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ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 1  |  Page : 114-118
 

Impact of post-operative radiation on coronary arteries in patients of early breast cancer: A pilot dosimetric study from a tertiary cancer care center from India


1 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Radiology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication3-Feb-2016

Correspondence Address:
D Mondal
Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175562

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 » Abstract 

Background: The significant impact of postoperative radiotherapy (PORT) on cardiac morbidity in patients of early breast cancer (EBC) undergoing breast-conserving surgery has been shown in different studies. The present study was conducted to assess the impact of surgery and the side of involvement on radiation dose to left anterior descending artery (LAD) and Left circumflex coronary artery (LCx). Materials And Methods: Totally, 58 patients of EBC were randomly chosen for this dosimetric study and planned with tangential field technique without intensity modulation (IM). Heart, LAD, and LCx (n = 55) were contoured. Dose volume histograms were analyzed to determine the Dmax (maximum dose) and Dmean (mean dose) of LAD and LCx. Student's t-test was used for comparative analysis of the means. Results: The mean Dmax of LAD for left (L) EBC was 3.17 Gray (Gy) while for right (R) EBC it was 0.86 Gy (P = 0.007;). The mean Dmean of LAD for L-EBC and R-EBC were 1.97 Gy and 0.79 Gy, respectively (P = 0.029;). The mean-Dmax of LCx for patients with L-EBC (2.9 Gy; range: 1.2–4.35 Gy) was statistically higher than that for R-EBC (1.3 Gy; range: 0.7–3.2 Gy) (P = 0.045). The mean-Dmean of LCx for L-EBC (2.1 Gy; range: 0.6–3.6 Gy) was also significantly higher than that of L-EBC (0.9 Gy; range: 0.7–2.1 Gy) (P = 0.03). There was no significant impact of the pattern of surgery on LAD dose, but significance was noted for LCx dose parameters (P = 0.04 and 0.08 for m-Dmax and m-Dmean of LCx). Conclusion: This pilot dosimetric study confirms the assumption that patients with left-sided EBC are at higher risk of developing long-term cardiac morbidity when treated with PORT due to increased dose to LAD.


Keywords: Breast-conserving surgery, early breast cancer, late cardiac morbidity, left anterior descending artery dose, left circumflex artery


How to cite this article:
Roy S, Mondal D, Melgandi W, Jana M, Chowdhury K K, Das S, Haresh K P, Gupta S, Sharma D, Julka P K, Rath G K. Impact of post-operative radiation on coronary arteries in patients of early breast cancer: A pilot dosimetric study from a tertiary cancer care center from India. Indian J Cancer 2015;52:114-8

How to cite this URL:
Roy S, Mondal D, Melgandi W, Jana M, Chowdhury K K, Das S, Haresh K P, Gupta S, Sharma D, Julka P K, Rath G K. Impact of post-operative radiation on coronary arteries in patients of early breast cancer: A pilot dosimetric study from a tertiary cancer care center from India. Indian J Cancer [serial online] 2015 [cited 2021 Jul 29];52:114-8. Available from: https://www.indianjcancer.com/text.asp?2015/52/1/114/175562



 » Introduction Top


Radiation therapy (RT) plays a pivotal role in the management of early breast cancer (EBC). It is an integral part of breast conservation therapy. It enhances local control as well as improves overall survival.[1],[2] However, RT (after modified radical mastectomy (MRM) or breast conservation surgery) has its own hazards. Multiple Studies with long-term follow-up and a number of meta-analyses have shown that delivery of radiation to chest wall or breast results in delayed cardiac morbidities ranging from ischemic heart disease (IHD) to acute coronary syndromes and finally congestive cardiac failure.[3] Patients with left-sided breast cancer have a higher propensity for developing cardiac complications than those right-sided breast cancers,[4],[5],[6] though some retrospective single-institutional analyses ruled out any impact of laterality on cardiac complications.[7],[8] Dosimetric evaluation of individual patient's plan indicates that abnormal cardiac findings may be dose dependent and sensitive to RT dosimetric parameters.[9],[10],[11],[12] A pilot dosimetric study was conducted at our institute to find whether the mode of surgery or the side of involvement has a significant impact on left anterior descending artery (LAD) and left circumflex coronary artery (LCx) dose, which we took as a dosimetric surrogate for IHD.


