RADIOTHERAPY AND BREAST RECONSTRUCTION: A META-ANALYSIS
M Barry and M.R. Kell.
Department of Breast Surgery, BreastCheck, Mater Misericordiae University
Hospital, Dublin. Ireland.
Address Correspondence to:
Malcolm R. Kell
Department of Breast Surgery,
Mater Misericordiae University Hospital,
Keywords: Postmastectomy radiotherapy, immediate and delayed breast
reconstruction, prosthetic breast reconstruction, autologous breast
reconstruction, postoperative morbidity.
Introduction: The optimum sequencing of breast reconstruction (BR) in patients
receiving postmastectomy radiation therapy (PMRT) is controversial.
Methods: A comprehensive search of published studies that examined
postoperative morbidity following immediate or delayed breast reconstruction
with combined radiotherapy was performed. Medical (MEDLINE & EMBASE)
databases were searched and cross-referenced for appropriate studies where
morbidity following BR was the primary outcome measured.
Results: 1,105 patients were identified from 11 appropriately selected studies.
Patients undergoing PMRT and BR are more likely to suffer morbidity compared
to patients not receiving PMRT ((OR) = 4.2; 95% CI, 2.4-7.2(no PMRT vs.
PMRT)). Reconstruction technique was also examined with outcome when
PMRT was delivered after BR and this demonstrated that autologous
reconstruction is associated with less morbidity in this setting ((OR) = 0.21; (95%
CI, 0.1-0.4 (autologous vs. implant based)). Delaying BR until after PMRT had no
significant effect on outcome ((OR) =0.87; 95% CI, 0.47-1.62 (delayed vs.
Conclusions: PMRT has a detrimental effect on BR outcome. These results
suggest that where immediate reconstruction is undertaken with the necessity of
PMRT, an autologous flap results in less morbidity when compared to implant
Breast conservation surgery provides excellent locoregional control with
improved quality of life when compared with mastectomy . However many
patients still require mastectomy as the optimum therapeutic cancer procedure,
and many opt to undergo immediate breast reconstruction . It is therefore
essential that an appropriate strategy be proposed regarding the timing of
reconstruction and postoperative radiotherapy. The enthusiasm for post-
mastectomy breast reconstruction aims to achieve good functional aesthetic
outcome and maintain their quality of life, without negatively affecting the
prognosis or detection of cancer recurrence .
The Danish Breast Cancer Cooperative Group, 82b and 82c, trials in conjunction
with findings from the Canadian trial, collectively demonstrate that patients
randomised to receive post-mastectomy radiation have a lower 10-year rate of
local regional recurrence and an additional survival advantage associated
with post-mastectomy radiotherapy [4, 5]. Based on these, and similar
studies, there are now clear guidelines regarding the indications for post-
mastectomy radiation which are; large tumour size, direct involvement of the
skin, and 4 or more metastatic axillary lymph nodes [6-8]. However, despite
reducing loco-regional recurrences and increasing disease-free survival , post
mastectomy radiotherapy may negatively affect reconstruction outcome.
As a consequence, several studies have demonstrated that immediate breast
reconstructions in irradiated patients are associated with the potential for
significant postoperative morbidity [10, 11]. As a result, breast reconstruction
may be delayed until the final pathological results are available from the
mastectomy specimen and the indication for radiotherapy can be established.
Immediate breast reconstruction without radiotherapy, offers enhanced
aesthetic and safe oncological outcomes, is more cost-effective and
provides a positive psychological effect [12-16]. Despite this, less than 20%
of patients having a mastectomy have immediate breast reconstruction in
the United States . This may be due to patient choice or possibly
apprehension on the part of the surgeon that radiotherapy maybe required
postoperatively which potentially could compromise the reconstruction.
Radiotherapy can cause unpredictable changes in all tissues and
prosthetic materials . It has a biphasic nature with the acute effects
occurring over days to weeks and a delayed response, which can occur
from months to years after completion of the therapy . The acute phase
usually involves acute inflammatory changes which may lead to
desquamation or even necrosis of tissue . The delayed phase involves
atrophy, fibrosis and inhibition of normal wound healing mechanisms .
