

The mean LAD dose of the cohort was 2.76 GyE. The high-dose region likely to correlate with the location of coronary stenosis was analyzed as the minimum dose received by 0.02 cc (D0.02cc) and was noted to be 6.46 GyE.
The mean left ventricular dose V5Gy is documented in Table 3. This was low in post-BCS proton therapy (i.e., 0.37%) and as well as in post mastectomy proton therapy (i.e., 1.02%).

4. Equivalent dose in 2 Gy (EQD2)

The EQD2 of the mean heart dose ranged from 0.15 to 0.62 GyE. The range for the mean LAD dose was 0.12–8.2 GyE (EQD2), and the max LAD dose was 0.01–23.7 GyE (EQD2).

5. Toxicities and outcomes

One patient had grade 2 dysphagia. Two patients had grade 2 and one, grade 3 dermatitis. The latter occurred in the patient in whom the chest wall contour was not clipped on account of the involvement of dermal lymphatics. The skin reactions required dressing with a hydrocolloid patch and resolved 10 days after completion of therapy. On median follow-up of 12.5 months, the locoregional control an overall survival was 100%.

Discussion and Conclusion

Our data on dosimetric and early clinical outcomes documents the first Indian experience of proton therapy for breast cancer. Our results document consistently low heart and cardiac substructure doses. These are particularly relevant in the background of a high prevalence of cardiovascular risk factors among Indians and other South Asians. These are a significant prevalence of obesity, 44%–72% [22,23] in certain communities, diabetes in >20% of the urban population [24] and a high age-standardized prevalence of hypertension and cardiovascular disease [25]. In our cohort of patients, six patients had cardiovascular risk factors, of which four patients had >1 risk factor.
In addition, patients in India are less likely to be screen-detected, a significant proportion thus requiring anthracyclines and trastuzumab [3]. The additive effect of these cardiotoxic drugs, on the risk of cardiac disease, has been documented in several studies [26].
Proton therapy offers dosimetric advantages in cardiac, opposite breast and lung doses over conventional radiotherapy in the treatment of breast cancer, this being first postulated in 1999. The advantage of protons lies in the abruptness of the energy deposition (i.e., Bragg peak) and therefore sparing of distal tissues, like the heart and lungs. Several dosimetric studies have underlined the advantage of proton therapy in reducing the mean dose to the heart in comparison with 3DCRT, IMRT, helical tomotherapy, and VMAT [27-32] (Table 4). Notably, with target coverage remaining adequate and equivalent to photons, the range of reduction in the mean dose to the heart is approximately 73%–90%. The reduction of heart dose by protons is expected to significantly reduce the relative risk of ACEs [12].
This is especially relevant for patients with the cardiovascular risk factors noted above. The correlation of cardiovascular risk factors with a doubling of the risk of ACE has already been elucidated in the landmark study by Darby et al. [12], Jacobse et al. [33], who studied exclusively, the risk of myocardial infarction, also identified that hypertension and BMI ≥30 kg/m2 were the only individual patient-related cardiovascular risk factors significantly associated with an increased myocardial infarction (MI) rate.

1. Mean heart dose

The mean heart dose for left-side breast cancer in our study listed in Table 3 ranges from 0.11 to 1.2 GyE. Notwithstanding internal mammary nodal irradiation in 19 of 20 patients, the mean heart dose in our patients was 0.87 GyE for left-sided and 0.41 GyE for right-sided treatments, respectively (Table 2). Other relevant heart parameters V25GyE, V5GyE, mean dose to left ventricle (LV), LV V5GyE, and mean dose to the LAD are 0.98%, 3.54%, 0.2 GyE, 0.74%, and 2.76 GyE, respectively.

