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The iBRA-2 (immediate breast reconstruction and adjuvant therapy audit) study: protocol for a prospective national multicentre cohort study to evaluate the impact of immediate breast reconstruction on the delivery of adjuvant therapy
  1. Rajiv Dave1,
  2. Rachel O'Connell2,
  3. Tim Rattay3,
  4. Zoe Tolkien4,
  5. Nicola Barnes2,
  6. Joanna Skillman5,
  7. Paula Williamson6,
  8. Elizabeth Conroy6,
  9. Matthew Gardiner7,8,
  10. Adrian Harnett9,
  11. Ciara O'Brien10,
  12. Jane Blazeby4,
  13. Shelley Potter4,
  14. Chris Holcombe11
  15. on behalf of the Breast Reconstruction Research Collaborative
  1. 1Nightingale Breast Unit, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
  2. 2Department of Breast Surgery, The Royal Marsden NHS Foundation Trust, Sutton, UK
  3. 3Department of Cancer Studies, Clinical Sciences Building, University of Leicester, Leicester, UK
  4. 4Bristol Centre for Surgical Research, School of Social and Community Medicine, University of Bristol, Bristol, UK
  5. 5Department of Plastic Surgery, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
  6. 6Department of Biostatistics, Clinical Trials Research Centre, University of Liverpool MRC North West Hub for Trials Methodology Research, University of Liverpool, Liverpool, UK
  7. 7Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Oxford, UK
  8. 8Department of Surgery and Cancer, Imperial College London, London, UK
  9. 9Norfolk and Norwich Hospital, Norwich, UK
  10. 10The Christie NHS Foundation Trust, Manchester, UK
  11. 11Linda McCartney Centre, Royal Liverpool and Broadgreen University Hospital, Liverpool, UK
  1. Correspondence to Shelley Potter; shelley.potter{at}bristol.ac.uk

Abstract

Introduction Immediate breast reconstruction (IBR) is routinely offered to improve quality of life for women with breast cancer requiring a mastectomy, but there are concerns that more complex surgery may delay the delivery of adjuvant oncological treatments and compromise long-term oncological outcomes. High-quality evidence, however, is lacking. iBRA-2 is a national prospective multicentre cohort study that aims to investigate the effect of IBR on the delivery of adjuvant therapy.

Methods and analysis Breast and plastic surgery centres in the UK performing mastectomy with or without (±) IBR will be invited to participate in the study through the trainee research collaborative network. All women undergoing mastectomy ± IBR for breast cancer between 1 July and 31 December 2016 will be included. Patient demographics, operative, oncological and complication data will be collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR will be compared to determine the impact that IBR has on the time of delivery of adjuvant therapy. Prospective data on 3000 patients from ∼50 centres are anticipated.

Ethics and dissemination Research ethics approval is not required for this study. This has been confirmed using the online Health Research Authority decision tool. This novel study will explore whether IBR impacts the time to delivery of adjuvant therapy. The study will provide valuable information to help patients and surgeons make more informed decisions about their surgical options. Dissemination of the study protocol will be via the Mammary Fold Academic and Research Collaborative (MFAC) and the Reconstructive Surgery Trials Network (RSTN), the Association of Breast Surgery (ABS) and the British Association of Plastic, Reconstructive and Aesthetic Surgeons (BAPRAS). Participating units will have access to their own data and collective results will be presented at relevant surgical conferences and published in appropriate peer-reviewed journals.

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Strengths and limitations of this study

  • Large multicentre prospective study involving data collection from breast and plastic surgical units across the UK.

  • Will produce valuable data regarding the impact of immediate breast reconstruction on the time to delivery of adjuvant therapy which will help inform decision-making for patients and surgeons.

  • Will strengthen the collaborative network between breast and plastic surgical trainees and consultants to facilitate the delivery of future research.

  • Observational design will not address causality.

  • Short-term data collection will not allow the long-term impact of delays to adjuvant therapy to be assessed.

