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Adjuvant postmastectomy radiotherapy might be associated with better survival in women with heart failure receiving total mastectomy

Adjuvant postmastectomy radiotherapy might be associated with better survival in women with heart... Background: To date, no data on the effect of adjuvant postmastectomy radiotherapy (PMRT ) on oncologic out ‑ comes, such as all‑ cause death, locoregional recurrence (LRR), and distant metastasis (DM), are available in women with left‑side breast invasive ductal carcinoma (IDC) and heart failure with reduced ejection fraction (HFrEF). Patients and methods: We enrolled 646 women with left‑breast IDC at clinical stages I–IIIC and HFrEF receiving radi‑ cal total mastectomy ( TM) followed by adjuvant PMRT or non‑adjuvant PMRT. We categorized them into two groups based on their adjuvant PMRT status and compared their overall survival (OS), LRR, and DM outcomes. We calculated the propensity score and applied inverse probability of treatment weighting (IPTW ) to create a pseudo‑study cohort. Furthermore, we performed a multivariate analysis of the propensity score–weighted population to obtain hazard ratios (HRs). Results: In the IPTW‑adjusted model, adjuvant PMRT (adjusted HR [aHR]: 0.52; 95% confidence interval [CI]: 0.37– 0.74) was a significant independent prognostic factor for all‑ cause death (P = 0.0003), and the aHR (95% CI) of LRR and DM for adjuvant PMRT was 0.90 (0.79–0.96; P = 0.0356) and 0.89 (0.54–1.50; P = 0.6854), respectively, compared with the nonadjuvant PMRT group. Conclusion: Adjuvant PMRT was associated with a decrease in all‑ cause death, and LRR in women with left IDC and HFrEF compared with nonadjuvant PMRT. Keywords: Breast cancer, Radiation‑induced cardiovascular toxicity, Total mastectomy, Radiotherapy, Survival Key points • Question: Is adjuvant postmastectomy radiotherapy (PMRT) worthy for women with left-side breast inva- sive ductal carcinoma (IDC) and heart failure with reduced ejection fraction (HFrEF) receiving total *Correspondence: szuyuanwu5399@gmail.com mastectomy (TM)? Jiaqiang Zhang and Shao‑ Yin Sum have contributed equally to this study • Findings: In the IPTW-adjusted models, adjuvant Division of Radiation Oncology, Lo‑Hsu Medical Foundation, Lotung Poh‑Ai Hospital, No. 83, Nanchang St., Luodong Township, Yilan County PMRT was associated with a decrease in all-cause 265, Taiwan Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhang et al. Radiation Oncology (2022) 17:33 Page 2 of 11 death and LRR in women with left IDC and HFrEF Patients and methods compared with no adjuvant PMRT. Study population • Meaning: We suggest adjuvant PMRT for women In this cohort study, data were retrieved from the Taiwan with left-side IDC receiving TM, even when they Cancer Registry Database (TCRD). We enrolled women have HFrEF. with HF with reduced ejection fraction (LVEF ≤ 40%; HFrEF) [7–9] who had received a diagnosis of left-side breast IDC between January 1, 2008, and December 31, 2018. The index date was the date of TM, and the Introduction follow-up duration was from the index date to Decem- Radiation-induced cardiovascular toxicity (RICT) is ber 31, 2019. The TCRD of the Collaboration Center of associated with a portion of the heart being placed in Health Information Application contains detailed cancer- a radiation field [1]. For patients with left-sided breast related information of patients, including their clinical cancers, careful treatment planning and usage of con- stage, pathologic stages, chemotherapy regimens, dose temporary radiotherapy (RT) techniques are critical to of chemotherapy, molecular status, drug use, hormone minimize cardiac exposure to radiation [1]. Incidental receptor status, radiation modalities and doses, and irradiation dose to the heart as part of the initial treat- surgical procedures [10–13]. The study protocols were ment for breast cancer can result in a range of cardio- reviewed and approved by the Institutional Review Board toxic effects, including coronary artery disease (CAD), of Tzu-Chi Medical Foundation (IRB109-015-B). cardiomyopathy, pericardial disease, valvular dysfunc- tion, and conduction abnormalities [2–4]. At present, no recommended minimum radiation dose that is Inclusion and exclusion criteria completely safe exists [3]. The diagnoses of the enrolled patients with HFrEF were The association of RICT is not dependent on the confirmed after their pathological data were reviewed, presence or absence of a breast but on the volume of and the women with newly diagnosed left-side IDC were radiation to the heart [3, 4]. Thus, cardiotoxicities confirmed to have no other cancers or distant metasta - associated with RT differ between the postlumpec- ses. The women with HFrEF were included if they had tomy and postmastectomy settings; this is because received a left-side IDC diagnosis, were 20  years old or in the postmastectomy setting, the RT field often older, and had clinical stage I–IIIC (American Joint Com- includes the nodal tissues, and these nodes are not mittee on Cancer [AJCC], 8th edition) without metas- always targeted in the postlumpectomy setting [5, 6]. tasis. Patients with HFrEF were excluded if they had a Thus, postmastectomy RT (PMRT) is more often asso- history of cancer before the IDC diagnosis date, unknown ciated with cardiac disease relative to postlumpectomy pathologic types, missing sex data, unclear staging, or RT, but this is likely a result of the usually larger irra- non-IDC histology. In addition, patients with unclear dif- diated volumes of the heart in postmastectomy RT ferentiation of tumor grade, missing HR status, missing [5, 6]. Therefore, RICT in patients with breast cancer data on hormone therapy or trastuzumab use, or unclear should be separately discussed by using different surgi- staging were excluded. Adjuvant treatments such as cal techniques of breast-conserving surgery (BCS) and adjuvant chemotherapy, hormone therapy, or the trastu- total mastectomy (TM). Hereby, we wanted to address zumab use did not constitute exclusion criteria based on the values of adjuvant PMRT for breast cancer patients the National Comprehensive Cancer Network (NCCN) with heart failure (HF) receiving TM with large RT guidelines [14]. We also excluded patients with HFrEF field and high dose-volume to the normal heart. with unclear data on surgical procedures such as TM or The crucial issue is whether adjuvant PMRT can be TM, ill-defined nodal surgery, unclear Charlson comor - safely given to women with HF and left-side breast bidity index (CCI), or unclear differentiation from our cancer who receive TM. No data are available to cohort. Hormone receptor positivity was defined as ≥ 1% address the value of adjuvant PMRT in women with of tumor cells demonstrating positive nuclear staining breast cancer and HF receiving TM. HF due to left through immunohistochemistry [15]. ventricle (LV) dysfunction is categorized according to After applying the inclusion and exclusion criteria, we LV ejection fraction (LVEF) as HF with reduced ejec- enrolled 646 women with HFrEF and AJCC clinical stage tion fraction (LVEF ≤ 40%, known as HFrEF) [7–9]. I–IIIC and left-side IDC who had received a TM fol- Until now, no study has estimated the oncologic out- lowed by sentinel lymph node biopsy (SLNB) or axillary comes of adjuvant PMRT in women with breast inva- lymph node dissection (ALND) and divided them into sive ductal carcinoma (IDC) and HFrEF receiving TM. two groups based on their adjuvant PMRT status to com- pare all-cause mortality: Group 1 (women with left-side Zhang  et al. Radiation Oncology (2022) 17:33 Page 3 of 11 IDC and HFrEF who received TM followed by adjuvant (LRR)–free survival, and distant metastasis (DM)–free PMRT) and Group 2 (women with left-side IDC and survival between women with left IDC and HFrEF HFrEF who received TM and no adjuvant PMRT). We receiving TM followed by adjuvant PMRT versus no also excluded women in Group 1 receiving nonstandard adjuvant PMRT were determined using a log-rank test. adjuvant PMRT. Standard postmastectomy RT is irra- After confounders were adjusted for, IPTW-adjusted diation to both the chest wall and to the regional nodes models were used to determine the time from the index with 50 Gy at least. These include the supraclavicular and date to all-cause mortality in the women with left IDC infraclavicular nodes. We also include RT to the axilla and HFrEF who received TM followed by adjuvant except in some patients who underwent complete axillary PMRT or no adjuvant PMRT. Subsequently, in a mul- dissection. Contemporary RT techniques were included tivariate analysis, HRs were adjusted for age, diagnosis in our study (intensity modulated radiation therapy year, CCI scores, differentiation, pT, pN, hypertension, [IMRT] and volumetric modulated arc therapy [VMAT]) CAD, diabetes, chemotherapy with anthracycline, and the conventional two-dimensional RT technique was hormone receptor status, trastuzumab use, nodal sur- excluded. The included contemporary RT techniques gery, and hospital levels. All analyses were conducted were three-dimensional RT and intensity-modulated using SAS (Version 9.4; SAS, Cary, NC, USA), and a radiation therapy. The incidence of comorbidities was two-tailed P value < 0.05 was considered statistically scored using the CCI [16, 17]. Hypertension, diabetes, significant. and coronary arterial diseases (CAD) were excluded from the CCI scores to avoid repetitive adjustment in mul- tivariate analysis. Only comorbidities observed within Results 6 months before the index date were included; they were Study cohort coded and classified according to the International Clas- We enrolled 646 women with left-breast IDC at clinical sification of Diseases, 10th Revision, Clinical Modification stages I–IIIC and HFrEF who received TM followed by (ICD-10-CM) codes at the first admission or based on adjuvant PMRT or no adjuvant PMRT (Table  1). Among more than two repetitions of a code issued at outpatient these women, 143 with left IDC and HFrEF received TM department visits. followed by adjuvant PMRT (Group 1) and 503 with left IDC and HFrEF received TM with no adjuvant PMRT (Group 2). After IPTW was executed using the propen- Study covariates and statistical analysis sity score, the covariates between Groups 1 and 2 were Significant independent predictors, namely age, diagno - found to be homogenous. The median follow-up dura - sis year, CCI score, differentiation, pT, pN, hypertension, tions after the index date were 6.96 and 5.09  years for CAD, diabetes, chemotherapy with anthracycline-based women with left IDC and HFrEF who received TM fol- regimen, hormone receptor status, trastuzumab use, lowed by adjuvant PMRT or no adjuvant PMRT, respec- nodal surgery, and hospital level (academic or nonaca- tively. All standardized differences in covariates were demic), were analyzed using a multivariate analysis of smaller than 0.1 (Table 1) and were homogenous between the propensity score–weighted population to determine the two groups [20]. hazard ratios (HRs). We calculated the propensity score and applied inverse probability of treatment weighting (IPTW) to create a pseudo-study cohort; the weighted Eec ff ts of adjuvant PMRT on oncologic outcomes in women cohort avoids covariate bias and mimics randomized with left‑side IDC and HFrEF receiving TM adjuvant PMRT or no adjuvant PMRT assignment: IPTW-adjusted models indicated that adjuvant PMRT IPTW for patients with PMRT = 1/p(PMRT); IPTW for was a significantly better independent prognostic factor patients without PMRT = 1/(1 − p[PMRT]) [18, 19]. The for OS, and LRR in the women with left IDC and HFrEF independent predictors were examined in multivariable receiving TM (Table  2). Adjuvant PMRT (adjusted HR analyses after IPTW adjustment. Moreover, they were [aHR]: 0.52; 95% confidence interval [CI]: 0.37–0.74) was controlled for and were stratified in the analysis. The a significant independent prognostic factor for all-cause endpoint was all-cause death in the women with left-side death (P = 0.0003; Table 2). In the IPTW-adjusted model, IDC and HFrEF who received TM followed by adjuvant the aHR (95% CI) for LRR in the adjuvant PMRT group PMRT (Group 1, case group) and in the women with left was 0.90 (0.79–0.96; P = 0.0356; Table  2) compared with IDC and HFrEF who received TM and had no adjuvant the no adjuvant PMRT group. Moreover, the aHR (95% PMRT (Group 2, control group). CIs) for DM in the adjuvant PMRT group was 0.89 (0.54– The cumulative incidence of death was estimated 1.50; P = 0.6854) compared with the no adjuvant PMRT using the Kaplan–Meier method, and differences in group (Table 2). the overall survival (OS), locoregional recurrence Zhang et al. Radiation Oncology (2022) 17:33 Page 4 of 11 Table 1 Demographics of patients with breast cancer and heart failure with reduced ejection fraction who received total mastectomy in the propensity score–weighted population through inverse probability of treatment weighting Propensity score weighting population Adjuvant RT Non‑RT Standardized N = 143 N = 503 difference n (%) n (%) Age Mean (SD) 67.5 (11.3) 67.7 (11.2) 0.0215 Median (Q1–Q3) 67 (57–72) 67 (61–77) 20–69 67 (46.9) 238 (47.9) 0.0096 70+ 76 (53.1) 259 (52.1) Diagnosis year 2009–2012 88 (50.9) 250 (50.3) 0.0115 2013–2016 85 (49.1) 247 (49.7) CCI scores 0 44 (30.8) 123 (24.5) 0.1433 1+ 99 (69.2) 380 (75.5) Differentiation I 20 (14.0) 72 (14.3) 0.0212 II 77 (53.8) 273 (54.3) 0.0311 III 46 (32.1) 158 (31.4) 0.0207 AJCC pathologic stage II 17 (12.8) 61 (12.1) 0.0114 IIIA 68 (47.6) 241 (47.9) 0.0162 IIIB–C 58 (40.6) 201 (40.0) 0.0142 pT pT1 9 (6.3) 30 (5.9) 0.0238 pT2 58 (40.6) 202 (40.2) 0.0149 pT3–4 76 (53.1) 271 (53.9) 0.0130 pN pN0 57 (39.8) 200 (39.8) 0.0000 pN1 43 (30.1) 151 (30.0) 0.0013 pN2–3 43 (30.1) 152 (30.2) 0.0001 Hypertension 110 (76.9) 387 (76.9) 0.0001 CAD 53 (37.1) 184 (36.6) 0.0092 Diabetes 60 (42.0) 215 (42.7) 0.0097 Anthracycline‑based chemotherapy 76 (53.1) 260 (51.7) 0.0280 Hormone receptor positive 59 (41.3) 229 (45.5) 0.0934 Trastuzumab use 69 (48.3) 246 (48.9) 0.0031 Nodal surgery ALND 87 (60.8) 302 (60.0) 0.0079 SLNB 56 (39.2) 201 (40.0) Hospital level Academic center 80 (55.9) 285 (56.7) 0.0181 Nonacademic center 63 (44.1) 218 (43.3) RT radiotherapy, IQR interquartile range, SD standard deviation, AJCC American Joint Committee on Cancer, HER2 human epidermal growth factor receptor-2, CCI Charlson comorbidity index, T tumor, N nodal, pT pathologic tumor stage, pN pathologic nodal stage, ALND axillary lymph node dissection, SNLB sentinel lymph node biopsy, CAD coronary arterial disease Zhang  et al. Radiation Oncology (2022) 17:33 Page 5 of 11 Table 2 Multivariate analysis of propensity score–weighted population with breast cancer and heart failure with reduced ejection fraction receiving total mastectomy Death Local recurrence Distant metastasis aHR* (95% CI) P value aHR* (95% CI) P value aHR* (95% CI) p value Adjuvant RT No Ref 0.0003 Ref 0.0356 Ref 0.6854 Yes 0.52 (0.37–0.74) 0.90 (0.79–0.96) 0.89 (0.54–1.50) Age 20–69 Ref 0.0020 Ref 0.1200 Ref 0.2901 70+ 1.63 (1.20–2.22) 1.29 (0.81–2.49) 0.75 (0.44–1.28) Diagnosis year 2009–2012 Ref 0.3507 Ref 0.2770 Ref 0.7421 2013–2016 0.79 (0.69–1.31) 0.73 (0.58–1.21) 0.81 (0.57–1.75) CCI scores 0 Ref 0.0322 Ref 0.1434 Ref 0.2112 1 1.26 (1.14–1.97) 1.21 (0.92–1.79) 1.35 (0.85–1.97) Differentiation I Ref 0.0177 Ref 0.0146 Ref 0.0046 II 1.09 (1.01–1.60) 1.36 (1.02–3.59) 1.36 (1.02–3.59) III 1.47 (1.09–2.40) 1.37 (1.11–3.71) 1.37 (1.01–3.71) pT pT1 Ref < 0.0001 Ref 0.0016 Ref 0.0196 pT2 1.38 (1.07–1.97) 1.35 (1.05–3.12) 1.09 (1.04–3.04) pT3–4 2.91 (1.90–4.44) 2.62 (1.19–4.72) 2.35 (1.13–4.89) pN pN0 Ref < 0.0001 Ref 0.0040 Ref 0.0082 pN1 1.94 (1.38–2.72) 1.09 (1.03–1.41) 2.38 (1.37–4.12) pN2–3 2.90 (2.01–4.18) 1.26 (1.06–1.37) 1.88 (1.01–3.51) Hypertension 1.08 (0.77–1.81) 0.4882 0.90 (0.59–1.56) 0.7217 0.95 (0.69–1.48) 0.8021 CAD 1.11 (0.71–1.92) 0.3427 0.84 (0.53–1.39) 0.6914 0.94 (0.78–1.59) 0.3426 Diabetes 1.11 (0.73–1.90) 0.3422 1.01 (0.70–1.51) 0.4521 0.90 (0.55–1.91) 0.8909 Hormone receptor positive 0.87 (0.80–0.91) 0.0312 0.77 (0.45–0.82) 0.0204 0.72 (0.63–0.97) 0.0322 Trastuzumab use 1.07 (0.87–1.42) 0.34661 1.09 (0.58–2.01) 0.3831 1.06 (0.81–1.54) 0.3421 Anthracycline‑based chemotherapy 0.94 (0.57–1.88) 0.4065 0.93 (0.78–1.83) 0.2412 0.84 (0.70–2.20) 0.1683 Nodal surgery ALND Ref 0.3322 Ref 0.2434 Ref 0.2112 SLNB 1.06 (0.54–1.09) 1.01 (0.82–1.79) 1.15 (0.85–2.97) Hospital level Academic center Ref 0.2177 Ref 0.2177 Ref 0.8146 Nonacademic center 0.99 (0.61–1.60) 0.99 (0.61–1.60) 1.36 (0.52–3.59) aHR adjusted hazard ratios, CIs confidence intervals, HR hormone receptor, Her-2 human epidermal growth factor receptor-2, CCI Charlson comorbidity index, T tumor, N nodal, pT pathologic tumor stage, pN pathologic nodal stage, ALND axillary lymph node dissection, SNLB sentinel lymph node biopsy, ref reference group, RT radiotherapy *All covariates mentioned in Table were adjusted Other independent predictors of all‑cause death, LRR, prognostic factors for OS (Table  2). IPTW-adjusted and DM in the women with left IDC and HFrEF receiving TM models were adjusted for age, diagnosis year, CCI Old age (> 70  years), CCI ≥ 1, advanced pT stages score, differentiation, pT, pN, hypertension, CAD, (pT2–4), advanced pN stages (pN1–3), hormone diabetes, chemotherapy with anthracycline-based receptor negative status, and differentiation Grade II regimen, hormone receptor status, trastuzumab use, and III were identified as crucial independent poor nodal surgery, and hospital levels; the aHRs (95% CIs) Zhang et al. Radiation Oncology (2022) 17:33 Page 6 of 11 Fig. 1 Kaplan–Meier overall survival curves of propensity score–weighted population with breast cancer and heart failure with reduced ejection fraction receiving total mastectomy Survival curves of adjuvant PMRT or no adjuvant PMRT of all-cause death for age > 70  years, CCI ≥ 1, differ- in women with left IDC and HFrEF receiving TM entiation Grades II and III, pT2, pT3–4, pN1, pN2– Figure  1 presents Kaplan–Meier curves that illustrate 3, and hormone receptor positive status were 1.63 the OS of the women with left IDC and HFrEF receiv- (1.20–2.22), 1.26 (1.14–1.97), 1.09 (1.01–1.60), 1.47 ing TM with adjuvant PMRT or no adjuvant PMRT. The (1.09–2.40), 1.38 (1.07–1.97), 2.91 (1.90–4.44), 1.94 5-year overall survival rates were 86.01% and 67.32% (1.38–2.72), 2.90 (2.01–4.18), and 0.87 (0.80–0.91) in the adjuvant PMRT and no adjuvant PMRT groups, compared with age 20–70  years, CCI = 0, differentia- respectively (Fig.  1); the OS rate was associated with an tion grade I, pT1, pN0, and hormone receptor negative increasing in the adjuvant PMRT group (log-rank test, status, respectively (Table  2). IPTW-adjusted models P = 0.0184) compared with the non-RT group. Addition- also revealed the aHRs (95% CIs) of LRR for differen- ally, the 5-year LRR-free survival in women with left IDC tiation grade II, differentiation grade III, pT2, pT3–4, and HFrEF receiving TM was 88.43% and 73.65% in the pN1, pN2–3, and hormone receptor positive status to adjuvant PMRT group and no adjuvant PMRT group, be 1.36 (1.02–3.59), 1.37 (1.11–3.71), 1.35 (1.05–3.12), respectively (Fig. 2; log-rank test, P = 0.0319). The 5-year 2.62 (1.19–4.72), 1.09 (1.03–1.41), 1.26 1.06–1.37), and DM-free survival in women with left IDC and HFrEF 0.77 (0.45–0.82) compared with differentiation grade receiving TM was 84.43% and 86.91% in the adjuvant I, pT1, pN0, and hormone receptor negative status, PMRT group and no adjuvant PMRT group, respectively respectively. Moreover, the aHRs (95% CIs) of DM for (Fig. 3; log-rank test, P = 0.8577). differentiation grade II, differentiation grade III, pT2, pT3–4, pN1, pN2–3, and hormone receptor positive Discussion status were 1.36 (1.02–3.59), 1.37 (1.01–3.71), 1.09 PMRT has two potential benefits: one is a decrease in (1.04–3.04), 2.35 (1.13–4.89), 2.38 (1.37–4.12), 1.88 the rate of locoregional recurrence, and another is an (1.01–3.51), and 0.72 (0.63–0.97) compared with dif increase in long-term breast cancer-specific and over - ferentiation grade I, pT1, pN0, and hormone receptor all survivals for certain patient populations. These ben - negative status, respectively. efits have been consistently reported in multiple studies Zhang  et al. Radiation Oncology (2022) 17:33 Page 7 of 11 Fig. 2 Kaplan–Meier locoregional recurrence‑free survival curves of propensity score–weighted population with breast cancer and heart failure with reduced ejection fraction receiving total mastectomy [21–23]. Decisions on who should receive PMRT depend explore the value of adjuvant PMRT for women with left- on the baseline risk for recurrence. The success of RT, side breast IDC and HFrEF receiving TM. As shown in used either alone or in combination with other modali- Table 2, adjuvant PMRT resulted in better OS, and LRR- ties, has resulted in large cohorts of breast cancer sur- free status compared with no adjuvant PMRT in women vivors who are vulnerable to late complications such as with left-side breast IDC and HFrEF receiving TM. The RICT from RT [5, 24–30]. Numerous treatment-related potential reasons might be the recent decline in mortality factors are responsible for cardiotoxicity in women with in women with HF [43, 44] and the advances in contem- breast cancer [31–41]. Thus, we conducted the study porary RT techniques with reduced irradiation volumes to determine the survival benefits offered by adjuvant to the heart [2, 26, 27]. PMRT in women with left-side IDC and HFrEF receiving According to our literature review, this is the first study TM. to estimate the oncologic outcomes of adjuvant PMRT Patients with breast cancer might experience adverse among women with left-side breast IDC and HFrEF effects from many cardiotoxic treatments such as adju - receiving TM. No consensus or evidence for the use of vant PMRT, anthracycline-based chemotherapy, or tras- adjuvant PMRT in women with left-side breast IDC and tuzumab [5, 6, 24–41]. Although cardiovascular diseases HFrEF receiving TM is present. In the IPTW-adjusted such as HF, heart attacks, and stroke remain the leading models, adjuvant PMRT was associated with a decrease cause of death in women, many believe breast cancer to in the risk of all-cause death, and LRR among women be more deadly [42]. In fact, the risk of RICT should be with left-side breast IDC and HFrEF receiving TM weighed against the potential benefits of adjuvant PMRT (Table  2). The improvement in contemporary RT tech - with respect to the patients’ prognosis and likely clinical niques with decreased irradiation doses and decreased benefit [5, 24–30]. Until now, no data have been available volumes to the heart and the long-term improvement in for the evaluation of oncologic outcomes (OS, LRR, and mortality rates in patients with HFrEF over time might DM) of adjuvant PMRT in women with left-side breast have caused the significant beneficial oncologic out - IDC and HFrEF receiving TM. This is the first study to comes of adjuvant PMRT in women with left-side breast Zhang et al. Radiation Oncology (2022) 17:33 Page 8 of 11 Fig. 3 Kaplan–Meier distant metastasis–free survival curves of propensity score–weighted population with breast cancer and heart failure with reduced ejection fraction receiving total mastectomy IDC and HFrEF receiving TM [2, 26, 27]. Our study is the prognostic factor has been identified in previous studies first to demonstrate that the potential benefits of adju - other than the ones determined in the current study irre- vant PMRT with contemporary RT techniques outweigh spective of whether underlying HFrEF was present. the risk of RICT given the patients’ prognosis and likely The potential reasons of better oncologic outcomes long-term OS and LRR benefits (Table  2). According to on adjuvant PMRT for breast IDC with HFrEF might be our findings, we strongly suggested that women with attributed to the modern RT techniques. The use of mod - left-side breast IDC and HFrEF receiving TM should also ern RT techniques (such as IMRT and VMAT) as well as receive adjuvant PMRT to decrease the risk of all-cause the reduction of treatment volumes (partial breast irradi- death, and LRR. ation) allow to reduce acute and late side effects [53–55]. As shown in Table  2, adjuvant PMRT was a significant The contemporary RT techniques allow more precise RT prognostic factor for OS and LRR compared with no field to target