What is the added value of using (acellular) dermal matrix products in patients with an implant reconstruction after mastectomy?
In case of immediate implant reconstruction after skin-sparing mastectomy:
* A clinical trial approved by a medical ethics committee, including an informed consent form signed by the patient prior to commencement of treatment.
The worldwide use of ADM products in breast reconstructions and publications on this topic are growing. Commonly mentioned advantages of ADM product use in breast reconstruction are: a better possibility to define the inframammary fold, as the serratus anterior and rectus abdominis muscles do not need to be released, as is the case for full submuscular placement of an expander; improved implant cover at the lower pole; better aesthetic results (Vardanian et al, 2011); protection against capsular contractures (Basu & Jeffers, 2012); less pain symptoms; a greater initial filling volume; and a shorter expansion period if a tissue expander is used.
McCarthy et al (2012) examined the differences in pain, medication use, thoracic and upper torso symptoms, preoperative filling volume and number of postoperative fills in 36 patients undergoing immediate reconstruction with a tissue expander and ADM compared with 33 patients with an immediate reconstruction with a submuscular tissue expander in a multi-center, double-blind RCT. Both groups were similar at baseline. Pain was measured with a Visual Analogue Scale, and physical complaints using the Physical Well-Being: Chest and Upper Body Scale from the validated BREAST-Q questionnaire. Measurements were performed preoperatively, immediately postoperatively, during the first, second and third phases of tissue expander filling, and before exchanging the expander for the definite prosthesis. Except for a small difference in average number of outpatient fills (TE+ADM 6.4 vs. TE 7.3; p=0.04), no statistically significant differences were found in either preoperative or postoperative outcomes at various points in time. No difference was found in the number of postoperative complications (McCarthy et al, 2012).
Another option is to perform immediate direct-to-implant reconstruction without prior use of a tissue expander. For surgeons who usually place a definite prosthesis during skin sparing mastectomy, without cover by the serratus anterior and/or rectus abdominis fascia, addition of ADM products between the lower edge of the pectoralis major and inframammary fold provides thicker, more sturdy covering for the implant, with less (visible and palpable) wrinkling, better definition of the inframammary fold, less chance of cranial displacement of the pectoralis major or animation of the skin if the pectoralis major is attached to the dermis. This may improve aesthetic results and patient satisfaction. One study by Vardanian et al (2011) of 337 implant reconstructions in 203 patients (208 with ADM, 129 without ADM) found improved cosmetic outcomes for implant reconstructions with use of ADM products.
A drawback to the use of ADM is the potentially greater risk of complications (infection, seroma and explantation) indicated by the previously discussed systematic review by Hoppe et al (2011). Another recent systematic review of 16 retrospective studies and a meta-analysis of 5 studies compared tissue expander reconstructions with tissue expander + ADM reconstructions in terms of seroma, cellulitis, infection, skin flap necrosis, hematoma, capsular contracture and reconstruction failure (Ho et al, 2012). Overall, the implant + ADM group had a greater risk of seroma (OR=3.9), infection (OR=2.7) and reconstruction failure (OR=3.0). The pooled effects of ADM use on seroma (OR=2.0), skin flap necrosis (OR=1.9) and hematoma (OR=2.0) were not statistically significant and thus less evident (Ho et al, 2012). The pooled capsular contracture percentage was 0.6% for the reconstructions with a tissue expander + ADM compared with 3-18% after tissue expander /implant reconstructions. This may indicate that the use of ADM protects against capsular contracture, however, follow-up time in the studies was short and only one of the studies was comparative, leaving insufficient evidence for a clear conclusion (Ho et al, 2012). Finally, a third systematic review of 54 studies and a meta-analysis of six found very similar results. Compared with tissue expander reconstructions, the relative risk after implant + ADM reconstructions for overall complications was 2.1. Relative risk was 2.7 for seroma, 2.5 for infection and 2.8 for reconstruction failure (Kim et al, 2012).
Another objection to the (routine) use of ADM products in implant reconstruction is the relatively high cost of these products. These additional costs are not currently reimbursed separately by health insurers under the current system in The Netherlands and will lead to a significant impact on care provider budgets. However, an additional procedure may potentially be avoided, which can benefit cost-effectiveness. Reducing the number of interventions (one procedure when using ADM versus two without ADM) was considered a relevant outcome measure by the working group, as high product costs (about €2,000 per breast per procedure) may be compensated by reducing operating and admission costs, thus making ADM use cost-effective. A number of authors conducted a cost analysis for the use of ADM products in breast reconstruction (De Blacam et al, 2012; Jansen & Macadam, 2011; Johnson et al, 2013). Costs and reimbursement differ per country, making direct comparison with the situation in The Netherlands impossible. However, in a cost analysis including sensitivity analyses for costs of ADM, operating time and capsular contracture, a 1-stage ADM implant reconstruction was found to be cost-effective compared with a 2-stage tissue expander/implant reconstruction (Jansen & Macadam, 2011).
