Toxicity of Adjuvant Radiotherapy in Patients with Breast Cancer: A Review Study

article information

Reports of Radiotherapy and Oncology: Vol.5, issue 1; e89328
published online: February 3, 2019
article type: Review Article
received: January 15, 2019
accepted: January 30, 2019
DOI: https://doi.org/10.5812/rro.89328
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Toxicity of Adjuvant Radiotherapy in Patients with Breast Cancer: A Review Study

authors:

avatar Seyed Alireza Javadinia ORCID 1 , avatar Mansoureh Dehghani 1 , avatar Gordon A. Ferns 2 , avatar Soodabeh Shahid Sales ORCID 3 , * , avatar Amir Avan 3 , *

Student Research Committee, Department of Radiation Oncology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Department of Medical Education, Brighton and Sussex Medical School Brighton and Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex UK
Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Corresponding Authors:

how to cite: Javadinia S A, Dehghani M , Ferns G A , Shahid Sales S, Avan A. Toxicity of Adjuvant Radiotherapy in Patients with Breast Cancer: A Review Study. Rep Radiother Oncol. 2018;5(1):e89328. https://doi.org/10.5812/rro.89328.

Abstract

Conservative treatment in early-stage breast cancer is considered a standard approach. Breast preserving surgery with adjuvant radiotherapy is as effective as mastectomy in the early stages of breast cancer to control local disease and distant metastasis and maintain the overall survival rate. Minimally invasive surgery for the treatment of axillary spread and new techniques of breast preservation surgery will probably lead to a reduction in mastectomy-related complications. However, the complications of adjuvant radiotherapy remain a challenge. Cutaneous, cardiac, and pulmonary toxicity are the main complications of adjuvant breast irradiation. The multidisciplinary features (systemic treatment, endocrine therapy, and surgery), patient profile (history of underlying diseases, age, and habits), and irradiation-associated parameters are the factors affecting safe adjuvant radiotherapy. Advances in irradiation techniques and facilities related to the preservation of organs at risk (such as IGRT, tracing and tracking systems, and respiratory gating) are modern tools for reducing the risk of toxicity. Reported data from clinical trials or retrospective surveys greatly help physicians in consulting the patients on the efficacy and potential side effects of treatment and leads to the improvement of the decision making process.

1. Context

The conservative treatment for breast cancer (BC) is a standard approach for the treatment of the early disease. Randomized trials have shown that breast-conserving surgery followed by adjuvant whole breast radiotherapy is as effective as total mastectomy in the local control of the disease and improvement of survival in patients with early-stage breast cancer (i.e., tumor size of fewer than five centimeters and lymph nodes without tumoral involvement) (1-3). However, it has been shown that the effect of breast-conserving surgery on quality of life (QoL) and the overall survival rate is superior to radical surgery. Less aggressive methods for dealing with the auxiliary region along with breast reconstruction techniques will probably further reduce the complications associated with mastectomy (4, 5).

The reported benefits of the whole breast and locoregional lymph nodes irradiation on survival have increased the potential indications of nodal radiotherapy (even in case of metastatic involvement in a small number of axillary lymph nodes). Therefore, the unwanted side effects of radiotherapy remain a challenge for BCS patients (6, 7).

Accordingly, this review article was designed to investigate evidence-based data published regarding toxicities of adjuvant radiotherapy on the heart, pulmonary system, and skin of patients with breast cancer.

2. Cardiac Toxicity

2.1. Side Effects Associated with Irradiation

Adjuvant radiotherapy, particularly for cancer of the left breast, potentially increases the risk of cardiac disease. Darby et al. showed that the dose applied to the cardiac region has a relationship with radiation-induced cardiac toxicities. The number of capillaries decreases following microvascular damages as a sub-acute injury, which is associated with low collateral circulation and vascular reserve, probably resulting in ischemia. In addition, coronary artery disease (CAD) can occur due to age-related atherosclerosis enhanced by macrovascular damages (8). The risk of CAD increases linearly as the cardiac dose increases, although due to variations in the position of cardiac structures, no specific relationship with the amount of cardiac tissue being irradiated has been yet determined, and no definite cutoff dose has been introduced (9). The high mortality rates in patients treated with old radiotherapy methods have been attributed to myocardial infarction (10, 11).

