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Tamoxifen with radiotherapy compared with Tamoxifen alone in elderly women with early-stage breast cancer treated with breast conserving surgery: A systematic review and meta-analysis

      Abstract

      Background

      Our aim was to assess the effect of adjuvant radiotherapy on recurrence and survival for elderly women (≥70) with early-stage hormone receptor-positive breast cancer treated with breast conserving surgery (BCS) and Tamoxifen.

      Materials and methods

      MEDLINE, EMBASE, and Evidence-Based Medicine Reviews were systematically searched through August 12, 2016 for randomized controlled trials (RCTs) comparing radiotherapy to no radiotherapy and presenting outcomes for women ≥70 years. Two investigators screened citations, abstracted results, and appraised studies using Cochrane Risk of Bias tool. Pooled risk ratios (RR) for breast, axillary, and distant recurrence, and overall survival were determined using weights from fixed-effects models.

      Results

      Four RCTs with low risk of bias were identified (2387 elderly women). Tamoxifen plus radiotherapy reduced breast recurrence compared to Tamoxifen alone from 60 to 10 (95% CI 6–20) per 1000 patients at 5 years (RR 0.18, 95% CI 0.10–0.34; 4 trials, 2387 patients). This effect was maintained at 10 years (RR 0.27, 95% CI 0.13–0.54; 2 trials, 891 patients). Radiotherapy minimally reduced axillary recurrence from 12 to 3 (95% CI 1–10) per 1000 at 5 years (RR 0.28, 95% CI 0.10–0.81; 3 trials, 2287 patients). Radiotherapy did not affect distant recurrence (RR 1.49, 95% CI 0.87–2.54; 3 trials, 2287 patients) or overall survival (RR 0.98, 95% CI 0.79–1.22; 3 trials, 2287 patients).

      Conclusion

      For elderly women (≥70), radiotherapy reduces the risk of breast and axillary recurrence, but does not impact distant recurrence or overall survival in early-stage breast cancer treated with BCS and Tamoxifen. The value of this risk reduction must be weighed by women and their physicians when considering the omission of adjuvant radiotherapy.

      Keywords

      Early-stage breast cancer is amenable to breast conserving surgery (BCS) with equivalent survival to mastectomy if adjuvant radiotherapy is included [
      • Fisher B.
      • Anderson S.
      • Bryant J.
      • et al.
      Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.
      ,
      • Clarke M.
      • Collins R.
      • Darby S.
      • et al.
      Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.
      ,
      • Veronesi U.
      • Cascinelli N.
      • Mariani L.
      • et al.
      Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer.
      ]. Radiotherapy and a radiation boost to the tumor bed also reduce local recurrence, but this risk reduction declines with advancing age [
      • Darby S.
      • McGale P.
      • et al.
      Early Breast Cancer Trialists' Collaborative G
      Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials.
      ,
      • Bartelink H.
      • Horiot J.C.
      • Poortmans P.M.
      • et al.
      Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881–10882 trial.
      ]. Additionally, elderly women more frequently have favorable tumor biology with a high frequency of low-grade, hormone receptor (HR) positive, HER2-negative tumors that respond to endocrine therapy potentially reducing the absolute benefit of radiotherapy [
      • Diab S.G.
      • Elledge R.M.
      • Clark G.M.
      Tumor characteristics and clinical outcome of elderly women with breast cancer.
      ,
      • Gennari R.
      • Curigliano G.
      • Rotmensz N.
      • et al.
      Breast carcinoma in elderly women: features of disease presentation, choice of local and systemic treatments compared with younger postmenopasual patients.
      ,
      • Rodrigues N.A.
      • Dillon D.
      • Carter D.
      • Parisot N.
      • Haffty B.G.
      Differences in the pathologic and molecular features of intraductal breast carcinoma between younger and older women.
      ,
      • Davies C.
      • Godwin J.
      • et al.
      Early Breast Cancer Trialists' Collaborative G
      Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.
      ,
      • Fisher B.
      • Costantino J.
      • Redmond C.
      • et al.
      A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors.
      ].
      Treatment of elderly breast cancer patients is often not guideline adherent with older women may receiving less radiotherapy following BCS, and variably more hormonal therapy [
      • Wyld L.
      • Garg D.K.
      • Kumar I.D.
      • Brown H.
      • Reed M.W.
      Stage and treatment variation with age in postmenopausal women with breast cancer: compliance with guidelines.
      ,
      • Angarita F.A.
      • Chesney T.
      • Elser C.
      • Mulligan A.M.
      • McCready D.R.
      • Escallon J.
      Treatment patterns of elderly breast cancer patients at two Canadian cancer centres.
      ,
      • Joerger M.
      • Thurlimann B.
      • Savidan A.
      • et al.
      Treatment of breast cancer in the elderly: a prospective, population-based Swiss study.
      ,
      • Kiderlen M.
      • Bastiaannet E.
      • Walsh P.M.
      • et al.
      Surgical treatment of early stage breast cancer in elderly: an international comparison.
      ,
      • van de Water W.
      • Markopoulos C.
      • van de Velde C.J.
      Association between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor-positive breast cancer.
      ]. Several randomized controlled trials (RCTs) have tested the safety of omitting radiotherapy, but the majority of women were younger than 65, and results had little initial impact on practice [
      • Tinterri C.
      • Gatzemeier W.
      • Zanini V.
      • et al.
      Conservative surgery with and without radiotherapy in elderly patients with early-stage breast cancer: a prospective randomised multicentre trial.
      ,
      • Potter R.
      • Gnant M.
      • Kwasny W.
      • et al.
      Lumpectomy plus tamoxifen or anastrozole with or without whole breast irradiation in women with favorable early breast cancer.
      ,
      • Soulos P.R.
      • Yu J.B.
      • Roberts K.B.
      • et al.
      Assessing the impact of a cooperative group trial on breast cancer care in the medicare population.
      ]. Available guidelines provide conflicting statements on the use of radiotherapy in elderly women after BCS. Two state that it is reasonable to omit radiotherapy, and the third states that there is no subgroup of fit older women in which radiotherapy can be systematically omitted [
      • Bellon J.R.
      • Harris E.E.
      • Arthur D.W.
      • et al.
      ACR Appropriateness Criteria(R) conservative surgery and radiation–stage I and II breast carcinoma: expert panel on radiation oncology: breast.
      ,
      • Hurria A.
      • Browner I.S.
      • Cohen H.J.
      • et al.
      Senior adult oncology.
      ,
      • Biganzoli L.
      • Wildiers H.
      • Oakman C.
      • et al.
      Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA).
      ].
      Attempting to clarify this question, a previous systematic review was conducted [
      • van de Water W.
      • Bastiaannet E.
      • Scholten A.N.
      Breast-conserving surgery with or without radiotherapy in older breast patients with early stage breast cancer: a systematic review and meta-analysis.
      ]. Unfortunately, in order to include a greater number of studies by defining elderly as postmenopausal, that review included many younger women, as young as 44 years. Further, it included one trial that had no women older than 69 years, and two trials with the majority of women under 65. The results are reported for the population as a whole without any outcomes reported specifically for elderly women.
      Our current systematic review therefore aims to clarify the effect of adjuvant radiotherapy for elderly women (≥70 years) with early-stage HR-positive breast cancer treated with BCS and endocrine therapy by synthesizing outcomes from RCTs specific to this unique population.