In conclusion, meta-analyses by Ho et al (2012) and Kim et al (2012), despite the same methodological weakness faced by Hoppe et al (2011), confirm that use of ADM products in implant breast reconstructions appears to result in a greater risk of complications. The potential protective effect of ADM products against capsular contracture remains unclear, as does the cost-effectiveness of ADM product use in implant breast reconstructions. Methodologically robust, prospective RCTs are required to evaluate the safety, efficacy and cost-effectiveness of ADM in breast reconstructions.
Acellular dermal matrix (ADM, acellular cadaveric dermis, tissue matrix, (allogenic) dermal graft) is derived from cadaver dermis. Cells are removed from donor skin, and the epidermis is removed from the skin. Collagen, elastin and laminin are retained. The ideal ADM does not trigger an immune response, and thus does not cause rejection or extrusion. Acting as a collagen dermal scaffold, ADM is vascularized, populated by fibroblasts and replaced with autologous collagen (Macadam et al, 2012). In practice, both human and animal (bovine and porcine) donor material is used, with or without growth factors. Bovine pericardium does not meet the definition of dermal matrix, but is used for the same application.
In breast reconstructions, ADM products are used in combination with implant reconstructions. In this case, the dermal matrix is used to strengthen the tissue cover over the implant, which is particularly important when the implant is partially placed under the pectoralis major muscle, with the lower pole of the implant not being covered by the muscle but lying subcutaneously. The attachment of the pectoralis major to the skin is also reduced if the matrix is placed between the caudal edge of the muscle and the inframammary fold. For surgeons striving to cover the entire implant with muscle tissue, the use of dermal matrix determines whether a two-stage reconstruction with a tissue expander or a direct-to-implant reconstruction can be performed, or whether a larger initial volume can be achieved by using a tissue expander, thus limiting the number of outpatient contacts required for filling the expander.
Currently, ADM products are not used routinely for implant reconstruction in The Netherlands. This may be due to the relatively high cost of such products, the potentially higher risk of complications, and the unclear effect on cosmetic result and prevention of capsular contractures.
The body of literature on the use of ADM products is growing steadily, despite a potentially higher risk of complications (seroma, infection and reconstruction failure). This chapter examines whether ADM products have a place in implant reconstructions due to the beneficial effect on the number of surgeries, cosmetic result and reduction in capsular contracture (Vardanian et al, 2011; Basu & Jeffers, 2012).
General quality of evidence very low (GRADE)
There is a great deal of uncertainty regarding the net (un)favorable effect of an immediate implant/expander breast reconstruction using acellular dermal matrix in patients with breast cancer.
Sources (Hoppe et al, 2011)
One systematic review (Hoppe et al, 2011) of 8 observational studies examined the complications of acellular dermal matrix (ADM) use in immediate implant/expander breast reconstructions. All 8 studies compared one type of ADM (AlloDerm, LifeCell, Branchburg, New Jersey) with traditional methods of immediate breast reconstruction using a definite implant or tissue expander. A meta-analysis of 7 studies showed that reconstructions with ADM were associated with a risk of infection twice as high as reconstructions without ADM (OR 2.33; 95% CI 1.55 to 3.49). Celullitis was also considered an infection. A meta-analysis of 6 studies showed that reconstructions using ADM were associated with a risk of seroma 3 times as high as for reconstructions without ADM (OR 3.0; 95% CI 1.96 t0 4.61). No distinction was made between seroma formation requiring intervention and seroma formation not requiring intervention. A meta-analysis of 7 studies showed that reconstructions with ADM were associated with a risk of repeat intervention with removal of prosthetic over twice as high compared to reconstructions without ADM (OR 2.41; 95% CI 1.59 to 3.64).
Level of evidence of the literature
The level of evidence for the outcome measure infection is low, as the study was not randomized (significant limitations in study design). All studies were of Alloderm (human product). Alloderm is not available in The Netherlands. Whether the study results can be extrapolated to the situation in The Netherlands is unclear. Therefore, the working group has decided not to lower the level of evidence further.
The level of evidence for the outcome measure ‘implant removal’ (explantations) is very low, as the studies were not randomized (bias due to limitations in study design) and the results are conflicting (heterogeneity; I2 = 49%).
Oncologic safety and patient satisfaction were not studied as outcome measures.
Search and select
In order to answer the primary question, a systematic literature review was performed for the following question:
What are the effects of using acellular dermal matrix products in implant reconstructions compared to not using acellular dermal matrix products?
Relevant outcome measures
The working group considered complication risk and oncologic safety critical outcome measures for decision-making; aesthetic result/patient satisfaction were considered important to decision-making.
Search and selection (Method)
Medline (OVID), Embase and Cochrane databases were searched for breast reconstructions using acellular dermal matrix products. 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, CCT); comparison of acellular dermal matrix products versus no acellular dermal matrix products in breast reconstructions; and oncologic safety, aesthetic result and patient satisfaction as outcome measures.
Six studies were selected based on title and abstract. After reading the full articles, one study was included in the literature analysis (Hoppe et al, 2011). The reasons for excluding the other 5 studies may be found in the appendix.
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
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
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.
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).
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).
Patients are represented by a delegate from the Netherlands Breast Cancer Association in this guideline.
Method of development
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
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.
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.
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.
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.