 » Materials and Methods Top


A total of 58 patients with early breast carcinoma (T1/T2 + N0 or N1 according to 7th edition of American Joint Committee on Cancer staging) was randomly selected from July 2013 to November 2013. RT was delivered to either chest wall or the entire breast (excluding skin) in these patients using tangential fields with computed tomography (CT) based planning. For postmastectomy radiation therapy (PMRT) 50 Gy in 25 fractions, five fractions a week were delivered to the chest wall. For patients undergoing breast-conserving surgery (BCS), whole breast radiation therapy to a dose of 50 Gy in 25 fractions, five fractions a week was delivered which was then followed by a boost dose to the tumor cavity to another 16 Gy in 8 fractions using appropriate electron energy as an institutional policy. Eclipse treatment planning system (TPS) version 6.5 (Varian Meical Systems, Palo Alto, United States of America) was used for planning and dosimetry.

Computed tomography simulation was done with the patients lying supine on the couch with the head turned to the opposite side and the ipsilateral arm abducted and externally rotated at the shoulder joint. Radio-opaque copper wire was used to mark the mastectomy scar and boundary of the chest wall or clinical breast volume. After the non-contrast CT scans of the chest and neck was acquired using PHILIPS large bore CT scanner with 3 mm slice thickness, the images were transferred to the Eclipse TPS version 6.5 with the help of DICOM system. No respiratory motion management was used during simulation, planning or treatment.

Left anterior descending artery was contoured in all these patients with the help of a radiologist, well versed with breast oncology and radiotherapy planning. The location of the LAD was identified using the course of the anterior inter-ventricular groove. In addition, the LCx was outlined for 55 patients of the same cohort. The LCx was contoured from its branch point off the left main coronary artery, and its course was identified using the left atrioventricular groove [Figure 1]. Entire heart was contoured along with the pericardial sac starting from the inferior aspect of the pulmonary artery passing the midline and extended inferiorly till the inferior aspect of the apex. This was done following the RTOG guideline available in RTOG website.[13]
Figure 1: The contouring for circumflex coronary artery (a), left anterior descending artery (b), and the tangential field arrangement with dose color wash (c) in the axial computed tomography slices for patient. The contouring slices are from two different patients

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The whole breast was considered as clinical target volume (CTV) excluding skin, underlying muscle, rib cage for patients with BCS. Field borders were defined based on anatomical landmark rather than target volume. Medial border was at midline. Lateral and inferior border were 1.5 cm below palpable breast tissue to account for the penumbra. Superior border was at the inferior border of the medial end of the clavicle. For a boost to the tumor cavity, a uniform margin of 1.5 cm was used from the CT identified seroma cavity or tumor cavity or surgical clips whichever applicable. For postmastectomy radiation entire chest wall with skin, muscle, and deep fascia including scar were included within the CTV. For scars extending too medially or laterally, individualization of borders was done. Inferior border was at a level 2 cm below the inferior extent of opposite normal breast. Anterior field border was 2 cm in air from the skin or highest point of breast tissue to allow adequate coverage.

