Introduction
Breast cancer is the second most common cancer in women, behind skin cancer, and the second most common cause of cancer death in women.¹ Approximately 276,480 new cases of invasive breast cancer in women will be diagnosed in 2020, along with approximately 48,530 new cases of carcinoma in situ cases, according to an estimation from the American Cancer Society.¹ One common treatment option for patients diagnosed with breast cancer is external beam radiation therapy. Improved overall survival and reduction in local recurrence are two benefits of post-lumpectomy radiation therapy when compared to surgery alone.2 Because of this, breast-conserving surgery followed by radiation therapy is a standard alternative to mastectomies.2
Due to the prevalence of breast cancer in the female population, it is important to continue to improve upon the treatment options available and limit any harm being done to the patient. The heart is located on the left side of the body near the breast and chest wall, causing it to be susceptible to low to moderate doses of radiation. Since radiation has adverse effects on the heart, it is important to keep the heart dose as low as possible when treating left-sided breast cancer. Mean heart doses in the 1970’s when treating left-sided breast cancer were as high as 13.3Gy.3 Because of this, new techniques and dose constraints have been developed to protect the heart and decrease the dose being given to the radiosensitive organ.
There are many different techniques that have been created and implemented to achieve lower heart doses. These techniques include deep-inspiration breath hold (DIBH), proton therapy, prone positioning, 3D techniques, hypofractionation, and continuous positive airway pressure (CPAP) therapy. The goal of this study is to compare these various heart-sparing techniques for treating left-sided breast cancer with external beam radiation therapy, and determine which technique leads to the largest impact on reducing the mean heart dose. The three techniques that will be the main focus are DIBH, proton therapy, and CPAP; hypofractionation, patient positioning, and 3D versus IMRT/VMAT will be briefly discussed, as well.
Literature Review
Breast cancer is typically treated with a multi-disciplinary approach. Studies have found that a lumpectomy followed by radiation therapy in early stage breast cancer yields the same results as a mastectomy.4 Many patients prefer the breast-conserving option over a mastectomy based on cosmesis. For invasive breast cancer, radiation is typically given after a mastectomy to improve locoregional disease control and prevent recurrence of the disease.4 Therefore, radiation therapy is an important and beneficial aspect of breast cancer management.
Although radiation therapy benefits typically outweigh its risks, ionizing radiation can have detrimental effects on the heart. A dose-response relationship exists between acute coronary events and ionizing radiation.5 At moderate dose levels, the risk of radiation-induced heart mortality follows a linear-quadratic function; at high dose levels, the risk is closer to a linear response.6 Studies have found that the risk of a major coronary event increases by 7.4% for every 1Gy of mean dose to the heart.7 The risk also has been seen to increase within the first 5 years after exposure, with no apparent threshold below which there was no risk.8
Although there is no threshold dose, QUANTEC data suggests that no more than 5% of the whole heart receives greater than 20Gy and no more than 30% of the whole heart receives greater than 10Gy for left-sided breast cancer.8 It is also recommended than the mean heart dose does not exceed a dose of 4Gy.8 Other studies have established stricter mean heart dose constraints of less than 2.5Gy or even less than 1.6Gy.9 Lastly, a V25Gy of less than 10%, using 200cGy per fraction, is associated with a less than 1% probability of cardiac mortality 15 years following radiation therapy treatment, according to the normal tissue complication probability model-based estimation.8
Dose constraints have been recommended for this radiosensitive organ because it is commonly found near tumor sites. Due to the location of the heart, higher cardiovascular mortality is seen following left breast irradiation compared to right breast irradiation.6 Myocardial infarction, ischemic heart disease, coronary revascularization, and a decrease in cardiac strain and strain rate are a few examples of heart toxicities that have been observed following breast irradiation.6 Other potential cardiac effects of radiation to the heart include valvular dysfunction, pericarditis, cardiomyopathy, coronary artery diseases, and heart failure.10 Because of these potential adverse cardiac events and the proximity of the heart to the left breast, it is important to implement techniques to decrease the risk of these toxicities developing, especially when irradiating the left breast.
