To evaluate the potential of proton therapy in sparing cardiac/coronary structures when compared with 3-dimensional conformal radiation therapy (3DCRT), helical tomotherapy (HT), and intensity-modulated radiation therapy using volumetric modulated arc therapy (VMAT).
Comparative treatment planning was performed using computed tomography scans of 10 patients with left-sided stage III breast cancer after mastectomy, targeting the chest wall, axilla levels I to III, and the supraclavicular and internal mammary nodes (IMN) to 50.4 Gy (radiobiologic equivalent [RBE]) in 28 fractions. Organs at risk were heart, lungs, contralateral breast, unspecified healthy tissues, and coronary arteries. Plans were also compared that included IMNs for protons, but not for photons.
Mean heart dose of 1.2 Gy (RBE) was lowest with protons when compared with 6.8, 10.2, and 8.2 Gy for 3DCRT, HT, and VMAT, respectively (P < .05). The mean left anterior descending artery (LAD) dose was 7.0 Gy (RBE) for protons and lowest compared with 20.9, 14.8, and 15.6 Gy, respectively (P < .05). Total lung V5Gy (RBE) was significantly lower with protons at 19.5% compared with 31.5%, 45.3%, and 54.0%, respectively (P < .05). Mean contralateral breast dose of 0.6 Gy (RBE) for protons was similar to 0.5 Gy for 3DCRT (P value not specified) but was significantly lower than 5.1 and 3.8 Gy for HT and VMAT (P < .05). Proton plans with IMN inclusion compared favorably to 3DCRT, intensity-modulated radiation therapy, and HT without IMN inclusion, with mean heart and mean LAD artery doses of 1.2 and 7.0 Gy (RBE) for protons versus 4.0 and 12.8 Gy for 3DCRT, 6.6 and 17.2 Gy for VMAT, and 7.4 and 11.4 Gy HT (P < .05).
Proton therapy provided maximum cardiac and coronary sparing, even when compared with photon plans not including IMNs, thus, allowing treatment of the IMNs without increased risks to heart and coronary arteries. Reduced dose to lungs, contralateral breast, and healthy tissues indicates a reduced risk for development of second malignancy.
Radiation therapy (RT) for locoregionally advanced, left-sided breast cancer remains a major challenge because radiation dose to the heart during a routine course of photon RT has been documented to increase cardiac morbidity and mortality [1–3]. Although several factors may contribute, the most significant determinants appear to radiation dose and exposed cardiac volumes [4, 5], where there is evidence of a dose-response relationship [6, 7]. The potential for increased cardiac dose is further compounded in patients requiring comprehensive regional nodal irradiation, including the internal mammary nodes (IMNs) [1, 5, 8].
According to Darby et al , rates of major coronary events increases linearly with the mean dose to the heart by 7.4% per Gy (95% confidence interval, 2.9 to 14.5; P < .001), with no apparent threshold. The use of cardiotoxic systemic therapy further highlights the need for improvements in RT delivery.
Technical advances, such as intensity-modulated RT (IMRT), volumetric modulated arc therapy (VMAT), helical tomotherapy (HT), deep inspiration breath hold (DIBH), and respiratory gating strategies, have contributed to reducing the cardiopulmonary doses [10–12].
Proton radiation therapy (PT) demonstrated increasing advantage with increasing target complexity when compared with 3-dimensional conformal radiation therapy (3DCRT) and IMRT in adjuvant RT for breast cancer .
MacDonald et al  found protons to enable delivery of radiation to the chest wall and regional lymph nodes with coverage and with improved sparing of surrounding structures when compared with tangent photon or the photon/electron technique.
The current study analyzes differences in dose distribution between PT, 3DCRT, and IMRT using VMAT and HT therapy focused on patients with stage III breast cancer and the effect of IMN inclusion. To our knowledge, this is the first treatment-planning comparison to comprehensively include dose-volume analysis of coronary arteries using those 4 treatment techniques.
Materials and Methods
Radiation therapy treatment planning was performed on 10 patients with stage III left-sided breast cancer after modified radical mastectomy.