2. Cardiac substructure dose

Thus far, there was a lack of clarity about the relative importance of sparing cardiac substructures, coronary arteries, versus myocardium versus both. This is reflected in the multiplicity of proposed dose constraints and cardiac structures [13,34,35]. Recently, however, relevant dose thresholds have been identified for the LAD and LV. Zureick et al. [36], treating a contemporary cohort of breast cancer patients, found that mean and max doses of LAD were correlated to adverse cardiac events in breast cancer patients. The potential dose threshold identified (by ROC curve analyses) for LAD Dmean was an EQD2 of 2.8 Gy, and for LAD Dmax, an EQD2 of 6.7 Gy for any cardiac event. Similarly, the threshold dose for heart Dmean was an EQD2 of 0.8 Gy for any cardiac event [36]. It is important to note that only 12.5% of patients in this study received adriamycin, and <10% received trastuzumab.
One of the distinct advantages of proton therapy is a reduction in dose to the LAD by as much as 90% compared to photon therapy (Table 4). The mean LAD dose achieved in our left-sided patients was 2.21 GyE, comparable with 2.8–5 Gy reported in various studies [14,36]. In our cohort, the mean and max LAD EQD2 were less than the dose threshold identified by Zureick et al. [36] in 13 of 15 left-sided patients. In one patient, the Dmax for LAD was 36.25 GyE, because of the proximity of the LAD to the chest wall. We used the deep inspiratory breath hold technique for this patient and were able to reduce the Dmax of the LAD to 8.01 GyE.
The LV V5 has been postulated to be a better correlate of cardiac dysfunction than the mean heart dose based on a retrospective study of 910 patients followed up for a median of 7.6 years by van den Bogaard et al. [13]. This parameter has only recently been addressed in published literature and was documented to range from 0 to 3.37% in this series. Abraham et al. [14], prospectively analyzed 181 breast patients, with a median follow-up of 127 months and recorded any cardiac events, viz., any ischemic event, conduction abnormality, congestive heart failure, pericarditis and valvular disease. The authors noted that mean left ventricular dose <5.85 Gy (p = 0.035), V5 <42 cc (p = 0.024) and V10 <38 cc (p = 0.081) reduces additional risk of radiation-related cardiac events to <5% at 10 years. Using proton therapy, our mean left ventricular dose was 0.2 GyE. The absolute V5 volume ranged from 0 to 3.7 cc.

3. Published data and ongoing studies

Clinical data published so far is detailed in Table 5 [17,18,37-44]. The largest cohort has been reported by the group at Massachusetts General Hospital, Boston, USA, with a documented locoregional failure rate of 1.6% at a median follow-up of 55 months in 69 evaluable patients treated with proton therapy [37]. The RADCOMP trial [45] comparing protons with photons in breast cancer patients is accruing patients to determine the margin of benefit, with the end point of reduction in major cardiovascular events. The Mayo Clinic trial (NCT02783690) compares hypofractionated radiotherapy with standard fractionation in patients undergoing post-mastectomy proton therapy [46]. The Danish Breast proton therapy (NCT04291378) is recruiting patients to compare photon and proton radiotherapy for early breast cancer, the primary endpoint being cardiac events at 10 years [47]. We have instituted HYPRO-B, CTRI/2020/11/029415, a prospective registry of patients undergoing hypofractionated proton therapy for breast cancer with the primary objective of determining ACEs at 5 years following hypofractionated proton therapy radiotherapy to the whole breast/chest wall. In addition, we plan to document locoregional control, quality of life, disease-free and overall survival, cardiac function and dosimetric analysis for the latter.

4. Cost-effectivity

We believe that the application of more sophisticated radiation treatment techniques based on better dosimetric parameters, in the absence of or preceding Phase III trials, has many precedents [48-50]. There are concerns about the cost of treatment without evidence of demonstrable benefit in overall survival thus far [51]. Models estimating the cost-effectivity of protons suggesting an advantage in patients with at least one coronary risk factor or a mean heart dose of 5 Gy or more are specific to country-based health systems [52]. In addition, cost-effectivity analyses may not be relevant for the individual patient and do not address benefits accruing from avoiding cardiac interventions besides percutaneous coronary intervention (PCI). Proton therapy may also become less expensive in the foreseeable future with the advent of single-room facilities [53].
The current case series and published data indicate that proton therapy fulfils the sound principles of better sparing of organs at risk with equivalent target coverage in breast cancer.
In conclusion, cardiac, lung and contralateral breast doses consistently documented to increase the morbidity of breast radiotherapy are significantly reduced by proton therapy. Early results of pencil beam scanning-based hypofractionated proton therapy with SIB merit the consideration of this treatment in managing breast cancer.

Acknowledgments

We thank Minnal Mookaiah (Radiotherapy Technologist) and Anusha T (Physician Assistant) for their contribution to this study. We also thank our patients and their families.

