Proton Therapy for Local-regionally Advanced Breast Cancer Maximizes Cardiac Sparing

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1 Proton Therapy for Local-regionally Advanced Breast Cancer Maximizes Cardiac Sparing Marcio Fagundes, MD 1 ; Eugen B. Hug, MD 2 ; Mark Pankuch, PhD 3 ; Christine Fang, MD 4 ; Shawn McNeeley, MS 5 ; Ling Mao, MS 5 ; Myra Lavilla, CMD 6 ; Stacey L. Schmidt, CMD 3 ; Clark Ward, MD 1 ; Oren Cahlon, MD 2 ; William F. Hartsell, MD 3 1 ProCure Proton Therapy Center, Oklahoma City, OK, USA 2 ProCure Proton Therapy Center, Somerset, NJ, USA 3 CDH Proton Center, Warrenville, IL, USA 4 Department of Radiation Oncology, University of Washington, Seattle, WA, USA 5 Princeton Radiation Oncology, Monroe Township, NJ, USA 6 Seattle Cancer Care Alliance, Seattle, WA, USA Abstract Submitted 08 Nov 2014 Accepted 05 Feb 2015 Published 19 Mar 2015 Corresponding author: Marcio Fagundes Provision Center for Proton Center 6450 Provision Cares Way Knoxville, TN USA Phone: þ1 (865) Fax: þ1 (865) Marcio.fagundes@ provisionproton.com Original Article DOI /IJPT * cc Copyright 2015 International Journal of Particle Therapy Distributed under Creative Commons CC-BY Purpose: 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). Materials and Methods: 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. Results: 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 V5 Gy (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). Conclusions: 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. Keywords: breast cancer; radiation therapy; proton beam therapy; cardiac toxicity; late effects OPEN ACCESS How to cite this article Fagundes M, Hug EB, Pankuch M, Fang C, McNeeley S, Mao L, Lavilla M, Schmidt SL, Ward C, Cahlon O, Hartsell WF. Proton Therapy for Local-regionally Advanced Breast Cancer Maximizes Cardiac Sparing. Int J Particle Ther 2015;1(4):

2 Introduction 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 [9], 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 [13]. MacDonald et al [14] 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 Patient Selection Radiation therapy treatment planning was performed on 10 patients with stage III left-sided breast cancer after modified radical mastectomy. Target Volumes 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 [15], 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 [12]. The coronary arteries were identified with the aid of angio-computed tomography scan fusion Fagundes et al. (2015), Int J Particle Ther 828

3 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. Treatment Planning 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. Statistics 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. Results 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 1A 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. Table 2A and 2B summarizes quantitatively the comparison between proton plans with IMN inclusion and the 3 photon modalities excluding IMN coverage. Target Coverage 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 ¼ 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. Fagundes et al. (2015), Int J Particle Ther 829

4 Figure 1. Photon-proton treatment planning comparison based on 3-dimensional conformal radiation therapy (3DCRT) using combined electron (IMC)/photon-tangent technique, volumetric modulated arc therapy (VMAT) intensity-modulated radiation therapy (IMRT)-technology, helical tomotherapy (HT), and proton therapy. Comparison is based on planning with a computed tomography (CT) scan for (A) axial image at supraclavicular level, (B) axial image at level of internal mammary lymph nodes, (C) axial image at cardiac level (midheart, interventricular level), and (D) sagittal image. Prescription dose was 50.4 Gy. Display of dose ranging from 2 Gy to 50.4 Gy. 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 ¼.004), largely as a consequence of inferior IMN coverage (Figure 4). Heart and Coronary Arteries The DVHs for heart and LAD artery are illustrated in Figure 4 and quantitatively listed in Table 1A and 1B and Table 2A and 2B. 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, Fagundes et al. (2015), Int J Particle Ther 830

5 Figure 2. Photon-proton treatment planning subtraction comparison. The dose distributions of a proton plan were subtracted from each photon-modality plan, and the resulting, excess photon dose is depicted. All plans had fulfilled target dose coverage requirements. The result after subtraction demonstrates the additional radiation dose deposited by various photon modalities into healthy tissues. Axial images are at the level of the supraclavicular lymph nodes. 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 cm 3, defined as diagonal-branch LAD (LADD1 0.2 cm 3 ). The proton LADD 0.2 cm 3 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 cm 3 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 cm 3 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 cm 3 was Fagundes et al. (2015), Int J Particle Ther 831