volume and decrease RT dose-volume to adjuvant PMRT in women with left-side IDC and HFrEF heart contributed to less RICT [53, 54]. Therefore, breast receiving TM; moreover, old age (> 70  years), CCI ≥ 1, IDC patients with HFrEF receiving TM and adjuvant advanced pT stages (pT2–4), advanced pN stages (pN1– PMRT could get benefits from PMRT and less acute and 3), hormone receptor negative status, and differentia - late toxicity to heart contributed to better oncologic out- tion Grade II–III were significant prognostic factors for comes like OS and LRR-free survival (Table 2, Figs. 1, 2). OS, compatible with findings of previous studies [10, 11, A strength of our study was that it was the first 45–52]. Moreover, advanced pT stages (pT2-4), pN stages cohort study to estimate the survival outcomes of adju- (pN1–3), hormone receptor negative status, and differen - vant PMRT or no adjuvant PMRT among women with tiation Grade II–III were significant poor prognostic fac - left-side IDC and HFrEF receiving TM. The covariates tors for LRR and DM in women with left-side breast IDC between the adjuvant PMRT and no adjuvant PMRT and HFrEF receiving TM, which is also compatible with groups were homogenous for women with left-side IDC findings of previous studies [10, 11, 45–52]. Our findings and HFrEF receiving TM, with no selection bias (Table 1). of prognostic factors for OS, LRR, and DM in women No study has estimated the effect of adjuvant PMRT on with IDC and HFrEF receiving TM are similar with those women with left-side IDC and HFrEF receiving TM. In of previous studies [10, 11, 45–52], and no additional our study, the poor prognostic factors for OS in women Zhang  et al. Radiation Oncology (2022) 17:33 Page 9 of 11 with left-side IDC and HFrEF receiving TM were old PMRT. We suggest adjuvant PMRT for women with age, CCI ≥ 1, advanced pT stages (pT2–4), advanced pN left-side IDC receiving TM, even if they have HFrEF. stages (pN1–3), hormone receptor negative status, and differentiation Grade II–III of (Table  2), which are con- Abbreviations sistent with factors in women with breast cancer without PMRT: Postmastectomy RT; LRR: Locoregional recurrence; DM: Distant HFrEF reported in previous studies [48–52]. Further- metastasis; IDC: Invasive ductal carcinoma; HFrEF: Heart failure with reduced ejection fraction; TM: Total mastectomy; OS: Overall survival; aHR: Adjusted more, our study is the first to demonstrate the benefits hazard ratio; HR: Hazard ratio; IPTW: Inverse probability of treatment weight‑ of adjuvant PMRT with contemporary RT techniques ing; CI: Confidence interval; AJCC: American Joint Committee on Cancer; for OS, LRR, and DM in women with left-side IDC and TCRD: Taiwan Cancer Registry Database; SD: Standard deviation; HER2: Human epidermal growth factor receptor‑2; SLNB: Sentinel lymph node biopsy; ALND: HFrEF receiving TM. Our findings should be considered Axillary lymph node dissection; CCI: Charlson comorbidity index; ICD‑10‑ CM: in future clinical practice and prospective clinical trials of International Classification of Diseases, 10th Revision, Clinical Modification; HF and RT for breast cancer. We suggest that adjuvant NCCN: National Comprehensive Cancer Network; RT: Radiotherapy; RICT: Radiotherapy‑related cardiotoxicity; TM: Total mastectomy; HF: Heart failure; PMRT is valuable to achieving better outcomes of OS, LV: Left ventricular; LVEF: Left ventricular ejection fraction; T: Tumor; N: Nodal; LRR, and DM in women with left-side IDC and HFrEF pT: Pathologic tumor stage; pN: Pathologic nodal stage; NHIRD: National receiving TM. Health Insurance Research Database. This study has some limitations. First, because all Acknowledgements women with left-side breast IDC and HFrEF were Lo‑Hsu Medical Foundation, Lotung Poh‑Ai Hospital, supports Szu‑ Yuan enrolled from an Asian population, the correspond- Wu’s work (Funding Number: 10908, 10909, 11001, 11002, 11003, 11006, and 11013). Taipei Medical University‑ Wan Fang Hospital (Funding Number: ing ethnic susceptibility compared with the non-Asian 107TMU‑ WFH‑08) supports Tsai‑Mu Cheng’s work. population remains unclear; hence, our results should Access to data statement: We used data from the National Health Insurance be cautiously extrapolated to non-Asian populations. Research Database (NHIRD) and Taiwan Cancer Registry database ( TCRD). The authors confirm that, for approved reasons, some access restrictions apply However, no evidence exists as to the differences in onco - to the data underlying the findings. The data utilized in this study cannot be logic outcomes in Asian versus non-Asian patients with made available in the manuscript, the supplemental files, or in a public reposi‑ breast IDC and HFrEF receiving TM. Second, a weak tory due to the “Personal Information Protection Act” executed by Taiwan’s government, starting from 2012. Requests for data can be sent as a formal pro‑ point of the study that the median follow up (6.96 and posal to obtain approval from the ethics review committee of the appropriate 5.09  years) could be too short for evaluation the impact governmental department in Taiwan. Specifically, links regarding contact info on breast cancer survival or late heart side effects. Third, for which data requests may be sent to are as follows: http:// nhird. nhri. org. tw/ en/ Data_ Subse ts. html# S3 and http:// nhis. nhri. org. tw/ point. html. Szu‑ Yuan the diagnoses of all comorbid conditions were based on Wu, MD, PhD had full access to all the data in the study and takes responsibil‑ ICD-10-CM codes. However, the combination of Tai- ity for the integrity of the data and the accuracy of the data analysis. wanese TCRD and National Health Insurance Research Role of funder statement: Lo‑Hsu Medical Foundation, Lotung Poh‑Ai Hos‑ pital, supports Szu‑ Yuan Wu’s work (Funding Number: 10908, 10909, 11001, Database (NHIRD) data appears to be a valid resource for 11002, 11003, 11006, and 11013) for design and conduct of the study. population research on cardiovascular diseases, stroke, or chronic comorbidities [56–58]. Moreover, the Taiwan Authors’ contributions Conception and design: JZ, S‑ YW; Financial support: Lo‑Hsu Medical Founda‑ Cancer Registry Administration randomly reviews charts tion, Lotung Poh‑Ai Hospital, supports Szu‑ Yuan Wu’s work (Funding Number: and interviews patients to verify the accuracy of the diag- 10908, 10909, 11001, 11002, 11003, 11006, and 11013). Taipei Medical noses, and hospitals with outlier chargers or practices University‑ Wan Fang Hospital (Funding Number: 107TMU‑ WFH‑08) supports Tsai‑Mu Cheng’s work. Collection and assembly of data: JZ, S‑ YS, S‑ YW. Data may be audited and subsequently be heavily penalized if analysis and interpretation: JZ, J‑ GH, M‑FC, T ‑SL. Administrative support: S‑ YW; any malpractice or discrepancy is detected. Accordingly, Manuscript writing: JZ, S‑ YS, M‑FC, S‑ YW. All authors read and approved the to obtain crucial information on population specificity final manuscript. and disease occurrence, a large-scale randomized trial Funding comparing carefully selected patients undergoing suit- Lo‑Hsu Medical Foundation, Lotung Poh‑Ai Hospital, supports Szu‑ Yuan able treatments is essential. Finally, the TCRD does not Wu’s work (Funding Number: 10908, 10909, 11001, 11002, 11003, 11006, and 11013). Taipei Medical University‑ Wan Fang Hospital (Funding Number: contain information regarding dietary habits or body 107TMU‑ WFH‑08) supports Tsai‑Mu Cheng’s work. mass index, which may be risk factors for mortality. Nevertheless, considering the magnitude and statistical Availability of data and materials The data sets supporting the study conclusions are included in this manu‑ significance of the observed effects in this study, these script and its supplementary files. limitations are unlikely to affect the conclusions. For software: Project name: not applicable; Project homepage: not appli‑ cable; Archived version: not applicable; Operating system(s): not applicable; Programming language: not applicable; Other requirements: not applicable; License: not applicable; Any restrictions for use by nonacademicians: not Conclusions applicable. Adjuvant PMRT was associated with a decrease in all-cause death and LRR among women with left-side breast IDC and HFrEF compared with no adjuvant Zhang et al. Radiation Oncology (2022) 17:33 Page 10 of 11 special contribution of the Heart Failure Association (HFA) of the ESC. Eur Declarations Heart J. 2016;37(27):2129–200. 9. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner Ethics approval and consent to participate MH, Filippatos GS, Fonarow GC, Givertz MM, et al. 2017 ACC/AHA/HFSA The study protocols were reviewed and approved by the Institutional Review focused update of the 2013 ACCF/AHA guideline for the management Board of Tzu‑ Chi Medical Foundation (IRB109‑015‑B). of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Consent for publication Failure Society of America. Circulation. 2017;136(6):e137–61. Not applicable. 10. Zhang J, Lu CY, Chen CH, Chen HM, Wu SY. Eec ff t of pathologic stages on postmastectomy radiation therapy in breast cancer receiving neoadju‑ Competing interests vant chemotherapy and total mastectomy: a cancer database analysis. The authors have no potential competing interests to declare. The data sets Breast. 2020;54:70–8. supporting the study conclusions are included in the manuscript. 11. Zhang J, Lu CY, Qin L, Chen HM, Wu SY. Breast‑ conserving surgery with or without irradiation in women with invasive ductal carcinoma of the Author details breast receiving preoperative systemic therapy: a cohort study. Breast. Department of Anesthesiology and Perioperative Medicine, Henan Provincial 2020;54:139–47. People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, 12. Zhang J, Lu CY, Chen HM, Wu SY. Neoadjuvant chemotherapy or Henan, China. Department of General Surgery, Lo‑Hsu Medical Foundation, endocrine therapy for invasive ductal carcinoma of the breast with high Lotung Poh‑Ai Hospital, Yilan, Taiwan. Graduate Institute of Business Adminis‑ hormone receptor positivity and human epidermal growth factor recep‑ tration, Fu Jen Catholic University, Taipei, Taiwan. Division of Gastroenterology tor 2 negativity. JAMA Netw Open. 2021;4(3):e211785. and Hepatology, Department of Internal Medicine, Lo‑Hsu Medical Founda‑ 13. Liu WC, Liu HE, Kao YW, Qin L, Lin KC, Fang CY, Tsai LL, Shia BC, Wu SY. tion, Lotung Poh‑Ai Hospital, Yilan, Taiwan. Department of Food Nutrition Definitive radiotherapy or surgery for early oral squamous cell carcinoma and Health Biotechnology, College of Medical and Health Science, Asia Univer‑ in old and very old patients: a propensity‑score ‑matched, nationwide, sity, Taichung, Taiwan. Big Data & Cancer Center, Lo‑Hsu Medical Foundation, population‑based cohort study. Radiother Oncol. 2020;151:214–21. Lotung Poh‑Ai Hospital, Yilan, Taiwan. Division of Radiation Oncology, Lo‑Hsu 14. NCCN Clinical practice guidelines in oncology. http:// www. nccn. org/ Medical Foundation, Lotung Poh‑Ai Hospital, No. 83, Nanchang St., Luodong profe ssion als/ physi cian_ gls/f_ guide lines. asp. Township, Yilan County 265, Taiwan. Department of Healthcare Administra‑ 15. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, tion, College of Medical and Health Science, Asia University, Taichung, Taiwan. Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, et al. American Society Cancer Center, Lo‑Hsu Medical Foundation, Lotung Poh‑Ai Hospital, Yilan, of Clinical Oncology/College Of American Pathologists guideline recom‑ Taiwan. Centers for Regional Anesthesia and Pain Medicine, Taipei Municipal mendations for immunohistochemical testing of estrogen and progester‑ Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. one receptors in breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(16):2784–95. Received: 18 November 2021 Accepted: 28 January 2022 16. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47(11):1245–51. 17. Chen JH, Yen YC, Yang HC, Liu SH, Yuan SP, Wu LL, Lee FP, Lin KC, Lai MT, Wu CC, et al. Curative‑intent aggressive treatment improves survival in elderly patients with locally advanced head and neck squamous References cell carcinoma and high comorbidity index. Medicine (Baltimore). 