Current perspectives on cell-assisted lipotransfer for breast cancer patients after radiotherapy

Literature search

The literature search initially yielded 2234 studies, including 378 clinical trials (Fig. 1). After the removal of duplicates, 1185 unique records were screened based on the titles and abstracts. Of these, 75 articles were screened based on the full texts. Ultimately, a total of seven studies, including two registered clinical trials (NCT00616135 and NCT01771913), published from 2012 to 2020, met all the inclusion and exclusion criteria of this systematic review (Fig. 1) [27,28,29,30,31,32,33].

Study characteristics

Table 2 shows the general characteristics of the included studies. There were six prospective studies [27,28,29,30,31, 33], four of which had one or two control groups; and one retrospective study that had two control groups [32]. In Tissiani’s study, to control the risk of bias, stratified block randomization was performed to evenly distribute patients with radiotherapy [28]. Moreover, they started with patient selection in the CAL group, followed by the control group; the two groups were matched by age, BMI, and radiotherapy [28]. A stratified blocked randomization was also performed to evenly distribute the irradiated patients to the three groups in Gentile’s study [32]. Otherwise, no random allocation method was used in the other five studies to assign study subjects [27, 29,30,31, 33]. The risks of other bias in the included studies are as follows: First, most studies focused more on the outcomes of CAL without providing sufficient radiotherapy information, such as the method or dose used. Second, most of the studies were based on subjective questionnaires to investigate their satisfaction with the treatment outcomes in terms of three or five possible responses, but with no option to report any potential negative outcomes [27,28,29, 32, 33], demonstrating a possible element of bias. Third, the occurrence of postoperative complications in the relevant studies might be associated with the personal experience and skills of the surgeons; thus, the results could be biased in the relevant studies.

All studies enrolled female patients who underwent CAL in the context of breast reconstruction after radiotherapy. But only Ito’s study solely enrolled irradiated patients underwent breast reconstruction with CAL, with a sample size of 10 [29]. The studies of Perez-Cano solely enrolled patients who underwent breast reconstruction with CAL; the sample size was 67, and the ratio of irradiated patients was 91.0% (61/67) [27]. Tissiani’s and Jeon’s studies both set up the CAL group and the lipofilling control group (fat graft without ADSC enrichment, also known as the conventional lipofilling group) [28, 33]. Mazur’s study had the CAL group and the control group untreated with lipofilling [31]. The remaining two studies had three groups: the CAL group, the lipofilling control group, and the control group untreated with lipofilling [30, 32].

Participants

As shown in Table 2, the mean age of the participants was under 60 years. The mean preoperative body mass index was less than 30 kg/m2, except that was not mentioned in the other three studies [30,31,32]. The TNM classification of the tumor was up to T2N2M0 [27, 29, 30, 32]. Only three studies reported the histological type of tumor; the ratio of ductal carcinoma in situ was 10% (1/10), 8.9% (5/56), and 10% (1/10) in the CAL group of Tissiani’s, Mazur’s, and Jeon’s studies [28, 31, 33], while it was 25% (2/8) and 20% (2/10) in the lipofilling control group in Tissiani’s and Jeon’s studies, respectively [28, 33].

Perez-Cana et al. and Ito et al. stated the patients’ radiation history, which had a mean cumulative dose of 60 and 50.9 Gy, respectively [27, 29]. However, the method of radiotherapy technique used was not reported in all seven studies. The Late Effects Normal Tissues—Subjective Objective Management Analysis (LENT-SOMA) scoring system [34] was used to assess the physical symptoms and function damage from radiotherapy in Perez-Cana’s, Tissiani’s, and Gentile’s studies, which only enrolled patients with grades 1 and 2 [27, 28, 32], while the Fitoussi classification system was used in Ito’s study [29].