Two-dimensional radiotherapy has been regarded as insufficient to avoid cardiac complications in breast cancer treatment, and thus has been replaced by 3-dimensional methods. Proper contouring of the cardiac and coronary arteries is strongly recommended although contouring of different parts of the heart is still challenging. Therefore, it is suggested that reproducible guidelines from the existing atlases be used (12). The mean cardiac radiation exposure recommended on the left and right sides is about 2 - 7 Gy and 1.5 Gy, respectively (13). Despite an obvious decrease in the mean cardiac dose in the past decades, in the assessment of patients undergoing low-dose irradiation, there were indications of increased risk of cardiac toxicity, even at limited doses (14).

According to Danish Breast Cancer Cooperative Group national guidelines, one of the most important priorities in radiotherapy is the preservation of organs at risk (OAR) as much as possible.

To comply with these priorities, the indication of the therapeutic dose to the tumor bed and the preservation of LADCA, heart, and lungs are required (15). It has been recommended a limitation of the dose applied on LADCA and heart to 20 Gy (V20) < 10% and V40 < 5%, respectively, using the fractionation standard. Hypofraction is recommended as an accepted method for total breast radiotherapy; with regard to the standard plan, it is increasingly being used (16).

There is no evidence that the cardiac side effects of hypo-fraction are higher and some authors have suggested that hypo-fraction radiotherapy may be a more likely approach for cardiac preservation (17).

2.2. Patient-Related Factors and Systematic Treatment

Some authors have tried to compare the risk of cardiovascular disease (CVD) in patients with left breast cancer who had undergone radiotherapy and those who had not. In a study conducted by Roychoudhuri et al., a middle age BC woman who survived by old age was estimated to have 22% risk of CVD mortality without radiotherapy and 30% definitive cumulative risk with radiotherapy (18). According to a report by Darby et al., the mortality risk from ischemic cardiac disease was estimated to increase from 1.9% to 2.4% prior to 80 years of age in a 50-year-old woman receiving a 3-Gy cardiac dose without underlying CVD (8).

New methods for delivering higher doses per fraction of irradiation in a shorter time such as accelerated partial breast irradiation (APBI) may decrease the dose received by the heart or even coronary arteries. The cardiac dose can be decreased by using a prone position setup (19, 20). Data regarding the role of intensity-modulated radiotherapy (IMRT) in the improvement of the toxicity profile of breast irradiation are conflicting and more research is required to conduct on IMRT and new techniques (21).

In adjuvant radiotherapy of BC, several patient and treatment-related factors affecting cardiac toxicity must be considered. Women with coronary heart disease have a 6.67 higher risk of major coronary accidents compared to healthy women. In addition, in diabetic and COPD patients, hearty smokers, and those with high BMI, the risk is higher (8).

The effect of concurrent use of cardiotoxic systematic drugs must be taken into account. The cardio-toxic effects of anthracycline-containing chemotherapy regimens are well-established (22). Therefore, it is not recommended to prescribe them simultaneously with RT. The safety of taking Trastuzumab along with standard adjuvant therapy for HER-2 plus BCs has widely been shown (23). There was no significant difference between the two drugs being used simultaneously with RT with respect to acute cutaneous complications, pneumonitis, dyspnea, coughing, and neutropenia (24, 25).

3. Pulmonary Toxicity

3.1. Irradiation-Related Side Effects

Irradiation-related lung injury occurs in up to 15% of BC patients who receive radiotherapy. These toxic effects are either as acute pneumonitis or as late fibrosis. Radiation pneumonitis usually occurs within six months after the completion of the radiotherapy course and may be subclinical or present with symptoms such as dyspnea, coughing, and occasional mild-to-severe fever. Radiographic findings, especially on computed tomography imaging, are often variable and not helpful. Clinical symptoms often respond to steroid treatment. In patients without an appropriate response, tumoral invasion and lymphangitis may be expected. Fibrosis due to irradiation is typically described as progressive chronic dyspnea that corresponds to a pulmonary scar at the site of treatment and occurs between a few months to several years after treatment. Treatment includes relieving symptoms by anti-fibrotic and anti-inflammatory drugs such as steroids, as well as oxygen therapy in many cases (26).

During a subclinical period, several genetic and molecular disorders can be observed successively due to irradiation. Several cytokines and growth factors (such as TNFα, PDGF, and TGFβ), cells (Macrophage, Epithelial, Pneumocystis, and Fibroblast), and gene products are involved in this process (27-29). Post-RT hypoxia appears to prolong pulmonary damage through the generation of several active oxygen species (30). SPECT perfusion and ventilation probably has higher sensitivity than planer perfusion/ventilation in detecting RT-caused pulmonary damage (31).

