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Implant–Based Breast Reconstruction and Postmastectomy Radiation for Breast Cancer
Practical Radiation Oncology (2019) xx, e1-e9
www.practicalradonc.org
Clinical Investigation
Long-Term Outcomes After Autologous or Tissue Expander/ImplanteBased Breast Reconstruction and Postmastectomy Radiation for Breast Cancer Bindu V. Manyam MD a, Chirag Shah MD a,*, Neil M. Woody MD a, Chandana A. Reddy MS a, Michael A. Weller MD a, Aditya Juloori MD a, Mihir Naik DO a, Stephanie Valente DO b, Stephen Grobmyer MD b, Paul Durand MD c, Risal Djohan MD c, Rahul D. Tendulkar MD a a
Taussig Cancer Institute, Department of Radiation Oncology, Cleveland Clinic; bBreast Services, Department of Breast Surgery, Cleveland Clinic; and cDermatology and Plastic Surgery Institute, Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio
Received 11 March 2019; revised 7 June 2019; accepted 11 June 2019
Abstract Purpose: The toxicity profile of breast reconstruction with postmastectomy radiation therapy (PMRT) varies by technique and timing, and long-term data are limited. We compared rates of complications requiring reoperation (CRR) and reconstruction failure (RF) between immediate autologous reconstruction (I-AR), immediate tissue expander/implant reconstruction (I-TE/I), delayed autologous reconstruction (D-AR), and delayed tissue expander/implant reconstruction (D-TE/I) in patients receiving PMRT. Methods and Materials: Patients who received autologous reconstruction (AR) or tissue expander/ implant reconstruction (TE/I) and PMRT between 2000 to 2008 were included. Reconstruction was immediate if performed on the same day as mastectomy followed by PMRT (I-AR or I-TE/I) or delayed if after PMRT (D-AR and D-TE/I). CRR was defined as an unplanned return to the operating room for infection, dehiscence, necrosis, hematoma, or hernia (with AR) and extrusion, leak, or contracture (with TE/I). RF was defined as unplanned conversion to another reconstruction technique or to flat chest wall. Cumulative incidence of CRR and RF was calculated using KaplaneMeier and compared using the logrank test. Logistic regression was used to identify variables associated with CRR and RF. Results: Two hundred four patients were included. Median follow-up was 8 years. There were 127 AR cases (63%) and 77 TE/I cases (38%). At 5 years, CRR was 18%, 38%, 34%, and 70% (P Z .010) and RF was 4%, 22%, 7%, and 56% (P < .0001) for I-AR, I-TE/I, D-AR, and D-TE/I, respectively. On multivariate analysis, TE/I (hazard ratio [HR] 2.0; P Z .011), body mass index 30 (HR 3.9; P Z .002), and smoking (HR 2.7; P Z .001) were significant predictors for CRR, and TE/I (HR 6.6; P < .0001), diabetes (HR 4.1; P Z .044), and hypertension (HR 3.5; P Z .005) were significant for RF. When excluding RF because of infection, the rate of RF was not significantly different among the 4 groups (P Z .23). Sources of support: This work had no specific funding. Disclosures: Dr Shah is a consultant for Impedimed, Grants Varian Medical Systems, and VisionRT. * Corresponding author. E-mail address: [email protected] (C. Shah). https://doi.org/10.1016/j.prro.2019.06.008 1879-8500/Ó 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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Conclusions: With PMRT, TE/I reconstruction in the immediate and delayed setting is associated with higher CRR and RF compared with AR. Patient factors should guide selection of technique. Efforts to reduce rates of RF with TE/I should focus on minimizing risks for infection. Ó 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction Approximately 50% of women who undergo mastectomy for breast cancer pursue breast reconstruction.1 Postmastectomy radiation therapy (PMRT) is recommended for appropriately selected patients with stage II and III breast cancer because randomized trials have demonstrated a locoregional control, disease-free survival, and overall survival benefit.2 Additionally, trends in breast reconstruction in conjunction with PMRT are changing, with an increase in the frequency of immediate reconstruction among patients receiving PMRT.3 Though significantly improved health-related quality of life (HRQOL) is associated with breast reconstruction after mastectomy, reconstruction in conjunction with PMRT is associated with higher rates of complications and reconstruction failures compared with patients who do not undergo radiation therapy (RT).4-7 The optimal approach for reconstruction in patients requiring PMRT remains uncertain, and practice patterns are highly variable. This is in part because toxicity profiles differ by technique and timing, and long-term data are limited. Currently, tissue expander/implantebased reconstruction (TE/I) is the most commonly used technique.8 However, data suggest that autologous reconstruction (AR) may be associated with decreased rates of complications and need for additional procedures in patients requiring RT, though this comes at the expense of a different toxicity profile, increased operative time, and potentially increased cost up-front.5,9 The optimal timing of reconstruction also presents a challenge because immediate reconstruction may be associated with better HRQOL but may also compromise the planning and delivery of PMRT.10,11 The current study is an effort to compare rates of complications requiring reoperation (CRR) and reconstruction failure (RF) between immediate AR (IAR), immediate TE/I reconstruction (I-TE/I), delayed AR (D-AR), and delayed TE/I (D-TE/I) in patients who received PMRT.
Materials and Methods Patients who received mastectomy, AR or TE/I, and PMRT for breast cancer between 2000 to 2008 were identified in an institutional review boardeapproved database. This period was selected to allow for 10 years
of potential follow-up time for all patients. Patients were excluded if they received prior breast conservation therapy (lumpectomy and whole-breast RT) and subsequent mastectomy and reconstruction for recurrence, reirradiation for recurrence, mantle field RT for lymphoma, or combined TE/I and AR. Immediate reconstruction was defined as AR or TE/I on the same day as mastectomy (IAR or I-TE/I), followed by PMRT. Delayed reconstruction was defined as mastectomy followed by PMRT to a flat chest wall, with AR or TE/I at a later date. AR included transverse rectus abdominis (TRAM) flap, deep inferior epigastric perforator (DIEP) flap, or latissimus dorsi flap. Our reconstruction techniques have been previously published.6 All surgery for patients in this data set was performed at a single tertiary-care comprehensive cancer center by breast oncologic surgeons and plastic surgeons specializing in breast reconstruction, with a yearly volume of 400 to 450 breast reconstructions. Patients received neoadjuvant or adjuvant chemotherapy at the discretion of the treating oncologist. Recommendation for PMRT was made based on clinical staging or after surgery based on final pathologic staging. Patients underwent 2-dimensional fluoroscopybased planning or 3-dimensional conformal RT with computed tomographyebased planning, depending on the technology available at the time of treatment. Patients were treated to the chest wall regional lymph nodes as clinically indicated. The dose and fractionation of PMRT was at the discretion of the treating radiation oncologist and ranged from 48.6 to 50.4 Gy at 1.8 to 2.0 Gy per fraction. Radiation was delivered at the same institution as surgery or at an outside facility. CRR was defined as an unplanned return to the operating room because of wound infection, dehiscence, necrosis (skin or flap), or hematoma at the donor site or breast for AR and at the breast for TE/I. For those patients who underwent TRAM flap reconstruction, hernia was considered a CRR. For those patients who underwent TE/ I, implant extrusion, leak, or capsular contracture were also considered CRR. Capsular contracture was graded according to the Baker system at the time of follow-up by the surgeon.12 Reoperations for anticipated cosmetic procedures such as nipple reconstruction, trimming, or excision of redundant skin (“dog ear” deformity) were not coded as CRR. RF was defined as an unplanned conversion to another reconstruction technique or to a flat chest wall and could be due to the aforementioned complications or significant volume loss. RF not because of
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infection was separately recorded. Patients who underwent upfront tissue expander placement with planned delayed exchange to permanent implant were not coded as a CRR or an RF. In patients who underwent immediate reconstruction, CRR and RF could have occurred either before or after PMRT. In patients who underwent delayed reconstruction, CRR and RF was only recorded after completion of both PMRT and reconstruction.
and RF. Logistic regression analysis was used to identify variables associated with CRR and RF. Cumulative incidence of CRR and RF was calculated using the KaplaneMeier method and compared using the log-rank test. A P value .05 was considered statistically significant. SAS version 9.4 was used for statistical analysis.