Clinical target volumes (CTVs) were defined as chest wall, axilla levels I to III, and supraclavicular region and IMN in accordance with the Radiation Therapy Oncology Group atlas guidelines , with the exception of the posterior (deep) limit defined as the anterior border of the ribs/intercostal muscles. The most superficial 5 mm from the skin were excluded from the CTV and planning target volume (PTV). The nodal and chest wall CTVs were expanded by 7 mm to generate the PTV.
Organs at Risk and Healthy Tissues
Heart, lungs, contralateral breast, and coronary arteries were defined as organs at risk (OARs) in accordance with Radiation Therapy Oncology Group consensus atlas . The coronary arteries were identified with the aid of angio-computed tomography scan fusion into the right coronary artery, circumflex, left coronary artery, left anterior descending (LAD) artery, and diagonal branch D1. Healthy tissue volume was defined as body minus PTV volume.
Plans were developed with the initial goal of delivering a minimum of 95% of the 50.4 Gy prescribed dose in 28 fractions to 95% of the PTV volume. Skin bolus was not used. Proton plans were based on uniform scanning technique. The OAR constraints were mean heart dose ≤ 400 centigray (cGy), heart V25Gy < 5%; ipsilateral lung V20 ≤ 30%, V10 ≤ 50%, and V5 ≤ 60%; total lung V20 ≤ 20%; contralateral breast mean dose ≤ 3.1 Gy. Dose-volume histograms (DVHs) were generated to compare the techniques in target coverage and dose to the OARs.
A series of repeated-measures analysis of variance (ANOVA) tests were performed to test the 7 therapy regimens of (1) proton, (2) 3DCRT, (3) HT, (4) VMAT, (5) 3DCRT no IMNs, (6) HT no IMNs, and (7) VMAT no IMNs. A 95% level of significance was set (P < .05) for all statistical analyses. The repeated-measures ANOVA assumption of sphericity was violated for most analyses; therefore, the omnibus test of overall effect for all analyses was measured via the Greenhouse-Geisser corrected P value. The ANOVA results are according to mean values.
Ten patients, after mastectomy without reconstruction with postoperative RT required for left-sided breast cancer, had undergone computed tomography–based treatment planning and RT. Plans were generated for 3DCRT, HT, and IMRT (VMAT) megavoltage photon external beam radiation technologies and were compared with protons. Representative dose distributions for 3DCRT, HT, VMAT, and protons are displayed in Figure 1.
Figures 2 and 3 show the dose subtraction generated by subtracting the dose deposited by proton plans from the photon plans, illustrating the excess dose deposited by each photon modality outside of the target region and displayed from a low-dose level starting at 2 Gy.
Table 1 A and 1B summarizes target coverage data as well as irradiated healthy tissues. Figure 4 displays the resulting DVHs, specifically for CTV coverage, total lung, heart, LAD artery, right breast, and irradiated healthy tissues.
The CTV and PTV coverage specifications were to deliver a minimum of 95% of the prescription dose of 50.4 Gy to 95% of the target volume (95% prescription dose = 47.9 Gy). However, based on those strict criteria, 3DCRT plans were not able to meet specifications; thus, the study permitted a minimum acceptable PTV coverage of ≥ 90% of the prescribed dose. All modalities met this requirement with the following value percentages: 95.7%, 92.1%, 96.8%, and 98.3% for protons, 3DCRT, HT, and VMAT, respectively.
To accomplish treatment plans acceptable in clinical practice, the study permitted target coverage acceptance criteria according to National Surgical Adjuvant Breast and Bowel Project–51 protocol with a minimum acceptable PTV coverage of 90% dose to ≥ 90% of the volume. All modalities met the requirement with the following value percentages: 95.7%, 92.1%, 96.8%, and 98.3% for protons, 3DCRT, HT, and VMAT, respectively.
The CTV 47.9-Gy coverage was 99.5%, 91.9%, 98.0%, and 99.2% for protons, 3DCRT, HT, and VMAT, respectively. The 3DCRT plans were not able to accomplish 95% prescription dose coverage of the CTV. Protons improved the CTV coverage compared with 3DCRT (P < .005), whereas the difference to HT and VMAT did not reach statistical significance. The corresponding PTV 47.9 Gy (radiobiologic equivalent [RBE]) values were 91.5%, 86.4%, 94.8%, and 95.6%, with 3DCRT faring significantly worse (P = .004), largely as a consequence of inferior IMN coverage (Figure 4).
