Is immediate autologous breast reconstruction with postoperative radiotherapy good practice?: A systematic review of the literature

Is immediate autologous breast reconstruction with postoperative radiotherapy good practice?: A systematic review of the literature

Journal of Plastic, Reconstructive & Aesthetic Surgery (2013) 66, 1637e1651 REVIEW Is immediate autologous breast reconstruction with postoperative ...

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Journal of Plastic, Reconstructive & Aesthetic Surgery (2013) 66, 1637e1651

REVIEW

Is immediate autologous breast reconstruction with postoperative radiotherapy good practice?: A systematic review of the literature Mark V. Schaverien a,b,*, R. Douglas Macmillan a,b, Stephen J. McCulley a,b a

Department of Plastic Surgery, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK Department of Breast Surgery, Nottingham Breast Institute, City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK

b

Received 2 January 2013; accepted 18 June 2013

KEYWORDS Systematic review; Meta-analysis; Autologous breast reconstruction; Radiotherapy; Immediate; Delayed; Complications; Outcomes; Fat necrosis; Volume loss; Revisional surgery; Aesthetic outcome

Summary Background: There remains controversy as to whether immediate autologous breast reconstruction with postoperative radiotherapy is associated with acceptable complications and aesthetic outcomes. This systematic review analyses the literature regarding outcomes of immediate autologous breast reconstruction with postoperative radiotherapy compared with no radiotherapy, as well as with delayed autologous breast reconstruction following post-mastectomy irradiation. Methods: Pubmed (1966 to October 2012), Ovid MEDLINE (1966 to October 2012), EMBASE (1980 to October 2012), and the Cochrane Database of Systematic Reviews (Issue 10, 2012) were searched. Overall complications (including fat necrosis), fat necrosis, revisional surgery, loss of volume, and aesthetic outcome, were analysed individually. Comparable data from observational studies were combined for meta-analysis where possible and quality assessment of the studies was performed. Results: The majority of studies of immediate autologous breast reconstruction and postoperative radiotherapy reported satisfactory outcomes (19 of 25 studies; n Z 1247 patients). Metaanalysis of observational studies demonstrated no significant differences in total prevalence of complications (p Z 0.59) or revisional surgery (p Z 0.38) and a summary measure for fat necrosis favouring the group without radiotherapy (OR 2.82, 95% CI 1.35e5.92, p Z 0.006). The majority of studies comparing immediate reconstruction and postoperative radiotherapy with

* Corresponding author. Department of Plastic Surgery, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. Tel.: þ44 1382 660 111. E-mail address: [email protected] (M.V. Schaverien). 1748-6815/$ - see front matter ª 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bjps.2013.06.059

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M.V. Schaverien et al. delayed reconstruction following post-mastectomy radiotherapy (10 of 12 observational studies; n Z 1633 patients) reported satisfactory outcomes following immediate reconstruction. Meta-analysis of observational studies demonstrated no significant difference in overall incidence of complications (p Z 0.53) and fat necrosis (OR 0.63, 95% CI 0.29 e1.38, p Z 0.25), and a summary measure for revisional surgery (OR 0.15, 95% CI 0.05e0.48, p Z 0.001) favouring the delayed surgery group. No randomised-controlled trials met the inclusion criteria, and all of the observational studies included were missing more than one important component for reporting of observational studies. Discussion: The majority of studies reported satisfactory outcomes and a similar incidence of complications for immediate autologous breast reconstruction and adjuvant radiotherapy when compared with no radiotherapy or delayed reconstruction following radiotherapy; the proportion that required revisional surgery was higher though for immediate than delayed breast reconstruction. The findings are limited by the paucity of high quality data in the published literature, and until better data is available the findings of this review suggest that immediate autologous breast reconstruction should at least be considered when adjuvant chest wall radiotherapy is anticipated. ª 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Introduction The current clinical indications for post-mastectomy radiotherapy lead many patients to receive radiotherapy as part of their treatment for breast cancer. Clinical evidence from randomised trials of post-mastectomy radiation and a metaanalysis of these studies has established the importance of local control on long-term breast cancer-specific and overall survival.1e8 The Early Breast Cancer Trialists’ Collaborative Group examined the effect of radiotherapy and extent of surgery on clinical outcomes using individual patient data from 42,000 women in 78 randomised trials and found that the absolute reduction in the 5-year rate of locoregional recurrence was proportional to the absolute reduction in 15year breast cancer mortality with a 4:1 ratio.7,8 There is international consensus that patients with T3 or T4 tumours or at least four positive axillary lymph nodes require adjuvant radiotherapy,1,5,9e12 however the role of post-mastectomy radiation therapy in the treatment of patients with T1 or T2 tumours and one to three positive axillary nodes remains the subject of randomised trials but has the potential to dramatically increase the number of patients that will require post-mastectomy radiotherapy. Immediate breast reconstruction surgery has wellestablished advantages including a single operation, period of hospitalisation, and postoperative recovery period, as well as reduced overall costs, superior cosmetic results, and a reduced need for symmetrising surgery when compared with delayed breast reconstruction.13e23 Reconstructive surgeons face the challenge of integrating radiotherapy and breast reconstruction in an increasing number of breast cancer patients. Whilst it is generally accepted that radiation negatively influences the outcome of implant-based breast reconstruction, the effects of radiotherapy on the late complications and aesthetic outcomes of autologous breast reconstruction remain unclear. Although some studies and reviews have advocated avoidance of post-reconstruction irradiation due to higher prevalence of complications, unpredictable volume loss,