Statement of Ethics

This study was approved by the Institutional Ethics Committee-Biomedical Research, Apollo Hospitals, Chennai, India (IEC Application No. API-I-C-S-004110-20; Protocol No. APCC20203, Breast Cancer Proton Registry HyPro-B). Written informed consent was obtained from participants to participate in the study.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author Contributions

Conceptualization, Nangia S. Investigation and methodology, Nangia S, Burela N. Project administration, Nangia S. Resources, Sharma D, Noufal MP, Patro K, Wakde MG, Burela N, Nangia S. Supervision, Nangia S, Sharma D. Writing of the original draft, Nangia S, Burela N, Sharma D. Writing of the review and editing, Nangia S, Burela N. Software, Noufal MP, Burela N. Validation, Nangia S. Formal analysis, Burela N. Data curation, Burela N. Visualization, Nangia S.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Fig. 1.
Axial slice from treatment plan showing two en-face beam arrangements for a left sided breast patient (whole breast + tumor bed [SIB]). (A) Beam 1 is gantry at 20°, (B) Beam 2 is gantry at 40°, and (C) isodose distribution after a combination of two beams.
roj-2023-00073f1.jpg
Fig. 2.
Radiation dose color wash of (A) right breast post-BCS, (B) left breast post-BCS, (C) right chest wall (with reconstruction), and (D) left chest wall, at the level of the left ventricle, showing coronary arterial segments and left ventricular myocardial segments. BCS, breast conservation surgery; RCA, right coronary artery; LAD, left anterior descending artery; RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle.
roj-2023-00073f2.jpg
Fig. 3.
Dosimetry of patients with internal mammary nodal irradiation. IMN, internal mammary nodal; LAD, left anterior descending artery; RCA, right coronary artery.
roj-2023-00073f3.jpg
Table 1.
Patient characteristics (n = 20)
Characteristic n
Comorbidities
 Prior cardiac ailment 1
 Hypertension 0
 Diabetes 0
Laterality
 Left 16
 Right 4
Quadrant
 Upper outer 7
 Lower outer 4
 Lower inner 2
 Upper inner 6
 Retro areolar 1
Surgery
 BCS 11
 MRM 9
Reconstruction using flaps 5
Any nodal irradiation 19
3 nodal stations treated (internal mammary chain + supraclavicular fossa + axilla) 9
Neo-adjuvant chemotherapy
 AC → paclitaxel + carboplatin 4
 AC → paclitaxel 2
 AC → paclitaxel + trastuzumab 2
 TCHP 1
Adjuvant chemotherapy
 AC → paclitaxel 5
 AC → paclitaxel + trastuzumab 2
Hormonal therapy alone 4

BCS, breast-conserving surgery; MRM, modified radical mastectomy; AC, doxorubicin plus cyclophosphamide; TCHP, trastuzumab, pertuzumab, carboplatin, and docetaxel.

Doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2, paclitaxel 80 mg/m2, carboplatin area under curve 5 or 6, trastuzumab starting dose 4 mg/kg followed by 6 mg/kg maintenance dose, pertuzumab starting dose 840 mg/kg followed by 420 mg/kg maintenance dose.

Table 2.
OAR dosimetry parameters
Parameter Value
V95%
 CTV40 99.82±0.26
 CTV37.5 99.57±0.70
 CTV48 99.75±28.30
Heart dose (GyE) 0.78±0.33
 Left sided patients 0.87
 Right sided patients 0.41
Heat
 V25GyE (%) 0.98±0.64
 V5GyE (%) 3.54±1.70
LAD (GyE) 2.76±4.49
 D0.02cc (GyE) 6.46±7.40
LV (GyE) 0.20±0.17
 V5GyE (%) 0.74±0.95
Ipsilateral lung (GyE) 6.87±2.76
Contralateral breast dose (GyE) 0.38±0.38
RCA (GyE) 0.38±0.88
 D0.02cc (GyE) 2.43±4.45

Values are presented as mean ± standard deviation.

OAR, organs-at-risk; CTV, clinical target volume; LAD, left anterior descending artery; LV, left ventricle; RCA, right coronary artery.

