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Oncology
Protocol
Optimum duration of extended adjuvant endocrine therapy in patients with hormone receptor-positive breast cancer: protocol for a network meta-analysis of randomised controlled trials
  1. Qiancheng Hu1,2,
  2. Daoli Ye3,
  3. Zhao Xudong4,
  4. Qingfeng Wang5,
  5. Hongfeng Gou1,2,
  6. Ting Luo1,6,7
  1. 1Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
  2. 2Gastric Cancer Center and Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
  3. 3Gastric Cancer Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
  4. 4Laboratory of Animal Tumor Models, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
  5. 5Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
  6. 6Breast Center, West China Hospital, Sichuan University, Chengdu, China
  7. 7Multi-omics Laboratory of Breast Diseases, State Key Laboratory of Biotherapy, National Collaborative, Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
  1. Correspondence to Dr Ting Luo; tina621{at}163.com

Abstract

Introduction The type of extended adjuvant endocrine therapy is not clear, nor is the optimum duration of extended adjuvant endocrine therapy for patients with early breast cancer. Our study aims to satisfy the requirements for systematically identifying and synthesising the available evidence on the clinical safety and efficacy of extended adjuvant endocrine therapy for patients with hormone receptor-positive early breast cancer.

Methods and analysis A comprehensive electronic literature database search will be performed using three electronic databases: PubMed, Cochrane Library and Embase (Ovid interface). Our main outcomes of interest were overall survival, disease-free survival, relapse-free survival, invasive contralateral breast cancer, acceptability and grades 3 and 4 non-haematological toxicities in this study. We will assess the risk of bias and overall quality of evidence using the Cochrane Collaboration’s tool and Grades of Recommendation, Assessment, Development and Evaluation, respectively. We will perform subgroup and sensitivity analyses in the selected trials. We will assess the three key assumptions of network meta-analysis: transitivity, consistency and homogeneity.

Ethics and dissemination The protocol was preregistered in the International Prospective Register of Systematic Reviews (PROSPERO) database. Ethics approval and patient consent are not required for the network meta-analysis. The final results of this network meta-analysis will be disseminated through national and international conferences and published in a peer-reviewed journal.

PROSPERO registration number CRD42021278271.

  • ONCOLOGY
  • Breast tumours
  • Pharmacology
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2022-070972

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    Strengths and limitations of this study

    • The comprehensive search strategy included searching electronic literature databases, citation searching and searching clinical trial registers to identify eligible studies.

    • The same searches will be updated close to publication to check for the most recent eligible studies.

    • We will assess the three key assumption of network meta-analysis: transitivity, consistency and homogeneity.

    • Cluster analysis for efficacy and safety will be applied to identify and rank the optimum duration of extended adjuvant endocrine therapy in patients with hormone receptor-positive breast cancer.

    • We will include only those randomised controlled trials published in English.

    Introduction

    Breast cancer is the most frequently diagnosed cancer in women worldwide, with an estimated 2.3 million new cancer cases occurring in 2020.1 Annually, breast cancer accounts for more than half a million deaths worldwide.2 The hormone receptor-positive subgroup represented approximately 70% of all patients with breast cancer,3 4 and endocrine therapy for a minimum of 5 years was a major treatment strategy for hormone receptor-positive early breast cancer in the updated guidelines from the National Comprehensive Cancer Network (NCCN).5 However, approximately three out of five (59.7%) patients with initial breast cancer experienced recurrence: either a first recurrence at a local site, contralateral breast cancer, a recurrence at a regional site or a recurrence at a distant site between year 5 and year 15.6 7 Of greater interest, extended adjuvant endocrine therapy was prescribed to patients with hormone receptor-positive breast cancer to prevent late recurrence after surgery.8

    The three recommended extended adjuvant endocrine therapies for early breast cancer are extended administration of tamoxifen after 5 years of adjuvant tamoxifen, extended administration of aromatase inhibitors after 5 years of adjuvant tamoxifen and extended administration of aromatase inhibitors after adjuvant endocrine therapy (aromatase inhibitors or tamoxifen).9 The question remains which type of extended adjuvant endocrine therapy is preferred. A meta-analysis involving 21 554 patients with early breast cancer evaluated clinical trials comparing extended adjuvant tamoxifen vs 5 years of tamoxifen. In unselected patients, extended adjuvant tamoxifen was not associated with a significant improvement in recurrence-free (OR 0.89, 95% CI 0.76 to 1.05; p=0.17) or overall survival (OR 0.99, 95% CI 0.84 to 1.16; p=0.88).10 Furthermore, a recent meta-analysis (n=19 345) based on eight randomised control trials revealed the efficacy of extended adjuvant treatment with aromatase inhibitors for hormone receptor-positive early breast cancer, with a 22% increase in disease-free survival (HR 0.78, 95% CI 0.68 to 0.90; p=0.0006) but no impact on overall survival (HR 0.99, 95% CI 0.87 to 1.12; p=0.84). However, a meta-analysis comparing tamoxifen beyond 5 years vs 5 years of tamoxifen showed no difference in disease-free and overall survival and only a minor number of patients with a positive lymph node decrease in distant recurrence (OR 0.87, 95% CI 0.79 to 0.97).11