and unsatisfactory aesthetic outcomes, others have challenged these assumptions, in particular recent studies using contemporary radiotherapy regimens.24e58 The aim of this systematic review was to comprehensively review and analyse the reported effects of postoperative radiotherapy on outcomes of immediate autologous breast reconstruction without implant compared with no radiotherapy, and also with delayed reconstruction following post-mastectomy irradiation. This review also evaluates and critically appraises the quality of the published studies that currently inform practice.

Methods Pubmed (1966 to October 2012; searched for Text Words), Ovid MEDLINE (1966 to October 2012), EMBASE (1980 to October 2012), and the Cochrane Database of Systematic Reviews (Issue 10, 2012) were searched for the following terms: breast reconstruction AND flap AND radiotherapy OR irradiation OR radiation. Only English language and full text articles were included. Full text articles were then crossreferenced. All studies that reported outcomes of autologous breast reconstruction without using a prosthesis were included. Potentially relevant publications were identified using the search strategy and screened for retrieval by authors MS and SM. The latest search was performed on 1st October 2012. More than 400 potentially relevant publications were identified using the search strategy (Figure 1). No randomised-controlled trials were identified. Only data on outcomes of immediate autologous breast reconstruction with postoperative adjuvant radiotherapy, immediate autologous reconstruction without postoperative radiotherapy, and delayed autologous breast reconstruction following adjuvant radiotherapy, were extracted from studies meeting the inclusion criteria. Studies where the data could not be accurately extracted or where patient number totalled less than ten were excluded. Only complications that were reported in all studies were included, and therefore anastomotic

Immediate autologous breast reconstruction

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Statistical analysis The data analysis was performed using the Cochrane software Review manager version 5. Comparable data from observational studies were combined for metaanalysis where possible. For dichotomous data, odds ratios with 95% confidence intervals were estimated based on the fixed-effects model and according to an intentionto-treat analysis. As I2 was greater than 50% in both analyses for fat necrosis, odds ratios with 95% confidence intervals were estimated based on the random-effects model and according to an intention-to-treat analysis (Figures 2 and 3). Observational studies quality assessment was performed using STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines.

Results Comparison of immediate autologous breast reconstruction and postoperative radiotherapy with immediate autologous breast reconstruction without radiotherapy

Figure 1 a) Study identification for the review for comparison of immediate autologous breast reconstruction followed by postoperative radiotherapy with immediate breast reconstruction without radiotherapy; b) Study identification for the review for comparison of immediate autologous breast reconstruction followed by postoperative radiotherapy with delayed breast reconstruction following post-mastectomy radiotherapy.

revisions and abdominal bulge or hernia were excluded from analysis. Overall complications (including fat necrosis), fat necrosis, revisional surgery, loss of volume, and aesthetic outcome, were analysed individually. Study outcomes were described as satisfactory or unsatisfactory using the following criteria: for observational studies outcomes were described as satisfactory where the prevalence of overall complications, fat necrosis, loss of volume, and revisional surgery, and aesthetic outcomes, where reported, were not significantly different to those of the comparator group, and the study authors concluded that outcomes in the study group were satisfactory/ acceptable or better; for non-observational studies outcomes were described as satisfactory where prevalence of overall complications, fat necrosis, loss of volume, and revisional surgery, and aesthetic outcomes, where reported, were satisfactory/acceptable or better, and the study authors concluded that outcomes were satisfactory/ acceptable or better. The summary outcome was determined by author MS using these criteria, and where it could not be determined for a study it was resolved by discussion between the authors.

Twenty-eight studies were identified, of which three were excluded due to inability to extract the required data or insufficient patient numbers included. Twenty-five studies met the inclusion criteria. Ten were observational studies that compared immediate autologous breast reconstruction with and without adjuvant radiotherapy, five were observational studies reporting other comparisons, nine were case-series studies, and one was an individual cohort study (Figure 1a). In ten studies (n Z 2786 patients) outcomes of a study and comparator group were reported (Table 1), and in 15 studies (n Z 1130 patients) only outcomes of a study group receiving postoperative radiotherapy were included (Table 2). Overall, therefore, 826 patients received postoperative radiotherapy and 3090 patients who did not receive radiotherapy either pre- or postoperatively acted as a comparator group. Of the 25 studies that met the inclusion criteria, 19 studies (n Z 1247 patients) reported satisfactory outcomes following immediate autologous breast reconstruction and postoperative irradiation,24e40,48 and six studies (n Z 2669 patients) reported unsatisfactory outcomes41e47 (note that the total study sizes are reported, rather than number of patients that experienced satisfactory or unsatisfactory outcomes). There was insufficient data to determine whether differences existed between different flap types. Overall complications (including fat necrosis) were reported in five observational studies and were not significantly different between the groups in any of the studies [Table 1].25,27,31,42,47 The prevalence of fat necrosis alone, reported in seven studies, was significant higher in the radiotherapy group in three studies.44,45,47 Aesthetic outcomes were reported in seven observational studies, with four studies reporting significantly better aesthetic outcomes for immediate breast reconstruction without postoperative radiotherapy,41,42,44,45 and three

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M.V. Schaverien et al.