1. Hooning MJ, Botma A, Aleman BM, Baaijens MH, Bartelink H, Klijn JG, 2016;95(14):e3268. Taylor CW, van Leeuwen FE. Long‑term risk of cardiovascular disease in 18. Lin SH, Wang L, Myles B, Thall PF, Hofstetter WL, Swisher SG, Ajani JA, Cox 10‑ year survivors of breast cancer. J Natl Cancer Inst. 2007;99(5):365–75. JD, Komaki R, Liao Z. Propensity score‑based comparison of long‑term 2. Travis LB, Ng AK, Allan JM, Pui CH, Kennedy AR, Xu XG, Purdy JA, outcomes with 3‑ dimensional conformal radiotherapy versus intensity‑ Applegate K, Yahalom J, Constine LS, et al. Second malignant neoplasms modulated radiotherapy for esophageal cancer. Int J Radiat Oncol Biol and cardiovascular disease following radiotherapy. J Natl Cancer Inst. Phys. 2012;84(5):1078–85. 2012;104(5):357–70. 19. Austin PC, Stuart EA. Moving towards best practice when using inverse 3. Moslehi J. The cardiovascular perils of cancer survivorship. N Engl J Med. probability of treatment weighting (IPTW ) using the propensity score 2013;368(11):1055–6. to estimate causal treatment effects in observational studies. Stat Med. 4. Darby SC, Ewertz M, McGale P, Bennet AM, Blom‑ Goldman U, Bronnum 2015;34(28):3661–79. D, Correa C, Cutter D, Gagliardi G, Gigante B, et al. Risk of ischemic heart 20. Austin PC. Balance diagnostics for comparing the distribution of baseline disease in women after radiotherapy for breast cancer. N Engl J Med. covariates between treatment groups in propensity‑score matched 2013;368(11):987–98. samples. Stat Med. 2009;28(25):3083–107. 5. Paszat LF, Mackillop WJ, Groome PA, Schulze K, Holowaty E. Mortality from 21. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, Godwin myocardial infarction following postlumpectomy radiotherapy for breast J, Gray R, Hicks C, James S, et al. Eec ff ts of radiotherapy and of differ ‑ cancer: a population‑based study in Ontario, Canada. Int J Radiat Oncol ences in the extent of surgery for early breast cancer on local recurrence Biol Phys. 1999;43(4):755–62. and 15‑ year survival: an overview of the randomised trials. Lancet. 6. Hojris I, Overgaard M, Christensen JJ, Overgaard J. Morbidity and mortal‑ 2005;366(9503):2087–106. ity of ischaemic heart disease in high‑risk breast ‑ cancer patients after 22. Danish Breast Cancer Cooperative G, Nielsen HM, Overgaard M, Grau C, adjuvant postmastectomy systemic treatment with or without radio‑ Jensen AR, Overgaard J. Study of failure pattern among high‑risk breast therapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy cancer patients with or without postmastectomy radiotherapy in addi‑ Committee of the Danish Breast Cancer Cooperative Group. Lancet. tion to adjuvant systemic therapy: long‑term results from the Danish 1999;354(9188):1425–30. Breast Cancer Cooperative Group DBCG 82 b and c randomized studies. J 7. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fon‑ Clin Oncol: Off J Amer Soc Clin Oncol 2006;24(15):2268–2275. arow GC, Geraci SA, Horwich T, Januzzi JL, et al. 2013 ACCF/AHA guideline 23. Ragaz J, Olivotto IA, Spinelli JJ, Phillips N, Jackson SM, Wilson KS, Knowling for the management of heart failure: executive summary: a report of the MA, Coppin CM, Weir L, Gelmon K, et al. Locoregional radiation therapy in American College of Cardiology Foundation/American Heart Association patients with high‑risk breast cancer receiving adjuvant chemotherapy: Task Force on practice guidelines. Circulation. 2013;128(16):1810–52. 20‑ year results of the British Columbia randomized trial. J Natl Cancer Inst. 8. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk 2005;97(2):116–26. V, Gonzalez‑ Juanatey JR, Harjola VP, Jankowska EA, et al. 2016 ESC guide‑ 24. Yu JM, Hsieh MC, Qin L, Zhang J, Wu SY. Metformin reduces radiation‑ lines for the diagnosis and treatment of acute and chronic heart failure: induced cardiac toxicity risk in patients having breast cancer. Am J Cancer the Task Force for the diagnosis and treatment of acute and chronic heart Res. 2019;9(5):1017–26. failure of the European Society of Cardiology (ESC) developed with the Zhang  et al. Radiation Oncology (2022) 17:33 Page 11 of 11 25. Lee CH, Zhang JF, Yuan KS, Wu ATH, Wu SY. Risk of cardiotoxicity induced 44. Shen L, Jhund PS, Petrie MC, Claggett BL, Barlera S, Cleland JGF, Dargie HJ, by adjuvant anthracycline‑based chemotherapy and radiotherapy in Granger CB, Kjekshus J, Kober L, et al. Declining risk of sudden death in young and old Asian women with breast cancer. Strahlenther Onkol. heart failure. N Engl J Med. 2017;377(1):41–51. 2019;195:629–39. 45. Zhang J, Sun M, Chang E, Lu CY, Chen HM, Wu SY. Pathologic response as 26. Giordano SH, Kuo YF, Freeman JL, Buchholz TA, Hortobagyi GN, Goodwin predictor of recurrence, metastasis, and survival in breast cancer patients JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J receiving neoadjuvant chemotherapy and total mastectomy. Am J Can‑ Natl Cancer Inst. 2005;97(6):419–24. cer Res. 2020;10(10):3415–27. 27. Darby SC, McGale P, Taylor CW, Peto R. Long‑term mortality from heart 46. Zhang J, Qin L, Chen HM, Hsu HC, Chuang CC, Chen D, Wu SY. Overall disease and lung cancer after radiotherapy for early breast cancer: survival, locoregional recurrence, and distant metastasis of definitive prospective cohort study of about 300,000 women in US SEER cancer concurrent chemoradiotherapy for cervical squamous cell carcinoma and registries. Lancet Oncol. 2005;6(8):557–65. adenocarcinoma: before and after propensity score matching analysis of 28. Patt DA, Goodwin JS, Kuo YF, Freeman JL, Zhang DD, Buchholz TA, Horto‑ a cohort study. Am J Cancer Res. 2020;10(6):1808–20. bagyi GN, Giordano SH. Cardiac morbidity of adjuvant radiotherapy for 47. Zhang J, Lu CY, Chen HM, Wu SY. Pathologic response rates for breast breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(30):7475–82. cancer stages as a predictor of outcomes in patients receiving neoadju‑ 29. Taylor CW, Bronnum D, Darby SC, Gagliardi G, Hall P, Jensen MB, McGale vant chemotherapy followed by breast‑ conserving surgery. Surg Oncol. P, Nisbet A, Ewertz M. Cardiac dose estimates from Danish and Swed‑ 2020;36:91–8. ish breast cancer radiotherapy during 1977–2001. Radiother Oncol. 48. Yoo S, Lee HB, Han W, Noh DY, Park SK, Kim WH, Kim JT. Total intravenous 2011;100(2):176–83. anesthesia versus inhalation anesthesia for breast cancer surgery: a 30. McGale P, Darby SC, Hall P, Adolfsson J, Bengtsson NO, Bennet AM, For‑ retrospective cohort study. Anesthesiology. 2019;130(1):31–40. nander T, Gigante B, Jensen MB, Peto R, et al. Incidence of heart disease 49. Oh TK, Kim HH, Jeon Y T. Retrospective analysis of 1‑ year mortality after in 35,000 women treated with radiotherapy for breast cancer in Denmark gastric cancer surgery: total intravenous anesthesia versus volatile anes‑ and Sweden. Radiother Oncol. 2011;100(2):167–75. thesia. Acta Anaesthesiol Scand. 2019;63(9):1169–77. 31. Boekel NB, Jacobse JN, Schaapveld M, Hooning MJ, Gietema JA, Duane 50. Lee JH, Kang SH, Kim Y, Kim HA, Kim BS. Eec ff ts of propofol‑based total FK, Taylor CW, Darby SC, Hauptmann M, Seynaeve CM, et al. Cardio‑ intravenous anesthesia on recurrence and overall survival in patients after vascular disease incidence after internal mammary chain irradiation modified radical mastectomy: a retrospective study. Korean J Anesthesiol. and anthracycline‑based chemotherapy for breast cancer. Br J Cancer. 2016;69(2):126–32. 2018;119(4):408–18. 51. Enlund M, Berglund A, Ahlstrand R, Wallden J, Lundberg J, Warnberg 32. Early Breast Cancer Trialists’ Collaborative G, Peto R, Davies C, Godwin J, F, Ekman A, Sjoblom Widfeldt N, Enlund A, Bergkvist L. Survival after Gray R, Pan HC, Clarke M, Cutter D, Darby S, McGale P, et al. Comparisons primary breast cancer surgery following propofol or sevoflurane general between different polychemotherapy regimens for early breast cancer: anesthesia—a retrospective, multicenter, database analysis of 6305 meta‑analyses of long‑term outcome among 100,000 women in 123 Swedish patients. Acta Anaesthesiol Scand. 2020;64(8):1048–54. randomised trials. Lancet. 2012;379(9814):432–44. 52. Makito K, Matsui H, Fushimi K, Yasunaga H. Volatile versus total intrave‑ 33. Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, nous anesthesia for cancer prognosis in patients having digestive cancer Hopkins JO, O’Shaughnessy JA, Dang CT, et al. Anthracyclines in early surgery. Anesthesiology. 2020;133(4):764–73. breast cancer: the ABC Trials‑USOR 06–090, NSABP B‑46‑I/USOR 07132, 53. Fiorentino A, Gregucci F, Mazzola R, Figlia V, Ricchetti F, Sicignano G, and NSABP B‑49 (NRG Oncology). J Clin Oncol Off J Am Soc Clin Oncol. Giajlevra N, Ruggieri R, Fersino S, Naccarato S, et al. Intensity‑modulated 2017;35(23):2647–55. radiotherapy and hypofractionated volumetric modulated arc therapy for 34. Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, elderly patients with breast cancer: comparison of acute and late toxici‑ Galderisi M, Habib G, Lenihan DJ, Lip GYH, Lyon AR, et al. 2016 ESC posi‑ ties. Radiol Med. 2019;124(4):309–14. tion paper on cancer treatments and cardiovascular toxicity developed 54. Meduri B, Gregucci F, D’Angelo E, Alitto AR, Ciurlia E, Desideri I, Marino L, under the auspices of the ESC Committee for Practice Guidelines: the Borghetti P, Fiore M, Fiorentino A, et al. Volume de‑ escalation in radiation Task Force for cancer treatments and cardiovascular toxicity of the Euro‑ therapy: state of the art and new perspectives. J Cancer Res Clin Oncol. pean Society of Cardiology (ESC). Eur Heart J. 2016;37(36):2768–801. 2020;146(4):909–24. 35. Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, 55. Fiorentino A, Mazzola R, Giaj Levra N, Fersino S, Ricchetti F, Di Paola G, Civelli M, Lamantia G, Colombo N, Curigliano G, et al. Early detection of Gori S, Massocco A, Alongi F. Comorbidities and intensity‑modulated anthracycline cardiotoxicity and improvement with heart failure therapy. radiotherapy with simultaneous integrated boost in elderly breast cancer Circulation. 2015;131(22):1981–8. patients. Aging Clin Exp Res. 2018;30(5):533–8. 36. Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, 56. Cheng CL, Lee CH, Chen PS, Li YH, Lin SJ, Yang YH. Validation of acute Muggia FM. Risk factors for doxorubicin‑induced congestive heart failure. myocardial infarction cases in the National Health Insurance Research Ann Intern Med. 1979;91(5):710–7. Database in Taiwan. J Epidemiol. 2014;24(6):500–7. 37. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients 57. Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. Validation of the National Health treated with doxorubicin: a retrospective analysis of three trials. Cancer. Insurance Research Database with ischemic stroke cases in Taiwan. Phar‑ 2003;97(11):2869–79. macoepidemiol Drug Saf. 2011;20(3):236–42. 38. Schwartz RG, McKenzie WB, Alexander J, Sager P, D’Souza A, Manatunga 58. Lin CC, Lai MS, Syu CY, Chang SC, Tseng FY. Accuracy of diabetes diag‑ A, Schwartz PE, Berger HJ, Setaro J, Surkin L, et al. Congestive heart failure nosis in health insurance claims data in Taiwan. J Formos Med Assoc. and left ventricular dysfunction complicating doxorubicin therapy. 2005;104(3):157–63. Seven‑ year experience using serial radionuclide angiocardiography. Am J Med. 1987;82(6):1109–18. Publisher’s Note 39. Keefe DL. Trastuzumab‑associated cardiotoxicity. Cancer. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 2002;95(7):1592–600. lished maps and institutional affiliations. 40. Perez EA, Rodeheffer R. Clinical cardiac tolerability of trastuzumab. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(2):322–9. 41. Fiuza M. Cardiotoxicity associated with trastuzumab treatment of HER2+ breast cancer. Adv Ther. 2009;26(Suppl 1):S9‑17. 42. Mehta LS, Watson KE, Barac A, Beckie TM, Bittner V, Cruz‑Flores S, Dent S, Kondapalli L, Ky B, Okwuosa T, et al. Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the American Heart Association. Circulation. 2018;137(8):e30–66. 43. Roger VL, Weston SA, Redfield MM, Hellermann‑Homan JP, Killian J, Yawn BP, Jacobsen SJ. Trends in heart failure incidence and survival in a community‑based population. JAMA. 2004;292(3):344–50. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Adjuvant postmastectomy radiotherapy might be associated with better survival in women with heart failure receiving total mastectomy

