Question

What are the indications for autologous fat grafting in patients with breast reconstruction following mastectomy or breast conserving therapy?

Recommendation

Indications in patients after breast conserving therapy:

Consider the use of autologous fat grafting in case of:

  • contour defects and fibrosis.

 

Indications in patients after mastectomy:

Consider the use of autologous fat grafting in addition to implant or autologous reconstruction in case of:

  • contour defects and fibrosis;
  • thin tissue cover of the prosthesis, making it palpable or visible;
  • asymmetry in breast shape and/or volume;
  • capsular contracture in implant reconstruction.

Only use autologous fat grafting with or without external expansion to create a full breast within the context of a clinical trial.*

 

* A clinical trial approved by a medical ethics committee, including an informed consent form signed by the patient prior to commencement of treatment.

 

Use of autologous fat grafting with addition of stem cells/growth factors after breast conserving treatment or mastectomy should only occur within the context of a clinical trial.*

 

* A clinical trial approved by a medical ethics committee, including an informed consent form signed by the patient prior to commencement of treatment.

Introduction

Autologous fat grafting [synonyms: lipofilling, lipomodelling, lipografting, autologous fat injection, autologous fat transfer (AFT), fat transplantation, autologous lipo-aspirate grafting (ALAG)] is the transplantation of fat cells from another location in the body. Various techniques may be used, most of which are based on or derived from the techniques described by Coleman (Coleman et al, 2006).

 

The uses of autologous fat grafting in breast reconstruction are correcting irregularities in breast shape or contour, adding volume, improving or thickening tissue layers over implants, and softening/masking fibrosis/fat necrosis due to radiation therapy after breast conserving therapy. Additionally, it can be used to optimize tissues for implant reconstruction after mastectomy and radiation therapy (Hsu et al, 2012; Sarfati et al, 2011). Permanent release of adhesions and scar tissue after mastectomy, and reducing a feeling of tightness are other clinical applications. It is also used to treat post-mastectomy pain syndrome (Caviggioli et al, 2011).

 

More recent developments in the field of autologous fat grafting are the injection of fat in combination with external expansion, for example BRAVA (Khouri et al, 2012) and enriching fat with stem cells (Tabit et al, 2011; Kølle et al, 2013).

 

Starting point

The starting point for answering the primary question is that we know autologous fat grafting of relatively small volumes in the face yields good aesthetic and functional results (Coleman et al, 2006). This technique is now one of the standard strategies for breast reconstruction (Krastev et al, 2012; Claro et al, 2012).

 

Bottlenecks

However, what remains unclear is the potential relationship between the use of autologous fat grafting and local recurrence, whether larger volumes of fat survive, and whether the fat graft survives in an irradiated breast. Furthermore, there is some debate regarding whether autologous fat grafting leads to false positive findings with regard to suspected local recurrence using diagnostic imaging during oncologic follow-up.

Conclusions

1. Autologous fat grafting compared with no autologous fat grafting

very low

(GRADE)

Local tumor recurrence

 

Autologous fat grafting in breast reconstructions does not appear to increase the number of local tumor recurrences.

 

Sources (Rigotti et al, 2010; Petit et al, 2012)

 

-

Interference with diagnostic imaging, volume maintenance

 

No comparative study examined the effect of a specific reconstruction technique combined with autologous fat grafting with the effect of the reconstruction technique alone on volume maintenance and diagnostic imaging in patients with breast reconstruction after mastectomy or breast conserving treatment.

 

2. Autologous fat grafting with external expansion (BRAVA) versus autologous fat grafting without external expansion.

very low

(GRADE)

Volume maintenance

 

The use of external expansion appears to improve volume maintenance in autologous fat grafting.

 

Source (Khouri et al, 2012)

 

3. Autologous fat grafting with addition of stem cells/growth factors versus traditional autologous fat grafting

-

Volume maintenance, local recurrence

 

No comparative study examined the effect of autologous fat grafting with the addition of stem cells/growth factors with traditional autologous fat grafting on volume maintenance and local recurrence in patients with breast reconstruction after mastectomy or breast conserving treatment.