Figure 2 Meta-analysis of pooled data from observational studies comparing patients that received immediate autologous breast reconstruction and postoperative radiotherapy with patients that did not receive radiotherapy before or after surgery included in Table 1; a) Forest plot of prevalence of complications; b) Forest plot of prevalence of fat necrosis; c) Forest plot of prevalence of revisional surgery.

studies reporting no significant difference between the groups.27,30,31 Three observational studies reported percentages of loss of volume, with significantly higher percentages being reported for the radiotherapy group in two of these studies.44,45 Six observational studies reported revisional surgery percentages, of which two reported significantly higher percentages in the group that received radiotherapy.42,44 Meta-analysis of pooled data from observational studies (Table 5a; Figure 2) demonstrated summary measures for fat necrosis (mean 23.8% compared with 8.5%; OR 2.82, 95% CI 1.35e5.92, p Z 0.006) favouring the no radiotherapy group, but no differences for overall complications (including fat necrosis; mean 33.9% compared with 28.6%; OR 1.10, 95% CI 0.78e1.54, p Z 0.59) or revisional surgery (mean 18.3% compared with 16.1%; OR 0.65, 95% CI 0.25e1.68, p Z 0.38). There was a significantly increased prevalence of loss of volume (mean 77.5% compared with 0%; p < 0.0001) following radiotherapy, although this was informed by only two studies and therefore the pooled data may be unreliable.

Comparison of immediate autologous breast reconstruction and postoperative radiotherapy with delayed autologous breast reconstruction following post-mastectomy radiotherapy Twenty-five studies were identified, of which nine were excluded due to inability to extract the required data or insufficient patient numbers included. It should be noted that the delayed group also included patients who had undergone previous breast-conserving surgery as it was not possible to extract these from the data in several studies. Twelve were observational studies that reported outcomes of immediate compared with delayed breast reconstruction (Table 3), three were observational studies reporting other comparisons, and one was a case-series study (Table 4; Figure 1b). In 12 studies (n Z 1761 patients) outcomes of a study and comparator group that compared immediate with delayed autologous breast reconstruction were reported (Table 3), and in four studies (n Z 590 patients) only outcomes of a study group receiving delayed breast

Immediate autologous breast reconstruction

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Figure 3 Meta-analysis of pooled data from observational studies comparing patients that received immediate autologous breast reconstruction and postoperative radiotherapy with patients that received radiotherapy before delayed autologous reconstruction included in Table 3; a) Forest plot of prevalence of complications; b) Forest plot of prevalence of fat necrosis; c) Forest plot of prevalence of revisional surgery.

reconstruction were included (Table 4). Overall, therefore, 891 patients received immediate breast reconstruction followed by radiotherapy and 1460 patients that received post-mastectomy irradiation followed by delayed autologous breast reconstruction acted as a comparator group. Of the 12 observational studies comparing immediate and delayed autologous breast reconstruction, ten studies (n Z 1633 patients) reported satisfactory outcomes following post-autologous reconstruction irradiation,24,25,27,28,31,38,42,43,47,48 and two studies (n Z 128 patients) reported unsatisfactory outcomes.41,46 It was not possible to extract data from the majority of studies to determine whether differences existed between different flap types. Overall complications (including fat necrosis) were reported in nine observational studies, with one study reporting a significantly higher prevalence following immediate reconstruction and radiotherapy [Table 3].43 The prevalence of fat necrosis was reported in eight observational studies, and was significantly higher in immediate reconstruction in two studies.43,46 Aesthetic outcomes were reported in six observational studies, with two studies reporting a significantly better aesthetic outcome for delayed reconstruction following radiotherapy,28,41 and

four studies reporting no significant difference between immediate and delayed groups.24,27,31,42 Prevalence of loss of volume was reported in two studies, with both reporting significantly higher percentages following immediate reconstruction,28,46 but one of these studies reported no significant difference at late follow-up.28 The proportions that required revisional surgery were reported in five observational studies and was significantly higher in one study in the immediate group.42 Meta-analysis of pooled data from observational studies (Table 5b; Figure 3) demonstrated summary measures for revisional surgery (mean 15.1% compared with 1.4%; OR 0.15, 95% CI 0.05e0.48, p Z 0.001) favouring the delayed surgery group, but no difference in overall complications (including fat necrosis; mean 32.6% compared with 32.5%; OR 1.13, 95% CI 0.77e1.65, p Z 0.53), or fat necrosis (mean 22.2% in the immediate group compared with 14.9% in the delayed group; OR 0.63, 95% CI 0.29e1.38, p Z 0.25). Only one study41 reported loss of volume (87.5% in the immediate group compared with 0% in the delayed group; p < 0.0001), and therefore the pooled data analysis may be unreliable. A quality assessment of the observational studies was performed using STROBE guidelines (Table 6). Only two