Table 3.
Target coverage and OAR dosimetry of 20 patients
Laterality Surgery S No. Age (yr) Target V95%
Heart
LAD
LV Mean ipsilateral lung (GyE) Mean contralateral breast (GyE) RCA
CTV40GyE CTV37.5GyE CTV48GyE Mean (GyE) V25GyE (%) V5GyE (%) Mean (GyE) Max D0.02cc (GyE) Mean (GyE) V5Gy (%) Mean (GyE) Max D0.02cc (GyE)
Left sided BCS 1 67 WB+SCF+IMC & tumor bed boost 99.6 100 99.9 1.1 1.79 4.4 0.43 3.59 0.12 0 6.02 0.48 0.14 0.1
2 29 WB+tumor bed boost 99.6 - 99 0.43 0.23 1.2 0.86 7 0.44 2 5.97 0.24 0.03 0
3 49 WB+SCF+IMC & tumor bed boost 99.9 100 99.9 0.57 0.36 2.69 3.05 15.1 0.28 0.68 6.55 - 0.09 0.01
4 52 WB+SCF+IMC+axilla & tumor bed boost 99.9 99.8 99.9 1.01 1.29 4.49 0.72 3.35 0.13 0.11 8.48 0.11 6.42 0.31
5 52 WB+SCF+IMC+axilla & tumor bed boost 99.8 99.8 9.99 0.93 1.15 4.18 1.13 4.09 0.13 0.02 9.18 0.38 0.1 0.02
6 69 WB+SCF+IMC 99.8 99.8 - 0.53 0.15 2.71 1.06 6.92 0.25 0.37 8.42 0.16 0.12 0.03
7 38 WB+SCF+ IMC 99.9 99.7 99.8 1.29 1.68 5.54 0.47 1.05 0.12 0.01 0.04 0.03 1.45 0.14
8 46 WB+SCF+IMC & tumor bed boost 98.75 99.24 98.63 0.85 1.13 3.49 0.8 3.26 0.14 0.04 5.46 0.28 0.17 0.05
9 43 WB+SCF+IMC & tumor bed boost 99.97 99.38 99.9 0.42 0.24 2.16 0.47 3.77 0.11 0.89 5.58 0.14 17.22 3.63
MRM 10 40 Chest wall+SCF+IMC+axilla 99.9 99.1 - 1.1 1.8 4.86 7.39 17.9 0.74 3.37 9.9 0.69 0.11 0.02
11 58 Chest wall+SCF+IMC 99.7 99.1 - 1.2 1.68 5.8 1.81 6.71 0.13 0.1 8.19 0.52 0.04 0.01
12 69 Chest wall+SCF+IMC 99.9 99.3 - 0.91 1.25 4.01 19.8 27.9 0.26 1.47 8.08 0.4 0.06 0.02
13 50 Chest wall+SCF+IMC+axilla 99.9 99.8 - 1.1 1.64 4.42 0.86 2.61 0.14 2.34 0.21 0.81 0.15 0.03
14 29 Chest wall+SCF+IMC+axilla 99.9 99.8 - 0.55 0.4 2.45 0.82 5.88 0.26 1.01 6.35 0.35 0.18 0.02
15 35 Chest wall+SCF+IMC+axilla 99.91 98.95 - 0.96 0.95 5.05 3.83 17.14 0.25 0.94 8.76 0.48 0.06 0.01
16 42 Chest wall+SCF+IMC 99.81 97.86 - 1.12 0.82 5.95 0.5 2.13 0.07 0.01 9.18 1.78 0.41 0.03
Right sided BCS 17 30 WB+SCF+IMC & tumor bed boost 99.9 99.6 99.9 0.58 0.06 0.15 0.11 0.66 0.13 0.02 6.93 0.21 10.29 1.97
18 52 WB+SCF+IMC & tumor bed boost 99.7 97.5 99.4 0.11 0 0.36 0.01 0.04 0 0 9.37 0.2 0.55 0.05
MRM 19 68 Chest wall+SCF+IMC 99.8 98.5 - 0.44 0.35 2.36 0.02 0.1 0 0 10 0.53 4.35 0.38
20 58 Chest wall+SCF+IMC+axilla 99.9 99.8 - 0.51 0.4 2.78 0 0.02 0 0 8.32 0.47 4.41 0.49

OAR, organs-at-risk; BCS, breast-conserving surgery; MRM, modified radical mastectomy; CTV, clinical target volume; LAD, left anterior descending artery; LV, left ventricle; RCA, right coronary artery; WB, whole breast; SCF, supraclavicular field; IMC, internal mammary chain; Vx, the volume of organ receiving ≥x Gy; Dx, minimum dose received by x% (or cc) of the organ.