In addition, irradiation-induced damage has been reported using pulmonary function tests. Diffusing capacity of the lungs for carbon monoxide (DLCO) is affected and FEV1/FVC may decrease, which is an indicator of the restrictive process (32, 33). Bronchiolitis obliterans organizing pneumonia is a rare but recognized event that usually occurs six to 12 months after radiotherapy (34).

The reported risk of RT-related pulmonary damage differs widely in previous studies in the range of 4.5 to 63% (31, 35, 36). These differences may be due to several reasons: diagnostic equipment, pulmonary function tests, and toxicity damage detection scales.

Several risk factors such as patient characteristics, RT techniques, environmental characteristics, and simultaneous systemic treatment must be considered in radiation-induced pulmonary sequelae (37).

There are several reported risk factors for radiation-induced lung disease. It seems that age is the main predictive factor for RT-induced pulmonary toxicity (38). Pre-existing pulmonary function damage and smoking are the other basic risks. The association between smoking and pulmonary damage is still under debate because the results are different in the published studies (39).

Dosimetric parameters such as total prescribed dose, daily dose, and the bulk of lung being irradiated are the predictors of pulmonary radiation damage. The mean ipsilateral pulmonary dose and lung volume receiving ≥ 20 Gy (V20) are considered the most important parameters. In total breast radiotherapy, mean lung dose (MLD) < 20 Gy and V20 < 20% are considered acceptable. A strong relationship between lung volume receiving ≥13 Gy (V13) and radiologic changes in CT scans has been reported (38, 40). The prone position seems to be associated with less damage (19).

Recent developments in radiotherapy such as IMRT, volumetric arc therapy (VMAT), helical tomography and image-guided radiation therapy (IGRT) have provided an improvement in the dose applied to PTV and decreased the dose of the organs at risk. The published papers on IMRT indicate more uniformity in the dose applied to PTV and less acute and delayed skin complications (37).

With respect to the uncommon radiotherapy modalities, major clinical trials on hypofractionated breast RT reported no significant difference in the extent of pulmonary damage (41). The reported risk of pulmonary damage following APBI is low and depends on the technique used. The common 3-dimensional method seems to be associated with a slightly higher pulmonary dose (21).

3.2. Treatment-Related Systemic Factors

Many studies have shown that a combination of radiotherapy and hormone therapy (Tamoxifen) may be a risk factor of pulmonary fibrosis (42). Patients for whom hormone therapy is required, radiotherapy and Tamoxifen are routinely used together, but the latter must be prescribed with caution in potentially radiosensitive patients. Contrarily, using aromatase inhibitors and RT appears to be a safe combination.

Although estrogen restriction should theoretically have a negative effect on post-radiotherapy remodeling, no differences were observed in the irradiated pulmonary tissues (43).

Pulmonary damage independently can be induced by several chemotherapy agents regardless of irradiation. It is known that the concurrent prescription of taxanes such as paclitaxel and docetaxel with radiotherapy has radio-sensitization effects that lead to the increased risk of pulmonary damage by the simultaneous indication of paclitaxel and radiotherapy, and thus it must be avoided (44).

Many studies on mortality due to pulmonary damage following RT have shown that more risk of damage conforms with the dose applied to the lungs. Therefore, an average dose of 7 - 18 Gy for the contra-lateral lung is recommended (45).

4. Cutaneous Toxicity

4.1. Radiation Therapy Side Effects

The quality of life and breast esthetics of BC patients can be influenced by acute and long-term skin complications from the standard radiotherapy for early-stage breast cancer.

The RT effects on esthetics are reportedly associated with short-term and long-term quality of life. A subjective/objective scale for late effects of normal tissues (LENT-SOMA scales) has been developed by the European organization for research and treatment of cancer (EORTC) and radiotherapy oncology group (RTOG) (28, 46). Current terminology criteria for adverse events comprise also a scale to assess the acute and chronic toxicity. The EORTC esthetics rating system (47) and Harvard’s NSABP/RTOG scoring system (48) are the widely used scales in the cosmetic fields. There are different factors to increase the risk of skin complications resulting from RT, including individual factors (nature, habits, associated diseases), pre and post-RT treatments (type and quality of surgery, chemotherapy, target therapy, and hormone therapy), and factors of radiation therapy (the irradiated volume, dose per fraction, total dose, and using boost and overall duration of treatment) (37).

Based on trials with an average of five-year follow-up on hypofraction radiation therapy (START A, START B, and a Canadian trial), a 40 - 45 Gy dose applied to the whole breast was safe in local control and acute toxicity profile without adverse effects on esthetics (49-51).