Statistical methods
A total of 204 patients were included in this analysis. There were 127 AR cases (63%) and 77 TE/I cases (38%). Median follow-up was 8 years after reconstruction. Patient and treatment characteristics are presented in Table 1. The median age of the cohort was 47.5 years (range, 21-78), median body mass index (BMI) was 25.5 (18.4-42.6), and median RT dose was 50 Gy. Rates of diabetes, hypertension, and active smoking (defined as current or quit within last 10 years) were similar between
Patient demographics and crude rates of complications were reported as a median range or percentage of patients and were compared between the 2 groups using Fisher’s exact test for categorical variables and unpaired t test for continuous variables. Time intervals were calculated from the date of tissue expander placement in the case of TE/I and the date of AR for determination of the rate of CRR
Table 1
Results
Patient, radiation, and surgical characteristics
Age at reconstruction Follow-up post reconstruction, mo Radiation dose Fractions Race Caucasian African American Other BMI 25 25.1-30.0 30.1 Postmenopausal Diabetes Hypertension Smoking Timing of Reconstruction Immediate Delayed Bilateral Reconstruction Chemotherapy None Neoadjuvant Adjuvant Both Type of autologous Reconstruction TRAM LDF DIEP
All patients (n Z 204)
Autologous (n Z 127)
Tissue expander/implant (n Z 77)
Median
Range
Median
Range
Median
Range
P value
48 96 50 25
21-78 3-181 48.6-50.4 25-28
45 84 50 25
21-65 3-181 48.6-50.4 25-28
48 97 50 25
27-78 3-177 48.6-50.4 25-28
.22 .58 .77 .11
Count
Percent
Count
Percent
Count
Percent
179 16 6
89.1 8.0 3
113 10 1
91.1 8.1 0.8
66 6 5
85.7 7.8 6.5
88 62 34 88 5 35 51
47.8 33.7 18.5 43.1 2.5 17.2 25.1
48 39 21 55 1 20 30
44.4 36.1 19.4 43.3 0.8 15.7 23.8
40 23 13 33 4 15 21
52.6 30.3 17.1 42.9 5.2 19.5 27.3
159 45 4
77.9 22.1 2.0
90 37 1
70.9 29.1 0.8
69 8 3
89.6 10.4 3.9
11 33 119 41
5.4 16.2 58.3 20.1
8 19 67 33
6.2 15.0 52.8 26.0
3 14 52 8
3.9 18.2 67.5 10.4
-
-
106 5 16
83.5 3.6 12.6
-
-
.08
.58
.99 .07 .57 .62 .002
.15 .10
Abbreviations: BMI Z body mass index; DIEP Z deep inferior epigastric perforator; LDF Z latissimus dorsi flap; TRAM Z transverse rectus abdominis.
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AR and TE/I. Neoadjuvant chemotherapy, adjuvant chemotherapy, or both were administered to 16%, 58%, and 20%, respectively, and 5% of patients received no chemotherapy. TRAM was the most common type of AR (83.5%). Immediate reconstruction was the most common reconstruction timing strategy and was performed in 159 patients (78%) overall. Of the patients who received AR, 90 (71%) underwent immediate reconstruction, and of the patients who received TE/I, 69 (90%) underwent immediate reconstruction. For patients who received immediate reconstruction, there was no significant difference in median months between reconstruction and start of PMRT for AR and TE/I (5.3 vs 5.6 months, respectively; P Z .54). For patients who received a delayed reconstruction, there was no significant difference in median time between the start of PMRT and reconstruction for AR and TE/I (11.6 months vs 4.8 months, respectively; P Z .12; Table 2). Crude rates of wound toxicity by reconstruction technique and timing are presented in Table 3. The rate of skin/flap necrosis was 10.0% and 10.8% and the rate of fat necrosis was 24.4% and 16.2% for I-AR and D-AR, respectively. Rates of wound infection requiring intravenous (IV) antibiotics and wound dehiscence were similar between AR and TE/I. In the delayed setting, 2 patients in the AR group and 1 patient in the TE/I group had wound infection requiring IV antibiotics. All patients who experienced wound infection requiring IV antibiotics received chemotherapy. The most common complications specific to TE/I were Baker grade 3 or 4 capsular contracture (24.6%) in the immediate setting and implant removal because of infection (37.5%) in the delayed setting.12 The most common complications requiring reoperation in the immediate setting were skin/flap necrosis for AR and implant removal because of infection for TE/I; in the delayed setting, they were skin/flap necrosis for AR and implant extrusion for TE/I. RF was significantly higher for TE/I compared with AR in both the immediate and delayed settings. On multivariate analysis, TE/I (hazard ratio [HR], 2.0; 95% CI, 1.18-3.44; P Z .011), BMI 30 (HR, 3.4; 95% CI, 1.56-6.54; P Z .002), and smoking (HR, 2.7; 95% CI, 1.49-4.24; P Z .001) were significant predictors for CRR, and TE/I (HR, 6.6; 95% CI, 2.66-16.39; P < .0001), diabetes (HR, 4.1; 95% CI, 1.04-15.87; P Z .044), and hypertension
Table 2
(HR, 3.5; 95% CI, 1.47-8.20; P Z .005) were significant predictors for RF (Table 4). Cumulative incidence of rates of CRR and RF are presented in Figures 1 and 2 by reconstruction technique and timing. Rates of RF excluding RF because of infections are presented in Figure 3. In the immediate setting, the overall rate of CRR was 20.0% versus 39.1% (P Z .007) for AR and TE/I, respectively (Table 3). In the immediate reconstruction setting, the majority of complications that required a return to the operating room occurred immediately postoperatively or during adjuvant chemotherapy, before the completion of PMRT. For patients who underwent delayed reconstruction, all CRR occurred after completion of PMRT. In the immediate setting, when evaluating the rate of CRR that occurred only after the completion of PMRT, AR continued to have significantly lower rates than TE/I (7.8% vs 24.6%, respectively; P Z .004; Table 3).
Discussion In patients undergoing PMRT, we identified rates of CRR and RF as significantly lower with AR compared with TE/I at median follow-up of 8 years, with I-AR demonstrating the lowest rate of CRR. Reconstruction timing was not a significant predictor for toxicity on multivariate analysis, but TE/I reconstruction technique was the factor most strongly associated with complications. Additionally, we identified that when omitting infection as a cause of RF, there was no significant difference in RF by reconstruction technique and timing, underscoring the importance of reducing the risk for infection to maximize reconstruction success. The findings of this study contribute to a growing body of literature that suggests that irradiation of autologous flaps is safe. Our findings are consistent with previous analyses, including a meta-analysis, that have identified increased rates of complications with TE/I compared with AR in irradiated patients.6,9,13,14 A meta-analysis of 4 studies by Barry et al demonstrated less morbidity with AR than with TE/I (odds ratio [OR], 0.2; 95% CI, 0.11-0.39), and a prospective study of 2247 patients demonstrated that the addition of PMRT significantly increased complication rates at 2 years inirradiated patients with TE/I (OR, 2.64;
Median months between radiation therapy and reconstruction by reconstruction technique
Immediate reconstruction Mastectomy/reconstruction / PMRT (n Z 159)
Delayed reconstruction Mastectomy þ PMRT / reconstruction (n Z 45)
All patients (n Z 159)
Autologous (n Z 90)
Tissue expander/ implant (n Z 69)
P value
All Patients (n Z 45)
Autologous (n Z 37)
Tissue expander/ implant (n Z 8)
P value
5.4
5.3
5.6
.54
10.5
11.6
4.8
.12
Abbreviation: PMRT Z postmastectomy radiation therapy.
