Intervention Protocol

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Autologous fat grafting for breast reconstruction

  1. Qiu-Wen Tan1,
  2. Chun-Xiang Tian1,
  3. Jin Chen2,
  4. Qing Lv1,*

Editorial Group: Cochrane Breast Cancer Group

Published Online: 21 OCT 2013

DOI: 10.1002/14651858.CD010793


How to Cite

Tan QW, Tian CX, Chen J, Lv Q. Autologous fat grafting for breast reconstruction (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD010793. DOI: 10.1002/14651858.CD010793.

Author Information

  1. 1

    West China Hospital, Sichuan University, Department of Breast Surgery, Chengdu, China

  2. 2

    West China Hospital, Sichuan University, Department of Evidence-Based Medicine and Clinical Epidemiology, Chengdu, Sichuan, China

*Qing Lv, Department of Breast Surgery, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu, 610041, China. lqlq1963@163.com. huaxilvqing@163.com.

Publication History

  1. Publication Status: New
  2. Published Online: 21 OCT 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Description of the condition

Breast cancer is one of the most common cancers diagnosed in women and the most frequent cause of cancer death in women in developed and developing countries (Jemal 2011). Based on the GLOBOCAN 2008 estimates, breast cancer accounts for 23% of all cancer cases and 14% of cancer deaths in women (Jemal 2011).

In the past few decades, the management of breast cancer has changed considerably. Surgery remains one of the most fundamental and efficacious treatments for breast cancer. Breast-conserving surgery and mastectomy are standard surgical options for women with breast cancer. The goals of breast-conserving surgery are the removal of the breast cancer with an adequate surgical margin and the maintenance of a cosmetically acceptable breast (Holmes 2011). The aesthetic success of breast-conserving surgery depends on tumour-related factors and patient-related factors. Tumour-related factors mainly include tumour size, tumour location and the distribution of tumour in the breast. Patient-related factors include breast size and breast contour (Waljee 2008). The increasing use of mammography screening and neoadjuvant chemotherapy has rendered 70 to 80% of women with breast cancer as potential candidates for breast-conserving surgery (Locker 2004). Women with multifocal located breast tumours, metastasis at diagnosis or a fear of radiotherapy are candidates for breast mastectomy.

Post-surgical deformity is a major complication for women with breast cancer. Post-surgical deformity may have many psychosocial effects, including anxiety, depression, dissatisfaction with sexual function, and can severely affect their quality of life (Rowland 2000). Breast reconstructive and cosmetic plastic surgeries after breast-conserving surgery or mastectomy can reshape the body figure and have benefits in psychological, social emotional and sexual adaptation (Atisha 2008; Holmes 2011; Schain 1991).

 

Description of the intervention

Breast reconstructive and cosmetic plastic surgeries are clinical procedures that involve rebuilding women's breasts with implant devices or autologous tissue (i.e. use of the patient's own body tissue). The goal of plastic breast surgery for women diagnosed with breast cancer is to restore breast contour and improve their quality of life without affecting the prognosis or detection of cancer recurrence (Cordeiro 2008). Cosmetic breast surgery is suitable for deformities caused by breast-conserving surgery. However, for breast mastectomy, reconstructive surgery is required. According to statistics from the American Society of Plastic Surgeons (ASPS) in 2011, nearly eighty percent of breast reconstructions are done by implants-based reconstruction (76,426 implant-based procedures in 96,277 breast reconstruction procedures) (ASPS 2011). Capsule contracture and leakage or even rupture of implants may cause serious complications and lead directly to failure of breast reconstruction. Autologous tissues are suitable for reconstruction for their perfect biocompatibility. The first autologous breast reconstruction was done by Vincent Czerny in 1895 who transplanted lipoma (i.e. a benign tumour composed of adipose (fat) tissue) from a patient's flank to the breast (Uroskie 2004). To date, the most commonly used autologous tissues are the latissimus dorsi musculocutaneous flap, transverse abdominal musculocutaneous flap and deep inferior epigastric perforator flap (ASPS 2011; Uroskie 2004). However, choosing autologous tissue as soft tissue filler may lead to another scar and potential muscle dysfunction (Bailey 2010). Today, surgeons desperately need to explore a reconstruction method with better breast appearance and fewer complications.

Autologous fat grafting is a century-old method that transfers adipose (fat) tissue to a target site in order to correct tissue deformation (Chan 2008). Adipose tissue is easy to harvest by liposuction. When injected into the breast, autologous adipose tissue does not cause hypersensitivity or foreign body reactions (Mu 2009; Saint-Cyr 2012). Theoretically, adipose tissue is an excellent filler for breast reconstructive and cosmetic surgeries (Chan 2008; Mu 2009; Kølle 2013). However, autologous fat grafting is still one of the most controversial reconstructive and cosmetic methods for the breast (Fraser 2011; Lohsiriwat 2011). The oncological safety of adipose tissue and its interference with imaging examinations have been under debate for decades. After the first report of autologous fat grafting in the breast by Czerny in 1895, autologous fat grafting for breast reconstruction has undergone a slow development.