      Methods

      We registered our protocol with the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42015024598) [
      • Yin J.
      • Chesney T.R.
      • Scheer A.
      Comparing breast-conserving surgery and Tamoxifen with and without radiation in elderly women with breast cancer: systematic review and meta-analysis.
      ]. We reported this systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) standards [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • Group P.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].

      Search strategy

      We systematically searched the electronic databases MEDLINE and EMBASE from inception through August 12, 2016 with no restriction for language or publication status. We similarly searched the Evidence Based Medicine Reviews (EBMR) database combining searches of Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), Cochrane CENTRAL, Cochrane Methodology Register (CMR), Health Technology Assessment (HTA), NHS Economic Evaluation Database (NHSEED), and ACP Journal Club. An information specialist developed a maximally sensitive search strategy to include terms for breast cancer, radiotherapy, and endocrine therapy (see Appendix Tables A1 and A2 for full search strategies). The search strategy was peer reviewed using the Peer Review of Electronic Search Strategies (PRESS) checklist [
      • Sampson M.
      • McGowan J.
      • Cogo E.
      • Grimshaw J.
      • Moher D.
      • Lefebvre C.
      An evidence-based practice guideline for the peer review of electronic search strategies.
      ]. Scanning of included studies and relevant reviews was conducted to ensure literature saturation.

      Eligibility criteria and outcomes

      We included RCTs comparing adjuvant radiotherapy to no radiotherapy in older women with early-stage breast cancer treated with BCS and adjuvant endocrine therapy. Early stage breast cancer included tumor stage T1 and T2, clinically node negative (N0) invasive breast cancers. Studies evaluating treatment of in-situ breast cancer, more advanced disease (T3/T4, clinically or biopsy-proven node positive), recurrent disease, or using neoadjuvant therapy were excluded. Primary outcomes included number of in-breast recurrences, axillary recurrences, distant recurrences, and all-cause deaths at 5 years, and 10 years if available. Studies were included only if at least one of our primary outcomes was available for older women defined as a group aged 70 years or above, or a group with median age of 70 years or above but no patients under 65 years. If these outcomes were not reported in the published manuscript, authors were contacted to obtain data for older women.

      Study selection

      After pilot-testing the eligibility criteria, two independent reviewers (TRC, JXY) evaluated all citations for eligibility. Level 1 screening of titles and abstracts identified all potentially relevant citations, and level 2 screening evaluated these citations in full-text for final inclusion. When several citations reported on the same trial at different time points, the reports with 5-year outcomes and 10-year outcomes were retained for inclusion. Five-year outcomes were selected due to availability across all included studies, and 10-year outcomes were available for in-breast recurrence in 2 trials. Discordance between reviewers was resolved by discussion.

      Data extraction

      A data extraction form was developed a priori and pilot tested [
      • Higgins J.P.
      • Green S.
      Cochrane handbook for systematic reviews of interventions.
      ]. Two reviewers (TRC, JY) independently extracted data from each included study. Discordance was resolved by discussion.
      Data were extracted on study-level information, inclusion and exclusion criteria, patient characteristics, intervention and comparator details, co-interventions, and outcomes. Outcomes were extracted from intention-to-treat analyses. For studies that only presented Kaplan–Meier survival curves, survival end points were extracted using Digitizelt software (Digitizelt, Bruanschweig, Germany) [
      • Guyot P.
      • Ades A.
      • Ouwens M.J.
      • Welton N.J.
      Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves.
      ]. Missing data were treated as “not reported”. Where possible, authors were contacted to obtain data not originally reported.

      Risk of bias assessment

      Risk of bias was assessed independently by two reviewers (TRC, JXY) using the Cochrane Risk of Bias tool [
      • Higgins J.P.
      • Altman D.G.
      • Gøtzsche P.C.
      • et al.
      The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
      ]. Funnel plots for assessment of publication bias were not constructed as no outcome had at least ten RCTs contributing data [
      • Egger M.
      • Smith G.D.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      ].