1642 Table 1 Observational studies that compared complications and aesthetic outcomes in patients who underwent immediate autologous breast reconstruction and postoperative radiotherapy with patients that did not receive radiotherapy before or after surgery. Results for patients that received postoperative radiotherapy are reported first. Study

Level of No. pts not No. pts Radiation evidence receiving receiving dose (Gy) and DXT post-recon regimen DXT

Berry et al., 201025

3b (level B)

274

78

Lee et al., 201027

3b (level B)

371

36

Leonardi et al., 4 26 201041 (level C) Chatterjee et al., 200933 Carlson et al., 200831

3b (level B) 3b (level B)

Thomson et al., 2b 200830 (level B)

7

46

22

149 flaps

25 flaps

7

13

Flap type

Follow-up

Complications Fat necrosis

ALD; pedicled TRAM; free TRAM; DIEP NK ALD; pedicled TRAM; free TRAM; DIEP; SIEA; SGAP Up to 50.4 Gy, e no bolus

e

25.6% (cw 32.5%)

e

63.6 months (cw 56.8 months)

Early 11.1% (cw 10.5%); late 19.4% (cw 10.5%) e

45 Gy (20 fractions) NK

Median 41 months 12 months

NK

50 Gy (25 fractions) in 77%; 46 Gy (20 fractions) in 23% NK

3b (level B)

78

34

Rogers and Allen, 200244

3b (level B)

30

30

Mean 50.5 (44e61.2 Gy)

Tran et al. 200045

4 1443 (level C)

41

50.99 Gy over 5 weeks

Pedicled TRAM

Loss of volume

Aesthetic outcome

e

e

e

11.1% 5.6% (cw 11.6%)

e

e

e

e

e

e

44% (cw 34.2%)

32% (cw 14.6%)

13.6% (cw 17.4%) 12% (cw 19%)

General 75% (cw 74.1%); Aesthetic 66.7% (cw 75.7%) 47.6% good to excellent (cw 68.6%*) e

No difference e Aesthetic score 5.89 (cw 5.83); Global score 2.56 (cw 3.02) e 3.3 (cw 4.5); Cosmesis score: 4 (cw 4)

ALD

Mean 32.5 months

e

0%

Pedicled TRAM

e

50% (cw 49.5%)

23.7% Significantly e (cw 12.1%) less in control group 23.3% 16.7% 56.7% (cw 0%*) (cw 0%*) (cw 0%*)

Significantly better in control group Significantly better in control group

34% (cw 7%*)

Loss of symmetry in 78%; significantly better in control group

Mean 14 e months (cw 19.9 months) TRAM (32 free; 12 months; e 9 pedicled) mean 36 months DIEP

e

24%

78%

M.V. Schaverien et al.

Spear et al., 200542

DIEP

e

Revisional surgery

DXT Z radiotherapy; Gy Z gray; NK Z not known; ALD Z autologous latissimus dorsi; TRAM Z transverse rectus abdominis musculocutaneous; DIEP Z deep inferior epigastric artery perforator; SIEA Z superficial inferior epigastric artery; SGAP Z superior gluteal artery perforator. *p < 0.05.

Williams et al., 199747

4 57 (level C)

19

50.3 Gy with 10e20 Gy boost in 4 patients (only known in 13 pts)

Pedicled TRAM

Mean 47.6 months

31.5% (cw 17.1%)

15.8% (cw 10%*)

e

e

e

Immediate autologous breast reconstruction

1643 prospective observational studies met the inclusion criteria,30,48 and none of the observational studies satisfied all of the criteria for reporting of observational studies.