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Rates of wound toxicity by reconstruction technique
Wound infection Requiring IV antibiotics Wound dehiscence Skin/flap necrosis Fat necrosis Implant removed for infection* Capsular contracture* Baker grade 3 Baker grade 4 Implant extrusion* Implant leak* Overall rate of CRR Return to OR for donor site complication Return to OR for breast complication CRR occurred after completion of PMRTy Overall rate of RF Conversion to flat chest wall Conversion to AR Conversion to TE/I RF occurred after completion of PMRTz
Immediate reconstruction (n Z 159)
Delayed reconstruction (n Z 45)
AR % (n Z 90)
P value
AR % (n Z 37)
6 7 9 22 -
18 7 11 7 4 0 2 2 4
TE/I % (n Z 69)
6.7 7.8 10.0 24.4 -
5 11 1 0 13 17 12 5 10 1 20.0 27
7.2 15.9 1.4 0.0 18.5 24.6 17.4 7.2 14.5 1.4 39.1
.99 .13 .81 -
2 3 4 6 -
.007x
12
7.8 12.2 7.8 4.4
24.6 24.6
.004x .0003x
6 6 2 0 0 2 -
4.4
17 17 10 7 0 14
20.2 .003x
TE/I % (n Z 8)
5.4 8.1 10.8 16.2 -
P value .45x .21 -
1 2 0 0 3 1 1 0 3 0 32.4 5
12.5 25.0 0.0 0.0 37.5 12.5 12.5 0.0 37.5 0.0 62.5
16.2 16.2 5.4
50.0 .006x
-
4 2 2 0 -
-
.16
-
Abbreviations: AR Z autologous reconstruction; CRR Z complications requiring reoperation; IV Z intravenous; OR Z operating room; PMRT Z postmastectomy radiation therapy; RF Z reconstruction failure; TE/I Z tissue expander and implant reconstruction. * TE/I only. y Some CRR occurred before the completion of PMRT in patients who underwent immediate reconstruction. z Some RF occurred before the completion of PMRT in patients who underwent immediate reconstruction. x Statistically significant.
P < .001), whereas the addition of PMRT did not significantly increase complication rates with AR.15,16 These data are supported by a previous analysis of 1037 total patients at our institution that identified no statistically significant difference in rate of CRR between irradiated and unirradiated patients who underwent AR (17.9% vs 20.5%, respectively; P Z .79), respectively. Conversely, PMRT was the greatest risk for major complications in patients who underwent TE/I, with an observed rate of CRR of 21.2% in unirradiated patients and 45.4% in irradiated patients (P Z .005).6 Logistical, practical, and cosmetic considerations factor into the timing of the reconstruction relative to PMRT. Generally, immediate reconstruction is associated with better HR-QOL than delayed or no reconstruction and allows for use of the native breast envelope.10,11 However, immediate reconstruction can increase the complexity of RT planning, particularly with the increasing treatment of the internal mammary lymph nodes and use of pre-pectoral techniques. Conversely, delayed reconstruction after PMRT is often associated with fibrotic overlying skin that may require healthy skin from a donor site for adequate reconstruction.7 Historic practice was to perform D-AR, based on data that suggested that D-AR after completion of
PMRT may be associated with fewer complications and better cosmetic outcomes than I-AR.17-19 More recent prospective cohort data demonstrate low rates of major wound healing (5.7%) and flap failure (0%) with immediate DIEP reconstruction followed by PMRT.20 Our study used a low rate of DIEP reconstruction; therefore, outcomes are likely to be better in the modern era than what we have reported. Our results are consistent with these findings and demonstrate that I-AR followed by PMRT was associated with the lowest rate of CRR and RF and may have an acceptable toxicity profile in appropriately selected patients. A shift in practice patterns is reflected by a US National Cancer Database study from 2017, which demonstrated an increase in the use of immediate breast reconstruction from 13% to 33% in patients receiving PMRT.21 We identified high rates of RF at 10 years with immediate and delayed TE/I, with 25% of patients requiring conversion to a flat chest wall because of complications. When omitting RF because of infection, we found the rate of RF decreased substantially and was no longer significantly different between AR and TE/I. This is consistent with the findings from Baschnagel et al, who demonstrated a 20% rate of RF at 2-year median follow-up, with
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Table 4 failure
Cox proportional hazards analysis of factors associated with complications requiring reoperation and reconstruction Complications requiring reoperation
Reconstruction failure
UVA
UVA
MVA
Prognostic factor
HR (95% CI)
TE/I recon Delayed recon BMI (>30 vs 25) (>30 vs 25.1-30) Smoking Diabetes Hypertension Age at recon Adjuvant chemotherapy Months between immediate recon and PMRT (n Z 159) Months between PMRT and delayed recon (n Z 45)
1.9 (1.18-3.21) .009* 1.5 (0.84-2.57) .17 2.9 2.3 2.1 2.8 3.1 1.0 0.6
(1.56-5.43) (1.20-4.50) (1.26-3.50) (0.86-8.77) (1.76-5.26) (1.00-1.05) (0.36-1.09)
P value
.001* .013* .005* .09 <.0001* .08 .10
HR (95% CI)
P HR (95% CI) value
2.0 (1.18-3.44) .011* 3.4 (1.56-6.54) .002* 2.2 (1.11-4.37) .023* 2.7 (1.49-4.24) .001* 1.9 (0.97-3.56) .06
MVA P value
HR (95% CI)
P value
6.7 (2.70-16.67) <.0001* 6.6 (2.66-16.39) <.0001* 1.1 (0.43-2.63) .90 1.8 2.4 1.2 12.2 4.2 1.0 0.9
(0.75-4.39) .18 (0.85-7.04) .10 (0.54-2.80) .63 (3.58-41.67) <.0001* 4.1 (1.04-15.87) (1.92-9.09) .0003* 3.5 (1.47-8.20) (0.99-1.06) .22 (0.37-2.27) .85
1.1 (0.96-1.24) .21
0.9 (0.78-1.13)
.50
1.0 (0.94-1.02) .33
0.6 (0.42-0.90)
.012*
.044* .005*
Abbreviations: BMI Z body mass index; CI Z confidence interval; HR Z hazard ratio; MVA Z multivariate analysis; PMRT Z postmastectomy radiation therapy; TE/I Z tissue expander and implant reconstruction; UVA Z univariate analysis. * Statistically significant.
Figure 1
Rate of complication requiring reoperation by reconstruction technique and timing.
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Figure 2
Figure 3
Expander versus autologous reconstruction and PMRT
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Rate of reconstruction failure by reconstruction technique and timing.
Rate of reconstruction failure by reconstruction technique and timing when omitting reconstruction failures due to infection.