Table 4.
Dosimetric studies showing OAR doses comparing proton therapy with other radiation techniques
Study, year Surgery n Dose prescription Technique Heart dose parameter LAD (Gy) Ipsilateral lung
Ares et al. [27], 2010 Breast conservation, mastectomy 20 50 Gy/25 fx IMPT Mean: 1.5 Gy Mean: 7.5 Gy
V5Gy: 3.5% V20Gy: 7.5%
V5Gy: 14.5%
IMRT Mean: 10.5 Gy Mean: 13.5 Gy
V5Gy: 36.5% V20Gy: 11%
V5Gy: 40%
3DCRT Mean: 9.5 Gy Mean: 20 Gy
V5Gy: 9.5% V20Gy: 19.5%
V5Gy: 35%
Fagundes et al. [28], 2015 Mastectomy 10 50.4 Gy/28 fx Uniform scanning Mean: 1.2 Gy Mean: 7 Gy V20Gy: 28.4%
Max: 27.6 Gy V5Gy: 41.3%
D0.2cc: 14.9 Gy
VMAT Mean: 8.2 Gy Mean: 15.5 Gy V20Gy: 27.3%
Max: 35.4 Gy V5Gy: 58%
D0.2cc: 27.8
Helical Tomotherapy Mean: 10.2 Gy Mean: 14.8 Gy V20Gy: 25.2%
Max: 36.4 Gy V5Gy: 58.4%
D0.2cc: 26.6
3DCRT Mean: 6.8 Gy Mean: 20.9 Gy V20Gy: 40.4%
Max: 41 Gy V5Gy: 66.4%
D0.2cc: 33.2
Stick et al. [29], 2017 Breast conservation 41 50 Gy/25 fx PBS-SFO Mean: 0.3 Gy
3DCRT Mean: 1.9 unit
Speleers et al. [30], 2019 Breast conservation 10 40.5 Gy/16 fx PBS-supine Mean: 1.02 Gy Mean: 3.4 Gy Mean: 3.5 Gy
VMAT-supine Mean: 5.6 Gy Mean: 21.4 Gy Mean: 11.54 Gy
PBS-prone Mean: 1.08 Gy Mean: 2 Gy Mean: 2.4 Gy
VMAT-prone Mean: 4.3 unit Mean: 9 Gy Mean: 5.3 Gy
De Rose et al. [31], 2020 Breast conservation, mastectomy 20 50 Gy/25 fx IMPT Mean: 0.4 Gy Mean: 6.2 Gy
V20Gy: 12.2%
V5Gy: 28.5%
VMAT Mean: 3.9 Gy Mean: 10.8 Gy
V20Gy: 18%
V5Gy: 57.6%
Kowalski et al. [32], 2020 Breast conservation NM IMPT Mean: 2.59 Gy V20Gy: 12.1%
VMAT Mean: 9.5 Gy V20Gy: 16.6%

OAR, organs-at-risk; LAD, left anterior descending artery; IMPT, intensity-modulated proton therapy; IMRT, intensity-modulated radiotherapy; 3DCRT, three-dimensional conformal radiotherapy; VMAT, volumetric modulated arc therapy; PBS, pencil beam scanning; SFO, single field optimization; Vx, the volume of organ receiving ≥x Gy; NM, not measured.

Table 5.
Comparison of OAR doses from clinical reports of proton therapy for breast cancer
Study, year Surgery n Dose prescription Technique Heart dose parameter LV dose parameters LAD/RCA Contralateral breast Ipsilateral lung Grade 3 skin reactions
MacDonald et al. [38], 2013 Mastectomy +/- reconstruction 12 50.4 Gy/28 fx Passive scattering Mean: 0.44 Gy, Mean: 0.09 Gy Mean: 6 Gy, V20: 12.7%
V20: 0.01% V20: 0.0004%
Cuaron et al. [18], 2015 Breast conservation 4, mastectomy +/- reconstruction 24, and WLE chest wall 2 30 50.4 Gy/28 fx Uniform scanning Mean: 0.88 Gy Mean: 0.29 Gy V20Gy: 6.5% Nil
For left-sided tumors (mean: 1 Gy, V20: 1.16%) Moist desquamation: 28.6%
DeCesaris et al. [39], 2019 Breast conservation, mastectomy 39 45–50.4 Gy/25–28 fx Pencil beam scanning 5.1%
Boost 5.4–12 Gy variable
Smith et al. [40], 2019 Mastectomy + reconstruction 51 50 Gy/25 fx Pencil beam scanning Mean: 0.6 Gy (left 0.7 Gy, right 0.4 Gy) LAD mean: 2.8 Gy V20Gy: 13.9% 4%
40 Gy/15 fx V25: 0.1% RCA mean: 0.8 Gy
Mutter et al. [41], 2017 Mastectomy + reconstruction 12 50 Gy/25 fx Pencil beam scanning Mean: 0.9 Gy Mean: 5 Gy V20Gy: 13%
V25Gy: 0.8% D0.01mL: 17 Gy
Verma et al. [42], 2017 Breast conservation, mastectomy 91 50.4 Gy/28 fx Uniform scanning and pencil beam scanning 5%
Boost 10 Gy variable
Liang et al. [43], 2018 Breast conservation, mastectomy 23 50–50.4 Gy/25–28 fx Passive scattering 43%
Luo et al. [17] 2019 Mastectomy 42 50.4 Gy/28 fx Uniform scanning Mean: 0.7 Gy (left 0.8 Gy, right 0.07 Gy) Mean: 0.3 Gy V20Gy: 16.1% Nil
V5Gy: 34%
Jimenez et al. [37], 2019 Breast conservation, mastectomy 69 45–50.4 Gy/25–28 fx Passive scattering, pencil beam scanning Mean: 0.5 Gy LAD V20: 14.5% 3%
Boost 14.4 Gy/8 fx Mean: 1.16 Gy
Max: 4.7 Gy
DeCesaris et al. [44], 2021 Breast conservation, mastectomy 172 50.4 Gy/28 fx Pencil beam scanning Mean: 0.9 Gy (left 1.1 Gy, right 0.7 Gy, bilateral 1.3 Gy) Right lung (V20: 16%, V5: 42.7%)
Boost 10 Gy Left lung (V20: 15%, V5: 41%)
Present study Breast conservation, mastectomy 20 48, 40, and 37.5 Gy in 15 fx Pencil beam scanning Mean: 0.78 Gy Mean: 0.2 Gy LAD Mean: 0.38 Gy Mean: 6.84 Gy 5%
Mean: 2.2 GyE V20Gy: 4.65%
Max: 6.46 GyE V5Gy: 39.1%
RCA
Mean: 0.36 GyE
Max: 2.31 GyE