Introduction

Approximately 51 000 women will be diagnosed with breast cancer each year,1 of whom, up to 40% may require a mastectomy as the primary surgical treatment.2 The loss of breast can profoundly impact a woman's quality of life and body image.3 Immediate breast reconstruction (IBR) is routinely offered in the UK to improve outcomes.4

While IBR may improve psychosocial outcomes for women facing mastectomy, these benefits need to be weighed against the increased risk of complications associated with more complex procedures. The National Mastectomy and Breast Reconstruction Audit (NMBRA) reported a stepwise increase in complication rates with procedure complexity with 10% of patients undergoing mastectomy experiencing a postoperative complication compared with 11% of patients undergoing an implant-based procedures; 16% of patients undergoing a pedicled flap and 18% of those undergoing immediate free-flap reconstruction.5 These complication rates are likely to represent an underestimation of the burden of postoperative morbidity as significant number of complications, in particular wound infections and seromas, continue to occur after discharge.

Complication rates following IBR are important as they may lead to the delay or omission of adjuvant cancer therapies in the form of adjuvant chemotherapy or biological therapy and postmastectomy radiotherapy. The clinical significance of short delays is unclear, but delays of between 76 and 12 weeks7 have been shown to adversely impact on key oncological outcomes, including recurrence-free and overall survival. Furthermore, a recent meta-analysis suggests a 15% decrease in overall survival for every 4-week delay in the delivery of adjuvant chemotherapy.8 Similarly, delays to radiotherapy adversely impact oncological outcomes, although the timeframes are less well established. An early meta-analysis suggested an increased risk of locoregional recurrence if radiotherapy was delayed by more than 8 weeks following surgery.9 More recent studies, however, suggest there to be no adverse effect on disease-free or overall survival if radiotherapy is started within 3 months of surgery,10–13 with one large UK cohort study showing no deleterious effects with delays of up to 20 weeks.10 To ensure timely delivery of adjuvant therapies, the National Institute of Health and Care Excellence (NICE) recommends that adjuvant chemotherapy or radiotherapy should be started ‘as soon as clinically possible [and] within 31 days of completion of surgery in patients with early breast cancer having these treatments’.4

Evidence regarding the impact of IBR on the delivery of adjuvant therapy, however, is inconsistent. Observational studies have generated conflicting results,14–39 and a recent systematic review40 of 14 studies failed to demonstrate any convincing adverse impact of IBR on the time to adjuvant treatments. This review, however, was based on small, poorly designed single-centre often retrospective case-series, the results of which cannot be relied on. Therefore, there is a lack of high-quality evidence to demonstrate the impact of IBR on the delivery of adjuvant therapies compared with mastectomy alone. Randomised controlled trials (RCTs) provide the best evidence of treatment effect, but in this context are largely inappropriate. A large-scale prospective cohort study is therefore required to provide high-quality evidence regarding the impact of IBR on the delivery of adjuvant therapy to allow patients and surgeons to make more informed decisions about potential treatment options.

The challenges to the design and conduct of large-scale cohort studies are well documented, but the trainee collaborative model has emerged as a time-effective and cost-effective means of delivering high-quality prospective research and audit.41–44 The ongoing iBRA (implant Breast Reconstruction evAluation) study (ISRCTN37664281),45 a national prospective cohort study to explore the feasibility, design and conduct of a pragmatic RCT in implant-based breast surgery, has demonstrated the trainee collaborative model is transferable to breast and plastic surgery, and has established a network of centres willing and able to participate in future projects. It is anticipated that this network of highly motivated and enthusiastic breast and plastic surgical trainees and consultants can be used to deliver a new study exploring the impact of IBR on the timing of adjuvant therapy.