      Synthesis and statistical analysis

      Descriptive synthesis was used to summarize study characteristics, patient characteristics, intervention details, and risk of bias results.
      For our meta-analyses, risk ratios (RR) were selected as the measurement of effect for our primary outcomes. Although hazard ratios are the most appropriate statistic for meta-analysis of time-to-event outcomes, neither hazard ratios nor sufficient statistical information to estimate them (e.g., Kaplan–Meier survival curves, p-values for log-rank test) using established methods, were available across studies [
      • Parmar M.K.
      • Torri V.
      • Stewart L.
      Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints.
      ]. Therefore, RR with their respective 95% confidence intervals (CI) were estimated for dichotomous outcomes at 5 years for each study, and at 10 years where available. For studies with zero events, the standard continuity correction of 0.5 was applied [
      • Friedrich J.O.
      • Adhikari N.K.
      • Beyene J.
      Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data.
      ].
      Meta-analyses were performed using weights from fixed-effects models using Mantel–Haenszel methods due to low event rates, and reported with corresponding 95% CI [
      • Mantel N.
      • Haenszel W.
      Statistical aspects of the analysis of data from retrospective studies.
      ]. The decision to use fixed-effects models was made a priori as the strict eligibility criteria used in RCTs were expected to create homogenous populations across studies. Heterogeneity of the data was evaluated visually using forest plots, and between-study statistical heterogeneity was assessed with Cochran’s Q test and quantified using the I2 statistic [
      • Higgins J.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      ]. I2 values of 25%, 50% and 75% corresponded to cut-off points of low, moderate and high degrees of heterogeneity, respectively [
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ].
      To ease communication of intervention effects we calculated clinically applicable absolute effect measures including comparative risk, which is expressed as number of events per 1000 patients at risk, and numbers needed to treat (NNT). These absolute effect measures were calculated using the pooled RR and the median Tamoxifen alone group risk across studies for each outcome [
      • Higgins J.P.
      • Green S.
      Cochrane handbook for systematic reviews of interventions.
      ,
      • Walter S.D.
      Choice of effect measure for epidemiological data.
      ].
      Statistical analyses were performed using Review Manager (RevMan) 5.3 (Cochrane Collaboration, Copenhagen, Denmark) [

      Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.

      ]. No pre-specified subgroup analysis or meta-regression was planned. To investigate the effect of radiotherapy on axillary recurrence in patients not having axillary lymph node dissection (ALND) a post hoc subgroup analysis pooling outcomes from trials with a low proportion of ALND was conducted.

      Results

      Systematic search

      Fig. 1 illustrates citation selection. Our initial search strategy yielded 7231 citations after removal of duplicates. Three citations were added after citation tracking. After level 1 screening of titles and abstracts, 7206 citations were excluded. After level 2 screening of the remaining 28 full-text articles, 22 were excluded. Five were excluded as multiple reports of the same trial, 3 did not have available full texts, 1 did not use adjuvant endocrine therapy, 6 were not RCTs, 1 did not have the designated comparator group, 5 did not have outcome measures available for elderly women, and 1 included patients with node-positive disease. Ultimately, 6 articles reporting on 4 RCTs were included.

      Study and patient characteristics

      Study and patient characteristics are detailed in Tables 1 and 2. The four included RCTs reported on 2387 women aged 70 years and older with study periods ranging from 1989 to 2009. Two of these trials specifically recruited elderly women, one 70 years and older, and the other 65 years and older with a median age of 70 [
      • Kunkler I.H.
      • Williams L.J.
      • Jack W.J.
      • Cameron D.A.
      • Dixon J.M.
      • investigators P.I.
      Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.
      ,
      • Hughes K.S.
      • Schnaper L.A.
      • Berry D.
      • et al.
      Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.
      ]. All patients from these two trials were included in the meta-analyses. The remaining two trials had outcomes available for the subgroup of elderly women (aged 70 years or older) [
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      ,
      • Fisher B.
      • Bryant J.
      • Dignam J.J.
      • et al.
      Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less.
      ]. Fisher reported these subgroup outcomes in the published manuscript (100 of 673 patients), and Fyles provided outcomes for this subgroup after contacting them (325 of 769 patients) [
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      ,
      • Fisher B.
      • Bryant J.
      • Dignam J.J.
      • et al.
      Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less.
      ].
      Table 1Study characteristics.
      Reference (year)N (total)N (70+)Study PeriodAgeInclusion CriteriaInterventionControlPrimary Outcome
      TumorHormone Receptor StatusSurgeryAxillary StagingAdjuvant Endocrine Therapy
      PRIME II
      • Kunkler I.H.
      • Williams L.J.
      • Jack W.J.
      • Cameron D.A.
      • Dixon J.M.
      • investigators P.I.
      Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.
      (2015)
      13261326
      Included patients 65years or older; median age 70 (IQR 67–74); 52% 70years or older, 48% 65–69years.
      2003–2009≥65T1/T2 (≤3 cm), N0, M0ER+ and/or PR+BCS Negative margin (≥1 mm)SLNB or ALNDTamoxifen 20 mg daily for 5 years recommended; other ET allowedWhole-breast RT; 40–50 Gy; boost 10–15 Gy permittedNo RTIpsilateral breast recurrence
      CALGB 9343
      • Hughes K.S.
      • Schnaper L.A.
      • Berry D.
      • et al.
      Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.
      (2004)
      6366361994–1999≥70T1 (≤2 cm), N0, M0ER+BCS Negative margin (no tumor at inked margin)Clinical ALND allowed, but discouragedTamoxifen 20 mg daily for 5 yearsWhole-breast RT; 45 Gy; boost up to 14 GyNo RTLocal or regional recurrence
      Fyles
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      (2004)
      7693251992–2000≥50T1/T2 (≤5 cm), N0Any hormone-receptor status (81% ER+)BCS negative margin (no tumor at inked margin)ALND or ClinicalTamoxifen 20 mg daily for 5 yearsWhole-breast RT; 40 Gy; boost 12.5 GyNo RT
      This trial had three arms: RT and placebo, RT and Tamoxifen, Tamoxifen alone. Only the RT and Tamoxifen and Tamoxifen alone arms were included in this systematic review.
      Disease-free survival
      Defined as the time from randomization to the first treatment failure (in the ipsilateral breast, in the axillary nodes, or at a distant site) or death (if no recurrence had been noted).
      Fisher
      • Fisher B.
      • Bryant J.
      • Dignam J.J.
      • et al.
      Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less.
      (2002)
      This trial had three arms: RT and placebo, RT and Tamoxifen, Tamoxifen alone. Only the RT and Tamoxifen and Tamoxifen alone arms were included in this systematic review.
      6731001989–1994, 1996–1998AnyT1 (<1 cm), N0Any hormone-receptor statusBCS Negative marginsALNDTamoxifen 10 mg BID for 5 yearsWhole-breast RT; 50 Gy; no boostNo RTIpsilateral breast recurrence
      Abbreviations: ALND, axillary lymph node dissection|BCS, breast conserving surgery|ET, endocrine therapy|IQR, interquartile range|N, number of patients|RT, radiotherapy|SLNB, sentinel lymph node biopsy.
      a Included patients 65 years or older; median age 70 (IQR 67–74); 52% 70 years or older, 48% 65–69 years.
      b Defined as the time from randomization to the first treatment failure (in the ipsilateral breast, in the axillary nodes, or at a distant site) or death (if no recurrence had been noted).
      c This trial had three arms: RT and placebo, RT and Tamoxifen, Tamoxifen alone. Only the RT and Tamoxifen and Tamoxifen alone arms were included in this systematic review.
      Table 2Patient characteristics.
      Reference (year)Treatment ArmNAgeTumor StageHR+GradeBCSAxillary SurgeryReceived TamoxifenReceived Radiotherapy
      PRIME II
      • Kunkler I.H.
      • Williams L.J.
      • Jack W.J.
      • Cameron D.A.
      • Dixon J.M.
      • investigators P.I.
      Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.
      (2015)
      TamRT65869 (IQR 67–73)T1 584 (89%)