Furthermore, opponents of immediate breast reconstruction, suggest it
may alter chest wall anatomy and therefore distort the geometrics of the
radiation field design leading to under/overdosing the targeted and
underlying tissues [20, 21]. However, Stralman et al demonstrated a loco-
regional recurrence rate of 6% in 100 patients who had a mastectomy with
immediate (implant/autologous) reconstruction followed by radiotherapy
with a mean follow up of 108+/- 26 months. This suggests, there is no
significant decrease in efficacy or delivery of radiation post-immediate
implant or autologous reconstruction . Furthermore, Huang et al,
compared the incidence of local recurrence and distant metastasis of post-
mastectomy radiotherapy for breast cancer patients with and without
immediate TRAM flap reconstruction. They reported no statistical
differences in the incidences of locoregional recurrence or distant
metastasis between the TRAM flap and the non-TRAM flap patients .
Therefore, the objective of this meta-analysis is to examine the published
evidence on whether patients requiring post-mastectomy radiotherapy should
have an immediate or delayed reconstruction and whether a prosthesis or
autologous reconstruction is associated with the optimum outcome in terms of
Identification of studies
MEDLINE and EMBASE were searched by entering the following in the
searching algorithm: breast reconstruction AND (surgery OR radiation) AND
(clinical trial OR randomized controlled trial OR double-blind OR single-blind OR
random OR randomized OR placebo OR retrospective study OR prospective
study). English was set as a language restriction. The latest search was
performed on January 1, 2010. Two authors (M.B. and M.R.K.) independently
examined the title and abstract of citations and the full texts of potentially eligible
trials were obtained and disagreements were resolved by discussion.
All trials whether randomized or non-randomized, prospective or retrospective
were eligible that examined the effects of radiotherapy on immediate or delayed
breast reconstruction using either a prosthesis or autologous tissue (Latissimus
Dorsi (LD) or Trasversus Rectus Abdominis Muscle (TRAM). Case series or
reports were not included. Studies where the data could not be accurately
extracted were also excluded.
Data Extraction and Outcomes
The following information regarding each eligible trial was recorded: authors’
names, journal, patient numbers, timing and method of reconstruction, addition of
radiotherapy and the post-operative complication rate. The primary end point of
this meta-analysis was postoperative morbidity including capsular contracture,
fibrosis, fat necrosis, surgical site infections requiring removal of prosthesis/re-
operation (see tables 2, 4 and 6).
For post-operative complications in each study, the odds ratio (O.R.) of the
simple proportions of events was estimated with its variance and 95% CI.
Heterogeneity between the O.R.s for the same outcome between studies was
assessed by use of the X2 – based Q statistic . Data were then combined
across studies by the use of general variance methods with fixed and random
effects models . Analyses were conducted using StatsDirect version 2.5.6
(StatsDirect Ltd, Chesire, United Kingdom) and SPSS version 12.0 (SPSS, Inc,
Chicago, IL). All statistical tests were two tailed.
20 potentially eligible studies were identified that examined the effects of
radiotherapy on immediate or delayed breast reconstructions. 9 studies were
excluded from the meta-analysis due to low numbers (e.g. n < 15) or
incomplete data set regarding postoperative morbidity. Of the 11 studies
selected, 4 were studies that examined the effects of RT on immediate BR using
implant or expanders. 4 were studies that examined the effects of RT on
immediate BR using either a prosthesis or autologous flap. Finally 4 remaining
studies evaluated the effects of RT on immediate versus delayed autologous BR.
(See Consort flow of study selection (Figure 1)).
A total of 1,105 patients were identified from 11 selected studies [10, 11, 15,
22, 25-31]. These were subsequently divided into 3 cohorts for subgroup
analyses. The first group (n = 424) were patients’ with immediate BR using a
prosthesis alone with/without RT. The second subgroup (n = 380) compared
patients with immediate autologous BR versus prosthesis alone in the presence
of RT. The last subgroup analysis (n = 301) compared the effects of RT on
immediate versus delayed autologous BR.
Postoperative complications in BR in the presence of RT
Patients undergoing PMRT and immediate BR (n = 196) are more likely to suffer
morbidity when compared to patients not receiving PMRT (n = 229) ((OR) = 4.2;
95% CI, 2.4-7.2(no PMRT vs. PMRT) see figure 2.). Finally reconstruction
technique was examined when PMRT was delivered after BR and this
demonstrated that autologous reconstruction is the superior reconstruction
technique in terms of postoperative morbidity ((OR) = 0.20; (95% CI, 0.1-0.4
(autologous vs. implant based) see figure 3). Postoperative morbidity was
defined in terms of capsular contracture, infection, fat necrosis, fibrosis
and the necessity to re-operate on the patient. The rates of these
complications are displayed in tables 2, 4 and 6. Interestingly, the effect of
delaying BR until after PMRT had no significant effect on outcome ((OR) =0.87;
95% CI, 0.47-1.62 (delayed vs. immediate) see figure 4.).
