Advertisement

Timing of postmastectomy radiotherapy following adjuvant chemotherapy for high-risk breast cancer: A post hoc analysis of a randomised controlled clinical trial

  • Author Footnotes
    1 Si-Ye Chen, Guang-Yi Sun, and Yu Tang contributed equally to this work.
    Si-Ye Chen
    Footnotes
    1 Si-Ye Chen, Guang-Yi Sun, and Yu Tang contributed equally to this work.
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Author Footnotes
    1 Si-Ye Chen, Guang-Yi Sun, and Yu Tang contributed equally to this work.
    Guang-Yi Sun
    Footnotes
    1 Si-Ye Chen, Guang-Yi Sun, and Yu Tang contributed equally to this work.
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Author Footnotes
    1 Si-Ye Chen, Guang-Yi Sun, and Yu Tang contributed equally to this work.
    Yu Tang
    Footnotes
    1 Si-Ye Chen, Guang-Yi Sun, and Yu Tang contributed equally to this work.
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

    Department of Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Hao Jing
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Yong-Wen Song
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Jing Jin
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Yue-Ping Liu
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Xu-Ran Zhao
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Yu-Chun Song
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Bo Chen
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Shu-Nan Qi
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Yuan Tang
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Ning-Ning Lu
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Ning Li
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Hui Fang
    Correspondence
    Corresponding author:
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Ye-Xiong Li
    Correspondence
    Corresponding author:
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

    State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Shu-Lian Wang
    Correspondence
    Corresponding author:
    Affiliations
    Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
    Search for articles by this author
  • Author Footnotes
    1 Si-Ye Chen, Guang-Yi Sun, and Yu Tang contributed equally to this work.
Open AccessPublished:August 20, 2022DOI:https://doi.org/10.1016/j.ejca.2022.07.023

      Highlights

      • Delays in initiating PMRT compromise distant control and survival.
      • Up to 210 days after mastectomy and 42 days after chemotherapy may be acceptable.
      • Studies on RT should evaluate endpoints beyond locoregional recurrence.

      Abstract

      Purpose

      To investigate the appropriate timing of radiotherapy (RT) after mastectomy and adjuvant chemotherapy for women with high-risk breast cancer.

      Patients and methods

      Post hoc analyses of 584 patients with stage II and III breast cancer from a randomised controlled clinical trial were performed. All patients underwent mastectomy followed by sequential chemotherapy and RT. The optimal cut-off values for the surgery-RT interval (SRI) and the chemotherapy-RT interval (CRI) for overall survival (OS) were determined using the hazard ratio for continuous predictors. The locoregional recurrence (LRR), distant metastasis (DM), disease-free survival (DFS), and OS rates were estimated using the Kaplan–Meier method. Multivariate analyses were performed using Cox proportional hazards regression.

      Results

      Median follow-up time was 83.5 months. Median SRI and CRI were 168 and 27 days, respectively. An SRI of >210 days was independently associated with higher DM (HR 2.65, 95% CI: 1.49–4.71; HR 2.78, 95% CI 1.51–5.26), lower OS (HR 2.44, 95% CI: 1.28–4.54; HR 2.50, 95% CI: 1.41–4.35), and lower DFS (HR 2.57, 95% CI: 1.45–4.57; HR 2.70, 95% CI: 1.45–5.00) than SRI of <180 or 180–210 days. Furthermore, a CRI of more than 42 days was independently associated with higher DM (HR 1.89, 95% CI: 1.17–3.06; HR 1.96, 95% CI: 1.19–3.22), lower OS (HR 2.44, 95% CI: 1.41–4.35; HR 1.92, 95% CI: 1.10–3.33), and lower DFS (HR 1.84, 95% CI: 1.14–2.96; HR 1.82, 95% CI: 1.12–2.94) than a CRI of <28 or 28–42 days. However, SRI and CRI had no significant effect on LRR.

      Conclusions

      Based on the present findings, the timing of the initiation of RT both after mastectomy and after the completion of adjuvant chemotherapy is crucial for patients with high-risk breast cancer.

      Keywords

      1. Introduction

      For patients with high-risk breast cancer who undergo upfront mastectomy, both adjuvant chemotherapy and post-mastectomy radiotherapy (PMRT) play an important role in reducing the risk of tumour recurrence and mortality [
      • Early Breast Cancer Trialists' Collaborative G.
      Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.
      ,
      • Ebctcg
      • McGale P.
      • Taylor C.
      • Correa C.
      • Cutter D.
      • Duane F.
      • et al.
      Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials.
      ]. Currently, there is little controversy regarding the sequence of chemotherapy and radiotherapy (RT) after surgery for high-risk breast cancer, with adjuvant chemotherapy commonly administered prior to RT [
      • Pinnaro P.
      • Rambone R.
      • Giordano C.
      • Giannarelli D.
      • Strigari L.
      • Arcangeli G.
      Long-term results of a randomized trial on the sequencing of radiotherapy and chemotherapy in breast cancer.
      ,
      • Geurts Y.M.
      • Witteveen A.
      • Bretveld R.
      • Poortmans P.M.
      • Sonke G.S.
      • Strobbe L.J.A.
      • et al.
      Patterns and predictors of first and subsequent recurrence in women with early breast cancer.
      ]. However, the appropriate length of PMRT delay that does not adversely impact the outcomes has not been specifically addressed. Additionally, there are no evidence-supported standard guidelines on the timing of RT after mastectomy, especially in the modern treatment era.
      When adjuvant chemotherapy precedes RT, the determination of the interval between surgery and RT is complicated by multiple factors, such as the initiation of chemotherapy, course of chemotherapy, and initiation of RT. Due to its ability to improve tumour control and survival, long-course chemotherapy with anthracyclines and taxanes is currently recommended for most patients with node-positive disease [
      • Curigliano G.
      • Burstein H.J.
      • Winer E.P.
      • Gnant M.
      • Dubsky P.
      • Loibl S.
      • et al.
      De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen international expert consensus conference on the primary therapy of early breast cancer 2017.
      ,
      • Early Breast Cancer Trialists' Collaborative G.
      • Peto R.
      • Davies C.
      • Godwin J.
      • Gray R.
      • Pan H.C.
      • et al.
      Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.
      ]. As a result, the interval between surgery and RT has accordingly been extended because of the increase in the number of chemotherapy cycles. However, the majority of previous studies investigating the potential negative impacts of delayed RT used the interval between surgery and RT as a definition for the time frame. The interval between surgery and RT is influenced by the duration of the prescribed chemotherapy regimen and the waiting time between chemotherapy and RT. In this context, determining the interval between the last dose of chemotherapy and RT would be a better and more modifiable approach than evaluating the interval between surgery and RT alone. Nonetheless, research on the effect of chemotherapy-RT interval on outcomes is even scarcer. Therefore, this study sought to investigate the effect of the timing of RT initiation both after mastectomy and adjuvant chemotherapy on tumour recurrence and survival in women with high-risk breast cancer who had enrolled in a prospective randomised clinical trial.