      T2 74 (11%)
      656 (99%)1 292 (44%)

      2 352 (53%)

      3 13 (2%)
      658SLNB
      Also included ipsilateral four-node lower axillary node sampling for axillary staging.
      516 (78%)

      ALND 135 (21%)
      NR573/584 (98%)
      Tam Alone66870 (IQR 67–74)T1 584 (87%)

      T2 84 (13%)
      658 (99%)1 271 (41%)

      2 368 (55%)

      3 23 (3%)
      668SLNB
      Also included ipsilateral four-node lower axillary node sampling for axillary staging.
      502 (75%)

      ALND 158 (24%)
      NR0 (0%)
      CALGB 9343
      • Hughes K.S.
      • Schnaper L.A.
      • Berry D.
      • et al.
      Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.
      (2004)
      TamRT31770–74 y 139 (44%)

      ≥75 y 178 (56%)
      T1 312 (98%)

      T2 5 (2%)
      308 (97%)NR317ALND 117 (37%)NR317 (100%)
      Tam Alone31970–74 y 146 (46%)

      ≥75 y 173 (54%)
      T1 310 (97%)

      T2 9 (3%)
      310 (97%)NR319ALND 115 (36%)NR0 (0%)
      Fyles
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      (2004)
      Where denominators are shown, this reflects values for the entire population, not just the subgroup ≥70.
      TamRT171≥70T1 142 (84%)

      T2 28 (17%)
      161 (94%)1 8/386 (22%)

      2 179/386 (46%)

      3 57/386 (15%)
      171118 (69%)169 (99%)167 (98%)
      Tam Alone154≥70T1 128 (83%)

      T2 25 (16%)
      144 (94%)1 81/383 (21%)

      2 181/383 (47%)

      3 67/383 (18%)
      154104 (68%)153 (99%)1 (0.6%)
      Fisher
      • Fisher B.
      • Bryant J.
      • Dignam J.J.
      • et al.
      Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less.
      (2002)
      Where denominators are shown, this reflects values for the entire population, not just the subgroup ≥70.
      TamRT57≥70T1 332/334 (99%)197/334 (59%)

      Unknown 94/334 (28%)
      NR57ALND 57 (100%)57 (100%)57 (100%)
      Tam Alone43≥70T1 330/334 (99%)181/334 (54%)

      Unknown 108/334 (32%)
      NR43ALND 43 (100%)43 (100%)0 (0%)
      Abbreviations: N, number of patients|NR, not reported|Tam, Tamoxifen|TamRT, Tamoxifen plus radiotherapy.
      Data are median (IQR) or number of patients (%).
      a Also included ipsilateral four-node lower axillary node sampling for axillary staging.
      b Where denominators are shown, this reflects values for the entire population, not just the subgroup ≥70.
      Across studies, the tumor size cut-offs varied from 1 cm to 5 cm; however, these cutoffs still correspond to early-stage (T1-2) tumors. The proportion of T1 tumors ranged from 83 to 99% across studies. Two trials had limited inclusion to HR-positive tumors resulting in 97% and 99% HR-positive patients [
      • Kunkler I.H.
      • Williams L.J.
      • Jack W.J.
      • Cameron D.A.
      • Dixon J.M.
      • investigators P.I.
      Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.
      ,
      • Hughes K.S.
      • Schnaper L.A.
      • Berry D.
      • et al.
      Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.
      ]. Two trials did not limit to only HR-positive tumors, but had HR-positive rates of 84% and 57% (with 30% unknown status) [
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      ,
      • Fisher B.
      • Bryant J.
      • Dignam J.J.
      • et al.
      Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less.
      ]. Tumor grade was reported in only two trials, but was largely grades 1 and 2 tumors with fewer than 20% of grade 3 tumors. Axillary staging requirements for inclusion varied across studies: one required either sentinel lymph node biopsy (SLNB) or ALND, two accepted clinical staging or pathological staging, and one required ALND. Actual axillary surgery ranged from 100% ALND in Fisher to 78% SLNB in PRIME II [
      • Kunkler I.H.
      • Williams L.J.
      • Jack W.J.
      • Cameron D.A.
      • Dixon J.M.
      • investigators P.I.
      Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.
      ,
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      ,
      • Fisher B.
      • Bryant J.
      • Dignam J.J.
      • et al.
      Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less.
      ].
      All women received BCS with a negative pathological margin defined as no tumor at inked margin in three trials, and ≥1 mm in PRIME II. Adherence to Tamoxifen was not reported in PRIME II and CALGB C9343, and was 99–100% in the other two trials [
      • Kunkler I.H.
      • Williams L.J.
      • Jack W.J.
      • Cameron D.A.
      • Dixon J.M.
      • investigators P.I.
      Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.
      ,
      • Hughes K.S.
      • Schnaper L.A.
      • Berry D.
      • et al.
      Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.
      ]. All women in the intervention arm received adjuvant whole-breast radiotherapy at a dose of 40–50 Gy; three trials gave boosts of 10–14 Gy. Receipt of radiotherapy was reported in 98–100% of women in the intervention arm across trials. Women in the control arm did not receive adjuvant radiotherapy with no crossover in three trials and 0.6% crossover in Fyles [
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      ].