Literature summary

Three systematic literature analyses were performed in order to answer the primary question, examining the following questions:

  1. What is the effect of a specific reconstruction technique in combination with autologous fat grafting on local tumor control, diagnostic imaging and volume maintenance compared with the reconstructions technique alone in breast reconstructions after mastectomy or breast conserving treatment?
  2. What is the effect of autologous fat grafting with external expansion (BRAVA) on volume maintenance compared with autologous fat grafting without external expansion in breast reconstructions after mastectomy or breast conserving treatment?
  3. What is the effect of autologous fat grafting with the addition of stem cells / growth factors on local recurrence and volume maintenance compared with traditional autologous fat grafting in breast reconstructions after mastectomy or breast conserving treatment?

 

Medline (OVID), Embase and Cochrane databases were searched for breast reconstructions using autologous fat grafting. The search justification is listed in the appendix to this chapter. The literature search yielded 149 results. Studies that met the following selection criteria were included in the literature summary: original studies; comparative studies (RCT; observational studies); comparison of a) autologous fat grafting versus no autologous fat grafting, b) autologous fat grafting with external expansion (BRAVA) versus without external expansion or c) autologous fat grafting with addition of stem cells/growth factors versus traditional autologous fat grafting; and at least one of the following outcome measures: local recurrence, interference with diagnostic imaging or volume maintenance.

Ten studies were selected based on title and abstract. After reading the full articles, one study was included in the literature summary (Rigotti et al, 2010). The reasons for excluding the other 9 studies may be found in the appendix.

 

After the search date, Krastev et al (2012) published one systematic review on this subject. However, the authors also included non-comparative studies in their review, so it did not qualify for inclusion. A recently published study included in the review by Krastev did meet the selection criteria, however, and was included in the current literature analysis (Petit et al, 2012).

 

After the search date, Khouri et al (2012) published one study about autologous fat grafting with external expansion that was also included in the literature analysis.

 

1. Autologous fat grafting compared with no autologous fat grafting

In one observational study (Rigotti et al, 2010), 137 patients who underwent a modified radical mastectomy (MRM) underwent breast reconstruction using autologous fat grafting. The authors compared the incidence of local tumor recurrence between the two following periods: 1) period 1: time between MRM and the first autologous fat grafting session; and 2) period 2: time between the first autologous fat grafting session and the end of follow-up. The results showed no difference in the number of recurrences.

 

In a retrospective cohort (Petit et al, 2012), 321 patients who underwent mastectomy or breast conserving surgery underwent autologous fat grafting. This group was compared with 462 matched controls selected from the same database based on common characteristics, such as age, surgery type and tumor size, but who did not receive autologous fat grafting. These results also showed no difference in the number of recurrences.

 

The effect on diagnostic imaging and volume maintenance was not studied.

 

Level of evidence of the literature

The level of evidence for the outcome measure local tumor recurrence is very low, as the studies were not randomized, and one study (Rigotti et al, 2010) did not have an independent control group (bias due to limitations in study design); the number of patients and local tumor recurrences was low (imprecision).

The level of evidence for the outcome measure volume maintenance and interference with diagnostic imaging could be assessed, as none of the comparative studies examined these endpoints.

 

2. Autologous fat grafting with external expansion (BRAVA) versus autologous fat grafting without external expansion.

One prospective, multi-center study by Khouri et al (2012) examined the outcomes after autologous fat grafting for breast augmentation in 81 patients using three-dimensional volume reconstruction MRI, preceded by at least four weeks and followed by at least one week of external expansion. The results were compared to those of a meta-analysis of six recently published studies about autologous fat grafting augmentation without expansion. After 12 months, an average augmentation volume of 233 ml per breast was observed for BRAVA, compared to 134 ml without expansion. Fat survival was 82±18% for BRAVA versus 55±18% without BRAVA.

 

3. Autologous fat grafting with addition of stem cells/growth factors versus traditional autologous fat grafting

The working group found no comparative studies answering this question.