Discussion This systematic review has found that the majority of studies that investigated complications and aesthetic outcomes in immediate autologous breast reconstruction without implant followed by postoperative adjuvant radiotherapy reported satisfactory outcomes. Pooled data analysis of observational studies revealed no significant difference in the prevalence of overall complications (including fat necrosis) for immediate autologous breast reconstruction with and without postoperative radiotherapy, but a significantly higher mean prevalence of fat necrosis in the radiotherapy group (OR 2.82, p Z 0.006). The more clinically relevant analysis of immediate reconstruction and postoperative radiotherapy compared with delayed reconstruction following mastectomy and radiotherapy, the two most common treatment algorithms for patients requiring post-mastectomy radiotherapy, found that the majority of observational studies reported satisfactory outcomes in the immediate reconstruction group. Pooled data analysis from observational studies revealed no significant differences in the mean prevalence of overall complications (including fat necrosis) and fat necrosis (OR 0.63, p Z 0.25) between the groups, but a significantly higher prevalence of revisional surgery (OR 0.15, p Z 0.001) in the immediate reconstruction group. Previous reviews and a meta-analysis with the most recent search date of 1st January 2010 have failed to reach agreement regarding outcomes of immediate autologous breast reconstruction followed by adjuvant radiotherapy.53e58 The meta-analysis found that there was no significant difference in outcome for autologous breast reconstruction in combination with radiotherapy regardless of sequencing (OR 0.87; CI 0.47e1.62), supporting the findings of this study.57 This review did not include the proportion requiring anastomotic revision in the complications analysis as it was not reported in the majority of studies, although the prevalence would be expected to be higher in the delayed compared with the immediate group.51,52 From both comparison groups of pooled data the mean prevalence of fat necrosis in immediate autologous reconstruction with post-reconstruction radiotherapy was between approximately 22.2e23.8%, compared with approximately 14.9% in those receiving that received radiotherapy and delayed reconstruction although this difference was not significantly different, and this remains one of the most prominent findings of this analysis. The actual increased risk of fat necrosis for women having immediate reconstruction with postoperative radiotherapy is therefore only approximately 7.3e8.9% [RR 1.47e1.60] when the clinically relevant comparison is made with those having delayed reconstruction after radiotherapy. The higher percentages of revisional surgery in the immediate compared with the delayed setting may be related more to the timing of surgery than radiotherapy, as the percentages that required revisional

Radiation dose (Gy) Level of No. pts and regimen evidence receiving post-recon DXT

Flap type

Follow-up

Adesiyun et al., 201124

3b (level B)

35

50.4 (45e50.4); bolus in 79%

Albino et al., 201026

4 (level C)

76

Mckeown et al., 200928

4 (level C)

13

50.23 (46.8e58.6; 1.8 Gy fractions); 28 Gy boost in 15% 50 (2 Gy fractions)

Pedicled TRAM; DIEP; SGAP; MS-TRAM Free TRAM; Gracilis; SGAP; DIEP; SIEA ALD

Jhaveri et al., 200829

4 (level C)

23

Wong et al. 200832

2b (level B)

47

Gill et al., 200443 Halyard et al., 200434

4 (level C) 4 (level C)

454 flaps

Mehta and Goffinet, 200435 Soong et al., 200436

4 (level C)

22

4 (level C)

25

Anderson et al., 200337

4 (level C)

35

Chawla et al., 200238

4 (level C)

14

15

Complications

Fat necrosis

Revisional Loss of surgery volume

Aesthetic outcome

Median 63.6 Early 8.3%; months late 17.1%

11%

e

e

General 75%; Aesthetic 67%

e

70%

12%

47%

e

e

51 months

e

15.4%

15.4%

Cosmetic score 2.9/5 (3.6/5 at late follow-up) 82.6% acceptable

50.4 in 1.8 Gy fractions with boost of 10e16 Gy in 2 Gy fractions in 17 patients 50.4 Gy (45e54 Gy) with boost of 6 Gy (4e16 Gy) in 5%; bolus in 45% NK

e

Median 38 months

8.7%

e

e

Score 2.9/5 (3.7/5 at late follow-up) e

Pedicled TRAM; ALD

Median 13 months

38%

e

9%

e

e

DIEP

60 Gy (50.4e60.6 Gy; 2 Gy fractions) with 10 Gy boost (9.6e12 Gy) in 14 pts; bolus in 13% 50.4 (1.8 Gy fractions)

Pedicled and free TRAM

Mean 13.2 Significant months increase Median 26.4 months

Pedicled TRAM

Median 18 months

50 Gy (2 Gy fractions); bolus in 16 pts 50e50.4 with boost of 10 Gy in 4 pts; bolus in all 50 (40e54; 1.8e2 Gy fractions); boost of 14 Gy (6e26 Gy) in 44%

TRAM; ALD

Significant e increase 13% 13%

e

e

13%

87% good or excellent

e

e

None

e

e

Mean 44.4 months

0%

e

e

e

85% good to excellent

TRAM

Median 28 months

27% (minor 17.1% complications)

0%

e

90% excellent/ good

TRAM

Median 37 months

e

0%

e

e

e

M.V. Schaverien et al.

Study

1644

Table 2 Studies that reported complications and aesthetic outcomes in patients that underwent immediate autologous breast reconstruction with postoperative radiotherapy.

e 49.5 (45e50.4) with 16 free and 3 10e15 Gy boost in 8 pts pedicled TRAM flaps 19 4 (level C) Hunt et al., 199740

53 Gy; 10e16 Gy boost in 6 pts 21

DXT Z radiotherapy; Gy Z gray; NK Z not known; ALD Z autologous latissimus dorsi; TRAM Z transverse rectus abdominis musculocutaneous; DIEP Z deep inferior epigastric artery perforator; SIEA Z superficial inferior epigastric artery; SGAP Z superior gluteal artery perforator.