Methods and analysis

Primary aim

The aim of iBRA-2 is to work with the Breast Reconstruction Research Collaborative network to evaluate the impact of IBR on the time to delivery of adjuvant therapy. The group undergoing mastectomy without IBR and the group undergoing mastectomy with IBR will be compared with respect to:

  1. the rate of postoperative complications,

  2. the requirement for adjuvant chemotherapy and/or radiotherapy,

  3. the experience of a delay to or omission of their adjuvant therapy as a result of a surgical complication,

  4. the time to adjuvant therapy.

Other non-comparative objectives are to:

  1. identify risk factors of patients who experience a delay to or omission of their adjuvant therapy as a result of surgical complication,

  2. explore the impact of delay to adjuvant therapy on key oncological outcomes, including locoregional recurrence; metastatic disease and breast cancer-specific death at 5 and 10 years,

  3. generate high-quality data to inform decision-making for patients and health professionals,

  4. build and strengthen the collaborative network created by the iBRA study to include oncologists and build future research capacity.

Hypothesis

IBR following mastectomy for breast cancer does not increase the time to delivery of adjuvant therapy compared with mastectomy alone.

Study design

We plan to undertake a national prospective multicentre cohort study using the research collaborative model previously reported42 ,43 coordinated by the iBRA-2 Steering Group.

Setting

Any breast or plastic surgical unit in the UK performing mastectomy with or without IBR will be eligible to participate to the study. Units will be invited to participate in the study through the Association of Breast Surgery (ABS), the Mammary Fold breast trainees’ group (MF), the Association of Surgeons in Training (ASiT), the Reconstructive Surgery Trials Network (RSTN), the British Association of Plastic Reconstructive and Aesthetic Surgeons (BAPRAS) and the national research collaborative network (NRCN).

Participants

Inclusion criteria: All women over the age of 18 who are undergoing a mastectomy with or without immediate reconstruction for pre-invasive or invasive breast cancer with curative intent.

Exclusion criteria: Women undergoing mastectomy for risk-reduction only; however, women who are undergoing a contralateral risk-reducing mastectomy at the same time as a therapeutic mastectomy for invasive or preinvasive disease may be included. Patients undergoing partial mastectomy, including lumpectomy or wide-local excision with volume replacement techniques (latissimus dorsi mini flaps; lateral intercostal perforator or thoracodorsal artery perforator flaps) or therapeutic mammoplasty, and patients with distant metastatic disease will be excluded.

Outcome measures

The primary outcome measure will be time in days from last definitive cancer surgery to the first adjuvant treatment. The last definitive cancer surgery will most commonly be the index mastectomy procedure, but may include completion axillary clearance or re-excision of margins as determined on review of the surgical pathology by the multidisciplinary team (MDT). Unplanned surgery such as implant explantation, debridement of skin necrosis, washout of haematoma or return to theatre for flap failure constitute complications and will not be classified as last definitive surgery for the purposes of this study. First adjuvant therapy will be defined as the first dose of chemotherapy or the first fraction of radiotherapy. Time to endocrine therapy will not be included. This definition is based on the National Institute for Health and Care Excellence guidance for early and locally advanced breast cancer (CG80) which states that adjuvant chemotherapy or radiotherapy should be started ‘as soon as clinically possible [and] within 31 days of completion of surgery in patients with early breast cancer having these treatments’.4 In patients for whom more than one modality of adjuvant treatment is recommended, only the start date for the first adjuvant therapy will be recorded. Secondary outcomes are listed in table 1.

Table 1

Secondary outcome measures

Data collection

It is expected that participating centres will recruit consecutive patients into the audit.

Patients undergoing mastectomy with or without immediate reconstruction will be identified prospectively from clinics, MDT meetings and theatre lists.

Simple demographic, comorbidity, operative and oncology data will be collected on all patients. Decisions regarding the recommendation for adjuvant treatment will be identified from the postoperative MDT meeting.

For patients in whom adjuvant therapy is recommended at the postoperative MDT meeting, data will be collected on whether or not the offer was accepted. In those patients electing to receive adjuvant therapy, date of the first treatment will be collected.