There is a doubt about RT-related effects on skin esthetics. However, many studies have shown a relationship between RT toxicity and further delay. RT augmentation has no significant impact on retraction and rigidity of glandular tissue but can increase telangiectasia.

According to the 22881/10882 EORT trial (no boost vs. 16 Gy boost vs. 26 Gy boost), the fibrosis level and intensity during 10 years in case groups showed significant differences (1.6, 3.3, and 4.14, respectively). Removing boost in the majority of patients aged over 60 has been reported, which may decrease the negative aesthetic effects in the future (52).

An alternative therapeutic approach for patients selected with BC is APBI that has some benefits such as shorter duration of treatment, improved esthetics because of low bulk in therapy, and low cost when compared with the standard method. Different esthetic outcomes have been observed for external APBI, such as excellent esthetic outcomes in 90% of patients (53) to 21% unacceptable outcomes (54). In accordance with the RAPID trial, 33% of the patients showed adverse esthetic outcomes and less than 35% for the bulk of breast receiving the dose of 95%. They expressed that this rate can be doubled for some patients (55). These poor results might be affected by high volume receiving 50% of the prescribed dose, or by more biological effects due to twice-daily dose in the study (39).

4.2. Patient Factors and Other Treatment-Related Items

Age, size of the breast, obesity, previous history of vascular disorders, and lifestyle habits such as active or passive cigarette smoking or alcoholism are the features that have been studied the most. Older age and post-menopausal situation seem to be related to esthetic results (52). Its pathological cause may be due to the higher percentage content of adipose tissue in the glands or partially because of the resection of a greater bulk of tissue in surgery. Data regarding the theory of increased cutaneous complications related to the concomitant use of RT and hormone therapy are controversial. These treatments are basically indicated simultaneously with no obvious effect on esthetics (56).

Acute and delayed cutaneous toxicity of irradiation has been proven that are related to systemic adjuvant chemotherapy regimens (i.e., the use of Taxane and Anthracycline) (56-59). Thus, the concurrent use of RT and anthracycline or Taxan is generally not recommended. In contrast, the old CME regimen plan did not seem to be toxic in accompaniment with RT (48). The surgical approach determines the esthetic results. The amount of tissue resected is considered the characteristic mostly related to aesthetics. Regarding the rapid extension of oncoplastic techniques, post-RT esthetics and cutaneous results probably depend on the severity, timing, and technique of the surgery. The tolerance and esthetic results of breast preservation in BC patients in the areas being irradiated pre or post-surgery distinctively depend on the type of surgery method. However, further investigations are required to scrutinize the contradictory results obtained from the best succession of reconstruction and RT, the period between these two interventions, and the RT technique (60, 61).

5. Conclusions

Cutaneous, cardiac, and pulmonary complications are the most important side effects of adjuvant radiotherapy in BC. Quantitative analyses of normal tissue effects in the clinic (QUANTEC) has been developed in 2010 after great efforts by Emami et al. on a better understanding of radiation-related normal tissue toxicities.

The analysis of data from multiple studies is difficult due to primary suboptimal analysis, inadequate reporting, and variation in the analyzed models and predictors. The clinical limitation of the current data on the safety of RT is strongly related to the multidisciplinary approach to each case (systemic treatment, hormone therapy, and surgical complications), patient characteristics (such as age, associated diseases, and habits), and different aspects of irradiation.

The use of irradiation techniques (such as IMRT and VMAT) and equipment related to the preservation of organs at risk (like IGRT, tracking systems, and respiratory gating) provide new approaches for oncologists because they have demonstrated a reduction in irradiation-related toxicity. The findings reported in the published articles are helpful for physicians in consulting patients on the effectiveness and side effects of RT and optimizing the decision-making process.

Acknowledgements

References

  • 1.

    Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347(16):1233-41. [PubMed ID: 12393820]. https://doi.org/10.1056/NEJMoa022152.

  • 2.

    van Dongen JA, Voogd AC, Fentiman IS, Legrand C, Sylvester RJ, Tong D, et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst. 2000;92(14):1143-50. [PubMed ID: 10904087].

  • 3.

    Veronesi U, Salvadori B, Luini A, Greco M, Saccozzi R, del Vecchio M, et al. Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients. Eur J Cancer. 1995;31A(10):1574-9. [PubMed ID: 7488404].

  • 4.

    Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet. 2005;366(9503):2087-106. [PubMed ID: 16360786]. https://doi.org/10.1016/S0140-6736(05)67887-7.