      Risk of bias assessment

      Risk of bias assessment is summarized in Appendix Table A3. All trials are at low risk of bias overall; however, the use of blinding is not well reported in three trials. PRIME II did not blind patients to treatment received, but blinding was maintained for outcome assessors and data analysis. The remaining three trials did not report on blinding; nonetheless, as the outcomes of interest were objective outcomes, the risk of bias can be assumed to be low.

      Outcomes

      All trials provided data on in-breast recurrence for elderly women at 5 years. There is strong evidence that adjuvant Tamoxifen plus radiotherapy reduced in-breast recurrence compared to adjuvant Tamoxifen alone in elderly women with early-stage breast cancer following BCS (RR 0.18, 95% CI 0.10–0.34, p < 0.001; 2387 patients) with low heterogeneity (I2 = 0%, p = 0.96) (Fig. 2). The addition of radiotherapy to adjuvant Tamoxifen reduces the number of in-breast recurrences from 60 to 10 (95% CI 6–20) per 1000 patients at 5 years (Table 3). As such, 21 patients must be treated with radiotherapy to prevent one additional breast recurrence in 5 years (NNT 21). Two trials had 10-year follow-up outcomes for in-breast recurrence [
      • Hughes K.S.
      • Schnaper L.A.
      • Bellon J.R.
      • et al.
      Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343.
      ,
      • Fyles A.W.
      • McCready D.R.
      • Olivotto I.A.
      • et al.
      Mature results of a randomized trial of tamoxifen with or without breast radiation in women over 50 years of age with T1/2 N0 breast cancer.
      ]. At 10-years of follow-up the effect of radiotherapy combined with adjuvant Tamoxifen compared with Tamoxifen alone following BCS is maintained (RR 0.27, 95% CI 0.13–0.54, p < 0.001; 891 patients) with low heterogeneity (I2 = 0%, p = 0.44) (Fig. 2). The addition of radiotherapy to adjuvant Tamoxifen reduces the number of in-breast recurrences from 80 to 20 (95% CI 10–40) per 1000 patients at 10 years (Table 3). Compared to 5 years where 21 patients must be treated with radiotherapy to prevent one additional breast recurrence, at 10 years 17 women must be treated with radiotherapy for the same effect (NNT 17).
      Figure thumbnail gr2
      Fig. 2Effect of radiotherapy plus Tamoxifen (Tam RT) compared to Tamoxifen alone (Tam) on breast recurrence at 5 years (A) and 10 years (B). Risk ratios were pooled using fixed-effects models.
      Table 3Summary of findings.
      OutcomesIllustrative comparative risks, per 1000 patients
      The basis for the assumed risk was derived from median Tamoxifen alone group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the Tamoxifen group and the relative effect of the addition of radiotherapy (and its 95% CI). These are rounded for ease of interpretation.
      (95% CI)
      Risk difference, per 1000 patients (95% CI)Relative effect (95% CI)
      Pooled RRs taken from the meta-analyses.
      NNT
      Calculated from the median Tamoxifen alone group risk across studies and RR: NNT=1/(median Tamoxifen alone group risk×(1−RR)). These are rounded to the nearest whole number by convention for ease of interpretation.
      No. of Participants (studies)
      Assumed riskCorresponding risk
      Tamoxifen AloneTamoxifen and Radiotherapy
      In-breast Recurrence at 5 years6010 (6 to 20)50 fewer (40 fewer to 54 fewer)RR 0.18 (0.10 to 0.34)212387 (4)
      In-breast Recurrence at 10 years8020 (10 to 40)60 fewer (40 fewer to 70 fewer)RR 0.27 (0.13 to 0.54)17891 (2)
      Axillary Recurrence at 5 years123 (1 to 10)9 fewer (2 fewer to 11 fewer)RR 0.28 (0.10 to 0.81)1162287 (3)
      Distant Recurrence at 5 years2230 (20 to 50)8 more (28 more to 2 fewer)RR 1.49 (0.87 to 2.54) not significant932287 (3)
      Overall Survival at 5 years165160 (130 to 200)5 fewer (35 more to 35 fewer)RR 0.98 (0.79 to 1.22) not significant3012287 (3)
      Abbreviations: CI, Confidence interval|NNT, Number Needed to Treat|RR, Risk Ratio.
      a The basis for the assumed risk was derived from median Tamoxifen alone group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the Tamoxifen group and the relative effect of the addition of radiotherapy (and its 95% CI). These are rounded for ease of interpretation.
      b Pooled RRs taken from the meta-analyses.
      c Calculated from the median Tamoxifen alone group risk across studies and RR: NNT = 1/(median Tamoxifen alone group risk × (1 − RR)). These are rounded to the nearest whole number by convention for ease of interpretation.
      Three trials provided data for axillary recurrence for elderly women at 5 years [
      • Kunkler I.H.
      • Williams L.J.
      • Jack W.J.
      • Cameron D.A.
      • Dixon J.M.
      • investigators P.I.
      Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.
      ,
      • Hughes K.S.
      • Schnaper L.A.
      • Berry D.
      • et al.
      Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.
      ,
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      ]. Adjuvant Tamoxifen plus radiotherapy reduced axillary recurrence compared to adjuvant Tamoxifen alone (RR 0.28, 95% CI 0.10–0.81, p = 0.02; 2287 patients) with low heterogeneity (I2 = 0%, p = 0.81) (Fig. 3). The number of axillary recurrences was reduced from 12 to 3 (95% CI 1–10) per 1000 patients with the addition of radiotherapy to adjuvant Tamoxifen (Table 3). The NNT is 116 to prevent one axillary recurrence in 5 years. Two trials provided data for our subgroup analysis of trials with a low proportion of ALND: PRIME II had only 22% of patients with ALND, and CALGB 9343 had 36%. In this subgroup with low proportion of ALND, there was no statistical difference in the rate of axillary recurrence with the addition of radiotherapy (RR 0.34, 95% CI 0.10–1.13).
      Figure thumbnail gr3
      Fig. 3Effect of radiotherapy plus Tamoxifen (Tam RT) compared to Tamoxifen alone (Tam) on axillary recurrence (A), distant recurrence (B), and overall survival (C) at 5 years. Risk ratios were pooled using fixed-effects models.
      Three trials provided data for distant recurrence for elderly women at 5 years [
      • Kunkler I.H.
      • Williams L.J.
      • Jack W.J.
      • Cameron D.A.
      • Dixon J.M.
      • investigators P.I.
      Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.
      ,
      • Hughes K.S.
      • Schnaper L.A.
      • Berry D.
      • et al.
      Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.
      ,
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      ]. There is no clear evidence of a difference in distant recurrence with the addition of radiotherapy to adjuvant Tamoxifen compared to adjuvant Tamoxifen alone (RR 1.49, 95% CI 0.87–2.54, p = 0.14; 2287 patients) with low heterogeneity (I2 = 0%, p = 0.60) (Fig. 3).
      Three trials provided data for overall survival for elderly women at 5 years [
      • Kunkler I.H.
      • Williams L.J.
      • Jack W.J.
      • Cameron D.A.
      • Dixon J.M.
      • investigators P.I.
      Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.
      ,
      • Hughes K.S.
      • Schnaper L.A.
      • Berry D.
      • et al.
      Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.
      ,
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      ]. Similarly, there is an absence of evidence of effect on overall survival with the addition of radiotherapy to adjuvant Tamoxifen compared to adjuvant Tamoxifen alone (RR 0.98, 95% CI 0.79–1.22, p = 0.89; 2287 patients) with low heterogeneity (I2 = 0%, p = 0.63) (Fig. 3).