Data regarding complications, re-admission and re-operation will be collected prospectively until the patient begins adjuvant therapy or a decision is made that they will not undergo adjuvant therapy due to the complications they have experienced. Preliminary work suggests that, despite NICE guidelines, adjuvant therapy is unlikely to start earlier than 6 weeks postoperatively. For patients not requiring or electing not to receive adjuvant therapy, therefore, data collection will continue for 6 weeks following their last definitive cancer surgery either by clinical or note review in those not attending for follow-up. The required data fields are shown in table 2 and definitions and categorisation of complications summarised in table 3.

Table 2

Data fields for the iBRA-2 study

Table 3

Definitions of complications

Oncological outcomes (locoregional recurrence, distant metastasis and breast cancer-specific death) will be evaluated at 5 and 10 years following initial surgery by searching the UK Cancer Registry database. This phase of the study will be undertaken centrally by the iBRA-2 study team subject to appropriate ethical approval.

Data will be recorded in an anonymised format using a unique alphanumeric study identification number on a secure web-based database (REDCap) designed by Vanderbilt University47–49 (http://www.projectredcap.org/). Advanced data logic will be used such that only data fields relevant to the procedure and indication selected will be displayed in later data collection forms. It is anticipated this will reduce the burden of participation for collaborators and optimise the quality of data collected during the study.

The data forms will be extensively trialled in a three-centre pilot prior to national rollout of the study. This will validate the logic used; ensure the forms are complete and user-friendly and allow for any errors to be corrected prior to main study initiation.

Participating centres will be required to maintain and securely store an Excel spreadsheet linking study ID numbers with patient NHS numbers to allow long-term oncological outcomes to be evaluated at 5 and 10 years postoperatively.

Data validation and management

For quality assurance purposes, the consultant principal investigator at selected sites will be asked to identify an independent person to validate a proportion of the submitted data. These cases will be selected at random. Overall, ∼5% of the data sets will be independently validated. The independent assessors will also be asked to examine theatre logbooks, operating diaries and Trust computer systems to check case ascertainment. If concordance between the number of cases submitted on REDcap and those identified independently is <90%, the Unit's data will be excluded from the analysis. This is consistent with the quality assurance procedure used in other large collaborative audit projects.50

Data collection will occur in accordance with Caldicott II principles (http://systems.hscic.gov.uk/infogov/caldicott/caldresources). Data for each patient will be anonymised using a unique alphanumeric study identification number. Collaborators will be ask to store an Excel spreadsheet linking study ID to NHS number on a secure server locally to ensure patients are appropriately followed-up during the study. No patient identifiable data will be recorded centrally for the purpose of the audit.

Following the completion of data collection, appropriate ethical approvals will be obtained to allow the spreadsheets linking study ID to NHS number to be collated centrally. Only centres with ethical approval will be permitted to contribute to this phase of the study. The data will be stored securely in a central location until 5 years following study completion. Oncological outcomes will then be determined using a UK Cancer Registry search. This search will be repeated to determine 10-year oncological outcomes.

Study data will be collected and managed using REDCap electronic data capture tools hosted at the University of Oxford.47 REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages and (4) procedures for importing data from external sources.

Anticipated recruitment

The recent MASDA (MAStectomy Decisions Audit) Study (http://wmresearch.org.uk/) collected data on 1700 mastectomies ± IBR from 68 centres over a 3-month period. It is therefore anticipated that given its increased complexity, the iBRA-2 study will recruit ∼3000 patients over a 6-month period. Assuming an IBR rate of 21%,51 ,52 this should include ∼630 reconstructions comprising ∼220 implant-only reconstructions; 170 autologous pedicled flaps; 130 pedicled flaps with implants and 90 free flaps based on figures from the NMBRA.51

Study timelines

Data collection and analysis will be undertaken using the following time line:

  • May–June 2016—Three-centre pilot study, refining of data collection forms.