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the most common etiology of RF being infection.22 Therefore, minimizing infection risk may improve the integrity of reconstruction. There is substantial literature outlining risk factors for infection with TE/I.23 Optimal patient selection is essential, and factors such as obesity, hypertension, diabetes, active smoking, large breast size, and addition of PMRT and chemotherapy significantly increase the risk of implant-based infection and reconstruction failure.23,24 Best surgical practices including minimizing contamination, use of perioperative antibiotics (at least 1 week with at least 24 hours of IV antibiotics), and decreasing operative time have all been shown to significantly decrease infection rates. The use of human acellular dermal matrix (ADM) in TE/I reconstruction has the advantages of improving cosmesis and reducing capsular contracture; however, some data suggest a significantly increased relative risk of infection of 2.47-fold, though rates may be lower with different types of ADM such as AlloDerm (LifeCell Corporation, Bridgewater, NJ).25 Postoperatively, inpatient stays were shown to be associated with a 16-fold increase in development of periprosthetic infection compared with ambulatory stays. Additionally, regular follow-up after 1 month postoperatively is important; only 50% of infections present within the first 30 days.26,27 Similarly, patient factors and medical comorbidities contribute to the morbidity and viability of reconstruction strategies and should be factored into decision-making. Obesity is an independent risk factor for postoperative morbidity and increases the risk of failure of reconstruction 7-fold compared with nonobese patients.28 Our findings are supported by a retrospective analysis of 990 reconstructions, in which the difference in failure of reconstruction between TE/I and AR (25.4% vs 0%; P < .01) was most pronounced in obese patients.29 The present study also confirmed the impact of active smoking status on increased CRR and RF, which has been identified in prospective studies to significantly increase reconstruction failure (OR, 3.68; P Z .013).30 For patients undergoing mastectomy and PMRT, the approach to reconstruction is a multifactorial decision, including but not limited to length of surgery, recovery, and anesthesia time. Although patients who underwent AR had lower CRR and RF in this study, not all patients are optimal candidates for AR. Therefore, patients at high risk for complications, such as those with a BMI 30 or smokers, should be counseled appropriately. Despite lower complication rates, several challenges are associated with AR, including increased operative time, a longer hospital stay and recovery time, increased acute (30-day) complications, risk of flap failure and donor site complications, and increased cost.31 In carefully selected patients, the operative risk may be offset by the decreased risk of reoperation. A recent prospective cohort study from Spain compared the long-term outcomes and
cost of DIEP flaps and TE/I and found that although DIEP reconstruction had significantly longer total duration of operation, TE/I had significantly more surgical operations overall, and ultimately DIEP reconstruction was found to be more cost-effective.32 Data suggest AR may be more cost-effective over time, particularly for patients undergoing PMRT, who are at higher risk for reconstruction complications.31 Although we included a homogeneous population of patients who all received PMRT and stratified outcomes by timing of reconstruction, our analysis is limited by its retrospective nature and potential for confounding variables. The population was heterogeneous in terms of chemotherapy administration and sequencing, as well as dosing of PMRT, though modern techniques were used. Although the long follow-up of this study is a strength, it is also a limitation. Breast surgery and reconstruction techniques have evolved over the last decade for TE/I reconstruction, including the use of ADM, pre-pectoral reconstruction, and nipple-sparing mastectomy, as well as for AR, including the increased utilization of DIEP flaps, which have likely reduced complication rates and improved reconstruction integrity, particularly in irradiated patients. Our study included patients from an era when these techniques were not as widely used, and this could account, in part, for the higher rates of complications in patients who underwent TE/I. Additionally, it is not always known before surgery whether a patient will require PMRT. Therefore, the data we have presented may help guide reconstruction decisions only for patients who have clinical indications for PMRT before mastectomy. Data regarding cosmetic outcome and QOL were not captured in our analysis and would be important to include in future analyses addressing this topic. Finally, our study did not adjust for therapies used in the management of recurrence and therefore does not indicate how this might affect the occurrence of late complications and may confound the results. Nevertheless, this represents one of the largest single-institution series comparing AR- and TE/I-based reconstructions and timing using consistent modern RT with a median of 8 years of follow-up.
Conclusions In patients undergoing PMRT, TE/I reconstructions are associated with higher rates of complications requiring reoperation and reconstruction failures leading to a flat chest wall or different reconstruction strategy. Immediate reconstruction may be associated with lower rates of CRR and higher reconstruction integrity. Future strategies may include greater utilization of AR in appropriately selected patients who have clinical indications for PMRT before mastectomy.
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References 1. Greenberg CC, Lipsitz SR, Hughes ME, et al. Institutional variation in the surgical treatment of breast cancer: A study of the NCCN. Ann Surg. 2011;254:339-345. 2. EBCTCG, McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014; 383:2127-2135. 3. Sekiguchi K, Kawamori J, Yamauchi H. Breast reconstruction and postmastectomy radiotherapy: Complications by type and timing and other problems in radiation oncology. Breast Cancer. 2017;24: 511-520. 4. Thorarinsson A, Frojd V, Kolby L, Ljungdal J, Taft C, Mark H. Long-term health-related quality of life after breast reconstruction: Comparing 4 different methods of reconstruction. Plast Reconstr Surg Glob Open. 2017;5:e1316. 5. Shah C, Kundu N, Arthur D, Vicini F. Radiation therapy following postmastectomy reconstruction: A systematic review. Ann Surg Oncol. 2013;20:1313-1322. 6. Berry T, Brooks S, Sydow N, et al. Complication rates of radiation on tissue expander and autologous tissue breast reconstruction. Ann Surg Oncol. 2010;17(Suppl 3):202-210. 7. Ho AY, Hu ZI, Mehrara BJ, Wilkins EG. Radiotherapy in the setting of breast reconstruction: Types, techniques, and timing. Lancet Oncol. 2017;18:e742-e753. 8. Gurunluoglu R, Gurunluoglu A, Williams SA, Tebockhorst S. Current trends in breast reconstruction: Survey of American Society of Plastic Surgeons 2010. Ann Plast Surg. 2013;70:103-110. 9. Fischer JP, Wes AM, Nelson JA, et al. Propensity-matched, longitudinal outcomes analysis of complications and cost: Comparing abdominal free flaps and implant-based breast reconstruction. J Am Coll Surg. 2014;219:303-312. 10. Atisha D, Alderman AK, Lowery JC, Kuhn LE, Davis J, Wilkins EG. Prospective analysis of long-term psychosocial outcomes in breast reconstruction: Two-year postoperative results from the Michigan Breast Reconstruction Outcomes Study. Ann Surg. 2008;247:1019-1028. 11. Zhong T, Hu J, Bagher S, et al. A comparison of psychological response, body image, sexuality, and quality of life between immediate and delayed autologous tissue breast reconstruction: A prospective long-term outcome study. Plast Reconstr Surg. 2016; 138:772-780. 12. Spear SL, Baker JL Jr. Classification of capsular contracture after prosthetic breast reconstruction. Plast Reconstr Surg. 1995;96:11191123. discussion 1124. 13. Tanos G, Prousskaia E, Chow W, et al. Locally advanced breast cancer: Autologous versus implant-based reconstruction. Plast Reconstr Surg Glob Open. 2016;4:e622. 14. Tsoi B, Ziolkowski NI, Thoma A, Campbell K, O’Reilly D, Goeree R. Safety of tissue expander/implant versus autologous abdominal tissue breast reconstruction in postmastectomy breast cancer patients: A systematic review and meta-analysis. Plast Reconstr Surg. 2014;133:234-249. 15. Barry M, Kell MR. Radiotherapy and breast reconstruction: A metaanalysis. Breast Cancer Res Treat. 2011;127:15-22. 16. Jagsi R, Momoh AO, Qi J, et al. Impact of radiotherapy on complications and patient-reported outcomes after breast reconstruction. J Natl Cancer Inst. 2018;110.