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Abstract

Background: To date, no data on the effect of adjuvant postmastectomy radiotherapy (PMRT ) on oncologic out ‑ comes, such as all‑ cause death, locoregional recurrence (LRR), and distant metastasis (DM), are available in women with left‑side breast invasive ductal carcinoma (IDC) and heart failure with reduced ejection fraction (HFrEF). Patients and methods: We enrolled 646 women with left‑breast IDC at clinical stages I–IIIC and HFrEF receiving radi‑ cal total mastectomy ( TM) followed by adjuvant PMRT or non‑adjuvant PMRT. We categorized them into two groups based on their adjuvant PMRT status and compared their overall survival (OS), LRR, and DM outcomes. We calculated the propensity score and applied inverse probability of treatment weighting (IPTW ) to create a pseudo‑study cohort. Furthermore, we performed a multivariate analysis of the propensity score–weighted population to obtain hazard ratios (HRs). Results: In the IPTW‑adjusted model, adjuvant PMRT (adjusted HR [aHR]: 0.52; 95% confidence interval [CI]: 0.37– 0.74) was a significant independent prognostic factor for all‑ cause death (P = 0.0003), and the aHR (95% CI) of LRR and DM for adjuvant PMRT was 0.90 (0.79–0.96; P = 0.0356) and 0.89 (0.54–1.50; P = 0.6854), respectively, compared with the nonadjuvant PMRT group. Conclusion: Adjuvant PMRT was associated with a decrease in all‑ cause death, and LRR in women with left IDC and HFrEF compared with nonadjuvant PMRT. Keywords: Breast cancer, Radiation‑induced cardiovascular toxicity, Total mastectomy, Radiotherapy, Survival Key points • Question: Is adjuvant postmastectomy radiotherapy (PMRT) worthy for women with left-side breast inva- sive ductal carcinoma (IDC) and heart failure with reduced ejection fraction (HFrEF) receiving total *Correspondence: szuyuanwu5399@gmail.com mastectomy (TM)? Jiaqiang Zhang and Shao‑ Yin Sum have contributed equally to this study • Findings: In the IPTW-adjusted models, adjuvant Division of Radiation Oncology, Lo‑Hsu Medical Foundation, Lotung Poh‑Ai Hospital, No. 83, Nanchang St., Luodong Township, Yilan County PMRT was associated with a decrease in all-cause 265, Taiwan Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhang et al. Radiation Oncology (2022) 17:33 Page 2 of 11 death and LRR in women with left IDC and HFrEF Patients and methods compared with no adjuvant PMRT. Study population • Meaning: We suggest adjuvant PMRT for women In this cohort study, data were retrieved from the Taiwan with left-side IDC receiving TM, even when they Cancer Registry Database (TCRD). We enrolled women have HFrEF. with HF with reduced ejection fraction (LVEF ≤ 40%; HFrEF) [7–9] who had received a diagnosis of left-side breast IDC between January 1, 2008, and December 31, 2018. The index date was the date of TM, and the Introduction follow-up duration was from the index date to Decem- Radiation-induced cardiovascular toxicity (RICT) is ber 31, 2019. The TCRD of the Collaboration Center of associated with a portion of the heart being placed in Health Information Application contains detailed cancer- a radiation field [1]. For patients with left-sided breast related information of patients, including their clinical cancers, careful treatment planning and usage of con- stage, pathologic stages, chemotherapy regimens, dose temporary radiotherapy (RT) techniques are critical to of chemotherapy, molecular status, drug use, hormone minimize cardiac exposure to radiation [1]. Incidental receptor status, radiation modalities and doses, and irradiation dose to the heart as part of the initial treat- surgical procedures [10–13]. The study protocols were ment for breast cancer can result in a range of cardio- reviewed and approved by the Institutional Review Board toxic effects, including coronary artery disease (CAD), of Tzu-Chi Medical Foundation (IRB109-015-B). cardiomyopathy, pericardial disease, valvular dysfunc- tion, and conduction abnormalities [2–4]. At present, no recommended minimum radiation dose that is Inclusion and exclusion criteria completely safe exists [3]. The diagnoses of the enrolled patients with HFrEF were The association of RICT is not dependent on the confirmed after their pathological data were reviewed, presence or absence of a breast but on the volume of and the women with newly diagnosed left-side IDC were radiation to the heart [3, 4]. Thus, cardiotoxicities confirmed to have no other cancers or distant metasta - associated with RT differ between the postlumpec- ses. The women with HFrEF were included if they had tomy and postmastectomy settings; this is because received a left-side IDC diagnosis, were 20  years old or in the postmastectomy setting, the RT field often older, and had clinical stage I–IIIC (American Joint Com- includes the nodal tissues, and these nodes are not mittee on Cancer [AJCC], 8th edition) without metas- always targeted in the postlumpectomy setting [5, 6]. tasis. Patients with HFrEF were excluded if they had a Thus, postmastectomy RT (PMRT) is more often asso- history of cancer before the IDC diagnosis date, unknown ciated with cardiac disease relative to postlumpectomy pathologic types, missing sex data, unclear staging, or RT, but this is likely a result of the usually larger irra- non-IDC histology. In addition, patients with unclear dif- diated volumes of the heart in postmastectomy RT ferentiation of tumor grade, missing HR status, missing [5, 6]. Therefore, RICT in patients with breast cancer data on hormone therapy or trastuzumab use, or unclear should be separately discussed by using different surgi- staging were excluded. Adjuvant treatments such as cal techniques of breast-conserving surgery (BCS) and adjuvant chemotherapy, hormone therapy, or the trastu- total mastectomy (TM). Hereby, we wanted to address zumab use did not constitute exclusion criteria based on the values of adjuvant PMRT for breast cancer patients the National Comprehensive Cancer Network (NCCN) with heart failure (HF) receiving TM with large RT guidelines [14]. We also excluded patients with HFrEF field and high dose-volume to the normal heart. with unclear data on surgical procedures such as TM or The crucial issue is whether adjuvant PMRT can be TM, ill-defined nodal surgery, unclear Charlson comor - safely given to women with HF and left-side breast bidity index (CCI), or unclear differentiation from our cancer who receive TM. No data are available to cohort. Hormone receptor positivity was defined as ≥ 1% address the value of adjuvant PMRT in women with of tumor cells demonstrating positive nuclear staining breast cancer and HF receiving TM. HF due to left through immunohistochemistry [15]. ventricle (LV) dysfunction is categorized according to After applying the inclusion and exclusion criteria, we LV ejection fraction (LVEF) as HF with reduced ejec- enrolled 646 women with HFrEF and AJCC clinical stage tion fraction (LVEF ≤ 40%, known as HFrEF) [7–9]. I–IIIC and left-side IDC who had received a TM fol- Until now, no study has estimated the oncologic out- lowed by sentinel lymph node biopsy (SLNB) or axillary comes of adjuvant PMRT in women with breast inva- lymph node dissection (ALND) and divided them into sive ductal carcinoma (IDC) and HFrEF receiving TM. two groups based on their adjuvant PMRT status to com- pare all-cause mortality: Group 1 (women with left-side Zhang  et al. Radiation Oncology (2022) 17:33 Page 3 of 11 IDC and HFrEF who received TM followed by adjuvant (LRR)–free survival, and distant metastasis (DM)–free PMRT) and Group 2 (women with left-side IDC and survival between women with left IDC and HFrEF HFrEF who received TM and no adjuvant PMRT). We receiving TM followed by adjuvant PMRT versus no also excluded women in Group 1 receiving nonstandard adjuvant PMRT were determined using a log-rank test. adjuvant PMRT. Standard postmastectomy RT is irra- After confounders were adjusted for, IPTW-adjusted diation to both the chest wall and to the regional nodes models were used to determine the time from the index with 50 Gy at least. These include the supraclavicular and date to all-cause mortality in the women with left IDC infraclavicular nodes. We also include RT to the axilla and HFrEF who received TM followed by adjuvant except in some patients who underwent complete axillary PMRT or no adjuvant PMRT. Subsequently, in a mul- dissection. Contemporary RT techniques were included tivariate analysis, HRs were adjusted for age, diagnosis in our study (intensity modulated radiation therapy year, CCI scores, differentiation, pT, pN, hypertension, [IMRT] and volumetric modulated arc therapy [VMAT]) CAD, diabetes, chemotherapy with anthracycline, and the conventional two-dimensional RT technique was hormone receptor status, trastuzumab use, nodal sur- excluded. The included contemporary RT techniques gery, and hospital levels. All analyses were conducted were three-dimensional RT and intensity-modulated using SAS (Version 9.4; SAS, Cary, NC, USA), and a radiation therapy. The incidence of comorbidities was two-tailed P value < 0.05 was considered statistically scored using the CCI [16, 17]. Hypertension, diabetes, significant. and coronary arterial diseases (CAD) were excluded from the CCI scores to avoid repetitive adjustment in mul- tivariate analysis. Only comorbidities observed within Results 6 months before the index date were included; they were Study cohort coded and classified according to the International Clas- We enrolled 646 women with left-breast IDC at clinical sification of Diseases, 10th Revision, Clinical Modification stages I–IIIC and HFrEF who received TM followed by (ICD-10-CM) codes at the first admission or based on adjuvant PMRT or no adjuvant PMRT (Table  1). Among more than two repetitions of a code issued at outpatient these women, 143 with left IDC and HFrEF received TM department visits. followed by adjuvant PMRT (Group 1) and 503 with left IDC and HFrEF received TM with no adjuvant PMRT (Group 2). After IPTW was executed using the propen- Study covariates and statistical analysis sity score, the covariates between Groups 1 and 2 were Significant independent predictors, namely age, diagno - found to be homogenous. The median follow-up dura - sis year, CCI score, differentiation, pT, pN, hypertension, tions after the index date were 6.96 and 5.09  years for CAD, diabetes, chemotherapy with anthracycline-based women with left IDC and HFrEF who received TM fol- regimen, hormone receptor status, trastuzumab use, lowed by adjuvant PMRT or no adjuvant PMRT, respec- nodal surgery, and hospital level (academic or nonaca- tively. All standardized differences in covariates were demic), were analyzed using a multivariate analysis of smaller than 0.1 (Table 1) and were homogenous between the propensity score–weighted population to determine the two groups [20]. hazard ratios (HRs). We calculated the propensity score and applied inverse probability of treatment weighting (IPTW) to create a pseudo-study cohort; the weighted Eec ff ts of adjuvant PMRT on oncologic outcomes in women cohort avoids covariate bias and mimics randomized with left‑side IDC and HFrEF receiving TM adjuvant PMRT or no adjuvant PMRT assignment: IPTW-adjusted models indicated that adjuvant PMRT IPTW for patients with PMRT = 1/p(PMRT); IPTW for was a significantly better independent prognostic factor patients without PMRT = 1/(1 − p[PMRT]) [18, 19]. The for OS, and LRR in the women with left IDC and HFrEF independent predictors were examined in multivariable receiving TM (Table  2). Adjuvant PMRT (adjusted HR analyses after IPTW adjustment. Moreover, they were [aHR]: 0.52; 95% confidence interval [CI]: 0.37–0.74) was controlled for and were stratified in the analysis. The a significant independent prognostic factor for all-cause endpoint was all-cause death in the women with left-side death (P = 0.0003; Table 2). In the IPTW-adjusted model, IDC and HFrEF who received TM followed by adjuvant the aHR (95% CI) for LRR in the adjuvant PMRT group PMRT (Group 1, case group) and in the women with left was 0.90 (0.79–0.96; P = 0.0356; Table  2) compared with IDC and HFrEF