Considerations

Traditional autologous fat grafting

In recent years, extensive clinical experience has been gained with the use of autologous fat grafting in breast reconstruction (Hsu et al, 2012; Gutowski et al, 2009). Applications may be divided into adding volume, improving tissue quality and reducing functional and/or pain complaints. Volume may be added to improve contour of the reconstructed breast when using implants, in autologous reconstruction with volume deficits, or as a separate breast reconstruction technique after mastectomy. Volume suppletion and improvement of tissue quality are the goals of autologous fat grafting in lumpectomy with radiation therapy within the context of breast conserving therapy. Improving tissue quality after radiation therapy with (multiple sessions of) autologous fat grafting is used to prepare for secondary implant reconstructions to reduce the risk of extrusion and implant loss (Sarfati et al, 2011). Reduction in capsular contracture rates were also observed in (pericapsular) autologous fat grafting (Missana et al, 2007). Reducing symptoms is the goal of autologous fat grafting in post-mastectomy pain syndrome (Hsu et al, 2012). Autologous fat grafting is considered a minimally invasive technique with a low risk of complications and positive results (Rietjens et al, 2011; Delay et al, 2009; Choi et al, 2013). Hematoma formation is a common finding after autologous fat grafting, but is generally not of any clinical significance. Infections are no more common than with other forms of surgery, and can generally be treated in the usual manner. Experience from daily practice also indicates that the results of autologous fat grafting lead to greater patient satisfaction in the situations described above (Missana et al, 2007; Illouz et al, 2009). This makes autologous fat grafting a useful addition to the arsenal of interventions that can be used to improve the outcomes of breast reconstruction or correction after breast conserving treatment for above-mentioned indications.

 

Critics point to the effects of autologous fat grafting on the interpretability of mammograms. Calcifications due to fat necrosis and oil cysts may result from injecting fat into the breast. Using current digital mammography techniques, and with the availability of qualified radiologists with expertise in the domain of (other forms of) breast imaging, a distinction can be made between benign and malignant calcifications (Del Vecchio et al, 2011; Illouz et al, 2009; Rietjens et al, 2011). In practice, this has not proven to be an obstacle. Fat necrosis and oil cysts can yield palpable abnormalities during a breast exam. This can lead to uncertainty about the diagnosis and requires additional investigations.

 

A randomized, multi-center study examining the long-term effects of autologous fat grafting in the breast after breast conserving therapy is ongoing in France. The effect on diagnostic imaging is one of the primary endpoints, as is oncologic safety and cosmetic result (GRASTEC trial, Clinicaltrials.gov ID: NCT01035268 start date Jan 2010, follow-up 5 years, 440 patients).

 

Experience from daily practice shows the effect of autologous fat grafting on the interpretability of mammograms (Del Vecchio et al, 2011), the low risk of complications (Gutowski et al, 2009; Delay et al, 2009) and the effect on the risk of local recurrences (Claro et al, 2012; Petit et al, 2011) do not contraindicate the use of autologous fat grafting.

 

Autologous fat grafting with BRAVA

No special recipient site preparation is required before autologous fat grafting. However, some authors have described external tissue expansion using an external volume augmentation bra (BRAVA), which is assumed to stimulate tissue growth and autogenesis, as is described for VAC wound therapy (Schlenz et al, 2007; Smith et al, 2002). Expansion creates a larger tissue matrix, which serves as a recipient site for fat cells and is believed to reduce saturation. This allows a larger volume to be achieved per session (Khouri et al, 2012; Del Vecchio et al, 2009; Del Vecchio et al, 2011; Zocchi et al, 2008).

 

There is at least one registered prospective study of the use of BRAVA in autologous fat grafting of the breast, with results scored by both patients and by a panel based on photographs (BRAVA, clinicaltrials.gov ID: NCT00466765; running until 2012 in 50 patients).