 

How the intervention might work

Even though many mature techniques are reported, there are no universally accepted, standardised methods for autologous fat grafting (Saint-Cyr 2012). The techniques used by most surgeons can be briefly summarised as follows. The fat is harvested by liposuction or resection at the donor site. The donor site is usually the abdomen and buttocks (Chan 2008; Saint-Cyr 2012). Through centrifugation, blood cells, anaesthesia agents, damaged adipose tissue and other contaminants are removed. The prepared adipose tissue is transferred into the target site by injection or implantation to correct the deformities caused by breast surgery (Saint-Cyr 2012). However, due to the lack of standardised protocols, common procedures in fat grafting such as fat harvesting, fat preparation and delivery reveal many variations from study to study (Shiffman 2010). Recently, in order to improve volume stability, many techniques including cell-assisted lipotransfer and fat enhanced with platelet-rich plasma have been developed (Gentile 2012; Sterodimas 2010). These factors make an assessment of autologous fat grafting even more complex.

 

Why it is important to do this review

Autologous fat grafting has many complications such as anaesthesia-related complications, infections, bleeding, fat necrosis, cyst formation, fat calcifications, bruising, and temporary swelling and even fat embolism (Gutowski 2009; Shiffman 2010). Recently, concerns about the oncological safety of autologous fat grafting for women with breast cancer have arisen (Fraser 2011; Lohsiriwat 2011). Many studies report complications such as fat necrosis and fat calcification, which may interfere with physical examination and cancer surveillance (Saint-Cyr 2012). At the same time, some studies have confirmed that transplanted fat tissue including adipocyte, pre-adipocyte and progenitor cells can promote angiogenesis and cell growth. These endocrine reactions may promote tumour recurrence (Lohsiriwat 2011).

In 1987, the American Society of Plastic Surgeons was unanimous in the clinical use of fat grafting for breast augmentation (ASPRS 1987). In 2007, the American Society of Plastic Surgeons and the American Society for Aesthetic Plastic Surgery jointly released reports that 'strongly support the ongoing research efforts that will establish the safety and efficacy of autologous fat grafting' (ASPS 2007). However, in 2009, the American Society of Plastic Surgeons Fat Graft Task Force stated that 'based on the limited number of studies with few cases, no interference with breast cancer detection has been detected' (Gutowski 2009). The safety of autologous fat grafting still remains unclear. In this review, we will assess the safety and efficacy of autologous fat grafting for women with breast cancer.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Our primary objective is to assess the safety of autologous fat grafting for women who have had operable primary breast cancer. The safety of autologous fat grafting can be divided into oncological safety and operation-related safety. Oncological safety will be evaluated mainly by local breast cancer recurrence rate. The operation-related safety will be measured mainly by post-operative morbidity.

Our secondary objective is the efficacy of autologous fat grafting. The efficacy of autologous fat grafting will be measured mainly by quality of life questionnaires and cost-utility analysis. Fees for fat grafting will be accumulated if more than one grafting is needed.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

A standard procedure of autologous fat grafting has not been developed. Technique variants make the assessment more complex. In this review, autologous fat grafting is defined as the reconstructive or cosmetic procedure that contains the basic elements of fat grafting, that is fat harvesting, fat processing or preparing, and fat injection or transplantation. The detailed procedure of fat grafting in each study will be recorded.

We will first search for randomised controlled trials (RCTs). The RCTs will involve studies that evaluate the safety and efficacy of autologous fat grafting in operable primary breast cancer. However, for this review, we do not expect any existing RCTs. Therefore, we will extend our criteria to include non-randomised studies (NRSs) that assess the safety and efficacy of autologous fat grafting. In NRSs, women with operable primary breast cancer are allocated into an intervention group or control group based on their own preferences on whether or not to receive autologous fat grafting.

Selection bias, caused by a lack of a randomised allocation mechanism in NRSs, is a key difference between RCTs and NRSs. In our review, we will require that both groups have the same settings, that is, individuals are recruited in the study accept treatments in the same medical centre during the same period. We will only include studies with balanced baseline characteristics. Baseline characteristics mainly include age at diagnosis, menopausal status, tumour stage, hormone receptor status (including oestrogen receptor, progesterone receptor, ki-67%, Her2/neu) and systemic therapy received. In NRSs, only the generation of hypotheses are prospective. Considering these study features, cohort studies may be the most suitable NRSs. No restrictions will be placed on whether the studies are prospective or retrospective. Prospective cohort studies recruit participants before any intervention and follows them into the future. Retrospective cohort studies identify participants from past records describing the interventions received and follows them from the time of those records.

 

Types of participants

We will include women with pathologically diagnosed operable primary breast cancer. Operable primary breast cancer is defined as the primary breast tumour not fixed to underlying structures (includes TNM classification T1-3 and T4b where there is only minor skin involvement, N0-1, mobile lymph node (UICC 1987)).