  • 5.

    Early Breast Cancer Trialists' Collaborative G, Darby S, McGale P, Correa C, Taylor C, Arriagada R, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378(9804):1707-16. [PubMed ID: 22019144]. [PubMed Central ID: PMC3254252]. https://doi.org/10.1016/S0140-6736(11)61629-2.

  • 6.

    Poortmans PM, Collette S, Kirkove C, Van Limbergen E, Budach V, Struikmans H, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373(4):317-27. [PubMed ID: 26200978]. https://doi.org/10.1056/NEJMoa1415369.

  • 7.

    Whelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, et al. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373(4):307-16. [PubMed ID: 26200977]. [PubMed Central ID: PMC4556358]. https://doi.org/10.1056/NEJMoa1415340.

  • 8.

    Darby SC, Cutter DJ, Boerma M, Constine LS, Fajardo LF, Kodama K, et al. Radiation-related heart disease: Current knowledge and future prospects. Int J Radiat Oncol Biol Phys. 2010;76(3):656-65. [PubMed ID: 20159360]. [PubMed Central ID: PMC3910096]. https://doi.org/10.1016/j.ijrobp.2009.09.064.

  • 9.

    Feng M, Moran JM, Koelling T, Chughtai A, Chan JL, Freedman L, et al. Development and validation of a heart atlas to study cardiac exposure to radiation following treatment for breast cancer. Int J Radiat Oncol Biol Phys. 2011;79(1):10-8. [PubMed ID: 20421148]. [PubMed Central ID: PMC2937165]. https://doi.org/10.1016/j.ijrobp.2009.10.058.

  • 10.

    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(8):557-65. [PubMed ID: 16054566]. https://doi.org/10.1016/S1470-2045(05)70251-5.

  • 11.

    Hooning MJ, Aleman BM, van Rosmalen AJ, Kuenen MA, Klijn JG, van Leeuwen FE. Cause-specific mortality in long-term survivors of breast cancer: A 25-year follow-up study. Int J Radiat Oncol Biol Phys. 2006;64(4):1081-91. [PubMed ID: 16446057]. https://doi.org/10.1016/j.ijrobp.2005.10.022.

  • 12.

    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(3 Suppl):S77-85. [PubMed ID: 20171522]. https://doi.org/10.1016/j.ijrobp.2009.04.093.

  • 13.

    Taylor CW, McGale P, Povall JM, Thomas E, Kumar S, Dodwell D, et al. Estimating cardiac exposure from breast cancer radiotherapy in clinical practice. Int J Radiat Oncol Biol Phys. 2009;73(4):1061-8. [PubMed ID: 18973978]. https://doi.org/10.1016/j.ijrobp.2008.05.066.

  • 14.

    Azizova TV, Muirhead CR, Moseeva MB, Grigoryeva ES, Vlasenko EV, Hunter N, et al. Ischemic heart disease in nuclear workers first employed at the Mayak PA in 1948-1972. Health Phys. 2012;103(1):3-14. [PubMed ID: 22647906]. https://doi.org/10.1097/HP.0b013e3182243a62.

  • 15.

    Nielsen MH, Berg M, Pedersen AN, Andersen K, Glavicic V, Jakobsen EH, et al. Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: National guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group. Acta Oncol. 2013;52(4):703-10. [PubMed ID: 23421926]. https://doi.org/10.3109/0284186X.2013.765064.

  • 16.

    Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett-Lee PJ, et al. The UK standardisation of breast radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14(11):1086-94. [PubMed ID: 24055415]. https://doi.org/10.1016/S1470-2045(13)70386-3.

  • 17.

    Appelt AL, Vogelius IR, Bentzen SM. Modern hypofractionation schedules for tangential whole breast irradiation decrease the fraction size-corrected dose to the heart. Clin Oncol (R Coll Radiol). 2013;25(3):147-52. [PubMed ID: 22910644]. https://doi.org/10.1016/j.clon.2012.07.012.

  • 18.

    Roychoudhuri R, Robinson D, Putcha V, Cuzick J, Darby S, Moller H. Increased cardiovascular mortality more than fifteen years after radiotherapy for breast cancer: A population-based study. BMC Cancer. 2007;7:9. [PubMed ID: 17224064]. [PubMed Central ID: PMC1784099]. https://doi.org/10.1186/1471-2407-7-9.

  • 19.