      Discussion

      We identified four RCTs of low overall risk of bias comparing adjuvant Tamoxifen plus radiotherapy to adjuvant Tamoxifen alone reporting outcomes specific for elderly women with early-stage breast cancer treated with breast conserving surgery. There is strong evidence that the addition of radiotherapy reduces the risk of breast and axillary recurrence. However, the absolute risk reduction with the addition of radiotherapy in this population is low. Radiotherapy reduces the risk of breast recurrence from 60 to 10 per 1000 patients at 5 years; an absolute risk reduction of 5% (95% CI 4–5%) or a NNT of 21 to prevent one in-breast recurrence. This effect is maintained at 10 years when the addition of radiotherapy reduces the risk of breast recurrence from 80 to 20 per 1000, an absolute risk reduction of 6% (95% CI 4–7%). More modest is the reduction in axillary recurrence from 12 to 3 per 1000, an absolute risk reduction of 1% (95% CI 0.2–1%) or a NNT of 116 to prevent one axillary recurrence. Additionally, the meta-analyses do not demonstrate evidence that the addition of radiotherapy has an effect on distant recurrence or overall survival.
      Overall, these findings are consistent with the conclusions of the included RCTs regarding a modest effect on locoregional recurrence at 5 and 10 years. However, the published risk difference in Fyles at 5 years is higher at 7.1%, likely due to the inclusion of younger women in this estimate [
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      ]. Further, the individual RCTs were not powered for the outcome of axillary recurrence, which was significant in our meta-analysis albeit modest in effect size. Likewise, the included studies were not powered for the outcomes of distant recurrence or overall survival; thus, our meta-analysis improves the confidence in the null result.
      Our systematic review has several strengths. Most notable is the inclusion of outcomes specifically for elderly women. We obtained published elderly subgroup outcomes from one trial and previously unpublished subgroup outcomes from another (Fyles) [
      • Fyles A.W.
      • McCready D.R.
      • Manchul L.A.
      • et al.
      Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
      ,
      • Fisher B.
      • Bryant J.
      • Dignam J.J.
      • et al.
      Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less.
      ]. By carefully restricting the age criterion for inclusion, we were able to produce a homogeneous study population with results directly applicable to elderly women. Other strengths include our rigourous methodology based on an a priori protocol. Usefully, we present results using absolute effects for ease of interpretation and clinical applicability.
      Our review has several differences compared to the previous systematic review [
      • van de Water W.
      • Bastiaannet E.
      • Scholten A.N.
      Breast-conserving surgery with or without radiotherapy in older breast patients with early stage breast cancer: a systematic review and meta-analysis.
      ]. Our review includes outcomes specifically for elderly women not available in the previous review including published and unpublished subgroup outcomes, the results of PRIME II, and 10 year follow-up outcomes. The pooled estimates of effect were estimated at differing time-points across trials ranging from 4.5 to 13.7 years making the results difficult to interpret. Our review selected the clinically standard time-points of 5 and 10 years to estimate RRs. Additionally, odds ratios, as used in the prior review, can be difficult to interpret, and absolute estimates of effect should also be presented [
      • Walter S.D.
      Choice of effect measure for epidemiological data.
      ,
      • Murad M.H.
      • Montori V.M.
      • Ioannidis J.P.
      • et al.
      How to read a systematic review and meta-analysis and apply the results to patient care: users' guides to the medical literature.
      ]. The prior review calculates risk differences from sums of events across trials, which does not account for weighting, rather than from the pooled estimate calculated by meta-analysis as is standardly done. Finally, the search strategy only utilizes two databases, and a risk of bias assessment is not included in this previous review.
      In our systematic review, the included trials do not report on comorbidity or frailty. Prior cohort studies have observed the increased mortality from non-breast cancer causes and reduced absolute benefit of radiotherapy with increasing age and comorbidity [
      • Satariano W.A.
      • Ragland D.R.
      The effect of comorbidity on 3-year survival of women with primary breast cancer.
      ,
      • Yancik R.
      • Wesley M.N.
      • Ries L.A.
      • Havlik R.J.
      • Edwards B.K.
      • Yates J.W.
      Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older.
      ,
      • Smith B.D.
      • Gross C.P.
      • Smith G.L.
      • Galusha D.H.
      • Bekelman J.E.
      • Haffty B.G.
      Effectiveness of radiation therapy for older women with early breast cancer.
      ]. The importance of all-cause mortality in the elderly population is demonstrated in our meta-analysis with a pooled event rate of any recurrence (breast, axillary, and distant combined) of 144 compared to 275 deaths. Indeed, death is an important competing risk with increasing age and even more with increasing multimorbidity and frailty.
      We could not calculate hazard ratios because sufficient data were not available across studies. Even though hazard ratios are important in accounting for censoring and competing risk, our results using RRs are similar to those reported by the time-to-event analyses available in the trials. Although censoring cannot be accounted for in dichotomous outcomes, the rate of censoring was not different between treatment arms when reported in the trials.
      The included trials do not report on adverse effects or quality of life. Elderly women may also struggle with mobility, transportation, and other social supports that have not been measured. The literature evaluating the impact of radiotherapy on quality of life in elderly is limited. The PRIME RCT randomized women older than 65 years to standard adjuvant radiotherapy or no radiotherapy and found increased breast symptoms and fatigue in the radiotherapy group, but overall health-related quality of life was no different between groups [
      • Williams L.J.
      • Kunkler I.H.
      • King C.C.
      • Jack W.
      • van der Pol M.
      A randomised controlled trial of post-operative radiotherapy following breast-conserving surgery in a minimum-risk population. Quality of life at 5 years in the PRIME trial.
      ].
      Nevertheless, several advances in the delivery of radiotherapy have reduced the overall burden of radiotherapy. Intensity modulated radiation therapy (IMRT) improved cosmesis, fibrosis, toxicity and skin telangiectasia at 5 and 10 years in randomized trials [
      • Mukesh M.B.
      • Barnett G.C.
      • Wilkinson J.S.
      • et al.
      Randomized controlled trial of intensity-modulated radiotherapy for early breast cancer: 5-year results confirm superior overall cosmesis.
      ,
      • Mukesh M.B.
      • Qian W.
      • Wilkinson J.S.
      • et al.
      Patient reported outcome measures (PROMs) following forward planned field-in field IMRT: results from the Cambridge Breast IMRT trial.
      ,
      • Pignol J.P.
      • Truong P.
      • Rakovitch E.
      • Sattler M.G.
      • Whelan T.J.
      • Olivotto I.A.
      Ten years results of the Canadian breast intensity modulated radiation therapy (IMRT) randomized controlled trial.
      ]. Hypofractionation increases convenience by shortening treatment duration, and demonstrates reduced toxicity, edema, telangiectasia, fatigue, and trouble meeting family needs in RCTs [
