Autologous fat grafting to the breast has been proposed for indications that include breast augmentation following oncologic surgery. Grafting would be performed as an adjunct to reconstruction after mastectomy or lumpectomy, and it would be of benefit in the following areas: for contouring purposes, improving breast shape and volume; and for alleviating post-mastectomy pain syndrome (neuropathic pain) and irradiated skin (thereby reducing complication and failure rates of implant reconstruction). Variability in long-term results and oncologic concerns have limited application of autologous fat grafting in the breast.

This policy does not address the use of autologous fat tissue in aesthetic breast augmentation (ie, cosmesis).

Adipose-Derived Stem Cells

Stem cell biology and the related field of regenerative medicine involves multipotent stem cells that exist within a variety of tissues, including bone marrow and adipose tissue. A single gram of adipose tissue yields approximately 5000 stem cells; this is 100 to 500 times the number of mesenchymal stem cells found in an equivalent amount of bone marrow.^1, Stem cells, because of their pluripotentiality and unlimited capacity for self-renewal, offer promise for tissue engineering and advances in reconstructive procedures. In particular, adipose tissue represents an abundant and easily accessible source of ADSCs, which can differentiate along multiple mesodermal lineages. ADSCs may allow for improved graft survival and generation of new fat tissue after transfer from another site.^1,2,

The potentially therapeutic properties of ADSC have led to novel techniques of fat grafting in conjunction with ADSC therapy for breast fat grafting. Differentiation of ADSC into adipocytes may provide a reservoir for adipose tissue turnover. Differentiation of ADSC into endothelial cells, with the release of angiogenic growth factors by ADSC, may decrease the rate of graft resorption by increasing blood supply to the grafted fat tissue. Further, ADSC may serve to accelerate wound healing and protect the graft from ischemia reperfusion injury.^1, Current methods for isolating ADSCs can involve various processes, which may include centrifugation and enzymatic techniques that rely on collagenase digestion-which, in turn, is followed by centrifugal separation to isolate the stem cells from primary adipocytes. Isolated ADSCs can be expanded in a monolayer on standard tissue culture plastic surfaces with a basal medium containing 10% fetal bovine serum.^3, Newly developed culture conditions provide an environment in which the study of ADSCs can be done without the interference of animal serum and may also allow rapid expansion of autologous ADSCs in culture for use in human clinical trials. A standard expansion method has not yet been established.

To address the problems of unpredictability and low rates of fat graft survival, Yoshimura et al (2008) developed a technique known as cell-assisted lipotransfer, which produces autogenous fat rich in ADSCs.^4, In cell-assisted lipotransfer, half of the lipoaspirate is centrifuged to obtain a fraction of concentrated ADSCs; meanwhile, the other half is washed, enzymatically digested, filtered, and spun down to an ADSC-rich pellet. The latter is then mixed with the former, converting a relatively ADSC-poor aspirated fat to ADSC-rich fat.

A point-of-care system is available for concentrating ADSC from mature fat. The Celution System is designed to transfer a patient’s adipose tissue from one part of the body to another in the same surgical procedure.

Regulatory Status

In September 2006, Celution™ Cell Concentration System (Cytori Therapeutics; San Diego, CA) was cleared for marketing by the FDA through the 510(k) process as a cell saver device. The system is cleared for the collection, concentration, washing, and reinfusion of a patient’s cells for applications that may include, but are not limited to, cardiovascular, plastic and reconstructive, orthopedic, vascular, and urologic surgeries and procedures. In 2007, Cytori Therapeutics received the FDA 510(k) clearance to market the Autologous Fat Transfer system, which transfers a patient’s own adipose tissue from one part of the patient’s body to another. FDA product code: CAC.

In 2017, the Revolve Envi 600 Advanced Adipose System (LifeCell Corporation, Branchburg, NJ) was cleared for marketing by the FDA through the 510(k) process. The system harvests, filters, and transfers autologous adipose tissue for fat grafting. Uses include reconstructive surgery. FDA product code: MUU.

Related Policies

• None

(NOTE: According to the 2012 Post-Mastectomy Fat Graft/Fat Transfer ASPS Guiding Principles, "The number of fat grafting sessions required varies per patient. Studies suggest that a majority of patients require more than one fat grafting session to achieve adequate aesthetic results, and that each additional session will contribute to gradual improvement of the overall outcome."