      2. Materials and methods

      2.1 Patient selection

      This study was a secondary analysis of data from a prospective, randomised, open-label, phase 3 trial (ClinicalTrials.gov, ID: NCT00793962) conducted between 2008 and 2016, which evaluated the non-inferiority of hypofractionated RT to conventional fractionated RT after mastectomy. The initial study analysed data from 810 women (409 and 401 women assigned to the conventional fractionated and hypofractionated RT groups, respectively). They had an age range of 18–75 years, had high-risk invasive breast cancer (at least four pathologically positive axillary lymph nodes or T3–4 disease, in the absence of an ipsilateral supraclavicular node, internal mammary node, or distant metastasis), had undergone mastectomy with negative margins but without breast reconstruction, and had a mastectomy-RT interval of <8 months, if adjuvant chemotherapy was given first. Other details of the cohort have been described previously [
      • Wang S.L.
      • Fang H.
      • Song Y.W.
      • Wang W.H.
      • Hu C.
      • Liu Y.P.
      • et al.
      Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial.
      ]. In the present study, patients treated with adjuvant chemotherapy followed by PMRT were included. Patients who received neoadjuvant chemotherapy (N = 199), sandwich adjuvant chemotherapy (N = 22), or PMRT followed by chemotherapy (N = 2), as well as those with unknown entries for timing variables in the medical record (N = 3), were excluded. A total of 584 eligible patients who underwent adjuvant chemotherapy followed by PMRT were finally included in this study.

      2.2 Definitions and outcomes

      The surgery-chemotherapy interval (SCI) was defined as the duration between mastectomy and initiation of adjuvant chemotherapy. The surgery-RT interval (SRI) was defined as the duration between mastectomy and initiation of RT. The chemotherapy-RT interval (CRI) was defined as the duration between the last dose of chemotherapy and initiation of RT. Timing variables were calculated in days.
      Overall survival (OS), disease-free survival (DFS), locoregional recurrence (LRR), and distant metastasis (DM) were evaluated. OS was defined as the time from randomisation to the date of last follow-up or death from any cause. DFS was defined as the time from randomisation to the date of LRR, DM, or death. LRR was defined as disease recurrence in the ipsilateral chest wall or regional lymph nodes from the time of randomisation. DM was defined as any cancer occurrence outside the locoregional area.

      2.3 Statistical analyses

      Baseline characteristics of the cohort according to treatment intervals were determined by descriptive statistics, and the distribution of groups was compared using the chi-square test. Survival curves were estimated using the Kaplan–Meier method and compared with a log-rank test. Tumour- and treatment-related variables with a P-value of less than 0.1 for any oncologic outcome in the univariate analyses and all timing-related variables (including SCI, SRI, CRI, and chemotherapy cycles) were entered into multivariate analyses. Cox proportional hazards regression models were used to adjust for these potential confounding variables and further investigate the association between treatment intervals and oncologic outcomes. The findings were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). To identify the optimal cut-off values of the treatment intervals for predicting outcomes, we used the dfmacox (degrees of freedom in multivariable Cox models) function in smoothHR that enables the production of pointwise estimations of the HRs in nonlinear continuous predictors [
      • Meira-Machado L.
      • Cadarso-Suarez C.
      • Gude F.
      • Araujo A.
      smoothHR: an R package for pointwise nonparametric estimation of hazard ratio curves of continuous predictors.
      ]. Statistical analyses were performed using SPSS Statistics v25.0 (IBM Corp., Armonk, NY, USA) and the ‘survival’, ‘rms’, and ‘smoothHR’ packages of the R software v3.4.4 (http://www.r-project.org/).