No restrictions will be placed on race, age, menopausal status or hormone receptor status.

No restrictions will be placed on the conservative treatment including radiotherapy, neoadjuvant chemotherapy or hormonal therapy.

Participants will be allocated into the intervention (fat grafting) group or control (no fat grafting) group. Criteria for grouping will be explained in detail under the 'Types of interventions' section.

 

Types of interventions

In RCTs, participants are randomly allocated into the intervention group or control group. In NRSs, women who have undergone breast cancer surgery and autologous fat grafting are allocated into the intervention group. Those who have undergone breast cancer surgery only are allocated into the control group. In this review, autologous fat grafting will be the only option for breast reconstruction.

We will exclude women who have autologous fat grafting combined with other plastic methods (i.e. implant-based breast reconstruction, deep inferior epigastric perforator flap, transverse abdominal musculocutaneous flap) due to the potential interference when assessing safety and efficacy.

 

Types of outcome measures

 

Primary outcomes

Primary outcomes assessing the safety of autologous fat grafting will be the local recurrence rate and post-operative morbidity.

  • Post-operative morbidity: post-operative morbidity is defined as the rate of surgical complications including infections, formation of necrosis cysts, calcification of transplanted adipose tissues, bruising, temporary swelling and others.
  • Local recurrence rate: local recurrence is defined as breast cancer recurrence in the chest wall, axillary, supraclavicular, infraclavicular or internal mammary lymph nodes. Local recurrence will be considered as a time-to-event outcome. If time-to-event data are unavailable, 5- and 10-year follow-up data will be collected if available.

 

Secondary outcomes

Outcomes concerning the safety of autologous fat grafting will also be overall survival, disease-free survival, metastasis rate and metastasis-free survival.

Outcomes concerning the efficacy of autologous fat grafting will be quality of life and satisfaction of the reconstructed breast, cancer surveillance and radiological sequelae, and cost-utility analysis.

  • Overall survival, defined as the interval from the date of breast cancer diagnosis to the date of death from any cause.
  • Disease-free survival, defined as the interval from the primary cancer treatment to the date of first cancer recurrence.
  • Metastasis rate and metastasis-free survival: metastasis rate is defined as the percentage of women with metastasis among all women with breast cancer. Metastasis-free survival is defined as the interval from the date of breast cancer diagnosis to the date of first metastasis. These outcomes will be considered as time-to-event outcomes. If time-to-event data are unavailable, 5- and 10-year follow-up data will be collected if available.
  • Mortality rates, defined as the percentage of women who died from breast cancer and treatment procedures. Mortality will be considered as a time-to-event outcome. If time-to-event data are unavailable, 5- and 10-year follow-up data will be collected if available.
  • Quality of life and satisfaction of the reconstructed breast: the European Organisation for Research and Treatment of Cancer (EORTC) Breast Cancer-Specific Quality of Life Questionnaire (QLQ-BR23) and the BREAST-Q will be used to assess the cancer survivor's quality of life and satisfaction of the reconstructed breast. The QLQ-BR23 includes the body image, sexual functioning, arm symptoms, breast symptoms, systematic therapy side effects, sexual enjoyment and hair loss scale. The BREAST-Q includes seven domains and these are satisfaction with the breast, satisfaction with the outcome, psychosocial well-being, sexual well-being, satisfaction with the process of care and additional scales.
  • Cancer surveillance and radiological sequelae: fat grafting may cause fat necrosis and calcification that may interfere with cancer surveillance. We will assess burden brought by fat grafting during cancer surveillance and reconstruction follow-up by extracting the frequency of visits to clinics, imaging examinations (including mammography, ultrasound, computer tomography, magnetic resonance imaging and others) and biopsies during cancer surveillance.
  • Cost-utility analysis will be used for an economic evaluation and quality-adjusted life year (QALY) will be used to measure utility.

 

Search methods for identification of studies

 

Electronic searches

We will search the following databases with key words such as fat transplantation, fat grafting, lipo transfer, breast cancer and breast neoplasm.

  1. The Cochrane Breast Cancer Group's Specialised Register. The Cochrane Breast Cancer Group will search their Specialised Register. Details of the search strategies used by the Group for the identification of studies and the procedure used to code references are outlined in the Group's module (http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.html). We will extract trials with the key words or text words: 'Early Breast Cancer' 'Breast Cancer Unspecified', 'Surgery', 'Mammoplasty', 'Adipose Tissue', 'Autologous  Fat Graft', 'Autologous  Fat Grafting', 'Postmastectomy Autologous  Fat Graft', 'Postmastectomy Autologous  Fat Grafting', 'Autologous  Fat Graft for Breast Reconstruction', 'Lipo Transfer' 'Mammaplasty', 'Breast Reconstruction', 'Autogenous Fat Graft', 'Autologous  Fat Transplant', 'Autologous  Fat Transplantation', 'Postmastectomy Autologous  Fat Transplant', 'Postmastectomy Autologous  Fat Transplantation', 'Autogenous Fat Transplantation' and 'Lipofilling'.
  2. MEDLINE via OvidSP. Refer to the search strategy in Appendix 1.
  3. EMBASE via EMBASE.com. Refer to the search strategy in Appendix 2.
  4. The WHO International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/Default.aspx) for all prospectively registered and ongoing trials. Refer to the search strategy in Appendix 3.
  5. ClinicalTrials.gov (http://clinicaltrials.gov/ct2/search). Refer to the search strategy in Appendix 4.
  6. The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, current issue). Refer to the search strategy in Appendix 5.