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17. Rogers NE, Allen RJ. Radiation effects on breast reconstruction with the deep inferior epigastric perforator flap. Plast Reconstr Surg. 2002;109:1919-1924. discussion 1925-1916. 18. Tran NV, Chang DW, Gupta A, Kroll SS, Robb GL. Comparison of immediate and delayed free TRAM flap breast reconstruction in patients receiving postmastectomy radiation therapy. Plast Reconstr Surg. 2001;108:78-82. 19. Spear SL, Ducic I, Low M, Cuoco F. The effect of radiation on pedicled TRAM flap breast reconstruction: Outcomes and implications. Plast Reconstr Surg. 2005;115:84-95. 20. Taghizadeh R, Moustaki M, Harris S, Roblin P, Farhadi J. Does post-mastectomy radiotherapy affect the outcome and prevalence of complications in immediate DIEP breast reconstruction? A prospective cohort study. J Plast Reconstr Aesthet Surg. 2015;68:13791385. 21. Razdan SN, Cordeiro PG, Albornoz CR, et al. National breast reconstruction utilization in the setting of postmastectomy radiotherapy. J Reconstr Microsurg. 2017;33:312-317. 22. Baschnagel AM, Shah C, Wilkinson JB, Dekhne N, Arthur DW, Vicini FA. Failure rate and cosmesis of immediate tissue expander/implant breast reconstruction after postmastectomy irradiation. Clin Breast Cancer. 2012;12:428-432. 23. Ooi A, Song DH. Reducing infection risk in implant-based breastreconstruction surgery: Challenges and solutions. Breast Cancer (Dove Med Press). 2016;8:161-172. 24. Wengler CA, Valente SA, Al-Hilli Z, et al. Determinants of short and long term outcomes in patients undergoing immediate breast reconstruction following neoadjuvant chemotherapy. J Surg Oncol. 2017;116:797-802. 25. Kim JY, Davila AA, Persing S, et al. A meta-analysis of human acellular dermis and submuscular tissue expander breast reconstruction. Plast Reconstr Surg. 2012;129:28-41. 26. Leyngold MM, Stutman RL, Khiabani KT, et al. Contributing variables to post mastectomy tissue expander infection. Breast J. 2012; 18:351-356. 27. Cohen JB, Carroll C, Tenenbaum MM, et al. Breast implantassociated infections: The role of the national surgical quality improvement program and the local microbiome. Plast Reconstr Surg. 2015;136:921-929. 28. Alderman A, Gutowski K, Ahuja A, Gray D. Postmastectomy Expander Implant Breast Reconstruction Guideline Work Group. ASPS clinical practice guideline summary on breast reconstruction with expanders and implants. Plast Reconstr Surg. 2014;134:648e655e. 29. Garvey PB, Villa MT, Rozanski AT, Liu J, Robb GL, Beahm EK. The advantages of free abdominal-based flaps over implants for breast reconstruction in obese patients. Plast Reconstr Surg. 2012; 130:991-1000. 30. Santosa KB, Chen X, Qi J, et al. Postmastectomy radiation therapy and two-stage implant-based breast reconstruction: Is there a better time to irradiate? Plast Reconstr Surg. 2016;138:761-769. 31. Fischer JP, Fox JP, Nelson JA, Kovach SJ, Serletti JM. A longitudinal assessment of outcomes and healthcare resource utilization after immediate breast reconstruction-comparing implant- and autologousbased breast reconstruction. Ann Surg. 2015;262:692-699. 32. Lagares-Borrego A, Gacto-Sanchez P, Infante-Cossio P, BarreraPulido F, Sicilia-Castro D, Gomez-Cia T. A comparison of longterm cost and clinical outcomes between the two-stage sequence expander/prosthesis and autologous deep inferior epigastric flap methods for breast reconstruction in a public hospital. J Plast Reconstr Aesthet Surg. 2016;69:196-205.
www.practicalradonc.org
Clinical Investigation
Long-Term Outcomes After Autologous or Tissue Expander/ImplanteBased Breast Reconstruction and Postmastectomy Radiation for Breast Cancer Bindu V. Manyam MD a, Chirag Shah MD a,*, Neil M. Woody MD a, Chandana A. Reddy MS a, Michael A. Weller MD a, Aditya Juloori MD a, Mihir Naik DO a, Stephanie Valente DO b, Stephen Grobmyer MD b, Paul Durand MD c, Risal Djohan MD c, Rahul D. Tendulkar MD a a
Taussig Cancer Institute, Department of Radiation Oncology, Cleveland Clinic; bBreast Services, Department of Breast Surgery, Cleveland Clinic; and cDermatology and Plastic Surgery Institute, Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio
Received 11 March 2019; revised 7 June 2019; accepted 11 June 2019
Abstract Purpose: The toxicity profile of breast reconstruction with postmastectomy radiation therapy (PMRT) varies by technique and timing, and long-term data are limited. We compared rates of complications requiring reoperation (CRR) and reconstruction failure (RF) between immediate autologous reconstruction (I-AR), immediate tissue expander/implant reconstruction (I-TE/I), delayed autologous reconstruction (D-AR), and delayed tissue expander/implant reconstruction (D-TE/I) in patients receiving PMRT. Methods and Materials: Patients who received autologous reconstruction (AR) or tissue expander/ implant reconstruction (TE/I) and PMRT between 2000 to 2008 were included. Reconstruction was immediate if performed on the same day as mastectomy followed by PMRT (I-AR or I-TE/I) or delayed if after PMRT (D-AR and D-TE/I). CRR was defined as an unplanned return to the operating room for infection, dehiscence, necrosis, hematoma, or hernia (with AR) and extrusion, leak, or contracture (with TE/I). RF was defined as unplanned conversion to another reconstruction technique or to flat chest wall. Cumulative incidence of CRR and RF was calculated using KaplaneMeier and compared using the logrank test. Logistic regression was used to identify variables associated with CRR and RF. Results: Two hundred four patients were included. Median follow-up was 8 years. There were 127 AR cases (63%) and 77 TE/I cases (38%). At 5 years, CRR was 18%, 38%, 34%, and 70% (P Z .010) and RF was 4%, 22%, 7%, and 56% (P < .0001) for I-AR, I-TE/I, D-AR, and D-TE/I, respectively. On multivariate analysis, TE/I (hazard ratio [HR] 2.0; P Z .011), body mass index 30 (HR 3.9; P Z .002), and smoking (HR 2.7; P Z .001) were significant predictors for CRR, and TE/I (HR 6.6; P < .0001), diabetes (HR 4.1; P Z .044), and hypertension (HR 3.5; P Z .005) were significant for RF. When excluding RF because of infection, the rate of RF was not significantly different among the 4 groups (P Z .23). Sources of support: This work had no specific funding. Disclosures: Dr Shah is a consultant for Impedimed, Grants Varian Medical Systems, and VisionRT. * Corresponding author. E-mail address: [email protected] (C. Shah). https://doi.org/10.1016/j.prro.2019.06.008 1879-8500/Ó 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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Conclusions: With PMRT, TE/I reconstruction in the immediate and delayed setting is associated with higher CRR and RF compared with AR. Patient factors should guide selection of technique. Efforts to reduce rates of RF with TE/I should focus on minimizing risks for infection. Ó 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction Approximately 50% of women who undergo mastectomy for breast cancer pursue breast reconstruction.1 Postmastectomy radiation therapy (PMRT) is recommended for appropriately selected patients with stage II and III breast cancer because randomized trials have demonstrated a locoregional control, disease-free survival, and overall survival benefit.2 Additionally, trends in breast reconstruction in conjunction with PMRT are changing, with an increase in the frequency of immediate reconstruction among patients receiving PMRT.3 Though significantly improved health-related quality of life (HRQOL) is associated with breast reconstruction after mastectomy, reconstruction in conjunction with PMRT is associated with higher rates of complications and reconstruction failures compared with patients who do not undergo radiation therapy (RT).4-7 The optimal approach for reconstruction in patients requiring PMRT remains uncertain, and practice patterns are highly variable. This is in part because toxicity profiles differ by technique and timing, and long-term data are limited. Currently, tissue expander/implantebased reconstruction (TE/I) is the most commonly used technique.8 However, data suggest that autologous reconstruction (AR) may be associated with decreased rates of complications and need for additional procedures in patients requiring RT, though this comes at the expense of a different toxicity profile, increased operative time, and potentially increased cost up-front.5,9 The optimal timing of reconstruction also presents a challenge because immediate reconstruction may be associated with better HRQOL but may also compromise the planning and delivery of PMRT.10,11 The current study is an effort to compare rates of complications requiring reoperation (CRR) and reconstruction failure (RF) between immediate AR (IAR), immediate TE/I reconstruction (I-TE/I), delayed AR (D-AR), and delayed TE/I (D-TE/I) in patients who received PMRT.