Methods
Deep-Inspiration Breath Hold
Deep-inspiration breath hold consists of the patient ceasing respiration on inspiration while treatment is being delivered. For the DIBH technique, a computed tomography (CT) simulation scan was performed on each left-sided breast cancer patient in the standard breast positioning.11 The patient was coached through this breathing technique while breath amplitude was monitored.11 The monitoring system consisted of an infrared camera at the end of the treatment couch tracking a box with infrared markers that was placed on the patient.11 The upper and lower thresholds were also adjusted to ensure the highest acceptable movement was within 5mm of the upper and lower thresholds.11 Once the monitoring system was ready and the patient was comfortable with the breathing technique, both a DIBH and free breathing scan were completed with a slice thickness of 5mm.11
The treatment prescription was 50Gy in 25 fractions.11 Plans were made on both the DIBH and free-breathing scan.11 An intensity-modulation radiation therapy (IMRT) plan was made for both scans, as well as a 3D conformal radiation therapy (3D-CRT) plan.11 For the 3D-CRT plan, a dose rate was 600MU/min was used with 6MV photons.11 Opposed tangent fields for the breast/chest wall with an anterior supraclavicular field were used with a mono-isocentric technique.11 Half-beam blocks were implemented along with asymmetrical jaws to avoid divergence of the tangential fields into the healthy lung.11 The gantry angles were determined based on target coverage and the location of the organs at risk (OARs).11 Multi-leaf collimators (MLCs) were created to block the OARs without losing any coverage of the target, as well.11 A field-in-field technique and field weighting were used to create a dose distribution that was homogenous, as well.11 Lastly, the supraclavicular field used an angle of 340-345-degrees to avoid the spinal cord and esophagus; two dose normalization points were used for this three-field technique.11 For the IMRT plans, beams were created starting at 320-degrees and equally spaced every 20-degrees, resulting in six coplanar beams with a collimator angle of 0.11 Lastly, the PTV was required to be covered by at least 95% of the prescription dose, and dynamic MLCs were implemented to aid in meeting the dose constraints of the OARs.11
Proton Therapy
Proton therapy utilizes heavy proton particles opposed to the standard photon. Three plans were made for each left-sided breast cancer patient in this study, and two different proton techniques were used.12 The first plan was an IMRT photon plan with opposed tangential beams. The second plan was an uniform scanning proton plan.12 This plan consisted of an en face beam that maintained an equal air gap from source to skin distance with a 1.5cm MLC margin around the PTV, and a 0.5cm distal and 0.4cm proximal margin to account for any uncertainties within the treatment range.12 To decrease the dose at the lung/chest wall interface and increase the 95% isodose line, a compensator was added.12 The third plan was a pencil beam scanning proton plan. This plan consisted of an en face beam and 7cm bolus.12 The prescribed dose was 50Gy in 200cGy fractions, and the PTVeval was to be encompassed by the 95% isodose line. The hotspot was restricted to below 110%, as well.12
Continuous Positive Airway Pressure
CPAP machines are typically used for sleep apnea, but have just recently been tested for being beneficial in radiation therapy of the thorax.13 Multiple CT scans were done on each left-sided breast cancer patient.13 The scans completed were with CPAP, without CPAP, free-breathing, and 4D gating for simulation; when CPAP was used, the target pressure was 15mmHg.13 The plans were created using a 3D conformal technique.13 Two tangent fields with subfields were planned to create optimal dose homogeneity and to lower hotspots.13 Normal tissue constraints were utilized for the heart when planning; the constraint for the mean heart dose was less than 4Gy when treating the nodes and breast, and less than 3Gy when only the breast was being treated.13 It was required for 95% of the prescription dose to be delivered to 95% of the breast and nodal PTV, as well.13 If only the left breast was to be treated, the prescription dose was 42.72Gy in 16 fractions.13 If both the left breast and involved regional nodes were to be treated, the prescription dose was 50Gy in 25 fractions.13
Statistical Analysis
The goal of this study is to compare the impact of different heart-sparing techniques on the mean heart dose when treating left-sided breast cancer with external beam radiation therapy. Since the different techniques are from various studies, the statistical analysis was focused on making the techniques comparable. Three techniques were evaluated: DIBH (15 patients), proton therapy (10 patients), and CPAP therapy (20 patients).11,12,13 For each technique, the average mean heart dose with the heart-sparing technique was divided by the average mean heart dose without the heart-sparing technique. This value was then subtracted from one and multiplied by 100 to equal a percentage. The resulting percentage represented the reduction in mean heart dose when the heart-sparing technique was used compared to when the heart-sparing technique was not used. This percentage was used to analyze the impact each technique had on the mean heart dose. The detailed statistical analysis can be referenced on Figure 1 in the appendix.
Results
For the proton plans, ten patients were evaluated. Two different proton techniques, pencil beam scanning and uniform scanning, were compared to an IMRT photon plan. The average mean heart dose for the pencil scanning beam proton plan was 0.011Gy, the average mean heart dose for the uniform scanning proton plan was 0.009Gy, and the average mean heart dose for the IMRT proton plan was 1.612Gy.12 The pencil beam scanning proton plan decreased the mean heart dose by 99.3% when compared to the IMRT photon plan. The uniform scanning proton plan decreased the mean heart dose by 99.4% when compared to the IMRT photon plan. Therefore, the uniform scanning proton plan had the biggest impact on decreasing the mean heart dose by less than 1%. Proton therapy resulted in the largest reduction of mean heart dose in this study.