Heart and Coronary Arteries
Mean heart dose of 1.2 Gy (RBE) for protons was significantly lower than 6.8, 10.2, and 8.2 Gy for 3DCRT, HT, and VMAT respectively (P < .001). Photon plans without IMN inclusion were able to lower the mean heart doses to 4.0, 6.6, and 7.4 Gy with 3DCRT, HT, and VMAT respectively; However, these doses remained significantly higher than the proton plans (P < .001), despite inclusion of IMNs by protons. Therefore, protons significantly lowered the mean heart dose when compared with all 3 photon modalities with or without IMN inclusion in the photon plans.
Mean LAD artery dose for protons was 7.0 Gy (RBE) compared with 20.9, 14.8, and 15.5 Gy for 3DCRT, HT, and VMAT, respectively (P < .05). The high-dose region was analyzed in a small volume of 0.2 cm3, defined as diagonal-branch LAD (LADD1 0.2 cm3). The proton LADD–0.2 cm3 of 14.9 Gy (RBE) was significantly lower than 33.2, 26.6, and 27.8 Gy for 3DCRT, HT, and VMAT, respectively.
Consistently, protons resulted in depositions of statistically significant lower doses to the first diagonal branch of the LAD (LADD1): LADD1 mean dose of 1.9 Gy (RBE), LADD1–0.2 cm3 dose of 1.4 Gy (RBE), and LADD1 maximum dose of 7.5 Gy (RBE) corresponded favorably to doses ranging between 5.4 Gy and 20.5 Gy for the 3 photon modalities.
All dose parameters for left coronary artery dose were significantly lower for protons. The left coronary artery mean dose was 0.01 Gy (RBE) with protons, compared with 5.6, 16.4 and 6.6 Gy for 3DCRT, HT, and VMAT. The corresponding left coronary artery D–0.2 cm3 was 0.0 Gy (RBE), 5.1, 15.5, and 6.3 Gy. Protons delivered a maximum point dose to the left coronary artery of only 0.03 Gy (RBE), compared with 8.1, 21.1, and 8.2 Gy, respectively.
All dose parameters for the circumflex artery were significantly lower for protons. The circumflex mean dose was 0.01 Gy (RBE) with protons, compared with 5.5, 6.9, and 4.7 Gy for 3DCRT, HT, and VMAT, respectively. The corresponding circumflex D–0.2 cm3 was 0.02 Gy (RBE), 6.2, 9.5, and 5.0 Gy. Protons delivered a maximum point dose to the circumflex of 0.1 Gy (RBE) only, compared with 8.1, 15.9, and 6.0 Gy, respectively.
The right coronary artery mean and right coronary artery D–0.2 cm3 proton dose of 0.02 and 0.01 Gy (RBE) were significantly than the 12 and 16.8 Gy for HT and the 9.3 and 11.3 for VMAT (P < .05). The corresponding values of 4.9 and 6.9 for 3DCRT did not reach statistical significance. Protons delivered a significantly lower maximum point dose to the right coronary artery of 0.2 Gy (RBE), compared with 11.2, 26.3, and 14.9 Gy for 3DCRT, HT, and VMAT, respectively (P < .05).
Cardiac/left anterior descending Artery Dose with and without Internal Mammary Node Inclusion
Proton plans with IMN inclusion were also compared with photon plans without IMN inclusion (Table 2 A and 2B). Despite inclusion of IMNs for protons, the mean heart dose of 1.2 Gy (RBE) remained significantly lower compared with 4.0, 6.6, and 7.4 Gy for 3DCRT, HT, and VMAT without IMN inclusion. In addition, the mean LAD artery dose of 7.0 Gy (RBE) for protons with IMN inclusion remained significantly lower compared with 12.8, 17.2, and 11.4 Gy for 3DCRT, HT, and VMAT without IMN inclusion (P < .008, P < .001, and P < .001, respectively). There was no instance, in which proton plans resulted in higher dose deposition by inclusion of IMNs, compared with photons without IMN inclusion.