84e94% excellent/ good 11% 0% 11%

90% excellent/ good e

50 Gy 32

Free TRAM

Mean 19 months

No flap necrosis or loss e

e

e

e 87.5% 28% 43.8% e

NK

3b (level B) 4 (level C) 4 (level C) Alderman et al., 200248 Tran et al., 200146 Zimmerman et al., 199839

144

Free TRAM; Pedicled TRAM Free TRAM

24 months

No significant association e

e

e

e

e

Immediate autologous breast reconstruction

1645 surgery in the immediate reconstruction with postoperative radiotherapy group and no radiotherapy groups are similar (mean 14.3% cw 16.1% respectively). This would suggest that it is the immediate surgery setting that is the greater influence for revision surgery and not the radiotherapy. Aesthetic outcome was evaluated in six of nine observational studies comparing immediate with delayed breast reconstruction and radiotherapy, and two studies reported a significantly better aesthetic outcome for the delayed group, with four studies reporting no significant differences. It is therefore apparent that where adjuvant radiotherapy is required, sequencing does not appear to be a significant determinant of the aesthetic outcome for the majority of patients. There was considerable heterogeneity regarding the methods used for evaluation of cosmetic outcome, and future studies should include validated cosmetic outcome tools and Patient Reported Outcome Measures (PROMs). This review has found that if the radiotherapy dose was reported, which it was not in 14 of the 41 studies included, there were significant variations in the radiotherapy treatment variables between the studies and within the same study, including dose, delivery, and indications for radiotherapy (Tables 1 and 2). These treatment variables included fraction size, fractionation schedule, use of a boost, total dose delivered to the chest wall, use of a bolus to increase the skin dose, homogeneity of the dose delivery to target and non-target tissues, and the photon or electron beam energy used. Where the studies reported the total radiotherapy dose delivered, this varied from 45 to 86.6 Gy, with many studies varying from the historical international standard radiotherapy schedule of 50 Gy in 25 fractions of two Gray over five weeks. Recent randomised trials have demonstrated equivalent tumour control but fewer adverse effects using 40 Gy in 15 fractions over three weeks and this regimen has now been adopted in many centres for postreconstruction radiotherapy.59,60 Standardisation of chest wall radiotherapy treatment variables as well advances in 3D CT planning to reduce dose inhomogeneity are anticipated to further improve the better outcomes that are already being achieved in contemporary practice.61e63 Although not evaluated in this review, studies support that autologous reconstruction in the face of postoperative radiotherapy leads to better outcomes when compared with implant-based reconstructions,27,29,32,37,38,64 even in conjunction with an LD flap.27,30,64 A combined strategy may also be employed using a tissue expander to maintain the skin envelope prior to a delayed-immediate autologous reconstruction.65 Although this technique risks tissue expander loss and requires essentially delayed reconstruction, it does offer an option to avoid radiotherapy to the flap. The studies included in this review do not allow definite conclusions to be drawn as to whether the effects of radiotherapy differ depending on the type of flap, including composition of muscle and adipose tissue, and vascular perfusion.40 Until better evidence is available it would seem prudent to advocate consideration of maximal vigilance in the choice of flap vascular supply and flap planning in the immediate reconstruction setting where radiotherapy is anticipated.

1646 Table 3 Observational studies that compared complications and aesthetic outcomes in patients who underwent immediate autologous breast reconstruction followed by postoperative radiotherapy with patients that received radiotherapy before delayed autologous breast reconstruction. Results for the patients that received postoperative radiotherapy are reported first. Study

Level of No. pts evidence receiving pre- recon DXT

Radiation dose No. pts receiving (Gy) and post-recon regimen DXT

Flap type

Follow-up

Complications Fat necrosis Revisional surgery

Loss of volume

Aesthetic outcome

General 75% (cw 81%); aesthetic 67% (cw 59%) e

11% e (cw 16%; not significant)

e

e

e

e

11.1% (cw 11.6%)

5.6% (cw 0%)

e

NK

Pedicled TRAM

At least 12 months

44% (cw 33.3%)

32% (cw 13.3%)

3b 38 patients 34 patients NK Spear et al., 200542 (level B) (42 flaps) (38 flaps)

Pedicled TRAM

e

50% (cw 57.1%)

23.7% (cw 23.8%)

Gill et al., 200443

DIEP

Mean 13.2 months

Significant increase for post-recon DXT

Significant increase for post-recon DXT

35

3b 101 Berry et al., 201025 (level B)

78

Lee et al., 201027

36

3b 43 (level B)

4 19 Leonardi et al., 201041 (level C)

7

4 11 Mckeown et al., 200928 (level C)

13

Carlson 3b 15 flaps et al., 200831 (level B)

25 flaps

4 304 flaps (level C)

454 flaps

NK

e

15.4% (cw 9.1%)

General 75% (cw 74.1%); aesthetic 66.7% (cw 59.3%) e e 47.6% good to excellent (cw 69.4%*) 15.4% Volume Cosmetic (cw 18.2%) 2.9/5 score 2.9/5 (cw 3.9/5*); (cw 3.8/5); 3.7/5 at 3.6/5 at late FU late FU (cw 4.2/5) (cw 4.2/5*) 12% (cw 0%) e Aesthetic score 5.89 (cw 6.1); Global score 2.56 (cw 2.32) Significantly e Mean 2.76 less in DXT (cw 3.27); first group no significant difference e e e

M.V. Schaverien et al.