In addition, the 2012 National Institute for Health and Clinical Excellence guideline on Breast Reconstruction Using Lipomodelling after Breast Cancer Treatment states that, "Patients subsequently undergo repeat treatments (typically 2-4 sessions.")

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2011 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through December 4, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The RCTl is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Adipose-Derived Stem Cell Enrichment of Autologous Fat Grafts

Clinical Context and Therapy Purpose

The purpose of autologous fat grafting with ADSC enrichment in patients with breast cancer who have undergone reconstructive surgery is to improve graft survival.

The question addressed in this policy is: Does the use of autologous fat grafting with ADSC enrichment improve net health outcomes in patients with breast cancer who have undergone reconstructive surgery compared with autologous fat grafting without stem cell enrichment?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is women with breast cancer who have undergone reconstructive surgery and have received autologous fat grafting.

Interventions

The therapy being considered is ADSC enrichment of autologous fat grafting to the breast. Growth factors within the ADSC may promote neovascularization thereby increasing blood supply to the grafted fat tissue, which would decrease the rate of graft resorption, accelerate wound healing, and protect the graft from reperfusion injury. ADSC enrichment in autologous fat grafting to the breast is conducted in a tertiary care facility under general anesthesia. Plastic and reconstructive surgeons perform the procedure.

Comparators

The comparator of interest is autologous fat grafting to the breast without ADSC.

Outcomes

Absorption of the fat graft can be assessed after a few months. Long-term effects of the ADSC enhancement may not manifest for months to years following the procedure.

Due to the heterogeneity in outcome reporting in studies of autologous fat grafting to the breast, an international committee of experts in both breast and plastic surgery specialties used a Delphi consensus exercise to develop a core set of outcomes for determining safety and efficacy for this intervention.^5, Consensus was reached on 13 core outcomes within 6 domains:

• Oncologic outcomes: the rate of histologically confirmed locoregional cancer recurrence; the rate of distant cancer recurrence; and mortality rate
• Clinical outcomes: complications; and donor site morbidity
• Aesthetic and functional outcomes: surgeon assessment of volume, shape, symmetry, scarring, and improvements in skin quality; and ability to function and complete daily tasks (assessed by a validated instrument such as EQ-5D or BREAST-Q)
• Patient-reported outcomes: patient satisfaction (preferably assessed by BREAST-Q); and impact on quality of life
• Process outcomes: number of graft sessions needed to get optimal results; and readmission or unplanned surgery for any reason
• Radiological outcomes: incidence of radiological abnormalities; and number of interferences with subsequent mammography scannings.

Methodologically credible studies were selected using the following principles:

a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs controlled trials;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.

Rigotti et al (2007) reported on the results of a pilot study assessing the presence and effectiveness of ADSCs in 20 consecutive patients undergoing therapy for adverse events of radiotherapy to the breast, chest wall or supraclavicular region, with severe symptoms or irreversible function damage (LENT-SOMA scale grades 3 and 4).^6, Patients’ mean age was 51 years (range, 37-71 years). The rationale behind the study was that the ADSCs, which have been shown to secrete angiogenic and antiapoptotic factors and to differentiate into endothelial cells, could promote neovascularization in ischemic tissue (eg, irradiated tissue). Targeted areas included the supraclavicular region, the anterior chest wall after mastectomy (with or without breast prosthesis), and breast after quadrantectomy. A lipoaspirate purification procedure was performed by centrifugation to remove a large part of the triglyceride portion of the tissue and to disrupt the cytoplasm of the mature adipocytes to favor their rapid clearance after injection. A stromal-vascular fraction was isolated by enzymatic digestion of extracellular matrix, centrifugation, and filtration, and the fractions were cultured for 2 to 3 weeks to obtain a homogenous cell population. To assess the presence of mesenchymal stem cells, the stromal-vascular fraction derived from the adipose tissue was cultured and characterized by flow cytometry. The number of procedures was 1 in 5 patients, 2 in 8, 3 in 6, and 6 in 1. Clinical follow-up varied between 18 months and 33 months (mean, 30 months). Clinical results after treatment with lipoaspirates were assessed by the LENT-SOMA scale, which is a common system used to assess the late effects of radiotherapy. The 11 patients, who were initially classified as LENT-SOMA grade 4 (irreversible functional damage), progressed to grade 0 (no symptoms), grade 1 and grade 2 in 4, 5, and 1 cases, respectively. In one case, no improvements were observed. In the 4 patients who had undergone mastectomy and had breast prostheses and areas of skin necrosis, the necrosis showed complete remission. In the group of 9 patients classified as LENT-SOMA grade 3, fibrosis, atrophy, and retraction progressed to grade 0 and grade 1 in 5 and 4 cases, respectively.