6 Figure 3. Photon-proton treatment planning subtraction comparison. The dose distribution of proton plans are subtracted from photon plans, and the resulting, additional radiation dose is depicted. All plans had fulfilled target dose coverage requirements. The result after subtraction demonstrates the additional radiation dose deposited by various photon modalities into healthy tissues, which does not contribute to target coverage. Axial images at the interventricular, cardiac level 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 cm 3 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 2A 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. Fagundes et al. (2015), Int J Particle Ther 832

7 Table 1A. Comparison of mean target coverage and dose to organs at risk of proton therapy with 3DCRT, HT, and VMAT (n ¼ 10). All modalities included IMNs in the target volume definition. Treatment technique Target/dose, Gy (RBE) Proton (A) 3DCRT (B) (A B) P value HT (C) (A-C) P value VMAT (D) (A D) P value CTV minus skin V , V , V , PTV minus skin V , V V IMN CTV V V V Mean dose Left lung V , V , V , , Right lung V V V , , Both lungs V , V , , V , , , Heart Mean dose , , , V , Abbreviations: 3DCRT, 3-dimensional conformal radiation therapy; HT, helical tomotherapy; VMAT, volumetric modulated arc therapy; IMN, internal mammary nodes; CTV, clinical target volumes; PTV, planning target volume. Note: P values of,.001 were reported as,.001. Lung The total lung dose increasingly favored protons at decreasing dose levels, that is, from the V20 Gy to V10 Gy and to V5 Gy. 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 V5 Gy. 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 V5 Gy 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). Fagundes et al. (2015), Int J Particle Ther 833

8 Table 1B. Comparison of mean target coverage and dose to organs at risk of proton therapy with 3DCRT, HT, and VMAT (n ¼ 10). All modalities included IMNs in the target volume definition, continued. Treatment technique Target/dose, Gy(RBE) Proton (A) 3DCRT (B) (A B) P value Tomotherapy (C) (A C) P value VMAT (D) (A D) P value LAD Mean dose , D-0.2, cm Maximum dose LADD1 Mean dose , , D-0.2, cm , , , Maximum dose , LCA Mean dose , , D-0.2, cm , , , Maximum dose , , , RCA Mean dose , , D-0.2, cm , , Maximum dose , , Circumflex Mean dose , , , D-0.2, cm , , Maximum dose , , , Right breast Mean dose , , V , , V , , V , , Irradiated normal tissue (patient volume minus PTV) Mean dose , , , V45, cm , V , , , V , , , V , , , Abbreviations: 3DCRT, 3-dimensional conformal radiation therapy; HT, helical tomotherapy; VMAT, volumetric modulated arc therapy; IMN, internal mammary nodes; RBE, radiobiologic equivalent; LAD, left anterior descending artery; LADD1, first diagonal branch of the LAD; LCA, left coronary artery; RCA, right coronary artery; PTV, planning target volume. Note: P values of,.001 were reported as,.001. Contralateral Breast 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 Fagundes et al. (2015), Int J Particle Ther 834

9 Figure 4. Dose-volume histograms (DVHs) of clinical target volume (CTV) and several nontarget structures selected from Table 1A and 1B. Abbreviations: LAD, left anterior descending artery; unspecified tissues, any normal tissue in absolute volume (cm 3 ) minus planning target volume and minus defined organs at risk; OARs, organs at risk: lungs, heart, contralateral breast, and esophagus. Prescription dose was 50.4 Gy. 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 Fagundes et al. (2015), Int J Particle Ther 835