50.4 (45e50.4 Gy); Pedicled Median 63.6 Early 8.3% bolus in 79% TRAM; DIEP; months (cw (cw 20.9%); SGAP; MS-TRAM 28.3 months) late 17.1% (cw 11.6%); not significant NK ALD; pedicled e 25.6% TRAM; free (cw 30.7%) TRAM; DIEP NK ALD; pedicled 63.6 months Early 11.1% TRAM; free (cw 28.3 (cw 20.9%); TRAM; DIEP; months) late 19.4% SIEA; SGAP (cw 11.6%) Up to 50.4, no e e e bolus (cw 50 Gy with 10 Gy boost) 50 Gy (2 Gy ALD Mean 51 e fractions) months (cw mean 44.5)

Adesiyun 3b 43 et al., 201124 (level B)

Alderman et al., 200248 Tran et al., 200146 Williams et al., 199747

3b 102 (level B) 4 70 (level C) 4 108 (level C)

14

144 32 19

50 Gy (40e54 Gy; TRAM 1.8e2 Gy fractions) with boost of 14 Gy (6e26 Gy) in 44% NK Free TRAM; pedicled TRAM 50 Gy (cw 51 Gy) Free TRAM

Median 37 months

No significant e difference

e

e

e

24 months

e

e

e

Mean 47.6 months

28% (cw 0%) e

87.5% (cw 0%*) e

e

50.3 Gy with boost Pedicled of 10e20 Gy in 4 TRAM pts (dose only known in 13 pts)

No significant e association e 43.8% (cw 8.6%*) 31.5% 15.8% (cw 25%) (cw 17.6%)

e

e

DXT Z radiotherapy; Gy Z gray; NK Z not known; ALD Z autologous latissimus dorsi; TRAM Z transverse rectus abdominis musculocutaneous; DIEP Z deep inferior epigastric artery perforator; SIEA Z superficial inferior epigastric artery; SGAP Z superior gluteal artery perforator. *p < 0.05.

Table 4

Immediate autologous breast reconstruction

Chawla 4 16 et al., 200238 (level C)

Studies that reported complications and aesthetic outcomes in patients that received radiotherapy before autologous breast reconstruction.

Study

Level of evidence

No. patients receiving prereconstruction radiotherapy

Radiation dose (Gy) and regimen

Flap type

Follow-up

Complications

Fat necrosis

Revisional surgery

Loss of volume

Aesthetic outcome

Levine et al., 201249

3b (level B)

75

NK

e

28%

e

e

e

e

Momoh et al., 201250

3b (level B)

100

NK

Mean 33.3 months

36%

12%

e

e

e

Fosnot et al., 201151 Baumann et al., 201152

3b (level B) 3b (level B)

226 flaps 189

NK Median 60 Gy

MS-TRAM; pedicled TRAM; DIEP; supercharged pedicled TRAM; SIEA DIEP; free TRAM; pedicled TRAM; SGAP; ALD Free TRAM; DIEP; SIEA MS-TRAM; DIEP; SIEA

e e

e e

e e

Mean 11.3 months

40.3% 26%

8% 7.9%

Gy Z gray; NK Z not known; ALD Z autologous latissimus dorsi; TRAM Z transverse rectus abdominis musculocutaneous; DIEP Z deep inferior epigastric artery perforator; SGAP Z superior gluteal artery perforator.

1647

1648

M.V. Schaverien et al.

Table 5 a) Analysis of pooled data from observational studies comparing patients that received immediate autologous breast reconstructions and postoperative radiotherapy with patients that did not receive radiotherapy before or after surgery; b) Analysis of pooled data from observational studies comparing patients that received immediate autologous breast reconstructions and postoperative radiotherapy with patients that received post-mastectomy radiotherapy and delayed breast reconstruction (*p < 0.05). Pooled results

Complications

Fat necrosis

Revisional surgery

Loss of volume

a) Comparison of patients that received immediate autologous breast reconstructions and postoperative radiotherapy with patients that did not receive radiotherapy before or after surgery Control patients (percentage; mean, range) 28.6% (17.1e49.5%) 8.5% (0e14.6%) 16.1% (0e19%) 0% Patients that received postoperative 33.9% (25.6e50%) 23.8% (11.1e34%) 14.3% (12e16.7%) 77.5% (56.7e78%) radiotherapy (percentage; mean, range) Chi2 5.16 (4 df) 12.63 (5 df) 0.06 (1 df) e p-Value p Z 0.59 p < 0.00001* p Z 0.38 p < 0.0001* Odds ratio (95% confidence interval) 1.10 (0.78e1.54) 2.97 (1.97e4.47) 0.65 (0.25e1.68) not estimable b) Comparison of patients that received immediate autologous breast reconstructions and postoperative radiotherapy with patients that received post-mastectomy radiotherapy and delayed breast reconstruction Patients that received postoperative 32.6% (25.4e50) 22.2% (11e43.8) 15.1% (5.6e28) 87.5% radiotherapy (percentage; mean, range) Patients that received preoperative 32.5% (25e57.1) 14.9% (8.6e23.8) 1.4% (0e18.2) 0% radiotherapy (percentage; mean, range) 1.89 (5 df) 13.08 (6 df) 5.79 (3 df) e Chi2 p-Value 0.53 0.04* 0.001* p < 0.0001* Odds ratio (95% confidence interval) 1.13 (0.77e1.65) 0.60 (0.37e0.97) 0.15 (0.05e0.48) not estimable