The total lung dose increasingly favored protons at decreasing dose levels, that is, from the V20Gy to V10Gy and to V5Gy. This corresponded to the ability of multifield, conformal photon techniques, such as HT and VMAT, to indeed conform the dose to the target, but at the cost of higher lung exposure at increasing distance from the PTV, represented by V5Gy. The proton total lung V5 was 19.5%, significantly lower than 3DCRT (31.5%), HT (45.3%), and VMAT (54.0%), (P < .001). This proton advantage remained significant even without IMN inclusion in photon plans. Similarly, the left lung V5Gy of 41.2 Gy (RBE) for protons was significantly lower than 58.4 Gy (RBE) for 3DCRT and 62.9 Gy (RBE) for VMAT, even when these did not include the IMNs (P < .005).
The mean contralateral breast dose of 0.6 Gy (RBE) for protons was significantly lower than HT and VMAT, ranging from 3.4 to 5.1 Gy (P < .05). The volume receiving between 2 and 5 Gy (RBE) were 5.5% to 3.8% for protons, but ranged between 17.0% to 70.5% for HT and VMAT with or without IMN inclusion (P < .05). The mean contralateral breast dose was not significantly different when comparing protons to 3DCRT. This lack of difference can be explained in the use of different target volume coverage specifications, as outlined previously. Whereas proton planning adhered to the specification of “95% volume covered by the 95% isodose,” the specifications had been lowered to “90% volume covered by the 90% isodose” for 3DCRT so the 3DCRT plans reflected clinical routine practice concessions. Anatomically, this resulted in all 10 patient plans with a deficit in coverage of the most medial CTV/PTV by 3DCRT, which consequently resulted in the lowest amount of dose deposition in the contralateral breast.
Irradiated Healthy Tissues
Protons significantly lowered the dose deposited in healthy tissues, defined as “patient volume minus PTV” in all parameters studied (Figures 1 and 2). The advantage of protons over photons in accomplishing both target conformality for adjacent critical structures as well as sparing of surrounding healthy tissue became more pronounced as we compared the irradiated healthy tissue volumes receiving 10, 5, and 4 Gy, (Tables 1 A and 1B and 2A and 2B; healthy tissue volume receiving 45 Gy (RBE) was 303 cm3 for protons, compared with 1187, 453, and 400 cm3 for 3DCRT, HT, and VMAT (P < .05). The D10Gy (RBE) volume for PT was 1326 cm3 versus 3821, 4890, and 5024 cm3 for 3DCRT, HT, and VMAT (P < .05). The proton D4Gy (RBE) volume was 1548 cm3 compared with 4846, 10 162, and 10 273 cm3 for 3DCRT, HT, and VMAT, respectively (P < .05). In addition, these differences remained significant, favoring protons even when IMNs were not included in the photon plans.
The potential role of intensity-modulated protons in the treatment of the breast and regional nodes, evaluated in a comparative treatment planning study, was first reported by Lomax et al . The authors concluded that a 9-field photon IMRT approach could either produce similar dose homogeneity across the PTVs to that of the proton plan, or it could accomplish similar sparing of dose to both lungs and heart but could not accomplish both. The IMPT improved target coverage for complex scenario irradiation and simultaneously reduced dose to lungs, heart, and contralateral breast, thereby reduced the risk of late toxicity.
Our comparison not only focused on the ability of target coverage, but also on a multitude of normal tissue parameters. Figures 1 and 2 graphically demonstrate and Table 1 A and 1B quantify the importance that a dose comparison analysis extends to dose levels as low as 2 Gy. Increasingly, long-term follow-up data point toward the importance of taking second malignancy incidences into consideration and radiation-induced heart disease does not appear to have a threshold dose (vide infra). The healthy tissue exposure and contralateral lung data underline the striking benefit of protons over photons in covering highly complex targets while sparing normal tissues. In comparison, conformal photon modalities invariably increased low dose to healthy tissues. At ≤ 10 Gy, the volume differences between photons, with and even without IMN inclusion, compared with protons, was consistently significantly higher for photons: approximately 1.4 L for protons (V10 through V4) compared with 4.4 L and up to 10.2 L for VMAT or HT technology. At the 4 Gy level, the volume of healthy tissue was approximately 1.5 L with protons, compared with an almost six-fold to 7-fold increase to > 10 L by HT and VMAT.