      • Whelan T.J.
      • Pignol J.P.
      • Levine M.N.
      • et al.
      Long-term results of hypofractionated radiation therapy for breast cancer.
      ,
      • Haviland J.S.
      • Owen J.R.
      • Dewar J.A.
      • et al.
      The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials.
      ,
      • Shaitelman S.F.
      • Schlembach P.J.
      • Arzu I.
      • et al.
      Acute and short-term toxic effects of conventionally fractionated vs hypofractionated whole-breast irradiation: a randomized clinical trial.
      ,
      • James M.L.
      • Lehman M.
      • Hider P.N.
      • Jeffery M.
      • Hickey B.E.
      • Francis D.P.
      Fraction size in radiation treatment for breast conservation in early breast cancer.
      ]. Similarly, accelerated partial breast irradiation (APBI) is a localized form of radiation aimed at improving convenience for women with low-risk tumors [
      • Husain Z.A.
      • Mahmood U.
      • Hanlon A.
      • et al.
      Accelerated partial breast irradiation via brachytherapy: a patterns-of-care analysis with ASTRO consensus statement groupings.
      ,
      • Polgar C.
      • Van Limbergen E.
      • Potter R.
      • et al.
      Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009).
      ,
      • Shah C.
      • Vicini F.
      • Wazer D.E.
      • Arthur D.
      • Patel R.R.
      The American Brachytherapy Society consensus statement for accelerated partial breast irradiation.
      ,
      • Correa C.
      • Harris E.E.
      • Leonardi M.C.
      • et al.
      Accelerated partial breast irradiation: executive summary for the update of an ASTRO evidence-based consensus statement.
      ]. A recent systematic review of 8653 women across 8 RCTs confirms the safety of APBI on regional, distant, and overall survival, with a small increase in breast recurrence (2.9% vs 0.6% at 5 years; HR 4.45, 95% CI: 1.78–11.61) [
      • Marta G.N.
      • Macedo C.R.
      • Carvalho Hde A.
      • Hanna S.A.
      • da Silva J.L.
      • Riera R.
      Accelerated partial irradiation for breast cancer: systematic review and meta-analysis of 8653 women in eight randomized trials.
      ]. Importantly, the impact of locoregional recurrence on quality of life should be considered when weighing this against the omission of radiotherapy, and women may alternatively opt for treatment with an alternative radiotherapy delivery technique to reduce the burden of treatment. There are no studies directly reporting on elderly women’s preferences in weighing omission of radiotherapy against the risk of locoregional recurrence, nor are there published decision aids to assist women with this choice.
      It is well known that elderly women are undertreated with BCS in favor of mastectomy [
      • Angarita F.A.
      • Chesney T.
      • Elser C.
      • Mulligan A.M.
      • McCready D.R.
      • Escallon J.
      Treatment patterns of elderly breast cancer patients at two Canadian cancer centres.
      ,
      • Joerger M.
      • Thurlimann B.
      • Savidan A.
      • et al.
      Treatment of breast cancer in the elderly: a prospective, population-based Swiss study.
      ,
      • Kiderlen M.
      • Bastiaannet E.
      • Walsh P.M.
      • et al.
      Surgical treatment of early stage breast cancer in elderly: an international comparison.
      ]. There are many reasons for this such as logistical concerns related to radiotherapy; possibility of comorbidity, functional impairment, and frailty; ideas about body-image; among others. However, as long as this group of elderly patients who would otherwise underutilize BCS meets the selection criteria for this meta-analysis, they should expect to have similar outcomes as those reported in this meta-analysis, and this meta-analysis may improve the utilization of BCS in elderly women.
      Finally, these results apply only to women who are treated with endocrine therapy. For postmenopausal women, adjuvant endocrine therapy for 5, and up to 10 years, is recommended to reduce the risk of local recurrence and breast cancer-related mortality [
      • Davies C.
      • Godwin J.
      • et al.
      Early Breast Cancer Trialists' Collaborative G
      Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.
      ,
      • Burstein H.J.
      • Temin S.
      • Anderson H.
      • et al.
      Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update.
      ,
      • Senkus E.
      • Kyriakides S.
      • Ohno S.
      • et al.
      Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ]. Both Tamoxifen and aromatase inhibitors (AI) are options, but AIs have increased benefit [
      • Davies C.
      • Godwin J.
      • et al.
      Early Breast Cancer Trialists' Collaborative G
      Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.
      ,
      • Dowsett M.
      • Forbes J.F.
      Early Breast Cancer Trialists' Collaborative G
      Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.
      ]. Adverse effects are not common, but include thromboembolic events, endometrial hyperplasia, reduced bone density, musculoskeletal and sexual symptoms [
      • Davies C.
      • Godwin J.
      • et al.
      Early Breast Cancer Trialists' Collaborative G
      Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.
      ,
      • Burstein H.J.
      • Temin S.
      • Anderson H.
      • et al.
      Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update.
      ,
      • Senkus E.
      • Kyriakides S.
      • Ohno S.
      • et al.
      Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,
      • Dowsett M.
      • Forbes J.F.
      Early Breast Cancer Trialists' Collaborative G
      Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.
      ]. These can lead to poor adherence and nonpersitence [
      • Murphy C.C.
      • Bartholomew L.K.
      • Carpentier M.Y.
      • Bluethmann S.M.
      • Vernon S.W.
      Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review.
      ]. While several options for managing adverse effects exist, the option of omitting endocrine therapy has been proposed [
      • Burstein H.J.
      • Temin S.
      • Anderson H.
      • et al.
      Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update.
      ,
      • Walker G.A.
      • Kaidar-Person O.
      • Kuten A.
      • Morgan D.A.
      Radiotherapy as sole adjuvant treatment for older patients with low-risk breast cancer.
      ]. Two 2 × 2 factorial design RCTs demonstrate that adjuvant monotherapy with either Tamoxifen alone or radiotherapy alone had similar effects on reduction of local recurrence compared with no adjuvant treatment [
      • Winzer K.J.
      • Sauerbrei W.
      • Braun M.
      • et al.
      Radiation therapy and tamoxifen after breast-conserving surgery: updated results of a 2 x 2 randomised clinical trial in patients with low risk of recurrence.
      ,
      • Blamey R.W.
      • Bates T.
      • Chetty U.
      • et al.
      Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial.
      ]. Conversely, GBCG-V observed no difference between monotherapy with either Tamoxifen or radiotherapy compared with combined endocrine and radiotherapy, while BASO II observed increased local recurrence with monotherapy compared with combined therapy [
      • Walker G.A.
      • Kaidar-Person O.
      • Kuten A.
      • Morgan D.A.
      Radiotherapy as sole adjuvant treatment for older patients with low-risk breast cancer.
      ,
      • Blamey R.W.
      • Bates T.
      • Chetty U.
      • et al.
      Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial.
      ]. Based on these results, women who cannot tolerate or opt to omit endocrine therapy, may favor the inclusion of adjuvant radiotherapy.