      3. Results

      3.1 Patient characteristics and outcomes

      Baseline characteristics of the entire cohort are presented in Table 1. The median age at diagnosis was 50 years (range: 26–74 years). A total of 568 (97.3%) patients had stage III disease, whereas 16 (2.7%) patients had stage II disease. All patients were treated with mastectomy and axillary dissection followed by sequential adjuvant chemotherapy and RT. The median number of axillary lymph nodes dissected and positive axillary lymph nodes were 23 (range: 7–55) and 7 (range: 1–54), respectively. Only a few patients were node-negative (N = 9, 1.5%) with T3-4 disease. The chemotherapy regimens were anthracycline and taxane-based (86.8%), taxane-based (8.2%), and anthracycline-based (5.0%), with a median of six cycles (IQR: 6–8). Most patients with hormone receptor-positive tumour (87.1%) underwent endocrine therapy, which was administered after the completion of RT. Of the 167 patients with HER2-positive disease, 96 (57.5%) received anti-HER2-targeted therapy, whereas the remaining 71 (42.5%) patients did not, mainly because the drug had not been covered by health insurance until July 2017. The chest wall and supra-/infraclavicular nodal region were irradiated using the two-dimensional RT technique in 567 (97.1%) patients and three-dimensional conformal or intensity-modulated RT in 17 (2.9%) patients. In total, 287 (49.1%) and 297 (50.9%) patients were administered conventional fractionated RT (50 Gy in 25 fractions over five weeks) and hypofractionated RT (43.5 Gy in 15 fractions over three weeks), respectively.
      Table 1Baseline characteristics of the entire cohort and stratified by treatment-interval groups.
      CharacteristicAll (N = 584)SRICRI
      <180 days (N = 398)180–210 days (N = 146)>210 days (N = 40)P<28 days (N = 303)28–42 days (N = 185)>42 days (N = 96)P
      No. (%)No. (%)No. (%)No. (%)No. (%)No. (%)No. (%)
      Age (years)0.0350.865
       ≤40107 (18.3)84 (21.1)17 (11.6)6 (15.0)58 (19.1)32 (17.3)17 (17.7)
       >40477 (81.7)314 (78.9)129 (88.4)34 (85.0)245 (80.9)153 (82.7)79 (82.3)
      Histological grade0.6550.702
       1–2369 (63.2)247 (62.0)97 (66.4)25 (62.5)196 (64.7)113 (61.1)60 (62.5)
       3184 (31.5)130 (32.7)42 (28.8)12 (30.0)91 (30.0)62 (33.5)31 (32.3)
       Unknown31 (5.3)21 (5.3)7 (4.8)3 (7.5)16 (5.3)10 (5.4)5 (5.2)
      Lymphovascular invasion0.6810.198
       No395 (61.5)240 (60.3)94 (64.4)25 (62.5)55 (18.2)32 (17.3)10 (10.4)
       Yes225 (38.5)158 (39.7)52 (35.6)15 (37.5)248 (81.8)153 (82.7)86 (89.6)
      Pathological T stage0.5020.768
       T1198 (33.9)126 (31.6)57 (39.0)15 (37.5)109 (36.0)61 (33.0)28 (29.2)
       T2334 (57.2)238 (59.8)75 (54.1)21 (52.5)167 (55.1)108 (58.4)59 (61.5)
       T342 (7.2)27 (6.8)11 (7.5)4 (10.0)20 (6.6)14 (7.6)8 (8.3)
       T410 (1.7)7 (1.8)3 (2.1)0 (0)7 (2.3)2 (1.1)1 (1.0)
      Pathological N stage0.0930.074
       N0-124 (4.1)15 (3.8)6 (4.1)3 (7.5)10 (3.3)13 (7.0)1 (1.0)
       N2345 (59.1)231 (58.0)92 (63.0)22 (55.0)182 (60.1)105 (56.8)58 (60.4)
       N3215 (36.8)152 (38.2)48 (32.9)15 (37.5)111 (6.6)67 (36.2)37 (38.6)
      Tumour location0.8740.895
       Inner quadrant150 (25.7)100 (25.1)40 (23.4)10 (25.0)76 (25.1)49 (26.5)25 (26.0)
       Other quadrants428 (73.3)294 (73.9)105 (72.4)29 (72.5)226 (74.6)132 (71.4)70 (72.9)
       Unknown6 (1.0)4 (1.0)1 (0.6)1 (2.5)1 (0.3)4 (2.2)1 (1.1)
      Hormonal receptor status0.1590.198
       Negative97 (16.6)63 (15.8)23 (15.8)11 (27.5)55 (18.2)32 (17.3)10 (10.4)
       Positive487 (83.4)335 (84.2)123 (84.2)29 (72.5)248 (81.8)153 (82.7)86 (89.6)
      HER2 status0.0280.722
       Negative405 (69.3)280 (70.4)104 (71.2)21 (52.5)215 (71.0)123 (66.5)67 (69.8)
       Positive167 (28.6)110 (27.6)41 (28.1)16 (40.0)82 (27.0)59 (31.9)26 (27.1)
       Unknown12 (2.1)8 (2.0)1 (0.7)3 (7.5)6 (2.0)3 (1.6)3 (3.1)
      Endocrine therapy
      Only patients who were hormonal receptor-positive were included.
      0.4510.801
       Yes424 (87.1)290 (86.5)109 (88.6)25 (86.2)213 (85.9)135 (88.3)76 (88.4)
       No25 (5.1)20 (6.0)5 (4.1)0 (0)12 (4.8)8 (5.2)5 (5.8)
       Unknown38 (7.8)25 (7.5)9 (7.3)4 (13.8)23 (9.3)10 (6.5)5 (5.8)
      Anti-HER2-targeted therapy
      Only HER2-positive patients were included.
      0.8160.338
       Yes96 (57.5)64 (58.2)24 (58.5)8 (50.0)51 (62.2)33 (55.9)12 (46.2)
       No71 (42.5)46 (41.8)17 (41.5)8 (50.0)31 (37.8)26 (44.1)14 (53.8)
      Chemotherapy regimens0.1990.065
       Anthracycline-based29 (5.0)16 (4.0)8 (5.5)5 (12.5)6 (2.0)14 (7.6)9 (9.4)
       Anthracycline and taxane-based507 (86.8)350 (88.0)126 (86.3)31 (77.5)272 (89.8)158 (85.4)77 (80.2)
       Taxane-based48 (8.2)32 (8.0)12 (8.2)4 (10.0)35 (8.2)13 (7.0)10 (10.4)
      Chemotherapy cycles<0.0010.699
       <8339 (58.0)259 (65.1)68 (46.6)12 (30.0)173 (57.1)112 (60.5)54 (56.3)
       ≥8245 (42.0)139 (34.9)78 (53.4)28 (70.0)130 (42.9)73 (39.5)42 (43.8)
      Radiation fractionation0.3120.856
       CFRT287 (49.1)199 (50.0)73 (50.0)15 (37.5)147 (48.5)94 (50.8)46 (47.9)
       HFRT297 (50.9)199 (50.0)73 (50.0)25 (62.5)156 (51.5)91 (49.2)50 (52.1)
      SCI<0.0010.071
       ≤30 days430 (73.6)331 (83.2)78 (53.4)21 (52.5)225 (74.2)131 (70.8)74 (77.0)
       >30 days154 (26.4)67 (16.8)68 (46.6)19 (47.5)78 (25.8)54 (29.2)22 (23.0)
      CRI<0.001
       <28 days303 (51.9)245 (61.6)48 (32.9)10 (25.0)
       28–42 days185 (31.7)112 (28.1)55 (37.6)18 (45.0)
       >42 days96 (16.4)41 (10.3)43 (29.5)12 (30.0)
      Abbreviations: CFRT, conventional fractionated radiotherapy; HFRT, hypofractionated radiotherapy; SRI, surgery-radiotherapy interval; CRI, chemotherapy-radiotherapy interval; HER2, human epidermal growth factor receptor 2; SCI, surgery-chemotherapy interval.
      a Only patients who were hormonal receptor-positive were included.
      b Only HER2-positive patients were included.
      At a median follow-up period of 83.5 months (range: 15–152 months), 152 patients relapsed and 111 patients died. Of those who relapsed, 109/152 (71.7%) had DM only, 5/152 (3.3%) had LRR only, and 38/152 (25.0%) had both DM and LRR. Of those who died, 107/111 (96.4%) died of breast cancer, 3/111 (2.7%) died of second primary malignancies, and 1/111 (0.9%) died of other diseases. The eight-year OS, DFS, LRR, and DM rates of the entire cohort were 80.6%, 75.2%, 7.7%, and 23.8%, respectively.