  • March–June 2016—Registration of interest from breast and plastic surgical units. Local audit approvals obtained. Participating centres will be required to have registered the study and obtained local approvals prior to the main study start date of 1 July 2016.

  • 1 July—31 December 2016—Main study patient recruitment—patients undergoing mastectomy ± IBR with operation dates between 1 July and 31 December 2016 are eligible for inclusion in the study.

  • 28 February 2017—deadline for data submission via REDCap.

  • 1 May 2017—Data validation complete.

  • 30 June 2017—Initial data analysis completed.

  • July 2017—Ethical approval to store patient NHS numbers to evaluate oncological outcomes.

  • Early 2021—Assessment of 5-year oncological outcomes.

  • Early 2027—Assessment of 10-year oncological outcomes.

Statistical analysis

The study report will be prepared according to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guidelines for observational studies.53 All data analysis will occur centrally by the iBRA-2 study team with support from statisticians and methodologists in the RCS Surgical Trials Centre and the University of Liverpool Clinical Trials Research Centre.

All outcomes will be summarised using descriptive statistics overall and split by group (mastectomy ± IBR). Dichotomous, categorical and short ordinal outcomes will be summarised using counts and percentages. Time to adjuvant therapy will be summarised using the Kaplan-Meier curves. Continuous and long ordinal outcomes will be summarised by the mean, SD, minimum and maximum (medians and IQRs will be reported for skewed data).

Formal statistical testing for each outcome between groups (mastectomy ± IBR) will be approached as follows: Rates of postoperative complications, including readmission and reoperation; requirement for adjuvant therapy and delay or omission of planned adjuvant chemotherapy or radiotherapy will be analysed using a χ2 test and the effect estimate will be reported in terms of the relative risk and 95% CI. Time to the delivery of adjuvant therapy will be analysed using a log-rank test. Delays to the delivery of adjuvant therapy will be analysed, controlling for risk factors of interest, using logistic regression model. A p value of 0.05 or less will be used to declare statistical significance for all analyses. Rather than adjust for multiplicity, relevant results from other studies already reported in the literature will be taken into account in the interpretation of results.

Results for each participating Trust will be summarised and fed back to individual units to allow comparison with national averages and ranges.

The statistical analysis of the 5-year and 10-year oncological outcomes will be planned following completion of the initial phase of the study.

Discussion

IBR may improve psychosocial outcomes for women requiring a mastectomy for breast cancer, but more complex surgery may also result in complications that could delay the delivery of important adjuvant treatments and subsequently impact long-term oncological outcomes. As oncological safety is the central tenet of all oncoplastic surgery, the practice of IBR if adjuvant therapy is anticipated is an area of considerable controversy54 and one for which high-quality evidence is currently lacking. The iBRA-2 study will generate much needed novel data regarding the impact of IBR on the time to delivery of adjuvant therapy compared with mastectomy alone. It will provide valuable information that may help patients and professionals make more informed decisions about the type and timing of their reconstructive surgery in the future. It will provide a large, robust prospective observational data set that will allow predictors for complications to be explored and generate hypotheses that will lead to further work in this area. The study will also generate valuable contemporaneous data relating to the practice of postmastectomy radiotherapy following the emergence of data to suggest significant survival benefit in a group of women with one to three positive lymph nodes who would not traditionally have been offered treatment.55 The proposed assessment of locoregional recurrence, distant metastases and breast cancer-specific survival at 5 and 10 years following surgery will provide much needed high-quality data to determine the impact of delays to adjuvant therapy on key oncological outcomes which will support decision-making and practice. Finally, the study will provide a further data cycle following the NMBRA5 to demonstrate whether surgical outcomes for women undergoing mastectomy and IBR have improved. If they have not, this will focus the attention of breast and plastic surgeons on relevant areas and highlight the need for future research.