    Formenti SC, DeWyngaert JK, Jozsef G, Goldberg JD. Prone vs supine positioning for breast cancer radiotherapy. JAMA. 2012;308(9):861-3. [PubMed ID: 22948692]. https://doi.org/10.1001/2012.jama.10759.

  • 20.

    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(2):178-84. [PubMed ID: 20561695]. https://doi.org/10.1016/j.radonc.2010.05.014.

  • 21.

    Mast ME, van Kempen-Harteveld L, Heijenbrok MW, Kalidien Y, Rozema H, Jansen WP, et al. Left-sided breast cancer radiotherapy with and without breath-hold: Does IMRT reduce the cardiac dose even further? Radiother Oncol. 2013;108(2):248-53. [PubMed ID: 24044804]. https://doi.org/10.1016/j.radonc.2013.07.017.

  • 22.

    Florescu M, Cinteza M, Vinereanu D. Chemotherapy-induced cardiotoxicity. Maedica (Buchar). 2013;8(1):59-67. [PubMed ID: 24023601]. [PubMed Central ID: PMC3749765].

  • 23.

    Halyard MY, Pisansky TM, Dueck AC, Suman V, Pierce L, Solin L, et al. Radiotherapy and adjuvant trastuzumab in operable breast cancer: Tolerability and adverse event data from the NCCTG phase III trial N9831. J Clin Oncol. 2009;27(16):2638-44. [PubMed ID: 19349549]. [PubMed Central ID: PMC2690390]. https://doi.org/10.1200/JCO.2008.17.9549.

  • 24.

    Belkacemi Y, Gligorov J, Ozsahin M, Marsiglia H, De Lafontan B, Laharie-Mineur H, et al. Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: Acute toxicity analyses from the French multicentric study. Ann Oncol. 2008;19(6):1110-6. [PubMed ID: 18344537]. https://doi.org/10.1093/annonc/mdn029.

  • 25.

    Meattini I, Cecchini S, Muntoni C, Scotti V, De Luca Cardillo C, Mangoni M, et al. Cutaneous and cardiac toxicity of concurrent trastuzumab and adjuvant breast radiotherapy: A single institution series. Med Oncol. 2014;31(4):891. [PubMed ID: 24535610]. https://doi.org/10.1007/s12032-014-0891-x.

  • 26.

    Abid SH, Malhotra V, Perry MC. Radiation-induced and chemotherapy-induced pulmonary injury. Curr Opin Oncol. 2001;13(4):242-8. [PubMed ID: 11429481].

  • 27.

    Rubin P, Finkelstein J, Shapiro D. Molecular biology mechanisms in the radiation induction of pulmonary injury syndromes: Interrelationship between the alveolar macrophage and the septal fibroblast. Int J Radiat Oncol Biol Phys. 1992;24(1):93-101. [PubMed ID: 1512168].

  • 28.

    Rubin P, Johnston CJ, Williams JP, McDonald S, Finkelstein JN. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys. 1995;33(1):99-109. [PubMed ID: 7642437]. https://doi.org/10.1016/0360-3016(95)00095-G.

  • 29.

    Vujaskovic Z, Marks LB, Anscher MS. The physical parameters and molecular events associated with radiation-induced lung toxicity. Semin Radiat Oncol. 2000;10(4):296-307. [PubMed ID: 11040330].

  • 30.

    Vujaskovic Z, Anscher MS, Feng QF, Rabbani ZN, Amin K, Samulski TS, et al. Radiation-induced hypoxia may perpetuate late normal tissue injury. Int J Radiat Oncol Biol Phys. 2001;50(4):851-5. [PubMed ID: 11429211].

  • 31.

    Holli K, Pitkanen M, Jarvenpaa R, Rajala J, Lahtela S, Hyodynmaa S, et al. Early skin and lung reactions in breast cancer patients after radiotherapy: Prospective study. Radiother Oncol. 2002;64(2):163-9. [PubMed ID: 12242126].

  • 32.

    Smith LM, Mendenhall NP, Cicale MJ, Block ER, Carter RL, Million RR. Results of a prospective study evaluating the effects of mantle irradiation on pulmonary function. Int J Radiat Oncol Biol Phys. 1989;16(1):79-84. [PubMed ID: 2912958].

  • 33.

    Sunyach MP, Falchero L, Pommier P, Perol M, Arpin D, Vincent M, et al. Prospective evaluation of early lung toxicity following three-dimensional conformal radiation therapy in non-small-cell lung cancer: Preliminary results. Int J Radiat Oncol Biol Phys. 2000;48(2):459-63. [PubMed ID: 10974462].

  • 34.