      3.2 Treatment intervals and cut-off values

      The median SCI was 26 days (range: 6–67 days), with 73.6%, 25.4%, and 1.0% of the patients having an SCI of less than 30, 30–59, and ≥60 days, respectively. The median SRI was 168 days (range: 93–247 days), with 15.4%, 52.8%, and 31.8% of the patients having an SRI of less than 150, 150–179, and ≥180 days, respectively. The median CRI was 27 days (range: 5–96 days), with 22.9%, 29.0%, and 48.1% of the patients having a CRI of less than 21, 21–27, and ≥28 days, respectively. The median duration of chemotherapy was 110 days (range: 56–204 days).
      To quantify the treatment interval-dependent effect, we used P-splines in smoothHR to enter SCI, SRI, and CRI as continuous variables into the Cox regression, allowing for nonlinear correlations between these treatment intervals and OS. The finding demonstrated that patients with an SRI of <210 days and a CRI of <42 days had a decreased relative risk (ln HR) for OS. However, no appropriate cut-off value was identified for SCI, and no difference in risk of death was observed between SCI of >30 days and ≤30 days.
      Based on the calculated cut-off values and clinical practice, we classified patients into three groups according to either SRI (<180 days, 180–210 days, or >210 days) or CRI (<28 days, 28–42 days, or >42 days), respectively.