    Although extended adjuvant endocrine therapy was considered a preferred strategy for patients with high-risk hormone receptor-positive early breast cancer,11 the relationship between the duration of extended adjuvant endocrine therapy and its efficacy is still unknown. The seminal MA.17R trial involving postmenopausal women with breast cancer who had received 5 years of letrozole after completion of a standard 5 years of tamoxifen therapy showed that there was improvement in disease-free survival for extended endocrine therapy (HR 0.66, 95% CI 0.48 to 0.91; p=0.01).12 Conversely, the NSABP B-42 trial randomised almost 4000 patients to receive either 5 years of letrozole or placebo following an initial 5 years of adjuvant endocrine therapy and failed to show any statistically significant differences for disease-free (HR 0.96, 95% CI 0.76 to 1.20; p=0.70) and overall survival (HR 1.08, 95% CI 0.81 to 1.45; p=0.59).13 The ABCSG-16 trial likewise randomised patients after 5 years of adjuvant endocrine therapy to receive anastrozole for an additional 2 years or an additional 5 years and provided no benefit for extending hormone therapy by 5 years in postmenopausal women with hormone receptor-positive breast cancer (HR 0.99, 95% CI 0.85 to 1.15; p=0.90).14 The IDEAL (Investigation on the Duration of Extended Adjuvant Letrozoletreatment) multicentre trial randomised postmenopausal hormone receptor-positive women with early breast cancer to either short arms (2–3 years of letrozole) or long arms (5 years of letrozole), and suggested that long arms did not improve disease-free (HR 0.92, 95% CI 0.74 to 1.16; p=0.49) and overall survival (HR 1.04, 95% CI 0.78 to 1.38; p=0.79) compared with short arms.15 Several extended adjuvant endocrine therapies were compared only with the placebo-treated group, and the direct comparison of multiple therapies against breast cancer remained incomplete.

    As mentioned previously, the type of extended adjuvant endocrine therapy is not clear nor is the optimum duration of extended adjuvant endocrine therapy for patients with early breast cancer.16 Therefore, continued work is needed to identify the potential patients who will most likely benefit from extended adjuvant endocrine therapy. Our study aims to satisfy the requirements for systematically identifying and synthesising the available evidence on the clinical safety and efficacy of extended adjuvant endocrine therapy for patients with hormone receptor-positive early breast cancer.

    Methods

    The protocol will be conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines (see online supplemental file 1).17

    This protocol was preregistered in the International Prospective Register of Systematic Reviews database (registration number: CRD42021278271, registration date: 12 October 2021). The study period was scheduled for 2 years after subject registration (full study duration November 2021–November 2023).

    Inclusion and exclusion criteria

    All identified randomised controlled trials strictly fulfilling specified population, intervention, comparator and outcome (PICO)-based eligibility criteria listed as follows will be included in the review.

    Patients

    Patients with hormone receptor-positive early breast cancer were treated with extended adjuvant endocrine therapy (defined as adjuvant endocrine therapy prolonged after 5 years). All eligible participants will be included, regardless of age or race.

    Interventions

    Any duration of extended adjuvant endocrine therapy was given. Extended adjuvant endocrine therapy with tamoxifen or aromatase inhibitors was delivered for a total duration of more than 5 years. Ovarian function suppression in combination with aromatase inhibitors was allowed.

    Comparators

    Placebo/observation or other durations of extended adjuvant endocrine therapy in the control arm are included.

    Outcomes

    Our main outcomes of interest were overall survival, disease-free survival, relapse-free survival, invasive contralateral breast cancer, acceptability, and grades 3 and 4 non-haematological toxicities in this study.

    Language and other limitations

    We will include randomised controlled trials published in English regardless of publication status, date or geographical location.