      Conclusion

      Our meta-analysis provides the most robust estimate of effect for adjuvant radiotherapy, or its omission, in elderly women with early-stage breast cancer treated with BCS and adjuvant endocrine therapy. These findings provide precise estimates that can be included in guideline recommendations, can be used by patients and their physicians in shared decision-making, and provide data for the development of a decision aid to assist elderly women in making this choice. Indeed, the addition of adjuvant radiotherapy reduces the relative risk of breast recurrence and axillary recurrence. However, the absolute reduction in the risk of breast recurrence is modest, and even less for that of axillary recurrence. Further, there is no demonstrable evidence that radiotherapy affects the risk of distance recurrence or overall survival. The value of this risk reduction must be weighed by elderly women and their physicians when considering the omission of adjuvant radiotherapy. Women may also consider the impact of omitting endocrine therapy or using alternative radiotherapy techniques as other options to reduce treatment burden. Ultimately, the inputs of a multidisciplinary team including a global assessment of risks and prognosis such as a comprehensive geriatric assessment will facilitate patient-centered decision making [
      • Biganzoli L.
      • Wildiers H.
      • Oakman C.
      • et al.
      Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA).
      ].

      Funding source

      Andrea C. Tricco is funded by a Tier 2 Canada Research Chair in Knowledge Synthesis.

      Disclaimers

      There are no conflicts of interest to disclose.

      Acknowledgements

      Christine Neilson, information specialist.
      Bridget Morant, information specialist.

      Appendix A. Supplementary data

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