      3.3 Effect of treatment intervals on oncologic outcomes

      The distribution of baseline characteristics among different SRI or CRI groups was compared (Table 1). Patients older than 40 years, having HER2-positive disease, receiving at least eight cycles of chemotherapy, and experiencing extended SCI and CRI were more likely to have a longer SRI. However, the baseline characteristics among different CRI groups were well balanced.
      The univariate analyses of the association between variables and oncologic outcomes are listed in Table 2. All variables presented in Table 2 (P < 0.1 for at least one oncologic outcome in the univariate analyses) were entered into the multivariate analyses to further evaluate the association between treatment intervals and oncologic outcomes.
      Table 2Univariate analyses of the association between variables and oncologic outcomes for the entire cohort.
      VariablesLRRPDMPDFSPOSP
      HR (95% CI)HR (95% CI)HR (95% CI)HR (95% CI)
      Age (years)0.2310.1710.0670.634
       ≤401111
       >400.66 (0.33–1.30)0.76 (0.53–1.12)0.71 (0.49–1.03)0.89 (0.57–1.42)
      Histological grade0.6080.6280.8040.098
       1–21111
       30.84 (0.43–1.64)1.09 (0.77–1.54)1.04 (0.74–1.47)1.39 (0.94–2.05)
      Lymphovascular invasion0.2790.0840.0380.012
       No1111
       Yes1.40 (0.76–2.55)1.33 (0.96–1.85)1.40 (1.02–1.94)1.62 (1.11–2.35)
      Pathological T stage0.0220.0090.014<0.001
       T1-21111
       T3-42.45 (1.13–5.27)1.84 (1.16–2.92)1.78 (1.12–2.83)2.48 (1.54–3.98)
      Pathological N stage0.072<0.001<0.001<0.001
       N0-21111
       N31.73 (0.95–3.15)2.12 (1.53–2.93)2.05 (1.49–2.81)2.48 (1.70–3.61)
      Tumour location0.9970.020.0270.006
       Inner quadrant1111
       Other quadrants0.99 (0.71–1.41)0.82 (0.69–0.97)0.83 (0.70–0.98)0.76 (0.63–0.92)
      Chemotherapy regimens0.0050.1720.1870.103
       Anthracycline-based1111
       Taxanes w/o anthracyclines0.29 (0.12–0.69)0.64 (0.34–1.21)0.65 (0.34–1.23)0.57 (0.29–1.12)
      Chemotherapy cycles0.5380.8960.8770.803
       <81111
       ≥81.21 (0.66–2.22)0.98 (0.70–1.36)0.98 (0.70–1.35)1.05 (0.71–1.54)
      ER/PR status and endocrine therapy0.0110.0090.014<0.001
       Positive and yes1111
       Negative/‘positive and no’2.28 (1.21–4.31)1.65 (1.13–2.39)1.59 (1.10–2.31)2.65 (1.76–3.98)
      HER2 status and targeted therapy0.0810.0140.0150.436
       Positive and yes1111
       Negative0.86 (0.38–1.99)1.63 (0.95–2.80)1.46 (0.87–2.44)1.26 (0.71–2.23)
       Positive and no1.99 (0.75–5.22)2.52 (1.34–4.73)2.35 (1.28–4.30)1.59 (0.78–3.23)
      SCI0.7440.9820.9450.377
       ≤30 days1111
       >30 days0.89 (0.44–1.81)0.99 (0.69–1.44)1.01 (0.71–1.45)1.21 (0.80–1.83)
      SRI0.7130.0430.060.005
       >210 days1111
       <180 days0.72 (0.25–2.04)0.52 (0.31–0.88)0.54 (0.32–0.91)0.41 (0.24–0.71)
       180–210 days0.61 (0.19–1.99)0.61 (0.34–1.07)0.62 (0.35–1.09)0.53 (0.29–0.97)
      CRI0.2740.0010.002<0.001
       >42 days1111
       <28 days0.53 (0.25–1.15)0.49 (0.33–0.73)0.51 (0.34–0.75)0.41 (0.26–0.64)
       28–42 days0.70 (0.31–1.58)0.50 (0.32–0.78)0.55 (0.36–0.85)0.52 (0.32–0.86)
      Abbreviations: LRR, locoregional recurrence; DM, distant metastasis; DFS, disease-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; ER, oestrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; SCI, surgery-chemotherapy interval; SRI, surgery-radiotherapy interval; CRI, chemotherapy-radiotherapy interval.
      SRI was significantly associated with OS, DFS, and DM; however, no differences in LRR were observed among the three SRI groups (Fig. 1). For patients who had an SRI of <180, 180–210, and >210 days, the eight-year OS rates were 83.9%, 78.2%, and 57.9% (P = 0.004, Fig. 1A), respectively; the eight-year DFS rates were 77.1%, 72.8%, and 65.0% (P = 0.06, Fig. 1B), respectively; the eight-year DM rates were 21.9%, 25.9%, and 35.0% (P = 0.043, Fig. 1C), respectively; and the eight-year LRR rates were 7.8%, 6.8%, and 10.4% (P = 0.713, Fig. 1D), respectively. Multivariate analyses (Fig. 3) indicated that an SRI of >210 days was independently associated with a higher risk of DM and worse OS and DFS than an SRI of <180 and 180–210 days, but an SRI of >210 days was not associated with LRR. Additionally, a moderate delay of 180–210 days in SRI had no adverse effect on the outcome as compared to an SRI of less than 180 days.
      Fig. 1
      Fig. 1A comparison of survival curves among the surgery-RT interval (SRI) of <180 days, 180–210 days, and >210 days. (A) Overall survival (OS), (B) disease-free survival (DFS), (C) distant metastasis (DM), and (D) locoregional recurrence (LRR).
      Fig. 3
      Fig. 3Forest plots indicating the independent prognostic effects of the treatment intervals and other clinical variables on overall survival (OS), disease-free survival (DFS), distant metastasis (DM), and locoregional recurrence (LRR). Abbreviations: ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; SCI, surgery-chemotherapy interval; SRI, surgery-radiotherapy interval; CRI, chemotherapy-radiotherapy interval.
      CRI was significantly associated with OS, DFS, and DM, but not with LRR (Fig. 2). Compared to the CRI of 28–42 and < 28 days, the CRI of >42 days was associated with a lower eight-year OS rate (64.4%, 81.2%, and 85.0%, P < 0.001; Fig. 2A), a lower eight-year DFS rate (65.6%, 75.9%, and 77.8%, P = 0.002; Fig. 2B), and a higher eight-year DM rate (34.4%, 21.9%, and 21.5%, P = 0.001; Fig. 2C). However, no differences in LRR were observed among the three CRI groups (10.6%, 8.3%, and 6.5%, P = 0.265; Fig. 2D). After adjusting for potential confounders (Fig. 3), a CRI of >42 days was found to be independently associated with a higher risk of DM and worse OS and DFS than a CRI of <28 or 28–42 days. However, CRI had no significant influence on LRR, and a moderate delay in CRI (28–42 versus <28 days) was not associated with worse outcomes.
      Fig. 2
      Fig. 2A comparison of survival curves among the chemotherapy-RT interval (CRI) of <28 days, 28–42 days, and >42 days. (A) Overall survival (OS), (B) disease-free survival (DFS), (C) distant metastasis (DM), and (D) locoregional recurrence (LRR).