who received TM and had no adjuvant the no adjuvant PMRT group. Moreover, the aHR (95% PMRT (Group 2, control group). CIs) for DM in the adjuvant PMRT group was 0.89 (0.54– The cumulative incidence of death was estimated 1.50; P = 0.6854) compared with the no adjuvant PMRT using the Kaplan–Meier method, and differences in group (Table 2). the overall survival (OS), locoregional recurrence Zhang et al. Radiation Oncology (2022) 17:33 Page 4 of 11 Table 1 Demographics of patients with breast cancer and heart failure with reduced ejection fraction who received total mastectomy in the propensity score–weighted population through inverse probability of treatment weighting Propensity score weighting population Adjuvant RT Non‑RT Standardized N = 143 N = 503 difference n (%) n (%) Age Mean (SD) 67.5 (11.3) 67.7 (11.2) 0.0215 Median (Q1–Q3) 67 (57–72) 67 (61–77) 20–69 67 (46.9) 238 (47.9) 0.0096 70+ 76 (53.1) 259 (52.1) Diagnosis year 2009–2012 88 (50.9) 250 (50.3) 0.0115 2013–2016 85 (49.1) 247 (49.7) CCI scores 0 44 (30.8) 123 (24.5) 0.1433 1+ 99 (69.2) 380 (75.5) Differentiation I 20 (14.0) 72 (14.3) 0.0212 II 77 (53.8) 273 (54.3) 0.0311 III 46 (32.1) 158 (31.4) 0.0207 AJCC pathologic stage II 17 (12.8) 61 (12.1) 0.0114 IIIA 68 (47.6) 241 (47.9) 0.0162 IIIB–C 58 (40.6) 201 (40.0) 0.0142 pT pT1 9 (6.3) 30 (5.9) 0.0238 pT2 58 (40.6) 202 (40.2) 0.0149 pT3–4 76 (53.1) 271 (53.9) 0.0130 pN pN0 57 (39.8) 200 (39.8) 0.0000 pN1 43 (30.1) 151 (30.0) 0.0013 pN2–3 43 (30.1) 152 (30.2) 0.0001 Hypertension 110 (76.9) 387 (76.9) 0.0001 CAD 53 (37.1) 184 (36.6) 0.0092 Diabetes 60 (42.0) 215 (42.7) 0.0097 Anthracycline‑based chemotherapy 76 (53.1) 260 (51.7) 0.0280 Hormone receptor positive 59 (41.3) 229 (45.5) 0.0934 Trastuzumab use 69 (48.3) 246 (48.9) 0.0031 Nodal surgery ALND 87 (60.8) 302 (60.0) 0.0079 SLNB 56 (39.2) 201 (40.0) Hospital level Academic center 80 (55.9) 285 (56.7) 0.0181 Nonacademic center 63 (44.1) 218 (43.3) RT radiotherapy, IQR interquartile range, SD standard deviation, AJCC American Joint Committee on Cancer, HER2 human epidermal growth factor receptor-2, CCI Charlson comorbidity index, T tumor, N nodal, pT pathologic tumor stage, pN pathologic nodal stage, ALND axillary lymph node dissection, SNLB sentinel lymph node biopsy, CAD coronary arterial disease Zhang  et al. Radiation Oncology (2022) 17:33 Page 5 of 11 Table 2 Multivariate analysis of propensity score–weighted population with breast cancer and heart failure with reduced ejection fraction receiving total mastectomy Death Local recurrence Distant metastasis aHR* (95% CI) P value aHR* (95% CI) P value aHR* (95% CI) p value Adjuvant RT No Ref 0.0003 Ref 0.0356 Ref 0.6854 Yes 0.52 (0.37–0.74) 0.90 (0.79–0.96) 0.89 (0.54–1.50) Age 20–69 Ref 0.0020 Ref 0.1200 Ref 0.2901 70+ 1.63 (1.20–2.22) 1.29 (0.81–2.49) 0.75 (0.44–1.28) Diagnosis year 2009–2012 Ref 0.3507 Ref 0.2770 Ref 0.7421 2013–2016 0.79 (0.69–1.31) 0.73 (0.58–1.21) 0.81 (0.57–1.75) CCI scores 0 Ref 0.0322 Ref 0.1434 Ref 0.2112 1 1.26 (1.14–1.97) 1.21 (0.92–1.79) 1.35 (0.85–1.97) Differentiation I Ref 0.0177 Ref 0.0146 Ref 0.0046 II 1.09 (1.01–1.60) 1.36 (1.02–3.59) 1.36 (1.02–3.59) III 1.47 (1.09–2.40) 1.37 (1.11–3.71) 1.37 (1.01–3.71) pT pT1 Ref < 0.0001 Ref 0.0016 Ref 0.0196 pT2 1.38 (1.07–1.97) 1.35 (1.05–3.12) 1.09 (1.04–3.04) pT3–4 2.91 (1.90–4.44) 2.62 (1.19–4.72) 2.35 (1.13–4.89) pN pN0 Ref < 0.0001 Ref 0.0040 Ref 0.0082 pN1 1.94 (1.38–2.72) 1.09 (1.03–1.41) 2.38 (1.37–4.12) pN2–3 2.90 (2.01–4.18) 1.26 (1.06–1.37) 1.88 (1.01–3.51) Hypertension 1.08 (0.77–1.81) 0.4882 0.90 (0.59–1.56) 0.7217 0.95 (0.69–1.48) 0.8021 CAD 1.11 (0.71–1.92) 0.3427 0.84 (0.53–1.39) 0.6914 0.94 (0.78–1.59) 0.3426 Diabetes 1.11 (0.73–1.90) 0.3422 1.01 (0.70–1.51) 0.4521 0.90 (0.55–1.91) 0.8909 Hormone receptor positive 0.87 (0.80–0.91) 0.0312 0.77 (0.45–0.82) 0.0204 0.72 (0.63–0.97) 0.0322 Trastuzumab use 1.07 (0.87–1.42) 0.34661 1.09 (0.58–2.01) 0.3831 1.06 (0.81–1.54) 0.3421 Anthracycline‑based chemotherapy 0.94 (0.57–1.88) 0.4065 0.93 (0.78–1.83) 0.2412 0.84 (0.70–2.20) 0.1683 Nodal surgery ALND Ref 0.3322 Ref 0.2434 Ref 0.2112 SLNB 1.06 (0.54–1.09) 1.01 (0.82–1.79) 1.15 (0.85–2.97) Hospital level Academic center Ref 0.2177 Ref 0.2177 Ref 0.8146 Nonacademic center 0.99 (0.61–1.60) 0.99 (0.61–1.60) 1.36 (0.52–3.59) aHR adjusted hazard ratios, CIs confidence intervals, HR hormone receptor, Her-2 human epidermal growth factor receptor-2, CCI Charlson comorbidity index, T tumor, N nodal, pT pathologic tumor stage, pN pathologic nodal stage, ALND axillary lymph node dissection, SNLB sentinel lymph node biopsy, ref reference group, RT radiotherapy *All covariates mentioned in Table were adjusted Other independent predictors of all‑cause death, LRR, prognostic factors for OS (Table  2). IPTW-adjusted and DM in the women with left IDC and HFrEF receiving TM models were adjusted for age, diagnosis year, CCI Old age (> 70  years), CCI ≥ 1, advanced pT stages score, differentiation, pT, pN, hypertension, CAD, (pT2–4), advanced pN stages (pN1–3), hormone diabetes, chemotherapy with anthracycline-based receptor negative status, and differentiation Grade II regimen, hormone receptor status, trastuzumab use, and III were identified as crucial independent poor nodal surgery, and hospital levels; the aHRs (95% CIs) Zhang et al. Radiation Oncology (2022) 17:33 Page 6 of 11 Fig. 1 Kaplan–Meier overall survival curves of propensity score–weighted population with breast cancer and heart failure with reduced ejection fraction receiving total mastectomy Survival curves of adjuvant PMRT or no adjuvant PMRT of all-cause death for age > 70  years, CCI ≥ 1, differ- in women with left IDC and HFrEF receiving TM entiation Grades II and III, pT2, pT3–4, pN1, pN2– Figure  1 presents Kaplan–Meier curves that illustrate 3, and hormone receptor positive status were 1.63 the OS of the women with left IDC and HFrEF receiv- (1.20–2.22), 1.26 (1.14–1.97), 1.09 (1.01–1.60), 1.47 ing TM with adjuvant PMRT or no adjuvant PMRT. The (1.09–2.40), 1.38 (1.07–1.97), 2.91 (1.90–4.44), 1.94 5-year overall survival rates were 86.01% and 67.32% (1.38–2.72), 2.90 (2.01–4.18), and 0.87 (0.80–0.91) in the adjuvant PMRT and no adjuvant PMRT groups, compared with age 20–70  years, CCI = 0, differentia- respectively (Fig.  1); the OS rate was associated with an tion grade I, pT1, pN0, and hormone receptor negative increasing in the adjuvant PMRT group (log-rank test, status, respectively (Table  2). IPTW-adjusted models P = 0.0184) compared with the non-RT group. Addition- also revealed the aHRs (95% CIs) of LRR for differen- ally, the 5-year LRR-free survival in women with left IDC tiation grade II, differentiation grade III, pT2, pT3–4, and HFrEF receiving TM was 88.43% and 73.65% in the pN1, pN2–3, and hormone receptor positive status to adjuvant PMRT group and no adjuvant PMRT group, be 1.36 (1.02–3.59), 1.37 (1.11–3.71), 1.35 (1.05–3.12), respectively (Fig. 2; log-rank test, P = 0.0319). The 5-year 2.62 (1.19–4.72), 1.09 (1.03–1.41), 1.26 1.06–1.37), and DM-free survival in women with left IDC and HFrEF 0.77 (0.45–0.82) compared with differentiation grade receiving TM was 84.43% and 86.91% in the adjuvant I, pT1, pN0, and hormone receptor negative status, PMRT group and no adjuvant PMRT group, respectively respectively. Moreover, the aHRs (95% CIs) of DM for (Fig. 3; log-rank test, P = 0.8577). differentiation grade II, differentiation grade III, pT2, pT3–4, pN1, pN2–3, and hormone receptor positive Discussion status were 1.36 (1.02–3.59), 1.37 (1.01–3.71), 1.09 PMRT has two potential benefits: one is a decrease in (1.04–3.04), 2.35 (1.13–4.89), 2.38 (1.37–4.12), 1.88 the rate of locoregional recurrence, and another is an (1.01–3.51), and 0.72 (0.63–0.97) compared with dif increase in long-term breast cancer-specific and over - ferentiation grade I, pT1, pN0, and hormone receptor all survivals for certain patient populations. These ben - negative status, respectively. efits have been consistently reported in multiple studies Zhang  et al. Radiation Oncology (2022) 17:33 Page 7 of 11 Fig. 2 Kaplan–Meier locoregional recurrence‑free survival curves of propensity score–weighted population with breast cancer and heart failure with reduced ejection fraction receiving total mastectomy [21–23]. Decisions on who should receive PMRT depend explore the value of adjuvant PMRT for women with left- on the baseline risk for recurrence. The success of RT, side breast IDC and HFrEF receiving TM. As shown in used either alone or in combination with other modali- Table 2, adjuvant PMRT resulted in better OS, and LRR- ties, has resulted in large cohorts of breast cancer sur- free status compared with no adjuvant PMRT in women vivors who are vulnerable to late complications such as with left-side breast IDC and HFrEF receiving TM. The RICT from RT [5, 24–30]. Numerous treatment-related potential reasons might be the recent decline in mortality factors are responsible for cardiotoxicity in women with in women with HF [43, 44] and the advances in contem- breast cancer [31–41]. Thus, we conducted the study porary RT techniques with reduced irradiation volumes to determine the survival benefits offered by adjuvant to the heart [2, 26, 27]. PMRT in women with left-side IDC and HFrEF receiving According to our literature review, this is the first study TM. to estimate the oncologic outcomes of adjuvant PMRT Patients with breast cancer might experience adverse among women with left-side breast IDC and HFrEF effects from many cardiotoxic treatments such as adju - receiving TM. No consensus or evidence for the use of vant PMRT, anthracycline-based chemotherapy, or tras- adjuvant PMRT in women with left-side breast IDC and tuzumab [5, 6, 24–41]. Although cardiovascular diseases HFrEF receiving TM is present. In the IPTW-adjusted such as HF, heart attacks, and stroke remain the leading models, adjuvant PMRT was associated with a decrease cause of death in women, many believe breast cancer to in the risk of all-cause death, and LRR among women be more deadly [42]. In fact, the risk of RICT should be with left-side breast IDC and HFrEF receiving TM weighed against the potential benefits of adjuvant PMRT (Table  2). The improvement in contemporary RT tech - with respect to the patients’ prognosis and likely clinical niques with decreased irradiation doses and decreased benefit [5, 24–30]. Until now, no data have been available volumes to the heart and the long-term improvement in for the evaluation of oncologic outcomes (OS, LRR, and mortality rates in patients with HFrEF over time might DM) of adjuvant PMRT in women with left-side breast have caused the significant beneficial oncologic out - IDC and HFrEF receiving TM. This is the first study to comes of adjuvant PMRT in women with left-side breast Zhang et al. Radiation Oncology (2022) 17:33 Page 8 of 11 Fig. 3 Kaplan–Meier distant metastasis–free survival curves of propensity score–weighted population with breast cancer and heart failure with reduced ejection fraction receiving total mastectomy IDC and HFrEF receiving TM [2, 26, 27]. Our study is the prognostic factor has been identified in previous studies first to demonstrate that the potential benefits of adju - other than the ones determined in the current study irre- vant PMRT with contemporary RT techniques outweigh spective of whether underlying HFrEF was present. the risk of RICT given the patients’ prognosis and likely The potential reasons of better oncologic outcomes long-term OS and LRR benefits (Table  2). According to on adjuvant PMRT for breast IDC with HFrEF might be our findings, we strongly suggested that women with attributed to the modern RT techniques. The use of mod - left-side breast IDC and HFrEF receiving TM should also ern RT techniques (such as IMRT and VMAT) as well as receive adjuvant PMRT to decrease the risk of all-cause the reduction of treatment volumes (partial breast irradi- death, and LRR. ation) allow to reduce acute and late side effects [53–55]. As shown in Table  2, adjuvant PMRT was a significant The contemporary RT techniques allow more precise RT prognostic factor for OS and LRR compared with no field to target volume and decrease RT dose-volume to adjuvant PMRT in women with left-side IDC and HFrEF heart contributed to