It is anticipated that the iBRA-2 study will strengthen the collaborative network created by the iBRA (implant-breast reconstruction evaluation) study through the successful delivery of a second large-scale study in breast and reconstructive surgery. The study will reinforce the successful collaborative links between the breast and plastic surgical communities and create additional research capacity by broadening the network to include oncologists. The engagement and involvement of a wider community of trainees will lead to a new generation of consultants who understand the importance of research and audit, who can and will participate in high-quality collaborative studies resulting in more and better research. We believe that this will ultimately improve outcomes for patients.

The potential challenges to the success of this project require consideration. The proposed data set is complex and there is the risk of incomplete data. To address this, we will extensively pilot the data collection tools prior to study initiation. This will allow any redundant fields to be removed and any ambiguities clarified to optimise data quality. Furthermore, the REDCap data management system47 will be used for data collection. This system has the functionality to include complex logic such that only fields relevant to the procedure or indication initially entered are displayed in subsequent forms. It is anticipated that this will minimise the burden of data collection for local participants. Defining a ‘delay’ to adjuvant treatment is also a potential challenge as different centres may record their ‘decision to treat’ at different points in the patient's postoperative recovery, especially if postoperative complications are experienced. For this reason, we will collect ‘time to adjuvant therapy’ in the study. This is defined as the time (in days) from the last cancer surgery to the first dose of chemotherapy or fraction of radiotherapy. It is anticipated that this will allow any potential local biases to be addressed and comparable data to be obtained, so that the true impact of IBR on time to adjuvant therapy can be determined.

Ethics and dissemination

The proposed study will not affect clinical care and compares outcomes to published clinical standards. Research ethics approval is not required and this has been confirmed by the Health Research Authority (HRA) online decision tool (http://www.hra-decisiontools.org.uk/research/) and discussion with University of Bristol. A study lead will be identified at each participating centre. If the unit lead is a trainee, the named supervising consultant will act as the principal investigator for the unit for registration purposes. The study lead will be required to register the audit and obtain local audit approvals for study participation prior to starting patient recruitment. A copy of the approval will be also forwarded to the iBRA-2 study team. Patient consent is not required as no patient identifiable data are being recorded and there is no risk to patients.

Following completion of the audit phase of the study, proportionate ethical approval will be sought centrally by the iBRA-2 study team to collect the locally maintained spreadsheets linking study ID number to patient NHS numbers from participating centres. These data will be stored securely on a University of Bristol server until 5 years and 10 years, respectively, at which point a search of the UK Cancer Registry database will be performed. Only centres will appropriate ethical approvals will be able to contribute their data to this phase of the study.

The protocol will be disseminated via the collaborative network, including Mammary Fold Breast Trainees’ Group, RSTN, ASiT and the National Research Collaborative (NRC) as well as the professional associations the ABS and BAPRAS. The protocol and data collection sheets will be available online (http://www.ibrastudy.com). Individual centres will have access to their own data and the length of time from mastectomy to start of adjuvant therapy for each individual centre will be calculated and compared with the national average and quality standards determined by NICE. Data will be fed back to centres at the end of the audit. Overall audit results and results from individual centres will be fed back to ABS and BAPRAS.

Collective data will be analysed and the results of the study presented at appropriate scientific meetings and published in peer-reviewed journals. The results can then be used to inform patients and surgeons and aid decision-making for women considering breast reconstruction.

References

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Footnotes

  • RD, RO and TR are joint first authors; SP and CH are joint senior authors.

  • Contributors RD, RO and TR contributed to the design and writing of the protocol, EC and PW contributed to the study design and statistical analysis; JB, NB, JS, AH, CO and MG contributed to study design and advised on methodology; CH and SP contributed to the conception, design, writing and editing of the protocol. All authors read and approved the final manuscript.

  • Funding This work received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Ethics approval Proportionate ethical approval will be sought to evaluate long-term oncological outcomes by searching the UK Cancer Registry database.

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

  • Data sharing statement No additional data are available.

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