 

Searching other resources

  • Bibliographic searching

We will make attempts to identify further studies from the reference lists of identified relevant studies or reviews. A copy of the full text for each reference reporting potentially eligible studies will be obtained. Where this is not possible, attempts will be made to contact investigators for more information.

  • Grey searching

We will search conference abstracts from St. Gallen Oncology Conferences, Milan Breast Cancer Conference (Milan, Italy) and San Antonio Breast Cancer Symposium conference proceedings.

We will apply no restrictions on language or publication date during searching.

 

Data collection and analysis

 

Selection of studies

Studies evaluating autologous fat grafting in women with operable primary breast cancer may be eligible.

Two authors (JC, QWT) will separately assess each study. For RCTs, the inclusion criteria (details under the 'Types of studies' section) will first be used when screening the titles and abstracts. The full-text article will be obtained and assessed for all potentially eligible studies. We will correspond with investigators to clarify study eligibility, if necessary. We will apply similar procedures described above when screening NRSs. However, for most NRSs, the title and abstracts may not provide us with detailed information on study features and therefore full-text articles may be assessed for study selection.

Multiple publications of the one study will be linked by author information and study design details such as the intervention, number of the participants at baseline data, and follow-up protocol.

Any disagreements about study eligibility will be resolved by discussion among the three authors (JC, QL, QWT).

Excluded studies will be defined as studies that may appear to meet the eligibility criteria but on further inspection do not (Higgins 2011). The reason for excluding a study will be noted in the 'characteristics of excluded studies' table.

 

Data extraction and management

We will extract relevant data from eligible studies using pre-standardised data extraction forms. The data extraction form will mainly contain the following items: title of the form, revision date of data extraction form, name of author(s) completing the form, study/report identification, assessment of the eligibility of the study, details of the study design (including participants, intervention, comparison and outcome), details of the fat grafting techniques, and results. Pilot testing will be conducted twice to identify data that are missing from the form with sample studies. Consensus between the authors will be achieved before the form is modified. We will use two separate data extraction forms for RCTs and NRSs.

We will extract the following information.

  1. Basic study information: authors and year of publication
  2. Eligibility: For RCTs, we will extract the methods for randomisation and allocation concealment. For NRSs, we will assess the allocation mechanism and the comparability between groups. As NRSs have selection bias, similar baseline characteristics between the two groups will be essential. We will exclude studies without baseline comparability between groups. Items will be recorded as 'Yes', 'No' or 'Can't tell'. Reasons for excluding a study will be recorded in detail under the 'characteristic of the excluded studies' table.
  3. Methods: total study duration, sequence generation, allocation sequence concealment, blinding, measurement techniques for each outcome, and other concerns about bias.
  4. Participants: sample size of the two groups, age at diagnosis, menopausal status, country (race), diagnostic criteria of breast cancer, status of breast cancer at diagnosis, and type of the surgery undertaken.
  5. Intervention: total number of participants in the intervention group and details of the intervention especially the method of autologous fat grafting.
  6. Detailed fat injection method: as there is controversy concerning the fat grafting method, we will extract details from the trial protocol. This information will include: fat harvesting (donor site, tumescent technique, size of the syringe, harvested volume), fat processing (centrifugation or not, the duration and revolution per minute if centrifugation is applied), fat injection (injection instrumentation, injection planes and the injection volume) and others (for studies applying fat grafting in other forms, the detailed information will be recorded).
  7. Outcomes and results: local recurrence rate of breast cancer, post-operative morbidity and mortality, overall survival, disease-free survival, metastasis rate, metastasis survival, quality of life and satisfaction of the breast, cancer surveillance and radiological sequelae, the number of missing participants in each group, summary data for each group, the scoring systems used and other outcomes documented in the study publications.
  8. Others: funding source of the primary study, key conclusion of the study, comments from the investigators and comments from the review authors. Space will be left to extract sufficient details to allow an assessment of the risk of bias. Risk of bias assessment result will be contained in the 'Risk of bias tables'.

Two authors (QL, QWT) will extract data separately. The two data extraction forms will be checked by a third author (JC). Any disagreements will be resolved by discussion or by contacting the investigators, if necessary. For studies with more than one report, we will extract and compare data from all of the reports. If all the reported data are exactly identical, only one copy of data will be kept. If any discrepancies exist among the reported data, we will contact investigators for the original data.