The findings of this pooled data analysis are limited by the lack of high quality data found for inclusion. No randomised-controlled trials met the inclusion criteria and all of the observational studies included were missing

Table 6 Study

more than one component for reporting of observational studies (Table 6). The majority of the studies involved small numbers of patients in single centres with retrospective analysis and variable follow-up periods, and in

Observational studies quality assessment using STROBE studies in Epidemiology guidelines for observational studies. Design

A

No radiotherapy versus post-reconstruction radiotherapy Berry et al., 201025 Retrospective Y Retrospective Y Lee et al., 201027 Leonardi et al., 201041 Retrospective Y Chatterjee et al., 200933 Retrospective Y Carlson et al., 200831 Retrospective N Prospective Y Thomson et al., 200830 Spear et al., 200542 Retrospective Y Rogers and Allen, 200244 Retrospective N Retrospective Y Tran et al. 200045 Williams et al., 199747 Retrospective Y Immediate versus delayed breast reconstruction Retrospective Y Adesiyun et al., 201124 Mckeown et al., 200928 Retrospective Y Chawla et al., 200238 Retrospective Y Prospective Y Alderman et al., 200248 Tran et al., 200146 Retrospective Y Levine et al., 201249 Retrospective Y Momoh et al., 201250 Retrospective Y Retrospective Y Fosnot et al., 201151 Baumann et al., 201152 Retrospective Y

B

C

D

E

F

G

H

I

N Y P Y P Y Y Y Y Y

Y Y N N Y Y N Y N N

P P P Y P Y Y Y P P

N N N Y N N N N N N

N N N Y N Y N Y N N

Y Y Y Y Y Y Y N Y Y

N N N N N N N N N N

P Y N P N Y N Y Y Y

Y Y Y Y Y Y Y Y Y

N Y N Y N Y Y N Y

P P P Y P P Y P P

N N N N N N N N N

N N N Y N N N Y N

Y Y Y Y Y Y Y Y Y

N N N N N N N N N

Y N Y Y N N Y P Y

A. Objectives and pre-specified hypothesis in the introduction; B. Eligibility criteria of cohort in methods; C. Methods for recruitment of participant; D. Mention of outcomes, exposure, and confounder; E. Study size calculated; F. Potential biases addressed; G. Statistical methods described; H. Mention of how missing data was handled; I. Limitation of the study and the generalisations mentioned; Y, Yes; N, No; P, Partially.

Immediate autologous breast reconstruction addition there was considerable heterogeneity in the types of flaps included, as well as the outcome measures and definitions used. It is therefore clear that the research evidence available to women and their surgeons to help them make an informed choice when considering immediate reconstruction in the face of post-mastectomy radiotherapy is generally of poor quality. High quality multicenter prospective studies with adequate follow-up periods and standardised radiotherapy protocols are therefore warranted to better inform decision making in this setting. The clinical dilemma is a balance between the following: delaying reconstruction and performing it after radiotherapy with the incumbent issues of operating on an irradiated chest wall with an additional technical risk for microvascular surgery, and compensating for significant skin loss; or performing immediate reconstruction with its increased need for revisional surgery. The assessment of the net outcome may be influenced by the ability to offer reconstructive options that can reasonably be expected to mitigate the effects of radiotherapy or deal with the consequences of it. Other options, including fat grafting, are beyond the scope of this review.66 Until better data is available, the findings of this comprehensive systematic review of the available literature suggests that where adjuvant chest wall radiotherapy is expected, immediate autologous breast reconstruction should be considered. This review has not taken into account PROMs for the different pathways of care involved in this setting, and good quality research is required to enable us to better inform patients with regards this important outcome.

Conclusions This systematic review has found that the majority of published studies reported satisfactory outcomes for immediate autologous breast reconstruction with adjuvant radiotherapy, and pooled data analysis demonstrated a similar prevalence of complications in this group when compared with immediate reconstruction without radiotherapy or delayed reconstruction following radiotherapy; the proportion that required revisional surgery was higher though for immediate than delayed breast reconstruction. These findings, however, are limited by the paucity of good quality studies informing them, the variation in the radiotherapy doses and regimens used, and the lack of good quality of life outcome reporting. Prospective multicenter trials with standardised radiotherapy regimens are necessary to better inform breast reconstruction algorithms where chest wall radiotherapy is required. Until better data is available, this study suggests that patients and their surgeons should at least consider immediate autologous reconstruction when post-mastectomy radiotherapy is anticipated.

Conflict of interest None.

1649

Funding None.

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