      4. Discussion

      Due to the inconsistent findings of previous retrospective studies and the ethical constraints of prospective studies, the question of RT timing has been under debate. As a result of the widespread application of long chemotherapy courses prior to RT, the interval between surgery and RT has correspondingly been prolonged. At present, there is no established time frame within which RT after mastectomy does not compromise effectiveness. In this prospective cohort, we demonstrated that delayed initiation of RT, beyond either 210 days after mastectomy or 42 days after chemotherapy, is independently associated with inferior distant control and survival in women with high-risk breast cancer.
      In the present study, an SRI threshold of 210 days (seven months) was indicated for high-risk patients who received chemotherapy before PMRT. Current guidelines uniformly support upfront chemotherapy followed by RT; however, no universally accepted threshold for delay in surgery-RT interval has been established, especially for patients undergoing mastectomy. Two recent retrospective studies have shown that delaying the surgery-RT interval in order to administer chemotherapy does not adversely affect outcomes [
      • van Maaren M.C.
      • Bretveld R.W.
      • Jobsen J.J.
      • Veenstra R.K.
      • Groothuis-Oudshoorn C.G.
      • Struikmanset H.
      • et al.
      The influence of timing of radiation therapy following breast-conserving surgery on 10-year disease-free survival.
      ,
      • Zhang W.W.
      • Wu S.G.
      • Sun J.Y.
      • Li F.Y.
      • He Z.Y.
      Long-term survival effect of the interval between mastectomy and radiotherapy in locally advanced breast cancer.
      ]. A population-based study by van Maaren et al. [
      • van Maaren M.C.
      • Bretveld R.W.
      • Jobsen J.J.
      • Veenstra R.K.
      • Groothuis-Oudshoorn C.G.
      • Struikmanset H.
      • et al.
      The influence of timing of radiation therapy following breast-conserving surgery on 10-year disease-free survival.
      ] analysed the timing of RT in patients treated with breast-conserving surgery (BCS). Among the 669 patients in the chemotherapy-RT group, the time interval between RT and BCS was not significantly associated with LRR-free survival, distant metastasis-free survival (DMFS), DFS, or OS. However, only 58% of the patients had node-positive disease, the course of chemotherapy was not presented, and the BCS-RT interval of <112, 112–140, and >140 days used for analysis was within the acceptable interval of 210 days recommended by our study. Zhang et al. [
      • Zhang W.W.
      • Wu S.G.
      • Sun J.Y.
      • Li F.Y.
      • He Z.Y.
      Long-term survival effect of the interval between mastectomy and radiotherapy in locally advanced breast cancer.
      ] reported that an SRI of >180 days did not increase the risk of LRR, DM, or mortality in patients with stage III breast cancer treated with mastectomy. However, almost half of the patients had N3 disease, but only 22% received more than six cycles of chemotherapy, suggesting that the advantage of relatively early initiation of RT may have been offset by insufficient chemotherapy sessions [
      • Zhang W.W.
      • Wu S.G.
      • Sun J.Y.
      • Li F.Y.
      • He Z.Y.
      Long-term survival effect of the interval between mastectomy and radiotherapy in locally advanced breast cancer.
      ]. In contrast, 42% of patients in the present study received eight cycles of chemotherapy. After balancing the chemotherapy cycles and controlling for other confounders, we further observed that a moderate prolongation of SRI to 180–210 days had comparable outcomes to an SRI of <180 days. This indicated that delaying the initiation of RT up to 210 days for the administration of long-course chemotherapy does not compromise patient outcomes. A Cochrane review including three randomised trials showed that breast cancer recurrence or mortality was not affected by the sequence of adjuvant treatments, provided that both RT and chemotherapy were initiated within seven months after BCS [
      • Hickey B.E.
      • Francis D.P.
      • Lehman M.
      Sequencing of chemotherapy and radiotherapy for early breast cancer.
      ]. However, these trials do not assess modern chemotherapy agents, such as taxane, or anti-HER2-targeted therapy, as the women in these trials were treated in the early 2000s. Koh et al. [
      • Koh H.K.
      • Shin K.H.
      • Kim K.
      • Lee E.S.
      • Park I.H.
      • Lee K.S.
      • et al.
      Effect of time interval between breast-conserving surgery and radiation therapy on outcomes of node-positive breast cancer patients treated with adjuvant doxorubicin/cyclophosphamide followed by taxane.
      ] tried to establish an acceptable SRI in patients treated exclusively with four cycles of doxorubicin and cyclophosphamide followed by four cycles of taxane after BCS. They confirmed that the optimal cut-off value of SRI for DMFS and DFS was seven months, and an SRI of >7 months resulted in significantly poor DMFS and DFS in patients with node-positive breast cancer, but the significance was lost on multivariate analysis. Unlike the 38% of patients with stage III disease recorded by Koh et al. [
      • Koh H.K.
      • Shin K.H.
      • Kim K.
      • Lee E.S.
      • Park I.H.
      • Lee K.S.
      • et al.
      Effect of time interval between breast-conserving surgery and radiation therapy on outcomes of node-positive breast cancer patients treated with adjuvant doxorubicin/cyclophosphamide followed by taxane.
      ], 97% of patients in the present study had stage III disease. This may explain why the adverse effect of RT delay was more profound in the present study. Although it appears to be safe to prolong SRI appropriately if the number of chemotherapy cycles needs to be increased, the optimal SRI might be kept at ≤210 days in high-risk patients after mastectomy.
      Importantly, we discovered that a prolonged CRI beyond 42 days (six weeks) had a detrimental effect on distant tumour control and survival. However, no difference in outcomes was found between patients with a CRI of 28–42 days (four–six weeks) and those with a CRI of <28 days (four weeks). In comparison with cases in which chemotherapy is not administered after surgery, in cases where adjuvant chemotherapy is delivered, SRI will be more complicated and vulnerable to related clinical factors. Generally, SRIs are influenced by SCIs, the duration of chemotherapy, and CRIs. In the present study, elder patients, patients with HER2-positive disease, or those receiving more cycles of chemotherapy were likely to have a longer SRI. A longer SRI for elderly patients might be caused by prolongation of chemotherapy duration or recovery due to poor treatment tolerance. In addition, the eight-cycle anthracycline and taxane-based chemotherapy regimen more commonly chosen for patients with HER2-positive disease may possibly lead to a longer SRI. According to available evidence, the SCI should be kept within two months or especially within one month for triple-negative subtype to avoid compromising efficacy [