For the DIBH technique, fifteen patients were evaluated. The mean heart dose was decreased by 53.5% using the 3D DIBH plan compared to the 3D free-breathing plan. The average mean heart dose for the free-breathing technique was 7.1Gy, and the average mean heart dose for the DIBH technique was 3.3Gy.11 Utilizing the DIBH technique resulted in the second largest reduction of mean heart dose in this study.
For the CPAP technique, twenty patients were evaluated. When CPAP was used, the mean heart dose was reduced by 47% compared to when CPAP was not used. The average mean heart dose with CPAP was 1.6Gy, and the average mean heart dose without CPAP was 3.02Gy.13 The use of CPAP resulted in the third largest reduction of mean heart dose in this study.
Discussion
There are many different external beam radiation therapy treatment techniques for left-sided breast irradiation. Although there are a lot of aspects to consider when analyzing each technique, the purpose of this study was to focus on reducing the mean heart dose. This is because the risk of a major coronary event taking place increases by 7.4% for every 1Gy of mean heart dose.7 Multiple techniques have been developed to spare the heart when treating left-sided breast cancer, so this study compares the impact various heart-sparing techniques have on reducing the mean heart dose in patients.
Proton therapy with DIBH had the largest reduction in mean heart dose when compared to photons. There was no significant different between the two types of proton treatments, pencil beam scanning and uniform scanning, but there was a large reduction of mean heart dose by 99% when comparing protons to photon IMRT. A study performed by Mast et al., on twenty left-sided breast cancer patients, found a 93% reduction in mean heart dose using protons instead of IMRT photons, as well.14 These large reductions are most likely due to the characteristics of protons. Protons follow the Bragg peak curve, which allows these heavy particles to have a sharp fall-off after reaching the peak and give virtually no exit dose.4 Although this technique is great [A1] at sparing the heart, it is very sensitive to set-up errors and changes in patient anatomy. Also, due to protons being a new technology, there are currently only thirty-six operating proton therapy centers in the United States.15 This is the main reason proton therapy is not a commonly used technique despite its benefits in sparing normal tissue.
DIBH is one of the most common techniques used by physicians aiming to spare the heart in left-sided breast radiation therapy.16 DIBH had the second highest reduction in mean heart dose when compared to the free-breathing technique. Studies completed by Oechsner et al. and Yeung et al. also found average reductions of mean heart doses near 50% using DIBH when compared to free breathing.17,18 These studies had thirty-one patients and twenty patients, respectively.17,18 During the DIBH technique, patients are instructed stop breathing on inspiration. This moves the heart away from the chest wall and breast, increasing the distance from the heart to the target volume. The new location of the heart allows for sparing of the heart and typically leads to a decrease in heart dose[A2] . However, one disadvantage of this technique is that it is dependent on patient cooperation and subject to variations in daily reproducibility[A3] .
Another way to allow for movement of the heart that is independent of patient cooperation is to use CPAP therapy, so this technique can be used as an alternative to DIBH.19 Utilizing this technique lead to the third largest reduction in heart dose. CPAP inflates the thorax by continuously keeping the airways open.19 This inflation mimics the inflated thorax during DIBH.19 It was found that CPAP moves the heart away from chest wall/breast and inferiorly, as well.13 The new position of the heart helps to decrease the heart dose. In addition to moving the heart, CPAP was able to improve the stability of the breast by fixing the lung in a steady state, improving target reproducibility.13 Few studies exist on CPAP, but the referenced study provided a reduction in mean heart dose comparable to DIBH and combats a few of the disadvantages of DIBH.13
Since the preceding three techniques may not be available at all sites, other possible heart-sparing techniques do exist, however, some of this data is contradictory and limited. Prone positioning is one of these methods. Placing the patient in a prone position will pull the breast away from the chest wall, and subsequently away from the heart, by way of gravity.4 This technique provides the largest advantage for women with large breasts.4 However, the studies on whether prone positioning decreases heart dose are contradictory.20 Some studies have concluded that prone positioning decreases heart dose, others have concluded that prone positioning increases heart dose, and some have concluded that prone positioning is only beneficial in reducing heart dose for large breasted patients.20 Hypofractionation may be another option to reduce the mean heart dose in left-sided breast cancer patients. A study completed by Appelt et al. concluded that hypofractionated treatment schedules of 40Gy in 15 fractions, 39Gy in 13 fractions, and 42.5Gy in 16 fractions will result in lower doses to the heart compared to the standard fractionation schedule of 50Gy in 25 fractions.21 However, a study completed by James et al. concluded that fractionation schedule had no effect on ischemic cardiac disease for women being treated for breast cancer.22 Lastly, using a 3D technique may result in lower mean heart doses. A study done by Aras et al. found that using 3D-CRT yielded a lower mean heart dose than using IMRT.23 Volumetric modulated arc therapy (VMAT) was also found to increase the mean heart dose, so VMAT should be avoided to achieve a lower mean heart dose in left-sided breast cancer patients.24 The preceding techniques are just a few general techniques that are typically able to be implemented if newer technologies are not available.