For dichotomous outcomes, we will extract information on the sample size and number of participants who have positive outcomes from the primary study. For continuous outcomes, we will extract data on the number of participants, means and standard deviations (SDs) from the primary study. As we will be including NRSs in our review, the unadjusted effect estimates, adjusted effect estimates and the confounders that were adjusted for will be recorded. If more than one adjusted effect estimate is recorded, we will use the most suitable one based on the recommendation in the Cochrane Handbook for Systemic Review of Interventions (Higgins 2011).

 

Assessment of risk of bias in included studies

Risk of bias includes selection bias, performance bias, detection bias, attrition bias, reporting bias and other bias.

Selection bias is defined as the systemic difference between the baseline characteristics of the compared groups, and randomisation is the major solution for selection bias. For NRSs, the allocation mechanisms may bring more selection bias. Adequate assessment of selection bias for NRSs will be essential. Performance bias is defined as the systemic difference between groups that receive different care. Detection bias is defined as the systemic difference between groups in which the results are detected and interpreted (Higgins 2011). Blinding is designed for performance bias and detection bias. Attrition bias is defined as the systemic difference between groups that exclude participants or deposit outcome data from the study. In studies with comparisons, the evaluation of performance, detection, attrition and reporting biases are required (Higgins 2011).

 

Assessment of risk of bias in included RCTs

Two authors (JC, CXT) will assess the risk of bias of the included RCTs in terms of the sequence generation, allocation concealment, blinding of participants, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and reporting bias based on the recommendations in theCochrane Handbook for Systemic Reviews of Interventions (Higgins 2011). Detailed methods for assessing the reporting bias in RCTs will be documented under the "Assessment of reporting biases" section. Each domain will be judged as 'low risk of bias', 'high risk of bias' or 'unclear risk', according to the Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011).

 

Assessment of risk of bias in included NRSs

Two authors (JC, CXT) will assess the methodological quality of eligible NRSs using the customised Newcastle-Ottawa Scale as described in the Cochrane Handbook for Systemic Reviews of Interventions (Higgins 2011) (Appendix 6). The Newcastle-Ottawa Scale is a convenient tool for quality assessments of NRSs. It is judged on three aspects and these include the selection of the study groups, the comparability between groups and the ascertainment of exposure (Wells 2008). In addition to the customised Newcastle-Ottawa Scale, we will assess selective outcome reporting of each study. Detailed methods for assessing the reporting bias in NRSs will be documented under the "Assessment of reporting biases" section. During the assessment, the review authors will be blinded to the names of the trial authors, institutions, journal and results of the study. Missing information will be collected by contacting the trial investigators. Each bias will be judged using the following categories: "low risk" refers to a low risk of bias, "unclear risk" refers to an uncertain risk of bias and "high risk" refers to a high risk of bias. Independently, two authors (QWT, CXT) will assess the eligible studies. Consensus will be reached by discussion amongst the authors (JC, QWT, CXT).

 

Measures of treatment effect

We will include dichotomous, continuous and time-to-event data.

We will express dichotomous outcomes (including post-operative morbidity) as risk ratios (RRs) and 95% confidence intervals (CIs). We will interpret the RR as the following: RR > 1: the incidence in the intervention group is greater than in the control group; RR = 1: no statistically significant difference between the intervention group and control group; and RR < 1: the incidence in the intervention group is lower than in the control group.

For continuous outcomes (including quality of life, satisfaction of the breast and cost-effectiveness), we will use the standardised mean difference (SMD). The interpretation of the SMD will involve: SMD > 0, the intervention is beneficial compared to the control; and SMD<0, the intervention is inferior to the control.

We will assess time-to-event outcomes (including local recurrence, overall survival, disease-free survival) in the form of the hazard ratio (HR) and their standard errors.

 

Unit of analysis issues

We will be including women who have had autologous fat grafting post-surgery in one or both breasts. Therefore the unit of analysis will be the individual participant.

 

Dealing with missing data

We will contact authors by e-mail or telephone for missing data. For missing data that we are unable to retrieve by e-mail or telephone, we will perform an intention-to-treat analysis and sensitivity analysis.

 

Assessment of heterogeneity

As we will include NRSs, assessment of the homogeneity of the included studies is essential. We will assess clinical heterogeneity by checking the characteristics of the studies, type of participants, the interventions and outcomes. We will assess the statistical heterogeneity by the Chi-squared (Chi2) test with significance set at P value of < 0.01, and the I2 statistic (Higgins 2011). We will interpret the I2 as follows: 0% to 40%, might not be important; 30% to 60%, may represent moderate heterogeneity; 50% to 90%, may represent substantial heterogeneity; and 75% to 100%, considerable heterogeneity.

If there is no evidence of heterogeneity, we will use the fixed-effect model in the analysis. Otherwise, we will make a cautious attempt to reveal the reason for heterogeneity and apply the random-effects model. If sufficient data are available, we will use forest plots to show the original results of the included studies and the variation in the results of the studies.