Materials and Methods Patients who received mastectomy, AR or TE/I, and PMRT for breast cancer between 2000 to 2008 were identified in an institutional review boardeapproved database. This period was selected to allow for 10 years
of potential follow-up time for all patients. Patients were excluded if they received prior breast conservation therapy (lumpectomy and whole-breast RT) and subsequent mastectomy and reconstruction for recurrence, reirradiation for recurrence, mantle field RT for lymphoma, or combined TE/I and AR. Immediate reconstruction was defined as AR or TE/I on the same day as mastectomy (IAR or I-TE/I), followed by PMRT. Delayed reconstruction was defined as mastectomy followed by PMRT to a flat chest wall, with AR or TE/I at a later date. AR included transverse rectus abdominis (TRAM) flap, deep inferior epigastric perforator (DIEP) flap, or latissimus dorsi flap. Our reconstruction techniques have been previously published.6 All surgery for patients in this data set was performed at a single tertiary-care comprehensive cancer center by breast oncologic surgeons and plastic surgeons specializing in breast reconstruction, with a yearly volume of 400 to 450 breast reconstructions. Patients received neoadjuvant or adjuvant chemotherapy at the discretion of the treating oncologist. Recommendation for PMRT was made based on clinical staging or after surgery based on final pathologic staging. Patients underwent 2-dimensional fluoroscopybased planning or 3-dimensional conformal RT with computed tomographyebased planning, depending on the technology available at the time of treatment. Patients were treated to the chest wall regional lymph nodes as clinically indicated. The dose and fractionation of PMRT was at the discretion of the treating radiation oncologist and ranged from 48.6 to 50.4 Gy at 1.8 to 2.0 Gy per fraction. Radiation was delivered at the same institution as surgery or at an outside facility. CRR was defined as an unplanned return to the operating room because of wound infection, dehiscence, necrosis (skin or flap), or hematoma at the donor site or breast for AR and at the breast for TE/I. For those patients who underwent TRAM flap reconstruction, hernia was considered a CRR. For those patients who underwent TE/ I, implant extrusion, leak, or capsular contracture were also considered CRR. Capsular contracture was graded according to the Baker system at the time of follow-up by the surgeon.12 Reoperations for anticipated cosmetic procedures such as nipple reconstruction, trimming, or excision of redundant skin (“dog ear” deformity) were not coded as CRR. RF was defined as an unplanned conversion to another reconstruction technique or to a flat chest wall and could be due to the aforementioned complications or significant volume loss. RF not because of
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infection was separately recorded. Patients who underwent upfront tissue expander placement with planned delayed exchange to permanent implant were not coded as a CRR or an RF. In patients who underwent immediate reconstruction, CRR and RF could have occurred either before or after PMRT. In patients who underwent delayed reconstruction, CRR and RF was only recorded after completion of both PMRT and reconstruction.
and RF. Logistic regression analysis was used to identify variables associated with CRR and RF. Cumulative incidence of CRR and RF was calculated using the KaplaneMeier method and compared using the log-rank test. A P value .05 was considered statistically significant. SAS version 9.4 was used for statistical analysis.
Statistical methods
A total of 204 patients were included in this analysis. There were 127 AR cases (63%) and 77 TE/I cases (38%). Median follow-up was 8 years after reconstruction. Patient and treatment characteristics are presented in Table 1. The median age of the cohort was 47.5 years (range, 21-78), median body mass index (BMI) was 25.5 (18.4-42.6), and median RT dose was 50 Gy. Rates of diabetes, hypertension, and active smoking (defined as current or quit within last 10 years) were similar between
Patient demographics and crude rates of complications were reported as a median range or percentage of patients and were compared between the 2 groups using Fisher’s exact test for categorical variables and unpaired t test for continuous variables. Time intervals were calculated from the date of tissue expander placement in the case of TE/I and the date of AR for determination of the rate of CRR
Table 1
Results
Patient, radiation, and surgical characteristics
Age at reconstruction Follow-up post reconstruction, mo Radiation dose Fractions Race Caucasian African American Other BMI 25 25.1-30.0 30.1 Postmenopausal Diabetes Hypertension Smoking Timing of Reconstruction Immediate Delayed Bilateral Reconstruction Chemotherapy None Neoadjuvant Adjuvant Both Type of autologous Reconstruction TRAM LDF DIEP
All patients (n Z 204)
Autologous (n Z 127)
Tissue expander/implant (n Z 77)
Median
Range
Median
Range
Median
Range
P value
48 96 50 25
21-78 3-181 48.6-50.4 25-28
45 84 50 25
21-65 3-181 48.6-50.4 25-28
48 97 50 25
27-78 3-177 48.6-50.4 25-28
.22 .58 .77 .11
Count
Percent
Count
Percent
Count
Percent
179 16 6
89.1 8.0 3
113 10 1
91.1 8.1 0.8
66 6 5
85.7 7.8 6.5
88 62 34 88 5 35 51
47.8 33.7 18.5 43.1 2.5 17.2 25.1
48 39 21 55 1 20 30
44.4 36.1 19.4 43.3 0.8 15.7 23.8
40 23 13 33 4 15 21
52.6 30.3 17.1 42.9 5.2 19.5 27.3
159 45 4
77.9 22.1 2.0
90 37 1
70.9 29.1 0.8
69 8 3
89.6 10.4 3.9
11 33 119 41
5.4 16.2 58.3 20.1
8 19 67 33
6.2 15.0 52.8 26.0
3 14 52 8
3.9 18.2 67.5 10.4
-
-
106 5 16
83.5 3.6 12.6
-
-
.08
.58
.99 .07 .57 .62 .002
.15 .10
Abbreviations: BMI Z body mass index; DIEP Z deep inferior epigastric perforator; LDF Z latissimus dorsi flap; TRAM Z transverse rectus abdominis.