It is important to note that this study was only focused on the advantages of these techniques regarding mean heart dose. There are other aspects of these plans that should be considered when determining if a certain technique should be used for a patient, such as conformality, other OAR doses, insurance approvals, target coverage, etc. Since the studies referenced in this paper were completed at different sites, there is a level of variability that should be taken into consideration, as well. Also, the mean heart dose considers the whole volume of the heart, but the dose being received by the heart is not homogenous. This means that certain structures of the heart may be receiving doses much higher than the mean heart dose which is important to take into consideration.3
Conclusion
Radiation treatments should be chosen based on the individual patient; not every patient is candidate for the previously listed treatment options, and not every technique may be available to use on every patient. There are many different techniques used to decrease heart dose when treating left-sided breast cancer with external beam radiation therapy since decreasing the mean heart dose had been associated with lower risks of late cardiac effects.3 Proton therapy showed the largest reduction in mean heart dose when being compared to IMRT. The technique that had the second largest impact on mean heart dose was utilizing a deep-inspiration breath hold instead of free-breathing. Lastly, administering continuous positive airway pressure was a comparable alternative to DIBH and resulted in the third largest reduction in mean heart dose. However, these three technologies may not be available to all clinics. Because of this, other techniques such as prone positioning, hypofractionated treatment schedules, and avoiding VMAT may be used to a lower the mean heart dose and decrease the risk of cardiac mortality.
References
1. American Cancer Society. How Common Is Breast Cancer? Breast Cancer Statistics. American Cancer Society. https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html. Published 2020.
2. Vicini F, Hayman J, Freedman G et al. RTOG 1005: A Phase III Trial of Accelerated Whole Breast Irradiation with Hypofractionation Plus Concurrent Boost Versus Standard Whole Breast Irradiation Plus Sequential Boost for Early-Stage Breast Cancer. NRG Oncology. 2014.
3. Piroth MD, Baumann R, Budach W, et al. Heart toxicity from breast cancer radiotherapy : Current findings, assessment, and prevention. Kardiale Toxizität durch Strahlentherapie bei Brustkrebs : Aktuelle Ergebnisse, Bewertung und Prävention. Strahlenther Onkol. 2019;195(1):1-12. doi:10.1007/s00066-018-1378-z
4. Washington CM, Leaver DT. Principles and Practice of Radiation Therapy. 4th ed. St. Louis, MO: Elsevier Mosby; 2016.
5. Chang J, Ko B, Bae J et al. Radiation-related heart disease after breast cancer radiation therapy in Korean women. Breast Cancer Res Treat. 2017;166(1):249-257. doi:10.1007/s10549-017-4398-y
6. Menezes K, Wang H, Hada M, Saganti P. Radiation Matters of the Heart: A Mini Review. Front Cardiovasc Med. 2018;5. doi:10.3389/fcvm.2018.00083
5. Desai N, Currey A, Kelly T, Bergom C. Nationwide Trends in Heart-Sparing Techniques Utilized in Radiation Therapy for Breast Cancer. Adv Radiat Oncol. 2019;4(2):246-252. doi:10.1016/j.adro.2019.01.001
8. Rygiel K. Cardiotoxic effects of radiotherapy and strategies to reduce them in patients with breast cancer: An overview.J Can Res Ther 2017;13:186-192
9. Piroth MD, Baumann R, Budach W, et al. Heart toxicity from breast cancer radiotherapy : Current findings, assessment, and prevention. Kardiale Toxizität durch Strahlentherapie bei Brustkrebs : Aktuelle Ergebnisse, Bewertung und Prävention. Strahlenther Onkol. 2019;195(1):1-12. doi:10.1007/s00066-018-1378-z
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12. Lin L, Vennarini S, Dimofte A et al. Proton beam versus photon beam dose to the heart and left anterior descending artery for left-sided breast cancer. Acta Oncol (Madr). 2015;54(7):1032-1039. doi:10.3109/0284186x.2015.1011756
13. Allen AM, Ceder YK, Shochat T, et al. CPAP (Continuous Positive Airway Pressure) is an effective and stable solution for heart sparing radiotherapy of left sided breast cancer. Radiation Oncology. 2020;15(1):1-6. doi:10.1186/s13014-020-01505-7
14. Corbin K, Mutter R. Proton therapy for breast cancer: progress & pitfalls. Breast Cancer Manag. 2018;7(1). doi:10.2217/bmt-2018-0001
15. The National Association for Proton Therapy. Map of Proton Therapy Centers. NAPT. https://www.proton-therapy.org/map/. Published 2020.