For radiotherapy planning, two tangential beams were used with matched posterior border to avoid divergence. Physical wedges of 15°–30° were used. All patients were planned with 6MV photon; 10MV photon were used where separation was >22 cm. For post-mastectomy radiation, skin bolus was not routine and used only for selective high-risk patients. For left-sided tumors gantry angles for medial and lateral tangents were 310°–318° and 131°–140°, respectively. The same for right-sided tumors were 44°–52° and 226°–235°, respectively. Individual CT slices were reviewed to assess dose distribution. Gantry angle, wedge angle, beam weightage were modified accordingly. Dose volume histograms (DVH) were reviewed for all the patients. Maximum and mean dose (Dmax and Dmean) to LAD and LCx was calculated from cumulative DVH. As an institutional protocol maximum heart distance (MHD) of 1 cm and a maximum central lung distance (CLD) of 2.5 cm were allowed before approving the plan for treatment. However, in some patients under coverage at the peripheral breast tissue were considered acceptable depending on the MHD and CLD value where these were prohibiting high. Though this is a dosimetric study and patients were not treated according to this plan, the same criteria for MHD and CLD were followed but not reported in this article. This study did not consider dose received from the boost phase of irradiation. We evaluated the impact of two variables on Dmax and Dmean of LAD and LCx: The laterality of disease and the mode of surgery. Student's t-test was used for comparative analysis of the means. SPSS version 17.0 (IBM) was used for statistical analysis.

All patients with primary tumor size 1 cm or more and/or node-positive disease received adjuvant chemotherapy (FEC) as per the institute's joint clinic decision. 42 patients have received FEC regime and 16 patients received AC × 4 cycles followed by Docetaxel × 4 cycle regime. Total 11 patients have also received Herceptin along with adjuvant chemo, and 3 patients have also received maintenance Herceptin as well. Cardiac function was assessed routinely before prescribing chemotherapy and Herceptin. All patients received chemotherapy under medical oncologist experienced in breast oncology.


 » Results Top


Totally, 33 patients underwent BCS while 25 patients underwent MRM. Left (L) and right (R) sided EBC were noted in 36 and 22 patients, respectively. The mean Dmax (m-Dmax) of LAD for left-sided disease was 3.17 Gy (range: 1.32 Gy–6.6 Gy) while that for right-sided disease was 0.86 Gy (range: 0.53 Gy–1.20 Gy), the difference being statistically significant (P = 0.007;) [Table 1]. The mean Dmean (m-Dmean) of LAD for left-sided disease and right-sided disease were 1.97 Gy (range: 0.90 Gy–3.07 Gy) and 0.79 Gy (range: 0.48–1.1 Gy), respectively and the difference was significant (P = 0.029;). There was no statistically significant difference in m-Dmax or m-Dmean of LAD for adjuvant RT after MRM (m-Dmax: 1.55 Gy; m-Dmean: 1.08 Gy) or BCS (m-Dmax: 2.64 Gy; m-Dmean: 1.72 Gy) (P value being 0.149 and 0.214 for comparison of m-Dmax and m-Dmean, respectively).
Table 1: The dosimetric parameters of LAD depending on the side of the tumor and type of surgery

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Among the 55 patients for whom LCx was delineated, 21 patients had right-sided disease while 34 patients had left-sided disease. 30 patients underwent BCS while 25 patients underwent MRM. The m-Dmax of LCx for patients with left-sided disease was 2.9 Gy (range: 1.2-3.75 Gy) while that for right-sided disease was 1.3 Gy (range: 0.7–3.2 Gy). The difference was statistically significant (P = 0.04). The mean-Dmean of LCx for left-sided disease (2.1 Gy; range: 0.6–3.6 Gy) was also significantly higher than that of right-sided disease (0.9 Gy; range: 0.7–2.1 Gy) (P = 0.03) [Table 2]. Statistically significant higher Dmax and Dmean of LCx were noted in patients undergoing post BCS RT (m-Dmax: 2.36 Gy, range: 1.93–3.1 Gy; m-Dmean: 1.48 Gy, range: 0.89–2.23 Gy) than those undergoing PMRT (m-Dmax: 1.29 Gy, range: 0.73–2.3 Gy; m-Dmean: 0.93 Gy, range: 0.49–1.73 Gy) (P value being 0.04 and 0.08 for comparison of m-Dmax and m-Dmean, respectively).
Table 2: The dosimetric parameters of LCx depending on the side of the tumor and type of surgery

Click here to view



 » Discussion Top


The current pilot dosimetric study clearly demonstrates a significant impact of laterality of EBC on the dose of LAD and LCx which can be considered as surrogate dosimetric marker for long-term cardiac morbidities. However, no impact of the nature of surgery on the dosimetric parameters for LAD could be demonstrated though a significant impact of surgery could be established on the Dmax or Dmean of LCx.