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AR and TE/I. Neoadjuvant chemotherapy, adjuvant chemotherapy, or both were administered to 16%, 58%, and 20%, respectively, and 5% of patients received no chemotherapy. TRAM was the most common type of AR (83.5%). Immediate reconstruction was the most common reconstruction timing strategy and was performed in 159 patients (78%) overall. Of the patients who received AR, 90 (71%) underwent immediate reconstruction, and of the patients who received TE/I, 69 (90%) underwent immediate reconstruction. For patients who received immediate reconstruction, there was no significant difference in median months between reconstruction and start of PMRT for AR and TE/I (5.3 vs 5.6 months, respectively; P Z .54). For patients who received a delayed reconstruction, there was no significant difference in median time between the start of PMRT and reconstruction for AR and TE/I (11.6 months vs 4.8 months, respectively; P Z .12; Table 2). Crude rates of wound toxicity by reconstruction technique and timing are presented in Table 3. The rate of skin/flap necrosis was 10.0% and 10.8% and the rate of fat necrosis was 24.4% and 16.2% for I-AR and D-AR, respectively. Rates of wound infection requiring intravenous (IV) antibiotics and wound dehiscence were similar between AR and TE/I. In the delayed setting, 2 patients in the AR group and 1 patient in the TE/I group had wound infection requiring IV antibiotics. All patients who experienced wound infection requiring IV antibiotics received chemotherapy. The most common complications specific to TE/I were Baker grade 3 or 4 capsular contracture (24.6%) in the immediate setting and implant removal because of infection (37.5%) in the delayed setting.12 The most common complications requiring reoperation in the immediate setting were skin/flap necrosis for AR and implant removal because of infection for TE/I; in the delayed setting, they were skin/flap necrosis for AR and implant extrusion for TE/I. RF was significantly higher for TE/I compared with AR in both the immediate and delayed settings. On multivariate analysis, TE/I (hazard ratio [HR], 2.0; 95% CI, 1.18-3.44; P Z .011), BMI 30 (HR, 3.4; 95% CI, 1.56-6.54; P Z .002), and smoking (HR, 2.7; 95% CI, 1.49-4.24; P Z .001) were significant predictors for CRR, and TE/I (HR, 6.6; 95% CI, 2.66-16.39; P < .0001), diabetes (HR, 4.1; 95% CI, 1.04-15.87; P Z .044), and hypertension
Table 2
(HR, 3.5; 95% CI, 1.47-8.20; P Z .005) were significant predictors for RF (Table 4). Cumulative incidence of rates of CRR and RF are presented in Figures 1 and 2 by reconstruction technique and timing. Rates of RF excluding RF because of infections are presented in Figure 3. In the immediate setting, the overall rate of CRR was 20.0% versus 39.1% (P Z .007) for AR and TE/I, respectively (Table 3). In the immediate reconstruction setting, the majority of complications that required a return to the operating room occurred immediately postoperatively or during adjuvant chemotherapy, before the completion of PMRT. For patients who underwent delayed reconstruction, all CRR occurred after completion of PMRT. In the immediate setting, when evaluating the rate of CRR that occurred only after the completion of PMRT, AR continued to have significantly lower rates than TE/I (7.8% vs 24.6%, respectively; P Z .004; Table 3).
Discussion In patients undergoing PMRT, we identified rates of CRR and RF as significantly lower with AR compared with TE/I at median follow-up of 8 years, with I-AR demonstrating the lowest rate of CRR. Reconstruction timing was not a significant predictor for toxicity on multivariate analysis, but TE/I reconstruction technique was the factor most strongly associated with complications. Additionally, we identified that when omitting infection as a cause of RF, there was no significant difference in RF by reconstruction technique and timing, underscoring the importance of reducing the risk for infection to maximize reconstruction success. The findings of this study contribute to a growing body of literature that suggests that irradiation of autologous flaps is safe. Our findings are consistent with previous analyses, including a meta-analysis, that have identified increased rates of complications with TE/I compared with AR in irradiated patients.6,9,13,14 A meta-analysis of 4 studies by Barry et al demonstrated less morbidity with AR than with TE/I (odds ratio [OR], 0.2; 95% CI, 0.11-0.39), and a prospective study of 2247 patients demonstrated that the addition of PMRT significantly increased complication rates at 2 years inirradiated patients with TE/I (OR, 2.64;
Median months between radiation therapy and reconstruction by reconstruction technique
Immediate reconstruction Mastectomy/reconstruction / PMRT (n Z 159)
Delayed reconstruction Mastectomy þ PMRT / reconstruction (n Z 45)
All patients (n Z 159)
Autologous (n Z 90)
Tissue expander/ implant (n Z 69)
P value
All Patients (n Z 45)
Autologous (n Z 37)
Tissue expander/ implant (n Z 8)
P value
5.4
5.3
5.6
.54
10.5
11.6
4.8
.12
Abbreviation: PMRT Z postmastectomy radiation therapy.
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Rates of wound toxicity by reconstruction technique
Wound infection Requiring IV antibiotics Wound dehiscence Skin/flap necrosis Fat necrosis Implant removed for infection* Capsular contracture* Baker grade 3 Baker grade 4 Implant extrusion* Implant leak* Overall rate of CRR Return to OR for donor site complication Return to OR for breast complication CRR occurred after completion of PMRTy Overall rate of RF Conversion to flat chest wall Conversion to AR Conversion to TE/I RF occurred after completion of PMRTz
Immediate reconstruction (n Z 159)
Delayed reconstruction (n Z 45)
AR % (n Z 90)
P value
AR % (n Z 37)
6 7 9 22 -
18 7 11 7 4 0 2 2 4
TE/I % (n Z 69)
6.7 7.8 10.0 24.4 -
5 11 1 0 13 17 12 5 10 1 20.0 27
7.2 15.9 1.4 0.0 18.5 24.6 17.4 7.2 14.5 1.4 39.1
.99 .13 .81 -
2 3 4 6 -
.007x
12
7.8 12.2 7.8 4.4
24.6 24.6
.004x .0003x
6 6 2 0 0 2 -
4.4
17 17 10 7 0 14
20.2 .003x
TE/I % (n Z 8)
5.4 8.1 10.8 16.2 -
P value .45x .21 -
1 2 0 0 3 1 1 0 3 0 32.4 5
12.5 25.0 0.0 0.0 37.5 12.5 12.5 0.0 37.5 0.0 62.5
16.2 16.2 5.4
50.0 .006x
-
4 2 2 0 -
-
.16
-
Abbreviations: AR Z autologous reconstruction; CRR Z complications requiring reoperation; IV Z intravenous; OR Z operating room; PMRT Z postmastectomy radiation therapy; RF Z reconstruction failure; TE/I Z tissue expander and implant reconstruction. * TE/I only. y Some CRR occurred before the completion of PMRT in patients who underwent immediate reconstruction. z Some RF occurred before the completion of PMRT in patients who underwent immediate reconstruction. x Statistically significant.