OAR, organs-at-risk; LV, left ventricle; LAD, left anterior descending artery; RCA, right coronary artery; WLE, wide local excision; Vx, the volume of organ receiving ≥x Gy.

References

1. Ranasinghe P, Jayawardena R, Gamage N, Sivanandam N, Misra A. Prevalence and trends of the diabetes epidemic in urban and rural India: a pooled systematic review and meta-analysis of 1.7 million adults. Ann Epidemiol 2021;58:128–48.
crossref pmid
2. Prabhakaran D, Jeemon P, Roy A. Cardiovascular diseases in India: current epidemiology and future directions. Circulation 2016;133:1605–20.
crossref pmid
3. Glass AG, Lacey JV, Hoover RN. The rise in breast cancer incidence, 1960-2003, is largely confined to ER+ tumors. Cancer Res 2005;65(9_Supplement):953–4.

4. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005;353:1784–92.
crossref pmid
5. Nair N, Shet T, Parmar V, et al. Breast cancer in a tertiary cancer center in India: an audit, with outcome analysis. Indian J Cancer 2018;55:16–22.
crossref pmid
6. Afifi AM, Saad AM, Al-Husseini MJ, Elmehrath AO, Northfelt DW, Sonbol MB. Causes of death after breast cancer diagnosis: a US population-based analysis. Cancer 2020;126:1559–67.
crossref pmid pdf
7. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998;339:900–5.
crossref pmid
8. Shimoyama M, Murata Y, Sumi KI, Hamazoe R, Komuro I. Docetaxel induced cardiotoxicity. Heart 2001;86:219.
crossref
9. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20:1215–21.
crossref pmid
10. Breast International Group (BIG) 1-98 Collaborative Group, Thurlimann B, Keshaviah A, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747–57.
crossref pmid
11. Taylor CW, Wang Z, Macaulay E, Jagsi R, Duane F, Darby SC. Exposure of the heart in breast cancer radiation therapy: a systematic review of heart doses published during 2003 to 2013. Int J Radiat Oncol Biol Phys 2015;93:845–53.
crossref pmid
12. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013;368:987–98.
crossref pmid
13. van den Bogaard VA, Ta BD, van der Schaaf A, et al. Validation and modification of a prediction model for acute cardiac events in patients with breast cancer treated with radiotherapy based on three-dimensional dose distributions to cardiac substructures. J Clin Oncol 2017;35:1171–8.
crossref pmid pmc
14. Abraham A, Sanghera KP, Gheisari F, et al. Is radiation-induced cardiac toxicity reversible? Prospective evaluation of patients with breast cancer enrolled in a phase 3 randomized controlled trial. Int J Radiat Oncol Biol Phys 2022;113:125–34.
crossref pmid
15. Drost L, Yee C, Lam H, et al. A systematic review of heart dose in breast radiotherapy. Clin Breast Cancer 2018;18:e819–24.
crossref pmid
16. Hug EB. Proton therapy for primary breast cancer. Breast Care (Basel) 2018;13:168–72.
crossref pmid pmc pdf
17. Luo L, Cuaron J, Braunstein L, et al. Early outcomes of breast cancer patients treated with post-mastectomy uniform scanning proton therapy. Radiother Oncol 2019;132:250–6.
crossref pmid
18. Cuaron JJ, Chon B, Tsai H, et al. Early toxicity in patients treated with postoperative proton therapy for locally advanced breast cancer. Int J Radiat Oncol Biol Phys 2015;92:284–91.
crossref pmid pmc
19. Mutter RW, Choi JI, Jimenez RB, et al. Proton therapy for breast cancer: a consensus statement from the Particle Therapy Cooperative Group Breast Cancer Subcommittee. Int J Radiat Oncol Biol Phys 2021;111:337–59.
crossref pmid pmc
20. White JR, Tai A, Arthur D, et al. Breast cancer atlas for radiation therapy planning: consensus definitions [Internet]. Philadelphia, PA: Radiation Therapy Oncology Group; 2018 [cited 2023 Apr 15]. Available from: https://www.nrgoncology.org/Portals/0/Scientific%20Program/CIRO/Atlases/BreastCancerAtlas_corr.pdf?ver=2018-04-18-144201-270.