      • Gagliato Dde M.
      • Gonzalez-Angulo A.M.
      • Lei X.
      • Theriault R.L.
      • Giordano S.H.
      • Valero V.
      • et al.
      Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer.
      ,
      • Zhan Q.H.
      • Fu J.Q.
      • Fu F.M.
      • Zhang J.
      • Wang C.
      Survival and time to initiation of adjuvant chemotherapy among breast cancer patients: a systematic review and meta-analysis.
      ,
      • Morante Z.
      • Ruiz R.
      • Araujo J.M.
      • Pinto J.A.
      • Cruz-Ku G.
      • Urrunaga-Pastor D.
      • et al.
      Impact of the delayed initiation of adjuvant chemotherapy in the outcome of triple negative breast cancer.
      ]. While almost all the patients in this study started chemotherapy within two months after mastectomy, SCI did not have a deleterious effect on outcomes. Meanwhile, the course of chemotherapy is dependent on the chemotherapy regimen and cycles, which are prescribed according to the risk of disease recurrence. In this circumstance, determining the CRI threshold is more relevant and practical for the clinician and patient. Moreover, the baseline characteristics were well balanced across the CRI groups in the present study; this suggests that evaluating CRI is more clinically modifiable than the sole evaluation of SRI. However, the studies on optimal CRI for breast cancer are limited. Raphael et al. [
      • Raphael M.J.
      • Saskin R.
      • Singh S.
      Association between waiting time for radiotherapy after surgery for early-stage breast cancer and survival outcomes in Ontario: a population-based outcomes study.
      ] reported that a CRI of ≥6 weeks was associated with worse event-free survival in patients with stage I and II breast cancer who underwent BCS (HR 1.50; 95% CI: 1.00–2.22). Cao et al. [
      • Cao L.
      • Xu C.
      • Cai G.
      • Qi W.X.
      • Cai R.
      • Wang S.B.
      • et al.
      How does the interval between completion of adjuvant chemotherapy and initiation of radiotherapy impact clinical outcomes in operable breast cancer patients?.
      ] reported that a CRI of >12 weeks was associated with worse breast cancer-specific survival and OS in patients with stage I–III breast cancer who underwent either BCS or mastectomy. In comparison, most patients in the present study had more advanced disease (97% being stage III), and all the patients underwent mastectomy. The threshold of 42 days for CRI was identified by statistical methods rather than by arbitrary choice. Therefore, initiating PMRT within 42 days after completion of chemotherapy, especially for patients with stage III disease, is more beneficial.
      Interestingly, delay in initiating RT did not increase the risk of LRR, but adversely affected DM, DFS, and OS. As a local treatment, RT was assumed to affect outcomes by directly controlling locoregional diseases. However, the limited number of LRR events in the present study is insufficient to detect any significant statistical difference. Advances in the treatment of early breast cancer have differentially reduced the proportion of LRR compared with DM. In recent trials, LRRs account for around 10–15% of all recurrences [
      • Bouganim N.
      • Tsvetkova E.
      • Clemons M.
      • Amir E.
      Evolution of sites of recurrence after early breast cancer over the last 20 years: implications for patient care and future research.
      ]. With LRR becoming an infrequent event in the modern treatment era, interventions designed to improve locoregional control may be increasingly difficult to examine. Additionally, with the adoption of extensive regional lymph node irradiation, the role of RT has been expanded beyond local control to include reducing the risk of distant failure [
      • Poortmans P.M.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • Peignaux-Casasnovas K.
      • Budach V.
      • et al.
      Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
      ,
      • Whelan T.J.
      • Olivotto I.A.
      • Parulekar W.R.
      • Ackerman I.
      • Chua B.H.
      • Nabid A.
      • et al.
      Regional nodal irradiation in early-stage breast cancer.
      ]. This implies that future studies on RT should evaluate endpoints beyond LRR.
      This study had some unique strengths. First, patients were identified from a prospective clinical trial with reliable data collection. Second, rather than making an arbitrary classification, we used treatment interval as a continuous variable to determine the most reliable threshold for influencing prognosis. Third, the independent hazards of delayed RT both after mastectomy and chemotherapy were verified after correcting for multiple covariates, including SCI, CRI, and chemotherapy cycles.
      The study has some limitations that need to be mentioned. First, the population from a clinical trial may not be representative of the real-world population. An SRI of >210 days poses a limitation, as one of our inclusion criteria was starting PMRT within eight months after surgery. We are unable to answer the question of whether further delay is still of value for starting RT, without comparing the outcomes of patients with further RT delay with those of patients who did not receive RT at all. However, there were some adverse effects of delayed RT, despite the relatively concentrated treatment intervals; this underlines the importance of timely administration of PMRT in high-risk patients. Second, anti-HER2 therapy was administered in only 57.5% of the patients with HER2-positive disease. However, the groups based on treatment timing had a comparable number of patients who received anti-HER2 therapy. Therefore, in the timing analysis, we have included ‘HER2 status and anti-HER2-targeted therapy’ as a confounder in the multivariate analyses. The results showed that both timing and ‘HER2 status and anti-HER2-targeted therapy’ were independently associated with prognosis. Third, a median follow-up of seven years is appropriate for assessing locoregional and distant recurrences, but may not be sufficient to identify the true impact on overall or breast cancer-specific survival, and long-term follow-up remains meritorious of additional investigation. Last, due to the small sample size of the subgroups, no further analyses were performed to identify different delay thresholds of PMRT among patients with different molecular subtypes, which have different proliferative and aggressive behaviours. Further studies using different cohorts and larger sample sizes are needed to validate our findings and explore different delay thresholds of PMRT in patients with different molecular subtypes.
      In conclusion, delay in initiating RT after mastectomy or adjuvant chemotherapy is associated with poor survival and a high risk of metastasis in patients with stage II or III breast cancer, but does not seem to affect LRR. Based on our data, the timing between mastectomy and the end of chemotherapy and RT initiation is crucial.