Techniques such as IMRT and tomotherapy can deliver varying amounts of exit-dose in the chest, raising concerns given the carcinogenic potential of radiation [17, 18], especially above doses of 4 to 5 Gy [19, 20]. Contralateral breast mean doses can significantly increase with IMRT, compared with conventionally planned left breast RTs planned with inclusion of the IMN, with an average increase to 4.3 Gy by use of IMRT from 2.9 Gy for a prescription dose of 50 Gy. Several large cohort studies showed increased second-malignancy risks becoming apparent in young women (age, < 45 years) treated with RT and followed for > 5 years .
Stovall et al  quantified the risk of second primary breast cancer in the contralateral breast after RT. The group analyzed 708 women with asynchronous bilateral breast cancer and 1399 women with unilateral breast cancer, counter-matched on the use of RT. Absorbed doses to quadrants of the contralateral breast were estimated. Women < 40 years old who received > 1.0 Gy of absorbed dose to the specific quadrant of the contralateral breast had a 2.5-fold greater risk for contralateral breast cancer than the unexposed women < 40 years old with a follow-up > 5 years, who had a relative risk (RR) of 3.0, and the dose response was significant (excess RR per 1.0 Gy).
In lung exposure, most patients with radiographically detectable radiation pneumonitis and fibrosis remain asymptomatic; hence, the focus of lung avoidance has shifted to the carcinogenesis risk. The risk of other secondary cancers (including sarcomas, primarily of lungs and esophagus) is higher for women with breast cancer treated with conventional radiation techniques [23, 24]. Berrington de Gonzalez et al  analyzed the Surveillance, Epidemiology and End Results Database of 5-year survivors of locoregional breast cancer diagnosed from 1973 to 2000 with a median follow-up of 13 years. Among 182 057 survivors, there were 15 498 secondary solid cancers, including 6491 contralateral breast cancers. The RR of a second malignancy was 1.45 for “high dose” (defined as ≥ 1 Gy) to esophagus, pleura, bone, and soft tissue. The RR was 0.89 for a medium dose (0.5 to 0.99 Gy) and 1.01 for a low dose (< 0.5 Gy). The estimated excess cases of second malignancies from RT were 5% for contralateral breast cancer and 6% for other solids tumors.
In our study, PT consistently provided the highest dose conformality throughout the entire dose spectrum. The dose differential increased significantly with increasing distance from the target and at lower dose volume parameters. For example, the V5 in both lungs was, on average, < 20% for protons, but increased to approximately one third for 3DCRT photons, to > 45% for HT and > 50% for VMAT.
Henson et al  estimated the radiation-related lung cancer risk following RT for 558 871 women recorded with breast cancer during 1973 to 2008 in the Surveillance, Epidemiology and End Results cancer registries and followed until January 2009. The dataset looked at women who received radiotherapy as part of their breast cancer treatment from 1973 to 1982. There was an increased risk of ipsilateral lung cancer mortality (on the previously irradiated side) when compared to the risk of death from contralateral lung cancer. This excess risk of lung cancer death, reported as a mortality ratio, for ipsilateral versus contralateral lung cancer increased with time since breast cancer diagnosis and treatment, reaching values of 1.05 (CI, 0.57 to 1.94) in the first decade, 2.04 (CI, 1.28 to 3.23) in the second decade, and 3.87 (CI, 2.19 to 6.82) in the third decade of follow up (two-sided P values for trend, 0.002).
Our study scrutinized various cardiac-dose parameters reportedly associated with a risk of cardiac damage. This included not only the mean heart dose but also the dose parameters for individual coronary arteries and their respective major branches. Our goal was to gain a better understanding of the dose effects on individual coronary arteries. At present, the most appropriate dosimetric parameter has not been established. We, therefore, included in our analysis for each coronary artery, the parameters of mean dose, the dose to a small but defined volume, ie, 0.02 cm3, and maximum point dose.