21. Duane F, Aznar MC, Bartlett F, et al. A cardiac contouring atlas for radiotherapy. Radiother Oncol 2017;122:416–22.
crossref pmid pmc
22. Ahirwar R, Mondal PR. Prevalence of obesity in India: a systematic review. Diabetes Metab Syndr 2019;13:318–21.
crossref pmid
23. Das M, Bose K. Presence of high rates of overweight and obesity among adult Marwaris of Howrah, West Bengal, India. Coll Antropol 2006;30:81–6.
pmid
24. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937–52.
crossref pmid
25. Huffman MD, Prabhakaran D, Osmond C, et al. Incidence of cardiovascular risk factors in an Indian urban cohort results from the New Delhi birth cohort. J Am Coll Cardiol 2011;57:1765–74.
pmid pmc
26. Zhang L, Wang Y, Meng W, Zhao W, Tong Z. Cardiac safety analysis of anti-HER2-targeted therapy in early breast cancer. Sci Rep 2022;12:14312.
crossref pmid pmc pdf
27. Ares C, Khan S, Macartain AM, et al. Postoperative proton radiotherapy for localized and locoregional breast cancer: potential for clinically relevant improvements? Int J Radiat Oncol Biol Phys 2010;76:685–97.
crossref pmid
28. Fagundes M, Hug EB, Pankuch M, et al. Proton therapy for local-regionally advanced breast cancer maximizes cardiac sparing. Int J Part Ther 2015;1:827–44.
crossref
29. Stick LB, Yu J, Maraldo MV, et al. Joint estimation of cardiac toxicity and recurrence risks after comprehensive nodal photon versus proton therapy for breast cancer. Int J Radiat Oncol Biol Phys 2017;97:754–61.
crossref pmid
30. Speleers BA, Belosi FM, De Gersem WR, et al. Comparison of supine or prone crawl photon or proton breast and regional lymph node radiation therapy including the internal mammary chain. Sci Rep 2019;9:4755.
crossref pmid pmc pdf
31. De Rose F, Cozzi L, Meattini I, et al. The potential role of intensity-modulated proton therapy in the regional nodal irradiation of breast cancer: a treatment planning study. Clin Oncol (R Coll Radiol) 2020;32:26–34.
crossref pmid
32. Kowalski ES, Feigenberg SJ, Cohen J, et al. Optimal target delineation and treatment techniques in the era of conformal photon and proton breast and regional nodal irradiation. Pract Radiat Oncol 2020;10:174–82.
crossref pmid
33. Jacobse JN, Duane FK, Boekel NB, et al. Radiation dose-response for risk of myocardial infarction in breast cancer survivors. Int J Radiat Oncol Biol Phys 2019;103:595–604.
crossref pmid pmc
34. Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S77–85.
crossref pmid
35. Munshi A, Khataniar N, Sarkar B, Bera ML, Mohanti BK. Spatial orientation of coronary arteries and its implication for breast and thoracic radiotherapy: proposing “coronary strip” as a new organ at risk. Strahlenther Onkol 2018;194:711–8.
crossref pmid pdf
36. Zureick AH, Grzywacz VP, Almahariq MF, et al. Dose to the left anterior descending artery correlates with cardiac events after irradiation for breast cancer. Int J Radiat Oncol Biol Phys 2022;114:130–9.
crossref pmid
37. Jimenez RB, Hickey S, DePauw N, et al. Phase II study of proton beam radiation therapy for patients with breast cancer requiring regional nodal irradiation. J Clin Oncol 2019;37:2778–85.
crossref pmid pmc
38. MacDonald SM, Patel SA, Hickey S, et al. Proton therapy for breast cancer after mastectomy: early outcomes of a prospective clinical trial. Int J Radiat Oncol Biol Phys 2013;86:484–90.
crossref pmid
39. DeCesaris CM, Rice SR, Bentzen SM, Jatczak J, Mishra MV, Nichols EM. Quantification of acute skin toxicities in patients with breast cancer undergoing adjuvant proton versus photon radiation therapy: a single institutional experience. Int J Radiat Oncol Biol Phys 2019;104:1084–90.
crossref pmid
40. Smith NL, Jethwa KR, Viehman JK, et al. Post-mastectomy intensity modulated proton therapy after immediate breast reconstruction: initial report of reconstruction outcomes and predictors of complications. Radiother Oncol 2019;140:76–83.
crossref pmid pmc
41. Mutter RW, Remmes NB, Kahila MM, et al. Initial clinical experience of postmastectomy intensity modulated proton therapy in patients with breast expanders with metallic ports. Pract Radiat Oncol 2017;7:e243–52.
crossref pmid
42. Verma V, Iftekaruddin Z, Badar N, et al. Proton beam radiotherapy as part of comprehensive regional nodal irradiation for locally advanced breast cancer. Radiother Oncol 2017;123:294–8.
crossref pmid
43. Liang X, Bradley JA, Zheng D, et al. Prognostic factors of radiation dermatitis following passive-scattering proton therapy for breast cancer. Radiat Oncol 2018;13:72.
crossref pmid pmc pdf
44. DeCesaris CM, Pollock A, Zhang B, et al. Assessing the need for adjusted organ-at-risk planning goals for patients undergoing adjuvant radiation therapy for locally advanced breast cancer with proton radiation. Pract Radiat Oncol 2021;11:108–18.
crossref pmid
45. Bekelman JE, Lu H, Pugh S, et al. Pragmatic randomised clinical trial of proton versus photon therapy for patients with non-metastatic breast cancer: the Radiotherapy Comparative Effectiveness (RadComp) Consortium trial protocol. BMJ Open 2019;9:e025556.
crossref pmid pmc
46. ClinicalTrials.gov. A trial of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring regional nodal irradiation (ClinicalTrials.gov identifier: NCT02783690) [Internet]. Bethesda, MD: US National Institutes of Health; 2022 [cited 2023 Apr 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT02783690.