      Author contributions

      S-LW and Y-XL designed the study. S-YC, S-LW, and G-YS collected and analysed data. S-YC and S-LW drafted the manuscript. All authors provided study materials or patients and approved the manuscript.

      Funding

      This work was supported by Beijing Hope Run Special Fund of Cancer Foundation of China (LC2008A06 and LC2019A10) and the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2020-I2M-C&T-B-075, 2021-I2M-1-014).

      Ethics approval

      Data from the study were approved by the local ethics committee of the National Cancer Center/Cancer Hospital, the Chinese Academy of Medical Sciences, and Peking Union Medical College (Approval No. 11-53/488).

      Conflict of interest statement

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      We would like to thank all the patients participating and all the researchers involved in this study.

      References

        • Early Breast Cancer Trialists' Collaborative G.
        Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.
        Lancet. 2005; 365: 1687-1717https://doi.org/10.1016/S0140-6736(05)66544-0
        • Ebctcg
        • McGale P.
        • Taylor C.
        • Correa C.
        • Cutter D.
        • Duane F.
        • et al.
        Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials.
        Lancet. 2014; 383: 2127-2135https://doi.org/10.1016/S0140-6736(14)60488-8
        • Pinnaro P.
        • Rambone R.
        • Giordano C.
        • Giannarelli D.
        • Strigari L.
        • Arcangeli G.
        Long-term results of a randomized trial on the sequencing of radiotherapy and chemotherapy in breast cancer.
        Am J Clin Oncol. 2011; 34: 238-244https://doi.org/10.1097/COC.0b013e3181dea9b8
        • Geurts Y.M.
        • Witteveen A.
        • Bretveld R.
        • Poortmans P.M.
        • Sonke G.S.
        • Strobbe L.J.A.
        • et al.
        Patterns and predictors of first and subsequent recurrence in women with early breast cancer.
        Breast Cancer Res Treat. 2017; 165: 709-720https://doi.org/10.1007/s10549-017-4340-3
        • Curigliano G.
        • Burstein H.J.
        • Winer E.P.
        • Gnant M.
        • Dubsky P.
        • Loibl S.
        • et al.
        De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen international expert consensus conference on the primary therapy of early breast cancer 2017.
        Ann Oncol. 2017; 28: 1700-1712https://doi.org/10.1093/annonc/mdx308
        • Early Breast Cancer Trialists' Collaborative G.
        • Peto R.
        • Davies C.
        • Godwin J.
        • Gray R.
        • Pan H.C.
        • et al.
        Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.
        Lancet. 2012; 379: 432-444https://doi.org/10.1016/S0140-6736(11)61625-5
        • Wang S.L.
        • Fang H.
        • Song Y.W.
        • Wang W.H.
        • Hu C.
        • Liu Y.P.
        • et al.
        Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial.
        Lancet Oncol. 2019; 20: 352-360https://doi.org/10.1016/S1470-2045(18)30813-1
        • Meira-Machado L.
        • Cadarso-Suarez C.
        • Gude F.
        • Araujo A.
        smoothHR: an R package for pointwise nonparametric estimation of hazard ratio curves of continuous predictors.
        Comput Math Methods Med. 2013; 2013745742https://doi.org/10.1155/2013/745742
        • van Maaren M.C.
        • Bretveld R.W.
        • Jobsen J.J.
        • Veenstra R.K.
        • Groothuis-Oudshoorn C.G.
        • Struikmanset H.
        • et al.
        The influence of timing of radiation therapy following breast-conserving surgery on 10-year disease-free survival.
        Br J Cancer. 2017; 117: 179-188https://doi.org/10.1038/bjc.2017.159
        • Zhang W.W.
        • Wu S.G.
        • Sun J.Y.
        • Li F.Y.
        • He Z.Y.
        Long-term survival effect of the interval between mastectomy and radiotherapy in locally advanced breast cancer.
        Cancer Manag Res. 2018; 10: 2047-2054https://doi.org/10.2147/CMAR.S163863
        • Hickey B.E.
        • Francis D.P.
        • Lehman M.
        Sequencing of chemotherapy and radiotherapy for early breast cancer.
        Cochrane Database Syst Rev. 2013; : CD005212https://doi.org/10.1002/14651858.CD005212.pub3
        • Koh H.K.
        • Shin K.H.
        • Kim K.
        • Lee E.S.
        • Park I.H.
        • Lee K.S.
        • et al.
        Effect of time interval between breast-conserving surgery and radiation therapy on outcomes of node-positive breast cancer patients treated with adjuvant doxorubicin/cyclophosphamide followed by taxane.
        Cancer Res Treat. 2016; 48: 483-490https://doi.org/10.4143/crt.2015.111
        • Gagliato Dde M.
        • Gonzalez-Angulo A.M.
        • Lei X.
        • Theriault R.L.
        • Giordano S.H.
        • Valero V.
        • et al.
        Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer.
        J Clin Oncol. 2014; 32: 735-744https://doi.org/10.1200/JCO.2013.49.7693
        • Zhan Q.H.
        • Fu J.Q.
        • Fu F.M.
        • Zhang J.
        • Wang C.
        Survival and time to initiation of adjuvant chemotherapy among breast cancer patients: a systematic review and meta-analysis.
        Oncotarget. 2018; 9: 2739-2751https://doi.org/10.18632/oncotarget.23086
        • Morante Z.
        • Ruiz R.
        • Araujo J.M.
        • Pinto J.A.
        • Cruz-Ku G.
        • Urrunaga-Pastor D.
        • et al.
        Impact of the delayed initiation of adjuvant chemotherapy in the outcome of triple negative breast cancer.
        Clin Breast Cancer. 2021; 21: 239-246 e4https://doi.org/10.1016/j.clbc.2020.09.008
        • Raphael M.J.
        • Saskin R.
        • Singh S.
        Association between waiting time for radiotherapy after surgery for early-stage breast cancer and survival outcomes in Ontario: a population-based outcomes study.
        Curr Oncol. 2020; 27: e216-e221https://doi.org/10.3747/co.27.5629
        • Cao L.
        • Xu C.
        • Cai G.
        • Qi W.X.
        • Cai R.
        • Wang S.B.
        • et al.
        How does the interval between completion of adjuvant chemotherapy and initiation of radiotherapy impact clinical outcomes in operable breast cancer patients?.
        Ann Surg Oncol. 2021; 28: 2155-2168https://doi.org/10.1245/s10434-020-09026-z
        • Bouganim N.
        • Tsvetkova E.
        • Clemons M.
        • Amir E.
        Evolution of sites of recurrence after early breast cancer over the last 20 years: implications for patient care and future research.
        Breast Cancer Res Treat. 2013; 139: 603-606https://doi.org/10.1007/s10549-013-2561-7
        • Poortmans P.M.
        • Weltens C.
        • Fortpied C.
        • Kirkove C.
        • Peignaux-Casasnovas K.
        • Budach V.
        • et al.
        Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
        Lancet Oncol. Dec 2020; 21: 1602-1610https://doi.org/10.1016/S1470-2045(20)30472-1
        • Whelan T.J.
        • Olivotto I.A.
        • Parulekar W.R.
        • Ackerman I.
        • Chua B.H.
        • Nabid A.
        • et al.
        Regional nodal irradiation in early-stage breast cancer.
        N Engl J Med. 2015; 373: 307-316https://doi.org/10.1056/NEJMoa1415340