A total of 83 non-duplicated publications were collected in the initial search, and 27 publications were assessed for eligibility. 21 publications fitted the inclusion criteria; however, 2 studies were later removed due to the irrelevant outcomes. The search process is illustrated in Figure 1. The interventions were variable (e.g., DIEP flap breast reconstructions, breast reconstruction using tissue expanders, TRAM flap, SGAP flap, TMG flap and SIEA flap etc.) but the focus of all selected reviews included the effects of NST breast reconstruction.
Study characteristics
Nineteen studies were analyzed in this systemic review. Four were prospective studies [29, 35, 44, 49] with one of them being randomized control trial (RCT) [35], six studies were retrospective RCT style [3, 5, 9, 12, 21, 31], and eight of them were retrospective cohort studies (Table 1) [13, 22, 24, 26, 30, 41-43, 46].
The mean age range of candidates was 46-59 years. A total of 49,217 patients were included in these 19 selected studies. All the patients were females (100%) with no male mastectomy case included in the studies. The duration of these studies ranged from three to 11 years with a mean duration of six years. Eight of the studies were conducted in the United States of America [9, 13, 21, 29, 41, 42, 44, 46]. One study was translated into English from Hebrew [22]. Fifteen studies had patients with flap reconstruction surgery [3, 22, 26, 29, 30, 31, 35, 43, 44, 49], six studies had patients with both flap and implant reconstruction surgery [9, 12, 13, 21, 42, 46] and two studies had patients with implant reconstruction surgery [5, 24]. From the available studies, a total of 671 patients were on implants following BRS and 48,416 with flap reconstruction.
Four studies were the timing of NST administration [9, 13, 42, 46], twelve studies assessed the complication rates of BRS due to NST [3, 5, 12, 13, 22, 24, 26, 30, 31, 35, 43], and three studies investigated complications and timing of NST [21, 46, 49]. Four studies [9, 21, 46, 49] included patients of AST and NST (Table 1).
Intervention characteristics
Invasive ductal carcinoma was the most common breast cancer diagnosis in seven of the studies [3, 9, 21, 35, 41, 46, 49]. The type of breast cancer diagnosis was not reported in the remaining 12 studies [5, 12, 13, 21, 22, 24, 26, 29-31, 43, 44]. The most used NST chemotherapy regimen was the ACT regimen (doxorubicin hydrochloride (Adriamycin) and cyclophosphamide, followed by treatment with paclitaxel (Taxol)) and fluorouracil, epirubicin, and cyclophosphamide [3, 5, 9, 12, 21, 24, 26, 30, 31, 35, 41-44, 46, 49].
Quality assessment
Quality assessment was performed by Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines that reported all included studies were of good and moderate quality (n=19, 91.6%). Points were given based on the -four indicators: random sequence: yes 1 no 0, allocation concealment: yes 1 no 0, complete outcome data: yes 1 no 0, selective reporting: yes 0 no 1 (Table 2). Any study that scored 2-3 was considered good quality and a score of 4 was regarded as an excellent quality study.
The risk of bias of the six included RCT was calculated by Cochrane Collaboration’s tool [20], majority of studies had low risk (Table 3). The risk of bias of all other non-randomized studies calculated by ROBINS-I [40] was also low (Table 4). Overall, the risk of bias of the included studies was low and the quality of this systematic review was good.
Impact of NST on complication rates in free flap and implant BRS
Fifteen studies (2721 patients out of total 49,217 patients received NST) assessed the effect of NST on the complication rate of BRS performed (Table 5) [3, 5, 12, 13, 21, 22, 24, 26, 29-31, 35, 43, 44, 46, 49]. The major complications identified were partial or total flap loss, venous congestion, infection, hematoma, seroma, fat necrosis, and wound dehiscence. Thirteen studies concluded there was no significant difference in the complication rates of patients who received NST and those who did not [3, 5, 12, 13, 21, 22, 24, 26, 31, 35, 43, 44, 46, 49]. In the pooled analysis, when comparing BRS complications with and without NST, the overall NST patient complication rates were higher (10.61%), but not statistically significant (NST = 44.07 %, Control = 33.46%, P=0.21). Based on the complications associated with the type of BRS done, 11.5% (275 out of 671 patients on implants or tissue) had complications after the procedure while 26.9% (1051 out of 48,416 with Flap reconstruction surgery) had complications. Thus it was concluded that there was no significant difference in the complication rates of patients who had flap reconstruction surgery and those on implants or tissue expanders. (Flap = 26.9%, Implants = 11.5%, P=0.4)
In the pooled analysis, major complication rates for NST were 14.5% (P=0.61) and 21.1% (P=0.69) with AST, while minor complication rates were 28.8% (P=0.97) with NST and 39.4% (P=0.59) with AST. When comparing NST and AST, overall rate of BRS major complications with NST were lower than the overall major complications of AST but did not reach significance (P=0.64). Similarly, the overall rate of minor complications of NST were also lower than the overall minor complications of AST without statistical difference (P=0.70) (Table 1). Mehrara et al., concluded NST significantly increased the rate of complications [29]. Most recorded complications were of minor nature and few major complications were observed (7.7%) [29]. Decker et al., deemed wound dehiscence was significantly (P=0.009) higher in patients who underwent BRS without NST [13]. Two other studies deemed the seromas, hematoma, and surgical site infections (SSIs) were not significantly lower in patients who received NST [22, 35].
NST optimum timing
Seven studies comprising of 1,810 patients (906 received NST) assessed the effect of timing on the postoperative complications of BRS [9, 21, 41, 42, 44, 46, 49]. While the time durations were variable, and no studies concluded a significant change in the complications with or without the use of NST. Postmastectomy patients with a time interval of cytotoxic chemotherapy to surgery <28 days had significantly (P=0.02) increased wound related complications compared to the patients >28 days [41]. Cohen et al., investigated complications rates over 3 different time points and concluded NST timing had no effect on complications [9]. Complications were fewer when surgery was performed >60 days after NST, but no statistical significance was found between those who performed surgery at <30 days and 30-60 days [9]. Compared with delayed BRS following NST, immediate BRS had statistically significant higher complication rates (37.1%, P=0.02) [21].
AST complications and timing
The impact of AST on postmastectomy complications was investigated in four studies [9, 21, 46, 49] and the optimum timing of administration was investigated in one [9]. When comparing AST BRS complications to no AST overall rates were higher without statistical significance (P=0.42) in AST patients. Major and minor complications were higher without statistical significance in AST patients (P=0.69, P=0.59, respectively). Peled et al. found among NST and AST patients, the AST cohort developed significantly more (44%) postmastectomy complications compared with the NST cohort (23%, P=0.05) [46]. These results differ from Hu et al. who found no statistical difference but more complications for NST (28.3%) than for AST (26.2%, P=0.72) [21]. Cohen et al. concluded that postmastectomy complications can be reduced by decreasing the time span between chemotherapy and reconstruction surgery although findings were not statistically significant [9]. The impact of AST on complication rates has been summarized in Table 6.