47. ClinicalTrials.gov. The DBCG proton trial: photon versus proton radiation therapy for early breast cancer (ClinicalTrials.gov identifier: NCT04291378) [Internet]. Bethesda, MD: US National Institutes of Health; 2020 [cited 2023 Apr 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT04291378.

48. Ringash J, Perkins G, Brierley J, et al. IMRT for adjuvant radiation in gastric cancer: a preferred plan? Int J Radiat Oncol Biol Phys 2005;63:732–8.
crossref pmid
49. Nangia S, Chufal KS, Tyagi A, Bhatnagar A, Mishra M, Ghosh D. Selective nodal irradiation for head and neck cancer using intensity-modulated radiotherapy: application of RTOG consensus guidelines in routine clinical practice. Int J Radiat Oncol Biol Phys 2010;76:146–53.
crossref pmid
50. Arbea L, Ramos LI, Martinez-Monge R, Moreno M, Aristu J. Intensity-modulated radiation therapy (IMRT) vs. 3D conformal radiotherapy (3DCRT) in locally advanced rectal cancer (LARC): dosimetric comparison and clinical implications. Radiat Oncol 2010;5:17.
crossref pmid pmc pdf
51. Chowdhary M, Lee A, Gao S, et al. Is proton therapy a “pro” for breast cancer? A comparison of proton vs. non-proton radiotherapy using the National Cancer Database. Front Oncol 2019;8:678.
crossref pmid pmc
52. Vega RM, Formenti SC, MacDonald S. Cost-effective analysis of proton therapy for breast irradiation. Int J Radiat Oncol Biol Phys 2015;93(3 Supplement):S91.
crossref
53. Mansur DB. Incorporating a compact proton therapy unit into an existing National Cancer Institute-designated comprehensive cancer center. Expert Rev Anticancer Ther 2014;14:1001–5.
crossref pmid
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