Yoshimura et al (2008) reported on the development of a novel strategy known as cell-assisted lipotransfer (CAL), in which autologous ADSCs are used in combination with lipoinjection.^4, From 2003 to 2007, the group performed CAL in 70 patients. Of these patients, CAL was performed in the breast for 60 patients (8 of whom had had breast reconstruction after mastectomy); for the remaining patients, CAL was performed in the face or hip. The authors reported outcomes for 40 patients with healthy thoraxes and breasts who underwent CAL for purely cosmetic breast augmentation; patients who were undergoing breast reconstruction for an inborn anomaly or following a mastectomy were not included. Nineteen of the 40 patients had been followed for more than 6 months, with a maximum follow-up of 42 months. The authors observed that the transplanted adipose tissue was gradually absorbed during the first 2 postoperative months, and the breast volume showed a minimal change thereafter. Final breast volume showed augmentation by 100 to 200 mL after a mean fat amount of 270 mL was injected. The difference in breast circumference (defined as the chest circumference at the nipple minus the chest circumference at the inframammary fold) had increased in all cases by 4 cm to 8 cm at 6 months. Cyst formation or microcalcification was detected in 4 patients. The authors concluded that their preliminary results suggested CAL is effective and safe for soft tissue augmentation and superior to conventional lipoinjection, but that additional study was necessary to evaluate the efficacy of this technique further.

Pérez-Cano et al (2012) conducted a single-arm, prospective, multicenter clinical trial of 71 women who underwent breast-conserving surgery for breast cancer and autologous adipose-derived regenerative cell-enriched fat grafting for reconstruction of defects 150 mL or less, a Clinical Evaluation Of Adipose Derived Regenerative Cells In The Treatment Of Patients With BrEast Deformities Post Segmental Breast ResecTion (Lumpectomy) With Or Without Radiation ThErapy (RESTORE-2 trial).^7,rial endpoints included patient and investigator satisfaction with functional and cosmetic results and improvement in overall breast deformity at 12 months after the procedure. Eligible female patients included women age 18 to 75 years who presented with partial mastectomy defects and without breast prosthesis. The RESTORE-2 protocol allowed for up to 2 treatment sessions, and 24 patients elected to undergo a second procedure following the 6-month follow-up visit. Of the 67 patients treated, 50 reported satisfaction with treatment results through 12 months. Sixty-one patients underwent radiotherapy as part of their treatment; 2 patients did not receive radiation, and the status of radiation treatment was not known for the other 4 patients. Using the same metric, investigators reported satisfaction with 57 of 67 patients. There were no serious adverse events associated with the adipose-derived regenerative cell-enriched fat graft injection procedure. There were no reported local cancer recurrences. The investigators found the LENT-SOMA scale insufficiently sensitive to reflect the clinical improvements seen in the trial population adequately. Patients with LENT-SOMA grade 3 and 4 scores (most severe symptoms) were excluded during screening (note: this may have contributed to the subtle LENT-SOMA score changes observed in the trial). The investigators reported improvement from baseline through 12 months in the degree of retraction or atrophy in 29 of 67 patients, while 34 patients had no change and 4 patients reported worse symptoms. Postradiation fibrosis at 12 months was reported as improved in 29 patients, while 35 patients had no change and 3 patients had worse symptoms. Management of atrophy was reported as improved in 17 patients, with 48 patients having no change and 2 patients reporting worse symptoms. Improvement in these measures was statistically significant. The authors concluded that future comparative studies are needed to determine the incremental benefit of adipose-derived regenerative cell-enriched fat grafting compared with traditional fat grafting in various clinical circumstances. The follow-up of the study was inadequate to conclude long-term risk of cancer recurrence.