P < .001), whereas the addition of PMRT did not significantly increase complication rates with AR.15,16 These data are supported by a previous analysis of 1037 total patients at our institution that identified no statistically significant difference in rate of CRR between irradiated and unirradiated patients who underwent AR (17.9% vs 20.5%, respectively; P Z .79), respectively. Conversely, PMRT was the greatest risk for major complications in patients who underwent TE/I, with an observed rate of CRR of 21.2% in unirradiated patients and 45.4% in irradiated patients (P Z .005).6 Logistical, practical, and cosmetic considerations factor into the timing of the reconstruction relative to PMRT. Generally, immediate reconstruction is associated with better HR-QOL than delayed or no reconstruction and allows for use of the native breast envelope.10,11 However, immediate reconstruction can increase the complexity of RT planning, particularly with the increasing treatment of the internal mammary lymph nodes and use of pre-pectoral techniques. Conversely, delayed reconstruction after PMRT is often associated with fibrotic overlying skin that may require healthy skin from a donor site for adequate reconstruction.7 Historic practice was to perform D-AR, based on data that suggested that D-AR after completion of
PMRT may be associated with fewer complications and better cosmetic outcomes than I-AR.17-19 More recent prospective cohort data demonstrate low rates of major wound healing (5.7%) and flap failure (0%) with immediate DIEP reconstruction followed by PMRT.20 Our study used a low rate of DIEP reconstruction; therefore, outcomes are likely to be better in the modern era than what we have reported. Our results are consistent with these findings and demonstrate that I-AR followed by PMRT was associated with the lowest rate of CRR and RF and may have an acceptable toxicity profile in appropriately selected patients. A shift in practice patterns is reflected by a US National Cancer Database study from 2017, which demonstrated an increase in the use of immediate breast reconstruction from 13% to 33% in patients receiving PMRT.21 We identified high rates of RF at 10 years with immediate and delayed TE/I, with 25% of patients requiring conversion to a flat chest wall because of complications. When omitting RF because of infection, we found the rate of RF decreased substantially and was no longer significantly different between AR and TE/I. This is consistent with the findings from Baschnagel et al, who demonstrated a 20% rate of RF at 2-year median follow-up, with
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Table 4 failure
Cox proportional hazards analysis of factors associated with complications requiring reoperation and reconstruction Complications requiring reoperation
Reconstruction failure
UVA
UVA
MVA
Prognostic factor
HR (95% CI)
TE/I recon Delayed recon BMI (>30 vs 25) (>30 vs 25.1-30) Smoking Diabetes Hypertension Age at recon Adjuvant chemotherapy Months between immediate recon and PMRT (n Z 159) Months between PMRT and delayed recon (n Z 45)
1.9 (1.18-3.21) .009* 1.5 (0.84-2.57) .17 2.9 2.3 2.1 2.8 3.1 1.0 0.6
(1.56-5.43) (1.20-4.50) (1.26-3.50) (0.86-8.77) (1.76-5.26) (1.00-1.05) (0.36-1.09)
P value
.001* .013* .005* .09 <.0001* .08 .10
HR (95% CI)
P HR (95% CI) value
2.0 (1.18-3.44) .011* 3.4 (1.56-6.54) .002* 2.2 (1.11-4.37) .023* 2.7 (1.49-4.24) .001* 1.9 (0.97-3.56) .06
MVA P value
HR (95% CI)
P value
6.7 (2.70-16.67) <.0001* 6.6 (2.66-16.39) <.0001* 1.1 (0.43-2.63) .90 1.8 2.4 1.2 12.2 4.2 1.0 0.9
(0.75-4.39) .18 (0.85-7.04) .10 (0.54-2.80) .63 (3.58-41.67) <.0001* 4.1 (1.04-15.87) (1.92-9.09) .0003* 3.5 (1.47-8.20) (0.99-1.06) .22 (0.37-2.27) .85
1.1 (0.96-1.24) .21
0.9 (0.78-1.13)
.50
1.0 (0.94-1.02) .33
0.6 (0.42-0.90)
.012*
.044* .005*
Abbreviations: BMI Z body mass index; CI Z confidence interval; HR Z hazard ratio; MVA Z multivariate analysis; PMRT Z postmastectomy radiation therapy; TE/I Z tissue expander and implant reconstruction; UVA Z univariate analysis. * Statistically significant.
Figure 1
Rate of complication requiring reoperation by reconstruction technique and timing.
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Figure 2
Figure 3
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Rate of reconstruction failure by reconstruction technique and timing.
Rate of reconstruction failure by reconstruction technique and timing when omitting reconstruction failures due to infection.
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the most common etiology of RF being infection.22 Therefore, minimizing infection risk may improve the integrity of reconstruction. There is substantial literature outlining risk factors for infection with TE/I.23 Optimal patient selection is essential, and factors such as obesity, hypertension, diabetes, active smoking, large breast size, and addition of PMRT and chemotherapy significantly increase the risk of implant-based infection and reconstruction failure.23,24 Best surgical practices including minimizing contamination, use of perioperative antibiotics (at least 1 week with at least 24 hours of IV antibiotics), and decreasing operative time have all been shown to significantly decrease infection rates. The use of human acellular dermal matrix (ADM) in TE/I reconstruction has the advantages of improving cosmesis and reducing capsular contracture; however, some data suggest a significantly increased relative risk of infection of 2.47-fold, though rates may be lower with different types of ADM such as AlloDerm (LifeCell Corporation, Bridgewater, NJ).25 Postoperatively, inpatient stays were shown to be associated with a 16-fold increase in development of periprosthetic infection compared with ambulatory stays. Additionally, regular follow-up after 1 month postoperatively is important; only 50% of infections present within the first 30 days.26,27 Similarly, patient factors and medical comorbidities contribute to the morbidity and viability of reconstruction strategies and should be factored into decision-making. Obesity is an independent risk factor for postoperative morbidity and increases the risk of failure of reconstruction 7-fold compared with nonobese patients.28 Our findings are supported by a retrospective analysis of 990 reconstructions, in which the difference in failure of reconstruction between TE/I and AR (25.4% vs 0%; P < .01) was most pronounced in obese patients.29 The present study also confirmed the impact of active smoking status on increased CRR and RF, which has been identified in prospective studies to significantly increase reconstruction failure (OR, 3.68; P Z .013).30 For patients undergoing mastectomy and PMRT, the approach to reconstruction is a multifactorial decision, including but not limited to length of surgery, recovery, and anesthesia time. Although patients who underwent AR had lower CRR and RF in this study, not all patients are optimal candidates for AR. Therefore, patients at high risk for complications, such as those with a BMI 30 or smokers, should be counseled appropriately. Despite lower complication rates, several challenges are associated with AR, including increased operative time, a longer hospital stay and recovery time, increased acute (30-day) complications, risk of flap failure and donor site complications, and increased cost.31 In carefully selected patients, the operative risk may be offset by the decreased risk of reoperation. A recent prospective cohort study from Spain compared the long-term outcomes and
cost of DIEP flaps and TE/I and found that although DIEP reconstruction had significantly longer total duration of operation, TE/I had significantly more surgical operations overall, and ultimately DIEP reconstruction was found to be more cost-effective.32 Data suggest AR may be more cost-effective over time, particularly for patients undergoing PMRT, who are at higher risk for reconstruction complications.31 Although we included a homogeneous population of patients who all received PMRT and stratified outcomes by timing of reconstruction, our analysis is limited by its retrospective nature and potential for confounding variables. The population was heterogeneous in terms of chemotherapy administration and sequencing, as well as dosing of PMRT, though modern techniques were used. Although the long follow-up of this study is a strength, it is also a limitation. Breast surgery and reconstruction techniques have evolved over the last decade for TE/I reconstruction, including the use of ADM, pre-pectoral reconstruction, and nipple-sparing mastectomy, as well as for AR, including the increased utilization of DIEP flaps, which have likely reduced complication rates and improved reconstruction integrity, particularly in irradiated patients. Our study included patients from an era when these techniques were not as widely used, and this could account, in part, for the higher rates of complications in patients who underwent TE/I. Additionally, it is not always known before surgery whether a patient will require PMRT. Therefore, the data we have presented may help guide reconstruction decisions only for patients who have clinical indications for PMRT before mastectomy. Data regarding cosmetic outcome and QOL were not captured in our analysis and would be important to include in future analyses addressing this topic. Finally, our study did not adjust for therapies used in the management of recurrence and therefore does not indicate how this might affect the occurrence of late complications and may confound the results. Nevertheless, this represents one of the largest single-institution series comparing AR- and TE/I-based reconstructions and timing using consistent modern RT with a median of 8 years of follow-up.
Conclusions In patients undergoing PMRT, TE/I reconstructions are associated with higher rates of complications requiring reoperation and reconstruction failures leading to a flat chest wall or different reconstruction strategy. Immediate reconstruction may be associated with lower rates of CRR and higher reconstruction integrity. Future strategies may include greater utilization of AR in appropriately selected patients who have clinical indications for PMRT before mastectomy.
Practical Radiation Oncology: --- 2019
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