    Studies not meeting the inclusion criteria will be excluded. The other exclusion criteria are as follows: (1) insufficient data availability to estimate one of the aforementioned outcomes of interest and (2) data about extended adjuvant endocrine therapy comes from the subgroup analysis.

    Outcomes

    The outcomes of interest are overall survival (defined as the time from randomisation to death from any cause), disease-free survival (defined as the time from randomisation to local, regional, distant relapse, contralateral breast cancer, second primary cancer or death from any cause, whichever occurred first), relapse-free survival (defined as the time interval between the randomisation and the date of local and regional recurrence of breast cancer), acceptability (defined as the proportion of patients who discontinued extended adjuvant endocrine therapy), and grades 3 and 4 non-haematological toxicities as defined by the Common Terminology Criteria for Adverse Events version. Standardised definitions for efficacy end points (STEEP V.2.0) are an important document for descriptions of good research practices and advice on how to deal with data integration in meta-analysis and network meta-analysis.18 At present, there are possibly several definitions of recurrence-free survival in the literature. We will construct a table in an effort to adequately understand how recurrence-free survival (RFS) outcomes are currently defined, reported and analysed in the available literature. If possible, we will conduct subgroup analysis based on RFS outcomes.

    Search strategy

    The comprehensive search strategy included searching electronic literature databases, citation searching and searching clinical trial registers to identify eligible studies. A comprehensive search of electronic literature databases will be performed using three electronic databases from the time of inception to 20 October 2021: PubMed, Cochrane Library and Embase (Ovid interface).We will also search for grey literature from the proceedings of the Annual Meetings of the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology and San Antonio Breast Cancer Symposium. In addition, two reviewers will manually search reference lists of relevant studies using a snowballing method to identify additional eligible studies independently. The search for relevant ongoing clinical trials will be performed viaClinicalTrials.gov. The search for eligible articles will be completed by two reviewers independently. The same searches will be updated close to publication to check for the most recent eligible studies. We will keep a record of the reasons for excluding ineligible studies and report the study selection process via the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.19

    Medical Subject Headings (MeSH) terms will be used (breast neoplasms) in PubMed (table 1) and the Cochrane Library (P1), and Emtree terms (breast cancer) will be used when searching Embase (P2). A combination of MeSH/Emtree terms and free-text terms (extended endocrine therapy) in research equations with Boolean operators and filters will be used for searching relevant randomised controlled trials. Core search terms will be adapted to meet the characteristics of individual databases according to PICO formulating questions.

    View this table:
    Table 1

    Search strategy used in PubMed

    We will evaluate the inter-rater reliability of the two reviewers and conduct a training exercise to ensure a robust search before each stage of screening when necessary. Two reviewers will judge the eligibility of the studies by reading titles and abstracts based on inclusion and exclusion criteria independently. Thereafter, we will retrieve the full texts of eligible or potentially eligible trials and extract the data of interest if the inclusion criteria are met. Any disagreements in the literature searches will be discussed and resolved.

    Data extraction

    All retrieved articles will be uploaded to EndNote X7 software (Thomson Reuters Corporation, Stanford, USA). Duplicates across searches will be automatically identified and manually removed before initial screening titles and abstracts. Data of interest will be collected in a standardised data abstraction form using Microsoft Excel V.2013 (Microsoft Corporation, Redmond, WA, USA). The extracted data of interest for this network meta-analysis will include study name, first author, study design, recruitment time frame, detailed interventions, sample size and outcome data (Overall survival (OS), Disease-free survival (DFS), relapse-free survival, invasive contralateral breast cancer, acceptability and grades 3 and 4 non-haematological toxicities). We will contact the pharmaceutical company or the corresponding authors to request any unclear or missing data up to three times over 6 weeks by email where needed. If there are multiple publications for one study, we will use the most comprehensive data. Disagreements in data extraction will be discussed with a third reviewer.

    Assessment of methodological quality

    We will assess the risk of bias using the Cochrane Collaboration’s tool (Higgins et al20), which is specifically developed to assess the methodological quality of randomised controlled trials. Potential risks of bias in the included studies come from randomisation sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other biases.20 Two reviewers will independently assess the included studies and categorise each item into one of three levels: ‘low risk’, ‘high risk’ or ‘uncertain’. A randomised controlled trial will be considered low risk of bias overall only if all individual bias domains are judged as having a low risk of bias. Any disagreements in the assessment of the risk of bias will be resolved by discussion with the help of the third reviewer.