Section Summary: Autologous Fat Grafting to the Breast with ADSC Enrichment

Evidence for the use of autologous fat grafting to the breast with ADSC enrichment consists of observational studies. The studies were heterogeneous in the patient selection, methods in harvesting stem cells, number of procedures, and outcomes measured. There were no comparative studies identified which demonstrated incremental benefits of using ADSC enrichment with autologous fat grafting over autologous fat grafting alone.

Summary of Evidence

For individuals who have breast cancer who receive autologous fat grafting to the breast with ADSC enrichment of the graft, the evidence includes small single-arm studies, some of which are prospective.Relevant outcomes are symptoms, morbid events, functional outcomes, quality of life, resource utilization, and treatment-related morbidity. The observational studies were heterogeneous in the patient selection, methods in harvesting stem cells, number of procedures, and outcomes measured. Studies have mainly reported patient and investigator satisfaction and functional and cosmetic results. Limitations of the data include sample sizes, short-term follow-up, and uncertainty about the possible oncologic influence ADSC may have on the fat grafting procedure. In addition, no studies were identified which demonstrated incremental benefits of using ADSC enrichment with autologous fat grafting over autologous fat grafting alone. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

American Society for Aesthetic Plastic Surgery and American Society of Plastic Surgeons

The American Society for Aesthetic Plastic Surgery and the American Society of Plastic Surgeons (2011) released a joint position statement on the use of stem cells in aesthetic surgery.^8, Based on a systematic review of the peer-reviewed literature, the Societies concluded that while there is potential for the future use of stem cells in aesthetic surgical procedures, the scientific evidence and other data are very limited in terms of assessing the safety or efficacy of stem cell therapies in aesthetic medicine.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

A currently ongoing trial that might influence this review is listed in Table 1.

Table 1. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02035085	This is a First in Man, Phase I Study Utilizing 19F Magnetic Resonance Imaging to Track Autologous, Adipose-Derived Stem Cells	6	Dec 2022

NCT: national clinical trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Adipose-Derived Stem Cells in Autologous Fat Grafting to the Breast
Autologous Fat Grafting to the Breast and Adipose-derived Stem Cells
Adipose-Derived Stem Cells, Breast Reconstruction
Breast Reconstruction with Adipose-Derived Stem Cells

References:
1. Mizuno H, Hyakusoku H. Fat grafting to the breast and adipose-derived stem cells: recent scientific consensus and controversy. Aesthet Surg J. May-Jun 2010;30(3):381-387. PMID 20601560

2. Wilson A, Butler PE, Seifalian AM. Adipose-derived stem cells for clinical applications: a review. Cell Prolif. Feb 2011;44(1):86-98. PMID 21199013

3. Sterodimas A, de Faria J, Nicaretta B, et al. Tissue engineering with adipose-derived stem cells (ADSCs): current and future applications. J Plast Reconstr Aesthet Surg. Nov 2010;63(11):1886-1892. PMID 19969517

4. Yoshimura K, Sato K, Aoi N, et al. Cell-assisted lipotransfer for cosmetic breast augmentation: supportive use of adipose-derived stem/stromal cells. Aesthetic Plast Surg. Jan 2008;32(1):48-55; discussion 56-47. PMID 17763894

5. Agha RA, Pidgeon TE, Borrelli MR, et al. Validated Outcomes in the Grafting of Autologous Fat to the Breast: The VOGUE Study. Development of a Core Outcome Set for Research and Audit. Plast Reconstr Surg. May 2018;141(5):633e-638e. PMID 29697603

6. Rigotti G, Marchi A, Galie M, et al. Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. Plast Reconstr Surg. Apr 15 2007;119(5):1409- 1422; discussion 1423-1404. PMID 17415234

7. Perez-Cano R, Vranckx JJ, Lasso JM, et al. Prospective trial of adipose-derived regenerative cell (ADRC)- enriched fat grafting for partial mastectomy defects: the RESTORE-2 trial. Eur J Surg Oncol. May 2012;38(5):382-389. PMID 22425137

8. Kamakura T, Ito K. Autologous cell-enriched fat grafting for breast augmentation. Aesthetic Plast Surg. Dec 2011;35(6):1022-1030. PMID 21533662

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

19499