Radiation takes its toll on heart's vascular supply by two most important pathway-synergistic effect on age-related coronary artery disease (CAD) resulting in increased frequency of infarctions or persistent progressive rarefaction of microvasculature leading to increased lethality of infarctions.[14] Simultaneous use of anthracycline and trastuzumab-based chemotherapy and even taxanes have an additive effect on this cardiac toxicity. Conspicuous evidences show that for every Gy increase in cardiac dose, there is an increase in mortality by 3% at 20 years. The recent update of the EBC Trialists' Collaborative Group meta-analysis, radiotherapy compared with no radiotherapy was associated with excess mortality (rate ratio 1.3) from heart disease [3] though substantial heterogeneity exists among the trials included in this overview in terms of target volume, fraction size, and radiotherapy techniques. In the modern era of conformal radiation using tangential coplanar beams of megavoltage energy, the dose to the cardiovascular structures can be limited but still the effects of radiation on EBC in terms of tolerance dose-toxicity parameter need to be quantified.

Previous studies have reported a high proportion of cardiac diagnostic test abnormalities among asymptomatic left-sided irradiated breast cancer patients. Gyenes et al. have shown that 6 of 12 new anterior perfusion defects took place in irradiated patients with left-sided breast cancer at 1-year follow-up.[15] Marks et al.[16] similarly found that 21 of 77 (27%) and 11 of 26 (42%) patients developed new myocardial perfusion defects at 6 months and 2 years after RT, respectively.

Study by Correa et al.[17] found that at a median of 12 years post-RT the incidence of cardiac diagnostic test abnormalities among symptomatic left-sided irradiated women was significantly higher than the predicted incidence of cardiovascular disease in the patient population. All patients were treated with standard tangents (median dose, 46 Gy), with a boost (median dose, 18 Gy) to the tumor bed. They also found the impact of median central lung distance (m-CLD) on the cardiac complications. The current study did not analyze the impact of m-CLD on the cardiac dose parameters.

Taylor et al.[18] concluded from their study that Heart dose from left-tangential radiotherapy has decreased considerably over the past 40 years, but part of the heart still receives >20 Gy for approximately half of left-sided patients. Cardiac dose for patients with right-sided disease was generally from scattered irradiation alone. Part of the heart received >20 Gy in 22 left-sided patients (44%). For the 5 patients given right-sided irradiation, average mean doses to all cardiac structures were in the range 1.2–2 Gy.

However, there are some studies which have ruled out any effect of laterality on cardiac dose. A study from Princess Margaret Hospital found no evidence for excess morbidity and mortality from CAD at 10.2 years of follow-up among women treated with radiation to the left breast after BCS.[8]

In addition, two SEER studies that analyzed patients treated in the early 1980s found no increased risk of cardiovascular mortality [19] or IHD [6] among left sided irradiated patients. However, the radiotherapy planning details and dose parameters were not available; so the impact of radiotherapy technique could not be assessed. In particular, it was not known how many patients had received treatment to the internal mammary lymph nodal basin which is often associated with a large cardiac dose.