 

Assessment of reporting biases

Reporting bias can be classified into publication bias, time lag bias, multiple publication bias, location bias, citation bias, language bias and outcome bias. If there are sufficient included studies, we will assess the reporting bias of eligible studies by funnel plot asymmetry, following the recommendations of the Cochrane Handbook for Systematic Review of Interventions (Higgins 2011). Funnel plot asymmetry may be caused by selection bias, small-study effect, and true heterogeneity. We will address this issue in the discussion section of the review, if necessary.

Reporting bias can result from selective outcome reporting (SOR) or selective analysis reporting (SAR). The ways to minimise SOR and SAR are to register key details of the study. For RCTs, SOR will be assessed by comparing the study protocol and registration information with all relevant publications to determine if the protocol was finalised before any comparative data analysis, locking of the study database, and access to variables describing how groups were formed. SAR will be assessed by comparing the consistency of the methods and results sections in the protocol and all related publications.

For NRSs, we will identify and document SOR and SAR for each included study. SOR will be assessed by searching for all related publications for each included study. We will also compare the method and results sections of the publications for potential discrepancies in the definitions and measurement techniques for each outcome. SAR will be assessed by checking whether analyses were defined in the methods section of the study publications in sufficient detail to prevent SAR. We will also compare the method and results sections of publications for potential discrepancies in the analytical methods proposed and actually used.

In order to minimise reporting biases, we will place no restrictions on language. We will try to include conference abstracts and other published studies. Data from studies with multiple publications will be included once in the review.

 

Data synthesis

In the event that both RCTs and NRSs exist, we will synthesise results from RCTs and NRSs separately. Two authors (QWT, JC) will analyse the extracted data based on recommendations in the Cochrane Handbook for Systematic Reviews of the Interventions (Higgins 2011). The adjusted effect estimates will be analysed using the inverse-variance method. The fixed-effect meta-analyses or random-effects meta-analyses will be applied based on the assessment of heterogeneity. We will perform all data syntheses and meta-analyses using the Cochrane Collaboration's statistical software, RevMan. We will report the meta-analysis results mainly by forest plots and summary of findings tables.

If the included studies are significantly clinically diverse or most of the included studies have a high risk of bias or serious reporting bias, we will not undertake a meta-analysis. In the case where a meta-analysis cannot be conducted, we will present a narrative synthesis of the included studies.

 

Subgroup analysis and investigation of heterogeneity

Where adequate studies and data are available, we will perform subgroup analysis. This will include grouping by primary breast cancer stage.

If heterogeneity is present during heterogeneity assessment, we will make an attempt to reveal the reason for heterogeneity and change the analysis method from the fixed-effect model to random-effects model.

 

Sensitivity analysis

If adequate data are available, we will perform sensitivity analysis by comparing results with or without studies of low quality. If we obtain similar results and conclusions during the two analyses, the results of the review will be regarded with a higher degree of certainty. However, if we obtain different results and conclusions, we will make attempts to resolve these uncertainties by checking the extracted data and contacting primary study investigators, if necessary. If consistency still cannot be achieved, we will interpret our result with an appropriate degree of caution.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Authors would like to acknowledge the support and help from the Cochrane Breast Cancer Group.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. MEDLINE


# ▲Searches

1exp Breast Neoplasms/

2breast neoplasm$.tw,ti,ab,kw.

3breast cancer$.tw,ti,ab,kw.

4early breast neoplasm$.tw,ti,ab,kw.

5early breast cancer$.tw,ti,ab,kw.

6(Breast adj6 cancer$).tw,ti,ab,kw.

7(Breast adj6 neoplasm$).tw,ti,ab,kw.

81 or 2 or 3 or 4 or 5 or 6 or 7

9exp Mammaplasty/

10mammoplasty.tw,ti,ab,kw.

11mammaplasty.tw,ti,ab,kw.

12autologous fat graft$.tw,ti,ab,kw.

13autogenous fat graft$.tw,ti,ab,kw.

14fat graft$.tw,ti,ab,kw.

15lipo transfer.tw,ti,ab,sh.

16fat transplant*.tw,ti,ab,sh,kw.

17lipofilling.tw,ti,ab,sh,kw.

18(postmastectomy adj5 autogenous fat graft$).tw,ti,ab,kw.

19(postmastectomy adj5 autologous fat graft$).tw,ti,ab,kw.

20(post-mastectomy adj5 autogenous fat graft$).tw,ti,ab,kw.

21(post-mastectomy adj5 autologousfat graft$).tw,ti,ab,kw.

22(breast reconstruction adj5 autogenous fat graft$).tw,ti,ab,kw.

23(breast reconstruction adj5 autologous fat graft$).tw,ti,ab,kw.

24(autogenous adj5 fat graft$).tw,ti,ab,kw.

25(autologous adj5 fat graft$).tw,ti,ab,kw.

26(adipose adj5 autogenous fat graft$).tw,ti,ab,kw.

27(adipose adj5 autologous fat graft$).tw,ti,ab,kw.

28(adipose adj5 fat graft$).tw,ti,ab,kw.