 

Comparative studies on the use of external expansion prior to autologous fat grafting are lacking, so any added value remains to be demonstrated (Khouri et al, 2012). There are indications from daily practice that BRAVA expansion in autologous fat grafting allows greater volumes of fat to be transplanted per treatment session (Khouri et al, 2012; Del Vecchio et al, 2009; Del Vecchio et al, 2011). This makes autologous fat grafting as an individual breast reconstruction technique after mastectomy potentially viable. A practical issue with BRAVA therapy is patient compliance, as the vacuum bra must be worn daily for several hours for a number of weeks. No literature is available on the use of BRAVA in cases of previous radiation therapy. There are no indications that use of BRAVA combined with autologous fat grafting is harmful. Potential adverse effects of BRAVA are skin irritation and blistering.

 

Autologous fat grafting with addition of stem cells/growth factors

The rationale for adding adipose derived stem cells (ASCs) in autologous fat grafting is that mature stem cells are potentially responsible for volume (maintenance), rather than mature fat cells. It is unclear whether mature fat cells survive autologous grafting or are replaced by maturation of precursor cells (stem cells), while the transplanted fat cells die. The mechanism may also involve stem cells stimulating the survival of mature fat cells, or inhibiting their resorption. This may be due to the differentiation in endothelial cells that stimulate angiogenesis and release angiogenic growth factors (Saint-Cyr et al, 2012). One recent RCT in 13 volunteers with a follow-up of 121 days showed that, compared with standard autologous fat grafting (30 ml introduced as a subcutaneous bolus in the dorsal upper arm), autologous fat grafting with the addition of 20x106 ASCs resulted in statistically significant better volume maintenance (80.9% vs. 16.3%, p<0.0001), higher residual total fat tissue (84.3% vs. 67.0%, p=0.0109), more formation of new connective tissue (5.3% vs. 0.5%, p=0.0115), less necrosis (4.6% vs. 16.1%, p=0.0105) and similar blood vessel density (20.9 vessels/mm2 vs. 26.3 vessels/mm2, p=0,39). No malignant transformations were observed (Kølle et al, 2013).

 

A potential downside to the addition of stem cells is the unclear role these cells play in the development or stimulation of (breast) cancer. Estrogen, produced by adipocyte aromatase, may stimulate tumor growth (Chan et al, 2008). However, there are no concrete indications or studies confirming this (Saint-Cyr et al, 2012). There are even studies suggesting the opposite is true (Manabe et al, 2003). Autologous fat grafting with ASCs has been performed in over 1000 people in clinical trials, without any serious complications. However, longer term follow-up of these individuals is necessary before definitive conclusions can be reached (Kølle et al, 2013).

Authorization date and validity

Last review : 01-03-2015

Last authorization : 01-03-2015

The Board of the Dutch Society for Plastic and Reconstructive Surgery (NVPC) will assess whether this guideline is still up-to-date in 2018 at the latest. If necessary, a new working group will be appointed to revise the guideline. The guideline’s validity may lapse earlier if new developments demand revision at an earlier date.

As the holder of this guideline, the NVPC is chiefly responsible for keeping the guideline up to date. Other scientific organizations participating in the guideline or users of the guideline share the responsibility to inform the chiefly responsible party about relevant developments within their fields.

Initiative and authorization

Initiative : Nederlandse Vereniging voor Plastische Chirurgie

Authorized by:
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Radiotherapie en Oncologie

General details

Guideline development was funded by the Quality Fund for Medical Specialists (SKMS) and The Netherlands Organization for Health Research and Development (ZonMw).

Scope and target group

Guideline goal

To develop a multidisciplinary, evidence-based guideline for breast reconstruction in women undergoing breast conserving therapy or mastectomy for breast cancer, or following prophylactic mastectomy.

 

Guideline scope

The guideline focuses on all patients with an indication for breast reconstruction following breast conserving therapy or mastectomy. Additionally, the guideline may be applied to breast reconstruction in patients who have undergone surgical treatment for a benign breast condition. The guideline does not comment on the treatment of breast cancer. We refer the reader to the NABON guideline for the treatment of breast cancer (www.richtlijnendatabase.nl), which this guideline complements.

 

Unfortunately, circumstances did not permit a medical oncologist representing the NVMO to participate in the working group. Thus, the current version lacks a module on chemotherapy and breast reconstruction. The working group strives to create such a module for this guideline in the near future.