less RICT [53, 54]. Therefore, breast receiving TM; moreover, old age (> 70  years), CCI ≥ 1, IDC patients with HFrEF receiving TM and adjuvant advanced pT stages (pT2–4), advanced pN stages (pN1– PMRT could get benefits from PMRT and less acute and 3), hormone receptor negative status, and differentia - late toxicity to heart contributed to better oncologic out- tion Grade II–III were significant prognostic factors for comes like OS and LRR-free survival (Table 2, Figs. 1, 2). OS, compatible with findings of previous studies [10, 11, A strength of our study was that it was the first 45–52]. Moreover, advanced pT stages (pT2-4), pN stages cohort study to estimate the survival outcomes of adju- (pN1–3), hormone receptor negative status, and differen - vant PMRT or no adjuvant PMRT among women with tiation Grade II–III were significant poor prognostic fac - left-side IDC and HFrEF receiving TM. The covariates tors for LRR and DM in women with left-side breast IDC between the adjuvant PMRT and no adjuvant PMRT and HFrEF receiving TM, which is also compatible with groups were homogenous for women with left-side IDC findings of previous studies [10, 11, 45–52]. Our findings and HFrEF receiving TM, with no selection bias (Table 1). of prognostic factors for OS, LRR, and DM in women No study has estimated the effect of adjuvant PMRT on with IDC and HFrEF receiving TM are similar with those women with left-side IDC and HFrEF receiving TM. In of previous studies [10, 11, 45–52], and no additional our study, the poor prognostic factors for OS in women Zhang  et al. Radiation Oncology (2022) 17:33 Page 9 of 11 with left-side IDC and HFrEF receiving TM were old PMRT. We suggest adjuvant PMRT for women with age, CCI ≥ 1, advanced pT stages (pT2–4), advanced pN left-side IDC receiving TM, even if they have HFrEF. stages (pN1–3), hormone receptor negative status, and differentiation Grade II–III of (Table  2), which are con- Abbreviations sistent with factors in women with breast cancer without PMRT: Postmastectomy RT; LRR: Locoregional recurrence; DM: Distant HFrEF reported in previous studies [48–52]. Further- metastasis; IDC: Invasive ductal carcinoma; HFrEF: Heart failure with reduced ejection fraction; TM: Total mastectomy; OS: Overall survival; aHR: Adjusted more, our study is the first to demonstrate the benefits hazard ratio; HR: Hazard ratio; IPTW: Inverse probability of treatment weight‑ of adjuvant PMRT with contemporary RT techniques ing; CI: Confidence interval; AJCC: American Joint Committee on Cancer; for OS, LRR, and DM in women with left-side IDC and TCRD: Taiwan Cancer Registry Database; SD: Standard deviation; HER2: Human epidermal growth factor receptor‑2; SLNB: Sentinel lymph node biopsy; ALND: HFrEF receiving TM. Our findings should be considered Axillary lymph node dissection; CCI: Charlson comorbidity index; ICD‑10‑ CM: in future clinical practice and prospective clinical trials of International Classification of Diseases, 10th Revision, Clinical Modification; HF and RT for breast cancer. We suggest that adjuvant NCCN: National Comprehensive Cancer Network; RT: Radiotherapy; RICT: Radiotherapy‑related cardiotoxicity; TM: Total mastectomy; HF: Heart failure; PMRT is valuable to achieving better outcomes of OS, LV: Left ventricular; LVEF: Left ventricular ejection fraction; T: Tumor; N: Nodal; LRR, and DM in women with left-side IDC and HFrEF pT: Pathologic tumor stage; pN: Pathologic nodal stage; NHIRD: National receiving TM. Health Insurance Research Database. This study has some limitations. First, because all Acknowledgements women with left-side breast IDC and HFrEF were Lo‑Hsu Medical Foundation, Lotung Poh‑Ai Hospital, supports Szu‑ Yuan enrolled from an Asian population, the correspond- Wu’s work (Funding Number: 10908, 10909, 11001, 11002, 11003, 11006, and 11013). Taipei Medical University‑ Wan Fang Hospital (Funding Number: ing ethnic susceptibility compared with the non-Asian 107TMU‑ WFH‑08) supports Tsai‑Mu Cheng’s work. population remains unclear; hence, our results should Access to data statement: We used data from the National Health Insurance be cautiously extrapolated to non-Asian populations. Research Database (NHIRD) and Taiwan Cancer Registry database ( TCRD). The authors confirm that, for approved reasons, some access restrictions apply However, no evidence exists as to the differences in onco - to the data underlying the findings. The data utilized in this study cannot be logic outcomes in Asian versus non-Asian patients with made available in the manuscript, the supplemental files, or in a public reposi‑ breast IDC and HFrEF receiving TM. Second, a weak tory due to the “Personal Information Protection Act” executed by Taiwan’s government, starting from 2012. Requests for data can be sent as a formal pro‑ point of the study that the median follow up (6.96 and posal to obtain approval from the ethics review committee of the appropriate 5.09  years) could be too short for evaluation the impact governmental department in Taiwan. Specifically, links regarding contact info on breast cancer survival or late heart side effects. Third, for which data requests may be sent to are as follows: http:// nhird. nhri. org. tw/ en/ Data_ Subse ts. html# S3 and http:// nhis. nhri. org. tw/ point. html. Szu‑ Yuan the diagnoses of all comorbid conditions were based on Wu, MD, PhD had full access to all the data in the study and takes responsibil‑ ICD-10-CM codes. However, the combination of Tai- ity for the integrity of the data and the accuracy of the data analysis. wanese TCRD and National Health Insurance Research Role of funder statement: Lo‑Hsu Medical Foundation, Lotung Poh‑Ai Hos‑ pital, supports Szu‑ Yuan Wu’s work (Funding Number: 10908, 10909, 11001, Database (NHIRD) data appears to be a valid resource for 11002, 11003, 11006, and 11013) for design and conduct of the study. population research on cardiovascular diseases, stroke, or chronic comorbidities [56–58]. Moreover, the Taiwan Authors’ contributions Conception and design: JZ, S‑ YW; Financial support: Lo‑Hsu Medical Founda‑ Cancer Registry Administration randomly reviews charts tion, Lotung Poh‑Ai Hospital, supports Szu‑ Yuan Wu’s work (Funding Number: and interviews patients to verify the accuracy of the diag- 10908, 10909, 11001, 11002, 11003, 11006, and 11013). Taipei Medical noses, and hospitals with outlier chargers or practices University‑ Wan Fang Hospital (Funding Number: 107TMU‑ WFH‑08) supports Tsai‑Mu Cheng’s work. Collection and assembly of data: JZ, S‑ YS, S‑ YW. Data may be audited and subsequently be heavily penalized if analysis and interpretation: JZ, J‑ GH, M‑FC, T ‑SL. Administrative support: S‑ YW; any malpractice or discrepancy is detected. Accordingly, Manuscript writing: JZ, S‑ YS, M‑FC, S‑ YW. All authors read and approved the to obtain crucial information on population specificity final manuscript. and disease occurrence, a large-scale randomized trial Funding comparing carefully selected patients undergoing suit- Lo‑Hsu Medical Foundation, Lotung Poh‑Ai Hospital, supports Szu‑ Yuan able treatments is essential. Finally, the TCRD does not Wu’s work (Funding Number: 10908, 10909, 11001, 11002, 11003, 11006, and 11013). Taipei Medical University‑ Wan Fang Hospital (Funding Number: contain information regarding dietary habits or body 107TMU‑ WFH‑08) supports Tsai‑Mu Cheng’s work. mass index, which may be risk factors for mortality. Nevertheless, considering the magnitude and statistical Availability of data and materials The data sets supporting the study conclusions are included in this manu‑ significance of the observed effects in this study, these script and its supplementary files. limitations are unlikely to affect the conclusions. For software: Project name: not applicable; Project homepage: not appli‑ cable; Archived version: not applicable; Operating system(s): not applicable; Programming language: not applicable; Other requirements: not applicable; License: not applicable; Any restrictions for use by nonacademicians: not Conclusions applicable. Adjuvant PMRT was associated with a decrease in all-cause death and LRR among women with left-side breast IDC and HFrEF compared with no adjuvant Zhang et al. Radiation Oncology (2022) 17:33 Page 10 of 11 special contribution of the Heart Failure Association (HFA) of the ESC. Eur Declarations Heart J. 2016;37(27):2129–200. 9. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner Ethics approval and consent to participate MH, Filippatos GS, Fonarow GC, Givertz MM, et al. 2017 ACC/AHA/HFSA The study protocols were reviewed and approved by the Institutional Review focused update of the 2013 ACCF/AHA guideline for the management Board of Tzu‑ Chi Medical Foundation (IRB109‑015‑B). of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Consent for publication Failure Society of America. Circulation. 2017;136(6):e137–61. Not applicable. 10. Zhang J, Lu CY, Chen CH, Chen HM, Wu SY. Eec ff t of pathologic stages on postmastectomy radiation therapy in breast cancer receiving neoadju‑ Competing interests vant chemotherapy and total mastectomy: a cancer database analysis. The authors have no potential competing interests to declare. The data sets Breast. 2020;54:70–8. supporting the study conclusions are included in the manuscript. 11. Zhang J, Lu CY, Qin L, Chen HM, Wu SY. Breast‑ conserving surgery with or without irradiation in women with invasive ductal carcinoma of the Author details breast receiving preoperative systemic therapy: a cohort study. Breast. Department of Anesthesiology and Perioperative Medicine, Henan Provincial 2020;54:139–47. People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, 12. Zhang J, Lu CY, Chen HM, Wu SY. Neoadjuvant chemotherapy or Henan, China. Department of General Surgery, Lo‑Hsu Medical Foundation, endocrine therapy for invasive ductal carcinoma of the breast with high Lotung Poh‑Ai Hospital, Yilan, Taiwan. Graduate Institute of Business Adminis‑ hormone receptor positivity and human epidermal growth factor recep‑ tration, Fu Jen Catholic University, Taipei, Taiwan. Division of Gastroenterology tor 2 negativity. JAMA Netw Open. 2021;4(3):e211785. and Hepatology, Department of Internal Medicine, Lo‑Hsu Medical Founda‑ 13. Liu WC, Liu HE, Kao YW, Qin L, Lin KC, Fang CY, Tsai LL, Shia BC, Wu SY. tion, Lotung Poh‑Ai Hospital, Yilan, Taiwan. Department of Food Nutrition Definitive radiotherapy or surgery for early oral squamous cell carcinoma and Health Biotechnology, College of Medical and Health Science, Asia Univer‑ in old and very old patients: a propensity‑score ‑matched, nationwide, sity, Taichung, Taiwan. Big Data & Cancer Center, Lo‑Hsu Medical Foundation, population‑based cohort study. Radiother Oncol. 2020;151:214–21. Lotung Poh‑Ai Hospital, Yilan, Taiwan. Division of Radiation Oncology, Lo‑Hsu 14. NCCN Clinical practice guidelines in oncology. http:// www. nccn. org/ Medical Foundation, Lotung Poh‑Ai Hospital, No. 83, Nanchang St., Luodong profe ssion als/ physi cian_ gls/f_ guide lines. asp. Township, Yilan County 265, Taiwan. Department of Healthcare Administra‑ 15. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, tion, College of Medical and Health Science, Asia University, Taichung, Taiwan. Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, et al. American Society Cancer Center, Lo‑Hsu Medical Foundation, Lotung Poh‑Ai Hospital, Yilan, of Clinical Oncology/College Of American Pathologists guideline recom‑ Taiwan. Centers for Regional Anesthesia and Pain Medicine, Taipei Municipal mendations for immunohistochemical testing of estrogen and progester‑ Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. one receptors in breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(16):2784–95. Received: 18 November 2021 Accepted: 28 January 2022 16. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47(11):1245–51. 17. Chen JH, Yen YC, Yang HC, Liu SH, Yuan SP, Wu LL, Lee FP, Lin KC, Lai MT, Wu CC, et al. Curative‑intent aggressive treatment improves survival in elderly patients with locally advanced head and neck squamous References cell carcinoma and high comorbidity index. Medicine (Baltimore). 