10 Table 2A. Mean target coverage and dose to organs at risk of proton therapy with IMN inclusion compared with 3DCRT, HT, and VMAT therapy without IMN inclusion (n ¼ 10). Treatment technique Target/dose, GY (RBE) With IMN Proton (A) No IMN 3DCRT (B) (A B) P value No IMN HT (C) (A C) P value No IMN VMAT (D) (A D) P value CTV minus skin V , V , V , PTV minus skin V , V , V , IMN CTV V N/A N/A N/A N/A N/A N/A V N/A N/A N/A N/A N/A N/A V N/A N/A N/A N/A N/A N/A Mean dose N/A N/A N/A N/A N/A N/A Left lung V V , V , , Right lung V V , V , Both lungs V V , , V , , Heart Mean dose , , , V Abbreviations: IMN, internal mammary nodes; 3DCRT, 3-dimensional conformal radiation therapy; HT, helical tomotherapy; VMAT, volumetric modulated arc therapy; RBE, radiobiologic equivalent; CTV, clinical target volume; PTV, planned target volume, NA, Not applicable. Note: P values of,.001 were reported as,.001. 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 1A and 1B and 2A and 2B; healthy tissue volume receiving 45 Gy (RBE) was 303 cm 3 for protons, compared with 1187, 453, and 400 cm 3 for 3DCRT, HT, and VMAT (P,.05). The D10 Gy (RBE) volume for PT was 1326 cm 3 versus 3821, 4890, and 5024 cm 3 for 3DCRT, HT, and VMAT (P,.05). The proton D4Gy (RBE) volume was 1548 cm 3 compared with 4846, , and cm 3 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. Fagundes et al. (2015), Int J Particle Ther 836

11 Table 2B. Mean target coverage and dose to organs at risk of proton therapy with IMN inclusion compared with 3DCRT, HT, and VMAT therapy without IMN inclusion (n ¼ 10), continued Treatment technique Target/dose, Gy (RBE) With IMN Proton (A) No IMN 3DCRT (B) (A B) P value No IMN HT (C) (A C) P value No IMN VMAT (D) (A D) P value LAD Mean dose , D-0.2, cm , Maximum dose LADD1 Mean dose , , D-0.2, cm , , Maximum dose LCA Mean dose , , D-0.2, cm , , Maximum dose , , RCA Mean dose , , , D-0.2, cm , , Maximum dose , Circumflex Mean dose , , D-0.2, cm , , Maximum dose , , Right breast Mean dose , , V , , V , , V , , Irradiated normal tissue (patient volume minus PTV) Mean dose , , , V45, cm , V , , , V , , , V , , , Abbreviations: IMN, internal mammary nodes; 3DCRT, 3-dimensional conformal radiation therapy; HT, helical tomotherapy; VMAT, volumetric modulated arc therapy; LAD, left anterior descending artery; LADD1, first diagonal branch of the LAD; LCA, left coronary artery; RCA, right coronary artery; PTV, planned target volume. Note. P values of,.001 were reported as,.001. Discussion 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 [16]. 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. Fagundes et al. (2015), Int J Particle Ther 837

12 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 1A 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 secondmalignancy risks becoming apparent in young women (age,, 45 years) treated with RT and followed for. 5 years [21]. Stovall et al [22] 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 [25] 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 survivors, there were 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. Fagundes et al. (2015), Int J Particle Ther 838

13 Henson et al [26] estimated the radiation-related lung cancer risk following RT for women recorded with breast cancer during 1973 to 2008 in the Surveillance, Epidemiology and End Results cancer registries and followed until January The dataset looked at women who received radiotherapy as part of their breast cancer treatment from 1973 to 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 cm 3, 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 cm 3. 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 cm 3, 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-cm 3 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 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 Fagundes et al. (2015), Int J Particle Ther 839

14 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 [1] 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 ¼.001) 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 ¼.01) 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 [9] 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 The result of the Darby et al [9] study prompted an editorial by the New England Journal of Medicine [30] 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) 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 [8] 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 [30] published a populationbased study comparing the outcomes of women with node-positive or high-risk nodenegative 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 nodenegative breast cancer did not demonstrate a significant benefit in survival attributable to Fagundes et al. (2015), Int J Particle Ther 840

15 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 [33] 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 [34] evaluated the influence of respiratory-controlled RT on cardiac exposure applying wide tangential fields, including the internal mammary lymph nodes in 11 patients with leftsided breast cancer. Use of DIBH lead to a lower cardiac exposure with a mean irradiated heart volume ( 20 Gy) of 14 cm 3 versus 35 cm 3 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 [33]. A potential disadvantage in using DIBH is the increase in contralateral breast dose as demonstrated by Zurl et al [35] 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. Conclusions 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. References 1. Correa CR, Litt HI, Hwang WT, Ferrari VA, Solin LJ, Harris EE. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. J Clin Oncol. 2007;25: Fagundes et al. (2015), Int J Particle Ther 841

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