    We will identify the overall quality of evidence using Grades of Recommendation, Assessment, Development and Evaluation (GRADE), which consists of five items: risk of bias, imprecision, inconsistency, indirectness and publication bias.21 22 The staging system categorises each criterion as high, moderate, low or very low quality, choosing the lowest quality as the overall quality of evidence. The initial confidence level for randomised controlled trials is set as high but will be rated down, depending on the judgements from the five items detailed previously. The strength of evidence will be graded into four levels based on the GRADE system in the Confidence in Network Meta-Analysis web tool.22

    Publication bias will be analysed visually by judging asymmetry in a comparison-adjusted funnel plot and statistically assessed by the Egger test.23 If asymmetry is detected, we will explore potential reasons by conducting a sensitivity analysis, including publication bias, small study effects, poor methodological quality and true heterogeneity.

    Statistical analysis plan

    The first step is to conduct pairwise meta-analysis. When appropriate, fixed-effect and random-effect network meta-analysis will be applied to HRs for overall survival, disease-free survival and relapse-free survival, and the binary outcomes of invasive contralateral breast cancer, acceptability and grades 3 and 4 non-haematological toxicities. The pooled HRs or ORs with 95% credible intervals between interventions will be presented as league tables. Random effect models will be used when moderate to severe heterogeneity is present (I2 >50%); otherwise fixed effect models will be used when statistical is low (I2 <50%).24 Traditional pairwise meta-analysis of direct comparisons will be conducted using Stata V.13.0. A two-sided p value of < 0.05 is considered statistically significant.

    A network diagram will be produced consisting of nodes and lines for each outcome, with larger network nodes representing a greater number of patients and thicker lines denoting a greater number of trials. Several durations of extended adjuvant endocrine therapy were found in previous randomised controlled trials, such as 6.0, 7.0, 7.5, 8.0, 9.0 and 10 years. Thus, these time points will be considered as different ‘nodes’ of treatments in the network meta-analysis. In previous randomised controlled trials, 5 years was usually considered as the control group, so it was also considered as the node of treatment connecting the rest of the evidence network. Surface under the cumulative ranking (SUCRA) will be used to assess the efficacy and safety, with a larger SUCRA indicating a more effective intervention. Network meta-analysis will be performed using WinBUGS V.1.4.3 (MRC Biostatistics Unit, Cambridge, UK).25 26

    Cluster analysis will be used to comprehensively assess the effects of the interventions on the dimensions of the efficacy and safety outcomes to rank the duration of extended adjuvant endocrine therapy and identify optimal usage in patients with hormone receptor-positive breast cancer.27

    In general, a fundamental assumption of network meta-analysis is that the studies are sufficiently similar in their distribution of clinical and methodological variation. To help assess the transitivity assumption, we will visually summarise and inspect the similarity of components of participant characteristics, interventions and outcome parameters across different types of interventions. We will also compare direct and indirect estimates for the consistency assumption, both locally for each comparison using a loop-specific method28 or a node-splitting method29 and globally across the whole network using a design-by-treatment interaction model.30 We will compare models using the deviance information criterion, with lower value indicating a better model fit.31 In addition, we will assess the methodological heterogeneity by examining risk of bias, study design and statistical tests (I2 measure for heterogeneity and χ2 test for homogeneity).32 33

    Subgroup analysis

    We will explore whether a specific duration of treatments with extended adjuvant endocrine therapy might be more appropriate for particular subtypes of breast cancer. We categorise breast cancer into the following groups when possible: hormone receptor (oestrogen receptor-positive vs oestrogen receptor negative), node status (positive vs negative), tumour size (>2 cm vs ≤2 cm), menopausal status (premenopausal vs postmenopausal) and drugs of extended adjuvant endocrine therapy (extended administration of tamoxifen after 5 years of adjuvant tamoxifen versus extended administration of aromatase inhibitors after 5 years of adjuvant tamoxifen versus extended administration of aromatase inhibitors after adjuvant endocrine therapy).

    Sensitivity analysis

    We plan to conduct several sensitivity analyses to evaluate the robustness and reliability of the findings and explore their potential impact on effect sizes. We will conduct sensitivity analysis according to risk of bias, including only studies with a low risk of bias in all domains. The sensitivity analysis will be restricted to studies with complete outcome publication (after 2000 vs before 2000). Last, the number of enrolled patients (<1000 and ≥1000) included in eligible studies will be considered for sensitivity analysis.