29(adipose adj5 breast reconstruct*).tw,ti,ab,kw.

30(postmastectomy adj5 autogenous fat transplant*).tw,ti,ab,kw.

31(postmastectomy adj5 autologous fat transplant*).tw,ti,ab,kw.

32(breast reconstruction adj5 autogenous fat transplant*).tw,ti,ab,kw.

33(breast reconstruction adj5 autologous fat transplant*).tw,ti,ab,kw.

34(autogenous adj5 fat transplant*).tw,ti,ab,kw.

35(autologous adj5 fat transplant*).tw,ti,ab,kw.

36(adipose adj5 fat transplant*).tw,ti,ab,kw.

379 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36

388 and 37

39Animals/

40Humans/

4139 not 40

4238 not 41

43limit 42 to yr="2008 -Current"



 

Appendix 2. EMBASE

#28 #27 AND [embase]/lim AND [2008-2013]/py

#27 #7 AND #22 AND #26

#26 #23 OR #24 OR #25

#25 'post-mastectomy'

#24 postmastectomy

#23 'breast reconstruction'/exp OR 'breast reconstruction'

#22 #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21

#21 'adipose tissue'/exp OR 'adipose tissue'

#20 'autogenous fat transplantation'

#19 'autologous fat transplantation'

#18 lipofilling

#17 'lipo transfer'

#16 autogenous NEAR/6 'fat grafting'

#15 autologous NEAR/6 'fat grafting'

#14 transplant*

#13 'fat transplant'

#12 'fat grafting'

#11 'autogenous fat grafting'

#10 'autologous fat grafting'

#9 'mammaplasty'/exp OR mammaplasty

#8 'mammoplasty'/exp OR mammoplasty

#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6

#6 (breast NEAR/6 neoplasm$):ab,ti

#5 (breast NEAR/6 cancer$):ab,ti

#4 'early breast neoplasm'

#3 'early breast cancer'

#2 'breast neoplasm'

#1 'breast cancer'/exp OR 'breast cancer'

 

Appendix 3. WHO ICTRP search portal

 

Basic search

  1. breast cancer AND autologous fat graft*
  2. breast neoplasm AND autologous fat graft*
  3. breast cancer AND autogenous fat graft*
  4. breast neoplasm AND autogenous fat graft*
  5. breast cancer AND fat graft*
  6. breast neoplasm AND fat graft*
  7. breast reconstruction AND autologous fat graft*
  8. breast reconstruction AND autogenous fat graft*
  9. breast reconstruction AND fat graft*
  10. postmastectomy autologous fat graft*
  11. post-mastectomy autologous fat graft*
  12. breast cancer AND autologous fat transplant*
  13. breast neoplasm AND autologous fat transplant*
  14. breast cancer AND autogenous fat transplant*
  15. breast neoplasm AND autogenous fat transplant*
  16. breast cancer AND fat transplant*
  17. breast neoplasm AND fat transplant*
  18. breast reconstruction AND autologous fat transplant*
  19. breast reconstruction AND autogenous fat transplant*
  20. breast reconstruction AND fat transplant*
  21. postmastectomy autologous fat transplant*
  22. post-mastectomy autologous fat transplant*
  23. lipofilling OR lipo transfer
  24. post-mastectomy autogenous fat graft*
  25. postmastectomy autogenous fat graft*

 

Advanced search

Title: Autologous fat grafting for breast reconstruction

Recruitment Status: ALL

Condition: breast cancer OR breast neoplasm

Intervention: autologous fat graft% OR autogenous fat graft% OR fat graft% OR lipo transfer

Recruitment Status: ALL

Condition: breast cancer OR breast neoplasm

Intervention: (autologous fat graft% OR autogenous fat graft% OR fat graft% OR lipo transfer) AND breast reconstruction

Recruitment Status: ALL

Condition: breast cancer OR breast neoplasm

Intervention: autologous fat transplant% OR autogenous fat transplant% OR fat transplant% OR lipo transfer

Recruitment Status: ALL

Condition: breast cancer OR breast neoplasm

Intervention: (autologous fat transplant% OR autogenous fat transplant% OR fat transplant% OR lipo transfer) AND breast reconstruction

Recruitment Status: ALL

 

Appendix 4. ClinicalTrials.gov

 

Basic search

  1. breast cancer AND autologous fat graft*
  2. breast neoplasm AND autologous fat graft*
  3. breast cancer AND autogenous fat graft*
  4. breast neoplasm AND autogenous fat graft*
  5. breast cancer AND fat graft*
  6. breast neoplasm AND fat graft*
  7. breast reconstruction AND autologous fat graft*
  8. breast reconstruction AND autogenous fat graft*
  9. breast reconstruction AND fat graft*
  10. postmastectomy autologous fat graft*
  11. post-mastectomy autologous fat graft*
  12. breast cancer AND autologous fat transplant*
  13. breast neoplasm AND autologous fat transplant*
  14. breast cancer AND autogenous fat transplant*
  15. breast neoplasm AND autogenous fat transplant*
  16. breast cancer AND fat transplant*
  17. breast neoplasm AND fat transplant*
  18. breast reconstruction AND autologous fat transplant*
  19. breast reconstruction AND autogenous fat transplant*
  20. breast reconstruction AND fat transplant*
  21. postmastectomy autologous fat transplant*
  22. post-mastectomy autologous fat transplant*
  23. lipofilling OR lipo transfer
  24. post-mastectomy autogenous fat graft*
  25. postmastectomy autogenous fat graft*