The current study is a dosimetric study which clearly points out a higher risk of radiation-induced cardiac morbidities in patients with Left-sided disease in terms of higher dose to LAD or LCx. Previous studies indicated a significant impact of radiation modality on cardiac chamber dose [20] and of positioning of the patient, supine versus prone, and laterality on possible cardiac effects.[21] Clinical validation of such finding is a must before drawing any conclusion on the impact of laterality of EBC on radiation-induced cardiovascular complications. We did not find the dosimetric significance of surgical technique on LAD dose while a significant impact was observed for LCx dose. It would be prudent to mention that recently published QUANTEC guideline does not provide recommendations for whole breast or chest wall radiation, rather it gives valuable recommendations for partial breast irradiation (V25 should be <10% to reduce the Normal tissue complication probabilyit to < 1%) and recent studies utilizing intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy for whole breast radiation used much stringent dose volume criteria.[22],[23],[24] The impact of CTV to planning target volume (PTV) margin on dose distribution is well-appreciated. While conventional tangents use generous CTP to PTV expansion, newer modalities with image guidance and respiratory gating technique are able to reduce this to as low as 5 mm. This definitely reduces the dose to organs at risk. A wider margin is expected to include more of normal breast tissue within the PTV and reduce cosmesis. Surgical technique also has its own implication in defining target volumes during radiotherapy planning. While postbreast conservation surgery, the tumor bed and the surrounding area are at greater risk of having recurrence, chest wall including skin, muscle, and the fascia are at increased risk of having recurrence in the postmastectomy patient. Current standard of care for EBC is breast-conserving therapy while more locally advanced tumors are managed either with mastectomy or BCS following neoadjuvant chemotherapy in suitable patients. This difference in target volume is also understood as already described. This difference in surgical technique leads to the difference in target volume for post BCS and postmastectomy patients. In postmastectomy patients, due to surgical removal the chest wall may be very thin which poses a difficulty in adequately covering the skin and very superficial tissue and delivers a higher dose to underlying lung and cardiac tissue. To the best of our knowledge, this is the first study showing a possible impact of surgical modality on radiation-induced cardiac morbidities in patients of EBC. Further large clinical studies with long-term follow-up are recommended before further validation of such association.

Evolution of RT techniques and emergence of IMRT have ushered a new era in the field of breast radiation. Use of IMRT can reduce the average percentage of the heart receiving ≥60% of the prescribed dose from 4.4% to 2.3%.[25] Inspiratory maneuvers that displace the heart posteriorly from the chest wall can also substantially reduce irradiated heart volumes.[26] The median volume of irradiated left anterior descending coronary artery was also substantially reduced with inspiratory gating and breathes hold techniques.[17]


 » Conclusion Top


This pilot dosimetric study confirms the assumption that patients with left-sided breast cancers are at higher risk of developing long-term cardiac complications after receiving radiotherapy irrespective of the nature of surgery. Patients who underwent BCS are also at a higher risk for radiation-induced damage to LCx. To the best of our knowledge, this is the first study showing a possible impact of surgical modality on radiation-induced cardiac morbidities in patients of EBC. Clinical trials with long-term follow-up are necessary to explore such association in a more confirmatory fashion. It is prudent to use modern high precision radiotherapy technique without compromising target coverage to give adequate tumor control with acceptable toxicity and further reduction of radiation-induced morbidity and mortality.

 
 » References Top

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Nixon AJ, Manola J, Gelman R, Bornstein B, Abner A, Hetelekidis S, et al. No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 1998;16:1374-9.  Back to cited text no. 7
    
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Vallis KA, Pintilie M, Chong N, Holowaty E, Douglas PS, Kirkbride P, et al. Assessment of coronary heart disease morbidity and mortality after radiation therapy for early breast cancer. J Clin Oncol 2002;20:1036-42.  Back to cited text no. 8
    
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Hurkmans CW, Borger JH, Bos LJ, van der Horst A, Pieters BR, Lebesque JV, et al. Cardiac and lung complication probabilities after breast cancer irradiation. Radiother Oncol 2000;55:145-51.  Back to cited text no. 9
    
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Hardenbergh PH, Munley MT, Bentel GC, Kedem R, Borges-Neto S, Hollis D, et al. Cardiac perfusion changes in patients treated for breast cancer with radiation therapy and doxorubicin: Preliminary results. Int J Radiat Oncol Biol Phys 2001;49:1023-8.  Back to cited text no. 10
    