Intervention (technical factors)

All participants in the included studies had undergone mastectomy or breast-conserving surgery. One study reported that a tissue expander temporary prosthesis was used before lipofilling when performing nipple-sparing mastectomy [30]. Tissiani et al., Mazur et al., and Gentile et al. reported that the ratio of prosthesis-based reconstruction in patients underwent CAL was 70% (7/10), 16.1% (9/56), and 15.7% (19/121) [28, 31, 32]. In addition, Tissiani et al., Mazur et al., and Jeon et al. enrolled participants who had undergone breast reconstruction with autologous flaps, either transverse rectus abdominis myocutaneous, or latissimus dorsi flaps [28, 31, 33]; the ratio of autologous flap-based reconstruction in the CAL group was 70% (7/10), 16.1% (9/56), and 100% (10/10), while the ratio was 37.5% (3/8) and 100% (10/10) in the lipofilling control group of Tissiani’s and Jeon’s studies [28, 33].

According to Coleman’s method, lipoaspirate was harvested from the abdominal region of patients [35]. Four studies applied the automated Celution® system (Cytori Therapeutics, San Diego, CA, USA) with a proteolytic enzyme to obtain ADSC-enriched grafts [27, 29, 30, 32], while the other three studies used collagenase [28, 31, 33]. The volume of harvested adipose varied across the studies. The mean volume of ADSC-enriched grafts was reported in five studies, which ranged from 82.9 to 136 mL [27,28,29, 31, 33]; while an average of 429.6 mL ADSC-enriched grafts was used in Gentile’s study [32], which was not stated in Calabrese’s study [30]. Tissiani et al. reported that the ratio of the adipose tissue needed for ADSC enrichment versus that needed for final injection was 2:1 [28], while that in the remaining six studies was 1:1. On the other hand, Ito et al., Mazur et al., and Gentile et al. reported that the cell number ranged from one hundred thousand to a million cells per milliliter ADSC-enriched graft [29, 31, 32]. Tissiani et al., Mazur et al., and Gentile et al. detected the immunophenotype and stem cell characterization of ADSCs [28, 31, 32].

Volumetric persistence (fat graft retention)

The breast volume was monitored by ultrasound, magnetic resonance imaging (MRI), or three-dimensional surface imaging [28, 32, 33]. Tissiani et al. reported that the volumetric persistence in the CAL group was higher (79.5% ± 78.9%) than that in the lipofilling group (51.4% ± 18.4%); however, the difference was statistically significant (P = 0.31) [28]. In Gentile’s and Jeon’s studies, volumetric persistence was higher in the CAL group than in the lipofilling group (P < 0.05) [32, 33]. Briefly, from the limited evidence, breast reconstruction with CAL had higher volumetric persistence than conventional lipofilling.

Aesthetic improvement, treatment satisfaction, and complications

Aesthetic improvement was assessed by clinical evaluation, including MRI, ultrasound, and surgeon peer analysis. As shown in Table 3, after more than 12 months of follow-up, most participants presented aesthetic improvements [27,28,29, 32]. Based on either the LENT-SOMA scale assessment [27] or satisfaction assessment questionnaire [28, 29, 32, 33], most available patients [27,28,29, 32, 33] and investigators [27] were satisfied with the treatment results. There were no serious adverse events associated with the CAL procedure, such as disease transmission or septicaemia resulting from bacterial contamination [36,37,38]. Fat necrosis was reported to be the most common complication in the three studies of Tissiani et al., Gentile et al., and Jeon et al.; neither the incidence rates between the CAL group and the lipofilling group were significantly different (P > 0.05) [28, 32, 33]. Therefore, reconstruction with CAL presented aesthetic improvement and had favorable satisfaction but did not have adverse complications.

Oncological safety and efficacy in irradiated patients

All seven studies enrolled patients who underwent breast reconstruction with CAL after radiotherapy. The follow-up duration ranged from 12 to 93.6 months. As shown in Table 3, neither loco-regional recurrence nor metastatic disease was observed in the three studies of Tissiani et al., Ito et al., and Jeon et al. [28, 29, 33]. Mazur et al. reported that the oncological recurrence rate of the CAL group was 3.6% (2/56), which did not differ significantly from that of the control group (10/252, 4.0%; P > 0.05) [31]. Thus, CAL did not increase recurrence risk following radiotherapy during the 3-year observation [31]. In the longer follow-up of C. Calabrese’s study [

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