Protons consistently reduced the mean dose to the LAD artery compared with the 3 photon modalities by ≥ 50% when IMNs were included. The distal portion of the LAD—considering its anatomic path in the interventricular groove toward the anterior apex of the heart—consistently received a smaller radiation dose by use of protons, but without reaching levels of significance. In this project, we did not attempt to tailor the proton radiation dose distribution to actively avoid the LAD artery. Rather, we applied the strictest possible standards of target coverage, regardless of the resulting dose to the LAD artery. If we had applied less-strict specifications for our proton plans (eg, the “90% isodose coverage of 90% of the volume”) we could have avoided irradiation of the LAD artery altogether by use of protons. This topic is the subject of a currently ongoing, separate project.
Protons allowed inclusion of the IMNs without an increased LAD dose deposition compared with photons even without IMN inclusion. The LADD1 takes a more-lateral path across the surface of the anterior heart. Similar to the path of the LAD, mean doses were significantly larger when using photons with IMN inclusion, and for LADD1, it included the parameters of D–0.2 cm3. The reduced dose to LADD1 by protons remained significant for 3D photons and VMAT even without IMN inclusion.
The left coronary artery, circumflex artery, and right coronary artery are vascular structures located more centrally and distant from the PTV and the anterolateral heart. Protons were able to almost completely avoid radiation as described by the 3 parameters of mean dose, D-0.2 cm3, and maximum dose. The maximum dose for the 3 arteries ranged between 0.00 and 0.24 Gy (RBE). In contrast, the 3 photon modalities either with or without inclusion of IMNs resulted in statistically significant dose deposition to the left coronary artery, the right coronary artery, and the circumflex artery for all dose parameters. The only exception was the mean dose and the D 0.2-cm3 dose to the right coronary artery using 3D photons, which was elevated but without reaching significance. The difference compared with photons was striking with the mean doses to the 3 arteries delivered by protons ranging between 0.0 and 0.02 Gy (RBE), yet photon techniques with inclusion of IMNs delivered between 4.89 and 16.39 Gy and without IMN inclusion between 1.8 and 8.08 Gy.
Recently, long-term outcome studies of breast cancer survivors have reported a significant increase in coronary artery disease as well as fatal and nonfatal myocardial infarction associated with RT for left-sided disease compared with right-sided RT or no RT [1, 5, 27–29].
The University of Pennsylvania experience  noted a significantly higher prevalence of stress test abnormalities found among patients irradiated on the left (27 of 46; 59%) versus right (3 of 36; 8%; P = .001) side. Additionally, the authors found a significant association between coronary artery disease and myocardial infarctions with the inclusion of IMN fields; coronary artery disease was found in 7% of patients without IMN compared with 18% with IMN (P < .001). Myocardial infarctions were significantly more common in association with IMN fields: 3% without IMN versus 9% with IMN (P = .01) inclusion.
“Mean radiation dose to the whole heart” emerges as a possibly suitable parameter and clinical surrogate to estimate the risk of cardiac disease induction by RT. Darby et al  reported a linear increase of 7.4% in the rates of major coronary artery events per 1 Gy of increase in mean heart dose with no apparent threshold. The rate of major coronary event (myocardial infarction, coronary revascularization, and death from ischemic heart disease) increased with increasing mean heart dose up to 116% for mean heart doses of 10 Gy or more. The absolute radiation-related risk was far greater for women with preexisting cardiac risk factors or ischemic heart disease, but the proportional increase was similar in women with and without cardiac risk factors. Increasing incidence of clinically symptomatic major coronary artery disease started at approximately 5 years after RT and continued into the third decade after RT. It also applied to radiation technology used after 1990.
The result of the Darby et al  study prompted an editorial by the New England Journal of Medicine  questioning whether the “findings by Darby et al may just represent the tip of the iceberg” in view of the known potential of RT to induce multiple other cardiac diseases, including valvular dysfunction, cardiomyopathy, and arrhythmias.
In our study, protons resulted in mean heart doses of 1.2 Gy (RBE) ± 0.42 compared with 7.2, 8.0, and 8.2 Gy for 3DCRT photons, HT, and VMAT, respectively. Even in cases with the exclusion of IMNs, the mean dose to the heart remained high with photons ranging between 4.0 and 7.4 Gy. The mean heart dose of 1.2 Gy (RBE) from protons was the lowest reported dose in the literature of IMN nodal coverage.