    Patient and public involvement

    There was no patient or public involvement in conceptualisation, design, implementation, data analysis, interpretation, manuscript preparation or dissemination. A plain summary of the findings will be provided to the Chinese Society of Clinical Oncology (CSCO) after completion of all data analysis as mentioned previously.

    Ethics and dissemination

    Ethics approval and patient consent are not required for the network meta-analysis. The final results of this network meta-analysis will be disseminated through national and international conferences and published in a peer-reviewed journal.

    Discussion

    Both the NCCN and ASCO guidelines did not give a robust conclusion about the optimal duration of extended adjuvant endocrine therapy.5 34 The updated ASCO clinical practice guideline recommends that patients with node-positive breast cancer receive extended adjuvant endocrine therapies for up to a total of 10 years. Any one of the following extended adjuvant endocrine therapy in the ASCO guidelines was recommended: tamoxifen for 10 years; tamoxifen for 5 years followed by aromatase inhibitors for 5 years; tamoxifen for 2–3 years followed by aromatase inhibitors for 7–8 years; aromatase inhibitors for up to a total of 10 years.34 However, the NCCN guidelines recommended one of the following extended adjuvant endocrine therapies for patients with hormone receptor-positive early breast cancer: tamoxifen for 2–3 years followed by 5 years of aromatase inhibitors; tamoxifen for 4.5–6.0 years followed by 5 years of aromatase inhibitors; tamoxifen for up to a total of 10 years.5 As a result, decisions related to extended adjuvant endocrine therapy are challenging and complex between patients and clinicians in daily clinical practice, and more evidence is needed to support the efficacy, safety, quality of life and cost-effectiveness of extended adjuvant endocrine therapy in patients with hormone receptor-positive early breast cancer.

    There are still major unanswered questions with respect to who should receive extended adjuvant endocrine therapy, for what purposes and for how long in patients with hormone receptor-positive early breast cancer.16 Several durations of extended adjuvant endocrine therapy were found in previous randomised controlled trials, such as 6.0, 7.0, 7.5, 8.0, 9.0 and 10.0 years.12–15 35–39 A recent multicentre randomised controlled trial challenged the approach of extended adjuvant endocrine therapy for 10 years. Extended aromatase inhibitor therapy (7–8 years) showed better overall survival benefit than the control group (5 years) (HR 0.77, 95% CI 0.60 to 0.98; p=0.036).40 There was no significant difference in disease-free survival (HR 1.08, 95% CI 0.93 to 1.26; p=0.31) or safety between extended intermittent letrozole use (9 years) and continuous letrozole use (10 years).37 The IDEAL and ABCSG16 studies showed that extended adjuvant endocrine therapy for 7.0–7.5 years was non-inferior to 10 years.14 15 Furthermore, two recent meta-analyses of randomised controlled trials concluded that extension of adjuvant endocrine therapy, including tamoxifen and aromatase inhibitors, was not associated with a significantly longer overall survival, and it significantly affected quality of life and increased the risk of other health problems in unselected patients with hormone receptor-positive early breast cancer.34 41 Direct comparisons of treatment durations cannot be performed in pairwise meta-analysis and previous randomised controlled trials, but they might be achieved in network meta-analyses through indirect comparisons.

    In brief, previous work has shown that adjuvant endocrine therapy for a minimum of 5 years was a major treatment strategy for hormone receptor-positive early breast cancer. Extended adjuvant endocrine therapy was initiated as a standard adjuvant treatment and showed a rapid increasing trend in patients with hormone receptor-positive breast cancer. Our study aims to satisfy the requirements for systematically identifying and synthesising the available evidence on the relative safety and efficacy of extended adjuvant endocrine therapy for patients with hormone receptor-positive early breast cancer. Continued work is needed to identify the potential biomarkers that recognise potential sensitive patients for either longer or shorter durations of extended adjuvant endocrine therapy.

    Ethics statements

    Patient consent for publication

    Acknowledgments

    Thanks to Lu Guan (Fisheries Oceans Canada) for providing a professional English editing service.

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • QH and DY are joint first authors.

    • Contributors QH and TL conceptualised and designed this protocol of network meta-analysis. QH and DY developed and ran the search strategy. QH and QW were major contributors in writing the initial draft of this protocol, whereas ZX and HG revised and suggested changes to the manuscript. The corresponding author (TL) accepted full responsibility for the contents as guarantor of this article. All authors reviewed the final version and agreed to submit the manuscript to the journal.

    • Funding This protocol of network meta-analysis was supported by the Project of Sichuan Department of Science and Technology (grant number 2021YES0235).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.