 

Intended audience for the guideline

The guideline aims to provide practical guidance for plastic surgeons and members of the multidisciplinary breast cancer team (surgical oncologist, medical oncologist, radiation oncologist, radiologist, pathologist, psychologist, breast care nurse specialist). A version for patients has recently been developed (https://www.b-bewust.nl/pif_borstreconstructie).

Members of the guideline panel

A multidisciplinary working group was appointed to develop the guideline in October 2011, consisting of representatives from all relevant specialties involved in the care for patients with breast reconstruction (see above for working group membership). Working group members were mandated by their professional organizations. The working group worked on developing the guideline for 2 years. The working group is responsible for the full text of this guideline.

 

  • Dr. M.A.M. Mureau (President), MD, PhD, plastic surgeon, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam
  • Professor Dr. R.R.W.J. van der Hulst, MD, PhD, plastic surgeon, Maastricht University Medical Center/Orbis Medical Center/Viecuri Medical Center, Maastricht
  • Dr. L. A.E. Woerdeman, MD, PhD, plastic surgeon, Antoni van Leeuwenhoek / Netherlands Cancer Institute, Amsterdam
  • Drs. A.A.W.M van Turnhout, MD, plastic surgeon, Tergooi Hospital, Hilversum Site
  •  N.A.S. Posch, MD, plastic surgeon, Haga Hospital, The Hague
  • Dr. M.B.E. Menke-Pluijmers, MD, PhD, oncologic surgeon, Albert Schweitzer Hospital, Dordrecht
  • Dr. E.J.T. Luiten, MD, PhD, oncologic surgeon, Amphia Hospital, Breda
  • Drs. A.H. Westenberg, MD, radiotherapist/oncologist, Arnhem Radiotherapy Institute, Arnhem
  • Dr. J.P. Gopie, PhD, psychologist, Leiden University Medical Center, Leiden
  • Dr. H.M. Zonderland, MD, PhD, radiologist, Academic Medical Center, Amsterdam
  • Drs. M. Westerhof, MSc, Netherlands Breast Cancer Association, Utrecht
  •  E.M.M. Krol-Warmerdam MA, V&VN Nurse Specialists, Leiden University Medical Center, Leiden

 

With support from

  • Drs. B.S. Niël-Weise, MD, microbiologist / epidemiologist, senior advisor, Knowledge Institute for Medical Specialists

Declaration of interest

Working group members declared any (financial) ties with commercial companies, organizations or institutions involved in the field covered by the guideline for the past five years in writing. An overview is available on request from the office of the Knowledge Institute for Medical Specialists (KIMS).

Patient involvement

Patients are represented by a delegate from the Netherlands Breast Cancer Association in this guideline.

Method of development

Evidence based

Implementation

Guideline implementation and practical applicability of the recommendations was taken into consideration during various stages of guideline development. Factors that may promote or hinder implementation of the guideline in daily practice were given specific attention.

 

The guideline is distributed digitally among all relevant professional groups. The guideline can also be downloaded from the Dutch Society for Plastic and Reconstructive Surgery website: www.nvpc.nl, the guideline website: www.richtlijnendatabase.nl and the Quality Organization for Medical Specialists.

Methods and proces

AGREE

The guideline has been drafted in accordance with the requirements outlined in the ‘Guidelines 2.0’ report of the Guideline Advisory Committee of the Council on Science, Education and Quality (WOK). This report is based on the AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II) (www.agreecollaboration.org), an instrument designed to assess the quality of guidelines with broad international support.

 

Primary questions and outcome measures

Based on the outcomes of the bottleneck analysis, the president and advisor formulated draft primary questions. These were discussed and defined together with the working group. Subsequently, the working group determined which outcome measures were relevant for the patient for each primary question, examining both desired and undesirable effects. The working group valuated these outcomes based on their relative importance as crucial, important and unimportant.