The clinical effect of inclusion of the internal mammary lymph nodes in locoregional RT of breast cancer remains clinically controversial. Coverage of IMNs in left-sided disease continues to pose a challenge in treatment planning and delivery. The principle issue is the balance between adequate nodal coverage and potentially increased risk of adverse cardiac events because of increased cardiac dose exposure from the complex field arrangements [5, 8].
Harris et al  analyzed a breast cancer patient cohort at the University of Pennsylvania (961 patients with stage I to II breast cancer treated from 1977 to 1995) and reported the incidence of late cardiac morbidity and mortality. At a median follow-up of 12 years (range, 2 to 27 years) in the second decade after treatment, there was a higher rate of cardiac death in patients treated on the left side, with a cumulative risk of 6.4% compared with 3.6% for patients treated on the right side. Statistically higher rates of chest pain, coronary artery disease, and myocardial infarction were diagnosed in patients treated on the left side.
The main argument against including the IMNs in the RT volume is the low incidence of clinically apparent disease recurrence in the IMNs. Olson et al  published a population-based study comparing the outcomes of women with node-positive or high-risk node-negative breast cancer according to the intent to include or exclude the IMN regions in the locoregional RT target volume. Analysis of 2413 women with node-positive or T3/4 node-negative breast cancer did not demonstrate a significant benefit in survival attributable to the intent to include the IMN regions in the RT volume. A trend toward improved survival with IMN RT was observed in patients with 1 to 3 positive nodes, and the absolute mortality risk reduction in this subgroup seemed to be consistent with the magnitude of benefit seen with locoregional RT in randomized trials [31, 32]. These data were consistent with IMN RT having a modest, but potentially important, role during adjuvant RT for breast cancer and suggested that women with a low burden of nodal disease are the ones most likely to benefit from the inclusion of IMNs in the RT volume.
We used treatment technologies and specifications as closely as possible reflecting our present clinical reality. Proton plans were generated, as presently implemented at ProCure Proton Centers and as currently specified in the ongoing prospective phase II clinical study on woman with stage III breast cancer. Three-dimensional photon/electron conformal techniques, VMAT, and HT plans were designed by physicians and medical physicists treating with those respective modalities. All plans were based on actual treatment planning computed tomography scans. However, no other optimized setup techniques reported in the literature, such as DIBH, were used.
Hayden et al  reported on the benefits of DIBH in reducing heart dose from RT for early stage, left-sided breast cancer without inclusion of regional lymph nodes or IMNs. The average mean heart dose was reduced from 6.9 to 3.9 Gy (P < .0001). Stranzl et al  evaluated the influence of respiratory-controlled RT on cardiac exposure applying wide tangential fields, including the internal mammary lymph nodes in 11 patients with left-sided breast cancer. Use of DIBH lead to a lower cardiac exposure with a mean irradiated heart volume (≥ 20 Gy) of 14 cm3 versus 35 cm3 for the free-breathing technique. Although contralateral mean breast dose increased with DIBH 1.4 Gy compared with the free-breathing at 1.2 Gy, that difference did not reach statistical significance . A potential disadvantage in using DIBH is the increase in contralateral breast dose as demonstrated by Zurl et al  in a comparison of 400 plans from 200 patients treated with tangents without inclusion of IMN.
In our study, the mean heart dose was much lower at 1.2 Gy (RBE) with protons, despite treatment to comprehensive lymph nodes, including IMNs.
Proton therapy provided maximum cardiac and coronary sparing. In addition, protons consistently deposited the smallest dose to lungs and contralateral breast in the low-dose range. Mean heart and coronary doses remained lower with protons, even in cases in which proton plans included IMNs but photons did not include them. Our plans indicate that protons can routinely cover IMNs in complex locoregional breast cancer with excellent and homogeneous target coverage and lower exposure to healthy tissue. Protons consistently irradiated the least amount of nontarget tissues. In summary, PT minimizes the risks of serious cardiac morbidity and possibly death from radiation-induced cardiac disease, concurrent with the potential to reduce the risk of induction of second malignancy during the life of breast cancer survivors.