16. Desai N, Currey A, Kelly T, Bergom C. Nationwide Trends in Heart-Sparing Techniques Utilized in Radiation Therapy for Breast Cancer. Adv Radiat Oncol. 2019;4(2):246-252. Published 2019 Jan 30. doi:10.1016/j.adro.2019.01.001
17. Oechsner M, Düsberg M, Borm K, Combs S, Wilkens J, Duma M. Deep inspiration breath-hold for left-sided breast irradiation: Analysis of dose-mass histograms and the impact of lung expansion. Radiation Oncology. 2019;14(1). doi:10.1186/s13014-019-1293-1
18. Yeung R, Conroy L, Long K, et al. Cardiac dose reduction with deep inspiration breath hold for left-sided breast cancer radiotherapy patients with and without regional nodal irradiation. Radiat Oncol. 2015;10:200. Published 2015 Sep 22. doi:10.1186/s13014-015-0511-8
19. Kil WJ, Pham T, Hossain S, Casaigne J, Jones K, Khalil M. The impact of continuous positive airway pressure on radiation dose to heart and lung during left-sided postmastectomy radiotherapy when deep inspiration breath hold technique is not applicable: a case report. Radiat Oncol J. 2018;36(1):79-84. doi:10.3857/roj.2018.00017
20. Saini AS, Hwang CS, Biagioli MC, Das IJ. Evaluation of sparing organs at risk (OARs) in left-breast irradiation in the supine and prone positions and with deep inspiration breath-hold. J Appl Clin Med Phys. 2018;19(4):195-204. doi:10.1002/acm2.12382
21. Appelt A, Vogelius I, Bentzen S. Modern Hypofractionation Schedules for Tangential Whole Breast Irradiation Decrease the Fraction Size-corrected Dose to the Heart. Clin Oncol. 2013;25(3):147-152. doi:10.1016/j.clon.2012.07.012
22. Johansson L, Dixit A, James M, Robinson B, Swadi S, Yi M. Ischaemic heart disease following conventional and hypofractionated radiation treatment in a contemporary breast cancer series. Journal of Medical Imaging & Radiation Oncology. 2018;62(3):425-431. doi:10.1111/1754-9485.12712
23. Aras S, İkizceli T, Aktan M. Dosimetric Comparison of Three-Dimensional Conformal Radiotherapy (3D-CRT) and Intensity Modulated Radiotherapy Techniques (IMRT) with Radiotherapy Dose Simulations for Left-Sided Mastectomy Patients. Eur J Breast Health. 2019;15(2):85-89. Published 2019 Apr 1. doi:10.5152/ejbh.2019.4619
24. Pham TT, Ward R, Latty D, et al. Left-sided breast cancer loco-regional radiotherapy with deep inspiration breath-hold: Does volumetric-modulated arc radiotherapy reduce heart dose further compared with tangential intensity-modulated radiotherapy?. J Med Imaging Radiat Oncol. 2016;60(4):545-553. doi:10.1111/1754-9485.12459
Appendix
Figure 1
| Technique | MHD w/ Technique | MHD w/o Technique | Reduction in MHD |
| DIBH (n=15) | 3.3Gy | 7.1Gy | 3.3/7.1=0.465 (1-0.465)(100)= 53.5% |
| Protons: PBS (n=10) | 0.009Gy | 1.612Gy | 0.009/1.612=0.0056 (1-0.0056)(100)= 99.4% |
| Protons: US (n=10) | 0.011Gy | 1.612Gy | 0.011/1.612=0.0068 (1-0.0068)(100)= 99.3% |
| CPAP Therapy (n=20) | 1.6Gy | 3.02Gy | 1.6/3.02=0.5298 (1-0.5298)(100)= 47% |
[A1]Try to use more academic language- significant, exceptional
[A2]Citation needed
[A3]Citation needed