    Epler GR. Post-breast cancer radiotherapy bronchiolitis obliterans organizing pneumonia. Expert Rev Respir Med. 2013;7(2):109-12. [PubMed ID: 23547987]. https://doi.org/10.1586/ers.13.1.

  • 35.

    Gagliardi G, Bjohle J, Lax I, Ottolenghi A, Eriksson F, Liedberg A, et al. Radiation pneumonitis after breast cancer irradiation: Analysis of the complication probability using the relative seriality model. Int J Radiat Oncol Biol Phys. 2000;46(2):373-81. [PubMed ID: 10661344].

  • 36.

    Lind PA, Wennberg B, Gagliardi G, Fornander T. Pulmonary complications following different radiotherapy techniques for breast cancer, and the association to irradiated lung volume and dose. Breast Cancer Res Treat. 2001;68(3):199-210. [PubMed ID: 11727957].

  • 37.

    Meattini I, Guenzi M, Fozza A, Vidali C, Rovea P, Meacci F, et al. Overview on cardiac, pulmonary and cutaneous toxicity in patients treated with adjuvant radiotherapy for breast cancer. Breast Cancer. 2017;24(1):52-62. [PubMed ID: 27025498]. https://doi.org/10.1007/s12282-016-0694-3.

  • 38.

    Kubo A, Osaki K, Kawanaka T, Furutani S, Ikushima H, Nishitani H. Risk factors for radiation pneumonitis caused by whole breast irradiation following breast-conserving surgery. J Med Invest. 2009;56(3-4):99-110. [PubMed ID: 19763021].

  • 39.

    Kahan Z, Csenki M, Varga Z, Szil E, Cserhati A, Balogh A, et al. The risk of early and late lung sequelae after conformal radiotherapy in breast cancer patients. Int J Radiat Oncol Biol Phys. 2007;68(3):673-81. [PubMed ID: 17350177]. https://doi.org/10.1016/j.ijrobp.2006.12.016.

  • 40.

    Rancati T, Wennberg B, Lind P, Svane G, Gagliardi G. Early clinical and radiological pulmonary complications following breast cancer radiation therapy: NTCP fit with four different models. Radiother Oncol. 2007;82(3):308-16. [PubMed ID: 17224197]. https://doi.org/10.1016/j.radonc.2006.12.001.

  • 41.

    Woel RT, Munley MT, Hollis D, Fan M, Bentel G, Anscher MS, et al. The time course of radiation therapy-induced reductions in regional perfusion: A prospective study with >5 years of follow-up. Int J Radiat Oncol Biol Phys. 2002;52(1):58-67. [PubMed ID: 11777622].

  • 42.

    Koc M, Polat P, Suma S. Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients. Radiother Oncol. 2002;64(2):171-5. [PubMed ID: 12242127].

  • 43.

    Azria D, Larbouret C, Cunat S, Ozsahin M, Gourgou S, Martineau P, et al. Letrozole sensitizes breast cancer cells to ionizing radiation. Breast Cancer Res. 2005;7(1):R156-63. [PubMed ID: 15642164]. [PubMed Central ID: PMC1064115]. https://doi.org/10.1186/bcr969.

  • 44.

    Varga Z, Cserhati A, Kelemen G, Boda K, Thurzo L, Kahan Z. Role of systemic therapy in the development of lung sequelae after conformal radiotherapy in breast cancer patients. Int J Radiat Oncol Biol Phys. 2011;80(4):1109-16. [PubMed ID: 21549513]. https://doi.org/10.1016/j.ijrobp.2010.03.044.

  • 45.

    Henson KE, McGale P, Taylor C, Darby SC. Radiation-related mortality from heart disease and lung cancer more than 20 years after radiotherapy for breast cancer. Br J Cancer. 2013;108(1):179-82. [PubMed ID: 23257897]. [PubMed Central ID: PMC3553540]. https://doi.org/10.1038/bjc.2012.575.

  • 46.

    Pavy JJ, Denekamp J, Letschert J, Littbrand B, Mornex F, Bernier J, et al. EORTC Late Effects Working Group. Late effects toxicity scoring: The SOMA scale. Int J Radiat Oncol Biol Phys. 1995;31(5):1043-7. [PubMed ID: 7713775].

  • 47.

    Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31(5):1341-6. [PubMed ID: 7713792]. https://doi.org/10.1016/0360-3016(95)00060-C.

  • 48.