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Lind PA, Pagnanelli R, Marks LB, Borges-Neto S, Hu C, Zhou SM, et al. Myocardial perfusion changes in patients irradiated for left-sided breast cancer and correlation with coronary artery distribution. Int J Radiat Oncol Biol Phys 2003;55:914-20.  Back to cited text no. 11
    
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Prosnitz RG, Hubbs JL, Evans ES, Zhou SM, Yu X, Blazing MA, et al. Prospective assessment of radiotherapy-associated cardiac toxicity in breast cancer patients: Analysis of data 3 to 6 years after treatment. Cancer 2007;110:1840-50.  Back to cited text no. 12
    
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RTOG guidelines for contouring of heart. Available from: http://www.rtog.org/CoreLab/ContouringAtlases/LungAtlas.aspx. [Last accessed on 2014 March 17].  Back to cited text no. 13
    
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Sardaro A, Petruzzelli MF, D'Errico MP, Grimaldi L, Pili G, Portaluri M. Radiation-induced cardiac damage in early left breast cancer patients: Risk factors, biological mechanisms, radiobiology, and dosimetric constraints. Radiother Oncol 2012;103:133-42.  Back to cited text no. 14
    
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Gyenes G, Fornander T, Carlens P, Glas U, Rutqvist LE. Detection of radiation-induced myocardial damage by technetium-99m sestamibi scintigraphy. Eur J Nucl Med 1997;24:286-92.  Back to cited text no. 15
    
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Marks LB, Yu X, Prosnitz RG, Zhou SM, Hardenbergh PH, Blazing M, et al. The incidence and functional consequences of RT-associated cardiac perfusion defects. Int J Radiat Oncol Biol Phys 2005;63:214-23.  Back to cited text no. 16
    
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Correa CR, Das IJ, Litt HI, Ferrari V, Hwang WT, Solin LJ, et al. Association between tangential beam treatment parameters and cardiac abnormalities after definitive radiation treatment for left-sided breast cancer. Int J Radiat Oncol Biol Phys 2008;72:508-16.  Back to cited text no. 17
    
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Taylor CW, Povall JM, McGale P, Nisbet A, Dodwell D, Smith JT, et al. Cardiac dose from tangential breast cancer radiotherapy in the year 2006. Int J Radiat Oncol Biol Phys 2008;72:501-7.  Back to cited text no. 18
    
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Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: Prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 2005;6:557-65.  Back to cited text no. 19
    
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Krueger EA, Schipper MJ, Koelling T, Marsh RB, Butler JB, Pierce LJ. Cardiac chamber and coronary artery doses associated with postmastectomy radiotherapy techniques to the chest wall and regional nodes. Int J Radiat Oncol Biol Phys 2004;60:1195-203.  Back to cited text no. 20
    
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Kirby AM, Evans PM, Donovan EM, Convery HM, Haviland JS, Yarnold JR. Prone versus supine positioning for whole and partial-breast radiotherapy: A comparison of non-target tissue dosimetry. Radiother Oncol 2010;96:178-84.  Back to cited text no. 21
    
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Formenti SC, Gidea-Addeo D, Goldberg JD, Roses DF, Guth A, Rosenstein BS, et al. Phase I-II trial of prone accelerated intensity modulated radiation therapy to the breast to optimally spare normal tissue. J Clin Oncol 2007;25:2236-42.  Back to cited text no. 22
    
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Scorsetti M, Alongi F, Fogliata A, Pentimalli S, Navarria P, Lobefalo F, et al. Phase I-II study of hypofractionated simultaneous integrated boost using volumetric modulated arc therapy for adjuvant radiation therapy in breast cancer patients: A report of feasibility and early toxicity results in the first 50 treatments. Radiat Oncol 2012;7:145.  Back to cited text no. 23
    
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Gagliardi G, Constine LS, Moiseenko V, Correa C, Pierce LJ, Allen AM, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys 2010;76:S77-85.  Back to cited text no. 24
    
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]

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