 

Advanced search

Title: Autologous fat grafting for breast reconstruction

Recruitment: All studies

Study Results: All studies

Study Type: All studies

Gender: All studies

Condition: breast cancer OR breast neoplasm

Intervention: autologous fat graft% OR autogenous fat graft% OR fat graft% OR lipo transfer

Recruitment: All studies

Study Results: All studies

Study Type: All studies

Gender: All studies

Condition: breast cancer OR breast neoplasm

Intervention: (autologous fat graft% OR autogenous fat graft% OR fat graft% OR lipo transfer) AND breast reconstruction

Recruitment: All studies

Study Results: All studies

Study Type: All studies

Gender: All studies

Condition: breast cancer OR breast neoplasm

Intervention: autologous fat transplant% OR autogenous fat transplant% OR fat transplant% OR lipo transfer

Recruitment: All studies

Study Results: All studies

Study Type: All studies

Gender: All studies

Condition: breast cancer OR breast neoplasm

Intervention: (autologous fat transplant% OR autogenous fat transplant% OR fat transplant% OR lipo transfer) AND breast reconstruction

Recruitment: All studies

Study Results: All studies

Study Type: All studies

Gender: All studies

 

Appendix 5. CENTRAL

#1 MeSH descriptor: [Breast Neoplasms] explode all trees

#2 MeSH descriptor: [Mammaplasty] explode all trees

#3 mammoplasty or autologous fat graft* or autogenous fat graft* or fat graft* or lipo transfer or fat transplant* or lipofilling or postmastectomy autologous fat graft* or autologous fat graft for breast reconstruction or mammaplasty or breast reconstruction or autologous fat transplant* or postmastectomy autologous fat transplant* or autogenous fat transplant*

#4 #2 or #3

#5 #1 and #4

 

Appendix 6. Customised Newcastle-Ottawa Scale

 

Selection

Were the relevant details of including criteria in the study provided?

  • Yes, adequate information including the breast cancer status, details on autologous fat grafting in study group and other important characteristics of the enrolled women were provided (low)
  • No, just mentioned but without enough description (unclear)
  • No, not mentioned (high)

Did the enrolled cases represent women with operable primary breast cancers?

  • Yes, the enrolled cases represented women with operable primary breast cancers (low)
  • No, the enrolled cases couldn't represent women with operable primary breast cancers well (high)
  • Unclear, potential for selection biases or not stated (unclear)

Were women with operable primary breast caners randomly assigned into study group and control group?

  • Yes, women with operable primary breast cancers were randomly assigned into groups and the randomisation method was mentioned in the study (low)
  • Yes, women with operable primary breast cancers were not randomly assigned into groups. However, the exact randomisation method was not mentioned in the study (unclear)
  • No description (high)

 

Comparability

Did groups in the study sharing balanced baseline characteristics?

  • Yes, there is a balanced baseline characteristics and listed detail baseline characteristics of the evolved women (low).
  • Yes, the study had a balanced baseline characteristics, however, details about the baseline characteristics of the evolved women were not listed (unclear).
  • No, the study didn't have a balanced baseline characteristics (high).

  • Not known, the study didn't mention any baseline characteristics (unclear).

Did the two different groups have similar oncological related treatments (including endocrine therapy, chemotherapy and radiotherapy) except autologous fat grafting?

  • Yes, reasons for oncological related treatments were irrelevant with group type (low).
  • No, reasons for oncological related treatments seems relevant with group type (high).
  • Not mentioned (unclear)

 

Exposure

Ascertainment of exposure

  • Secure record (e.g. surgical records) or structured interview where blind to case/control status (low)
  • Interview not blinded to case/control status, written self report or medical record only (high)
  • No description (unclear)

Same method of ascertainment for cases and controls

  • Yes (low)
  • No (high)

Non-response rate

  • Same rate for both groups (low)
  • Rate different and no designation (high)
  • Non-respondents described (unclear)

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

  1. Draft the protocol: QWT, JC
  2. Study selection: JC, QWT
  3. Extract data from studies:QL, QWT, CXT
  4. Enter data into RevMan: CXT, QWT
  5. Carry out the analysis: JC, QWT
  6. Interpret the analysis: JC, QWT, CXT
  7. Draft the final review: QWT, JC, QL, CXT
  8. Disagreement resolution: CXT, QWT, JC
  9. Update the review: QWT, JC, QL, CXT

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

The authors declare no conflicts of interest.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • None, Not specified.

 

External sources

  • None, Not specified.

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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