1. Hooning MJ, Botma A, Aleman BM, Baaijens MH, Bartelink H, Klijn JG, 2016;95(14):e3268. Taylor CW, van Leeuwen FE. Long‑term risk of cardiovascular disease in 18. Lin SH, Wang L, Myles B, Thall PF, Hofstetter WL, Swisher SG, Ajani JA, Cox 10‑ year survivors of breast cancer. J Natl Cancer Inst. 2007;99(5):365–75. JD, Komaki R, Liao Z. Propensity score‑based comparison of long‑term 2. Travis LB, Ng AK, Allan JM, Pui CH, Kennedy AR, Xu XG, Purdy JA, outcomes with 3‑ dimensional conformal radiotherapy versus intensity‑ Applegate K, Yahalom J, Constine LS, et al. Second malignant neoplasms modulated radiotherapy for esophageal cancer. Int J Radiat Oncol Biol and cardiovascular disease following radiotherapy. J Natl Cancer Inst. Phys. 2012;84(5):1078–85. 2012;104(5):357–70. 19. Austin PC, Stuart EA. Moving towards best practice when using inverse 3. Moslehi J. The cardiovascular perils of cancer survivorship. N Engl J Med. probability of treatment weighting (IPTW ) using the propensity score 2013;368(11):1055–6. to estimate causal treatment effects in observational studies. Stat Med. 4. Darby SC, Ewertz M, McGale P, Bennet AM, Blom‑ Goldman U, Bronnum 2015;34(28):3661–79. D, Correa C, Cutter D, Gagliardi G, Gigante B, et al. Risk of ischemic heart 20. Austin PC. Balance diagnostics for comparing the distribution of baseline disease in women after radiotherapy for breast cancer. N Engl J Med. covariates between treatment groups in propensity‑score matched 2013;368(11):987–98. samples. Stat Med. 2009;28(25):3083–107. 5. Paszat LF, Mackillop WJ, Groome PA, Schulze K, Holowaty E. Mortality from 21. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, Godwin myocardial infarction following postlumpectomy radiotherapy for breast J, Gray R, Hicks C, James S, et al. Eec ff ts of radiotherapy and of differ ‑ cancer: a population‑based study in Ontario, Canada. Int J Radiat Oncol ences in the extent of surgery for early breast cancer on local recurrence Biol Phys. 1999;43(4):755–62. and 15‑ year survival: an overview of the randomised trials. Lancet. 6. Hojris I, Overgaard M, Christensen JJ, Overgaard J. Morbidity and mortal‑ 2005;366(9503):2087–106. ity of ischaemic heart disease in high‑risk breast ‑ cancer patients after 22. Danish Breast Cancer Cooperative G, Nielsen HM, Overgaard M, Grau C, adjuvant postmastectomy systemic treatment with or without radio‑ Jensen AR, Overgaard J. Study of failure pattern among high‑risk breast therapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy cancer patients with or without postmastectomy radiotherapy in addi‑ Committee of the Danish Breast Cancer Cooperative Group. Lancet. tion to adjuvant systemic therapy: long‑term results from the Danish 1999;354(9188):1425–30. Breast Cancer Cooperative Group DBCG 82 b and c randomized studies. J 7. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fon‑ Clin Oncol: Off J Amer Soc Clin Oncol 2006;24(15):2268–2275. arow GC, Geraci SA, Horwich T, Januzzi JL, et al. 2013 ACCF/AHA guideline 23. Ragaz J, Olivotto IA, Spinelli JJ, Phillips N, Jackson SM, Wilson KS, Knowling for the management of heart failure: executive summary: a report of the MA, Coppin CM, Weir L, Gelmon K, et al. Locoregional radiation therapy in American College of Cardiology Foundation/American Heart Association patients with high‑risk breast cancer receiving adjuvant chemotherapy: Task Force on practice guidelines. Circulation. 2013;128(16):1810–52. 20‑ year results of the British Columbia randomized trial. J Natl Cancer Inst. 8. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk 2005;97(2):116–26. V, Gonzalez‑ Juanatey JR, Harjola VP, Jankowska EA, et al. 2016 ESC guide‑ 24. Yu JM, Hsieh MC, Qin L, Zhang J, Wu SY. Metformin reduces radiation‑ lines for the diagnosis and treatment of acute and chronic heart failure: induced cardiac toxicity risk in patients having breast cancer. Am J Cancer the Task Force for the diagnosis and treatment of acute and chronic heart Res. 2019;9(5):1017–26. failure of the European Society of Cardiology (ESC) developed with the Zhang  et al. Radiation Oncology (2022) 17:33 Page 11 of 11 25. Lee CH, Zhang JF, Yuan KS, Wu ATH, Wu SY. Risk of cardiotoxicity induced 44. Shen L, Jhund PS, Petrie MC, Claggett BL, Barlera S, Cleland JGF, Dargie HJ, by adjuvant anthracycline‑based chemotherapy and radiotherapy in Granger CB, Kjekshus J, Kober L, et al. Declining risk of sudden death in young and old Asian women with breast cancer. Strahlenther Onkol. heart failure. N Engl J Med. 2017;377(1):41–51. 2019;195:629–39. 45. Zhang J, Sun M, Chang E, Lu CY, Chen HM, Wu SY. Pathologic response as 26. Giordano SH, Kuo YF, Freeman JL, Buchholz TA, Hortobagyi GN, Goodwin predictor of recurrence, metastasis, and survival in breast cancer patients JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J receiving neoadjuvant chemotherapy and total mastectomy. Am J Can‑ Natl Cancer Inst. 2005;97(6):419–24. cer Res. 2020;10(10):3415–27. 27. Darby SC, McGale P, Taylor CW, Peto R. Long‑term mortality from heart 46. Zhang J, Qin L, Chen HM, Hsu HC, Chuang CC, Chen D, Wu SY. Overall disease and lung cancer after radiotherapy for early breast cancer: survival, locoregional recurrence, and distant metastasis of definitive prospective cohort study of about 300,000 women in US SEER cancer concurrent chemoradiotherapy for cervical squamous cell carcinoma and registries. Lancet Oncol. 2005;6(8):557–65. adenocarcinoma: before and after propensity score matching analysis of 28. Patt DA, Goodwin JS, Kuo YF, Freeman JL, Zhang DD, Buchholz TA, Horto‑ a cohort study. Am J Cancer Res. 2020;10(6):1808–20. bagyi GN, Giordano SH. Cardiac morbidity of adjuvant radiotherapy for 47. Zhang J, Lu CY, Chen HM, Wu SY. Pathologic response rates for breast breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(30):7475–82. cancer stages as a predictor of outcomes in patients receiving neoadju‑ 29. Taylor CW, Bronnum D, Darby SC, Gagliardi G, Hall P, Jensen MB, McGale vant chemotherapy followed by breast‑ conserving surgery. Surg Oncol. P, Nisbet A, Ewertz M. Cardiac dose estimates from Danish and Swed‑ 2020;36:91–8. ish breast cancer radiotherapy during 1977–2001. Radiother Oncol. 48. Yoo S, Lee HB, Han W, Noh DY, Park SK, Kim WH, Kim JT. Total intravenous 2011;100(2):176–83. anesthesia versus inhalation anesthesia for breast cancer surgery: a 30. McGale P, Darby SC, Hall P, Adolfsson J, Bengtsson NO, Bennet AM, For‑ retrospective cohort study. Anesthesiology. 2019;130(1):31–40. nander T, Gigante B, Jensen MB, Peto R, et al. Incidence of heart disease 49. Oh TK, Kim HH, Jeon Y T. Retrospective analysis of 1‑ year mortality after in 35,000 women treated with radiotherapy for breast cancer in Denmark gastric cancer surgery: total intravenous anesthesia versus volatile anes‑ and Sweden. Radiother Oncol. 2011;100(2):167–75. thesia. Acta Anaesthesiol Scand. 2019;63(9):1169–77. 31. Boekel NB, Jacobse JN, Schaapveld M, Hooning MJ, Gietema JA, Duane 50. Lee JH, Kang SH, Kim Y, Kim HA, Kim BS. Eec ff ts of propofol‑based total FK, Taylor CW, Darby SC, Hauptmann M, Seynaeve CM, et al. Cardio‑ intravenous anesthesia on recurrence and overall survival in patients after vascular disease incidence after internal mammary chain irradiation modified radical mastectomy: a retrospective study. Korean J Anesthesiol. and anthracycline‑based chemotherapy for breast cancer. Br J Cancer. 2016;69(2):126–32. 2018;119(4):408–18. 51. Enlund M, Berglund A, Ahlstrand R, Wallden J, Lundberg J, Warnberg 32. Early Breast Cancer Trialists’ Collaborative G, Peto R, Davies C, Godwin J, F, Ekman A, Sjoblom Widfeldt N, Enlund A, Bergkvist L. Survival after Gray R, Pan HC, Clarke M, Cutter D, Darby S, McGale P, et al. Comparisons primary breast cancer surgery following propofol or sevoflurane general between different polychemotherapy regimens for early breast cancer: anesthesia—a retrospective, multicenter, database analysis of 6305 meta‑analyses of long‑term outcome among 100,000 women in 123 Swedish patients. Acta Anaesthesiol Scand. 2020;64(8):1048–54. randomised trials. Lancet. 2012;379(9814):432–44. 52. Makito K, Matsui H, Fushimi K, Yasunaga H. Volatile versus total intrave‑ 33. Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, nous anesthesia for cancer prognosis in patients having digestive cancer Hopkins JO, O’Shaughnessy JA, Dang CT, et al. Anthracyclines in early surgery. Anesthesiology. 2020;133(4):764–73. breast cancer: the ABC Trials‑USOR 06–090, NSABP B‑46‑I/USOR 07132, 53. Fiorentino A, Gregucci F, Mazzola R, Figlia V, Ricchetti F, Sicignano G, and NSABP B‑49 (NRG Oncology). J Clin Oncol Off J Am Soc Clin Oncol. Giajlevra N, Ruggieri R, Fersino S, Naccarato S, et al. Intensity‑modulated 2017;35(23):2647–55. radiotherapy and hypofractionated volumetric modulated arc therapy for 34. Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, elderly patients with breast cancer: comparison of acute and late toxici‑ Galderisi M, Habib G, Lenihan DJ, Lip GYH, Lyon AR, et al. 2016 ESC posi‑ ties. Radiol Med. 2019;124(4):309–14. tion paper on cancer treatments and cardiovascular toxicity developed 54. Meduri B, Gregucci F, D’Angelo E, Alitto AR, Ciurlia E, Desideri I, Marino L, under the auspices of the ESC Committee for Practice Guidelines: the Borghetti P, Fiore M, Fiorentino A, et al. Volume de‑ escalation in radiation Task Force for cancer treatments and cardiovascular toxicity of the Euro‑ therapy: state of the art and new perspectives. J Cancer Res Clin Oncol. pean Society of Cardiology (ESC). Eur Heart J. 2016;37(36):2768–801. 2020;146(4):909–24. 35. Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, 55. Fiorentino A, Mazzola R, Giaj Levra N, Fersino S, Ricchetti F, Di Paola G, Civelli M, Lamantia G, Colombo N, Curigliano G, et al. Early detection of Gori S, Massocco A, Alongi F. Comorbidities and intensity‑modulated anthracycline cardiotoxicity and improvement with heart failure therapy. radiotherapy with simultaneous integrated boost in elderly breast cancer Circulation. 2015;131(22):1981–8. patients. Aging Clin Exp Res. 2018;30(5):533–8. 36. Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, 56. Cheng CL, Lee CH, Chen PS, Li YH, Lin SJ, Yang YH. Validation of acute Muggia FM. Risk factors for doxorubicin‑induced congestive heart failure. myocardial infarction cases in the National Health Insurance Research Ann Intern Med. 1979;91(5):710–7. Database in Taiwan. J Epidemiol. 2014;24(6):500–7. 37. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients 57. Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. Validation of the National Health treated with doxorubicin: a retrospective analysis of three trials. Cancer. Insurance Research Database with ischemic stroke cases in Taiwan. Phar‑ 2003;97(11):2869–79. macoepidemiol Drug Saf. 2011;20(3):236–42. 38. Schwartz RG, McKenzie WB, Alexander J, Sager P, D’Souza A, Manatunga 58. Lin CC, Lai MS, Syu CY, Chang SC, Tseng FY. Accuracy of diabetes diag‑ A, Schwartz PE, Berger HJ, Setaro J, Surkin L, et al. Congestive heart failure nosis in health insurance claims data in Taiwan. J Formos Med Assoc. and left ventricular dysfunction complicating doxorubicin therapy. 2005;104(3):157–63. Seven‑ year experience using serial radionuclide angiocardiography. Am J Med. 1987;82(6):1109–18. Publisher’s Note 39. Keefe DL. Trastuzumab‑associated cardiotoxicity. Cancer. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 2002;95(7):1592–600. lished maps and institutional affiliations. 40. Perez EA, Rodeheffer R. Clinical cardiac tolerability of trastuzumab. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(2):322–9. 41. Fiuza M. Cardiotoxicity associated with trastuzumab treatment of HER2+ breast cancer. Adv Ther. 2009;26(Suppl 1):S9‑17. 42. Mehta LS, Watson KE, Barac A, Beckie TM, Bittner V, Cruz‑Flores S, Dent S, Kondapalli L, Ky B, Okwuosa T, et al. Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the American Heart Association. Circulation. 2018;137(8):e30–66. 43. Roger VL, Weston SA, Redfield MM, Hellermann‑Homan JP, Killian J, Yawn BP, Jacobsen SJ. Trends in heart failure incidence and survival in a community‑based population. JAMA. 2004;292(3):344–50.

Journal

Radiation OncologySpringer Journals

Published: Feb 12, 2022

Keywords: Breast cancer; Radiation-induced cardiovascular toxicity; Total mastectomy; Radiotherapy; Survival

References