    Harris JR, Levene MB, Svensson G, Hellman S. Analysis of cosmetic results following primary radiation therapy for stages I and II carcinoma of the breast. Int J Radiat Oncol Biol Phys. 1979;5(2):257-61. [PubMed ID: 110740].

  • 49.

    Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ; Start Trialists' Group, et al. The UK standardisation of breast radiotherapy (START) trial B of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet. 2008;371(9618):1098-107. [PubMed ID: 18355913]. [PubMed Central ID: PMC2277488]. https://doi.org/10.1016/S0140-6736(08)60348-7.

  • 50.

    Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ; Start Trialists' Group, et al. The UK standardisation of breast radiotherapy (START) trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet Oncol. 2008;9(4):331-41. [PubMed ID: 18356109]. [PubMed Central ID: PMC2323709]. https://doi.org/10.1016/S1470-2045(08)70077-9.

  • 51.

    Whelan TJ, Pignol JP, Levine MN, Julian JA, MacKenzie R, Parpia S, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362(6):513-20. [PubMed ID: 20147717]. https://doi.org/10.1056/NEJMoa0906260.

  • 52.

    Bartelink H, Maingon P, Poortmans P, Weltens C, Fourquet A, Jager J, et al. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol. 2015;16(1):47-56. [PubMed ID: 25500422]. https://doi.org/10.1016/S1470-2045(14)71156-8.

  • 53.

    Livi L, Meattini I, Marrazzo L, Simontacchi G, Pallotta S, Saieva C, et al. Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer. 2015;51(4):451-63. [PubMed ID: 25605582]. https://doi.org/10.1016/j.ejca.2014.12.013.

  • 54.

    Jagsi R, Ben-David MA, Moran JM, Marsh RB, Griffith KA, Hayman JA, et al. Unacceptable cosmesis in a protocol investigating intensity-modulated radiotherapy with active breathing control for accelerated partial-breast irradiation. Int J Radiat Oncol Biol Phys. 2010;76(1):71-8. [PubMed ID: 19409733]. [PubMed Central ID: PMC4414125]. https://doi.org/10.1016/j.ijrobp.2009.01.041.

  • 55.

    Olivotto IA, Whelan TJ, Parpia S, Kim DH, Berrang T, Truong PT, et al. Interim cosmetic and toxicity results from RAPID: A randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy. J Clin Oncol. 2013;31(32):4038-45. [PubMed ID: 23835717]. https://doi.org/10.1200/JCO.2013.50.5511.

  • 56.

    Chargari C, Toillon RA, Macdermed D, Castadot P, Magne N. Concurrent hormone and radiation therapy in patients with breast cancer: What is the rationale? Lancet Oncol. 2009;10(1):53-60. [PubMed ID: 19111245]. https://doi.org/10.1016/S1470-2045(08)70333-4.

  • 57.

    Hanna YM, Baglan KL, Stromberg JS, Vicini FA, A Decker D. Acute and subacute toxicity associated with concurrent adjuvant radiation therapy and paclitaxel in primary breast cancer therapy. Breast J. 2002;8(3):149-53. [PubMed ID: 12047471].

  • 58.

    Ismaili N, Mellas N, Masbah O, Elmajjaoui S, Arifi S, Bekkouch I, et al. Concurrent chemoradiotherapy in adjuvant treatment of breast cancer. Radiat Oncol. 2009;4:12. [PubMed ID: 19351405]. [PubMed Central ID: PMC2679760]. https://doi.org/10.1186/1748-717X-4-12.

  • 59.

    Livi L, Meattini I, Scotti V, Saieva C, Simontacchi G, Marrazzo L, et al. Concomitant adjuvant chemo-radiation therapy with anthracycline-based regimens in breast cancer: A single centre experience. Radiol Med. 2011;116(7):1050-8. [PubMed ID: 21424317]. https://doi.org/10.1007/s11547-011-0652-2.

  • 60.

    Albornoz CR, Matros E, McCarthy CM, Klassen A, Cano SJ, Alderman AK, et al. Implant breast reconstruction and radiation: A multicenter analysis of long-term health-related quality of life and satisfaction. Ann Surg Oncol. 2014;21(7):2159-64. [PubMed ID: 24740825]. https://doi.org/10.1245/s10434-014-3483-2.

  • 61.

    Chawla AK, Kachnic LA, Taghian AG, Niemierko A, Zapton DT, Powell SN. Radiotherapy and breast reconstruction: Complications and cosmesis with TRAM versus tissue expander/implant. Int J Radiat Oncol Biol Phys. 2002;54(2):520-6. [PubMed ID: 12243831].