 

Literature search and selection strategy

Specific search terms were used to identify published scientific studies related to each individual primary question in Medline, Cochrane and, where necessary, Embase. Additionally, the references of the selected articles were screened for additional relevant studies. Studies offering the highest level of evidence were sought out first. Working group members selected articles identified by the search based on predetermined criteria. The selected articles were used to answer the primary question. The searched databases, the search string or terms used during the search and selection criteria applied are listed in the chapter for each individual primary question.

 

Quality assessment of individual studies

Individual studies were assessed systematically based on predefined methodological quality criteria in order to assess the risk of biased study results. These assessments may be found in the column ‘Study quality assessment’ in an evidence table.

 

Literature summary

The relevant study results from all selected articles were presented clearly in evidence tables. The key findings from the literature are described in the literature summary. If studies were sufficiently similar in design, data were also summarized quantitatively (meta-analysis) using Review Manager 5.

 

Assessment of the level of scientific evidence

A)   With regard to intervention questions:

The level of scientific evidence was determined using the GRADE method. GRADE is short for ‘Grading Recommendations Assessment, Development and Evaluation’ (see http://www.gradeworkinggroup.org/) (Atkins et al, 2004).

 

B)    With regard to questions about the value of diagnostic tests, harm or adverse effects, etiology and prognosis:

GRADE cannot be used (yet) for these types of questions. The level of evidence of the conclusion was determined based on the accepted EBRO method (van Everdingen et al, 2004).

 

Formulation of conclusions

With regard to questions about the value of diagnostic tests, harm or adverse effects, etiology and prognosis, the scientific evidence is summarized in one or more conclusions, listing the level of evidence for the most relevant data.

 

For interventions, the conclusion does not refer to one or more articles, but is drawn based on the body of evidence. The working group looked at the net benefits of each intervention. This was done by determining the balance between favorable and unfavorable effects for the patient.

 

Considerations

When making recommendations, scientific evidence was considered together with other key aspects, such as working group member expertise, patient preferences, costs, availability of facilities and/or organizational aspects. Insofar as they are not part of the systematic literature review, these aspects are listed under ‘Considerations’.

 

Formulation of recommendations

Recommendations provide an answer to the primary question, and are based on the best scientific evidence available and the most important considerations. The level of scientific evidence and the importance given to considerations by the working group jointly determine the strength of the recommendation. In accordance with the GRADE method, a low level of evidence for conclusions in the systematic literature review does not rule out a strong recommendation, while a high level of evidence may be accompanied by weak recommendations. The strength of the recommendation is always determined by weighing all relevant arguments.

 

Development of indicators

Along with developing a draft guideline, internal quality indicators were developed to allow monitoring of the implementation of the guideline in daily practice. More information about the method for indicator development may be requested from KIMS.

 

Knowledge gaps

During the development of this guideline, systematic searches were conducted for research contributing to answering the primary questions. For each primary question, the working group determined whether (additional) scientific research is desirable.

 

Commentary and authorization phase

The draft guideline was submitted to the (scientific) organizations involved for comment. The guideline was also submitted to the following organizations for comment: Netherlands Breast Cancer Association (BVN), Netherlands Society for Medical Oncology (NVMO), Dutch College of General Practitioners (NHG), Healthcare Insurers Netherlands (ZN), The Dutch Healthcare Authority (NZA), Health Care Insurance Board (CvZ), the Health Care Inspectorate (IGZ), Achmea, CZ, Menzis and VGZ. Comments were collected and discussed with the working group. The draft guideline was updated and finalized by the working group based on the comments. The final guideline was submitted for authorization to the (scientific) organizations involved and authorized by them.

 

Legal standing of guidelines

Guidelines are not legal prescriptions, but contain evidence-based insights and recommendations that care providers must meet in order to provide high quality care. As these recommendations are primarily based on ‘general evidence for optimal care for the average patient’, care providers may deviate from the guideline based on their professional autonomy when they deem it necessary for individual cases. Deviating from the guideline may even be necessary in some situations. If care providers choose to deviate from the guideline, this should be done in consultation with the patient, where relevant. Deviation from the guideline must always be justified and documented.