The findings of this meta-analysis, that an immediate BR using a prosthesis only
in the presence of RT is associated with an increased risk of postoperative
complications ((OR) = 4.2; 95% CI, 2.4-7.2(no PMRT vs. PMRT)), is supported
by Aschermann et al, who conducted a retrospective review of 104 patients (123
breasts) who underwent mastectomy followed by implant breast reconstruction
and demonstrated that complications requiring prosthetic device removal or
replacement, as well as total complications, were more frequent in breasts that
received radiation than breasts that did not (18.5 percent versus 4.2 percent for
complications requiring prosthetic removal or replacement, p < or = 0.025, and
40.7 percent versus 16.7 percent for total complications, p < or = 0.01) . On
analysis of table 1 and 2 below, it is apparent that patients with immediate
implant based reconstructions, receiving radiotherapy have significantly greater
incidences of complications, compared to those who did not receive
Immediate breast reconstruction following a skin-sparing mastectomy has a
number of advantages over the delayed reconstruction. Firstly, it provides a more
enhanced aesthetic result due to preservation of the infra-mammary fold,
allowing a more natural appearance and there is also the option to adjust the
position of the scar . More importantly for the patient, it provides enormous
psychosocial benefits by restoring femininity and improving vitality, sexuality and
quality of life . In the absence of implants, immediate breast reconstruction
has a very favourable morbidity profile even when exposed to adjuvant
radiotherapy . Moreover, it is oncologically safe with an acceptable local
recurrence rate . Despite this, advocates of delayed breast reconstruction
suggest that there are two main problems with immediate breast reconstruction
in the presence of radiotherapy. Firstly, radiation therapy can adversely affect the
cosmetic outcome and cause increased postoperative complications .
Secondly, immediate breast reconstruction can impair the efficacy and delivery of
radiotherapy . Autologous reconstructions have a more predictable response
than implants to radiotherapy however the exact sequencing of this therapy is
contentious. Kronowitz et al, suggested the concept of the delayed-immediate
breast reconstruction as a potential solution . This involves placing a tissue
expander at the time of a skin-sparing mastectomy and waiting for the final
pathological results of the specimen. If radiotherapy is not required, an
immediate reconstruction is proposed and if radiotherapy is required, a delayed
reconstruction is advised. Unfortunately, this requires two operations, which are
associated with significant psychological and cost implications.
McKeown et al, demonstrated that patient satisfaction with cosmetic outcome
was similar between patients undergoing immediate and delayed reconstruction
(autologous LD) plus radiotherapy . Interestingly, they also noted that most
patients in retrospect would have preferred an immediate reconstruction . In a
prospective study by Thomson that assessed 73 women post immediate
implant–assisted LD or autologous LD reconstruction with or without
radiotherapy, there was no difference between the groups in terms of overall
cosmetic outcome as determined by the patients. When a panel of independent
cosmetic assessors reviewed the photographic evidence at different intervals
over a defined time period, they concluded that while radiotherapy had an
adverse effect on aesthetic outcome (p=0.0002) this was more obvious in the
implant-assisted LD group .
Kroll and colleagues, reviewed 1,384 free-flap procedures performed for
reconstruction of the breast or of head and neck defects. They assessed the
effects of prior irradiation of the recipient site on the incidence of total flap loss
which were more common in flaps transferred to previously irradiated sites .
It is evident from this study (table 5 and 6) that exposure of an autologous flap to
radiotherapy increases the postoperative complication rates irrespective of
whether an immediate or delayed reconstruction is performed (30.1% versus
The potential limitations of this study are that patient selection criteria for
either prosthetic-based or autologous BR were poorly defined and may
have differed between centers and time periods. There was also variation in
the RT treatments used in terms of both dose and use of a boost. It is
possible that the incidence of postoperative BR complication rates varies
with the dose of RT used and this could not be assessed in our analysis.
Finally, in addition to selecting the appropriate timing of radiotherapy and
reconstruction, appropriate patient selection is also paramount to consistently
obtain successful outcomes. A BMI of less than 30 is associated with a better
outcome in all reconstructive surgical procedures . A history of smoking and
diabetes are also poor prognostic indicators for myocutaneous flap viability .
Patient selection for reconstruction was not stated in many of the studies
involved in this meta-analysis and therefore could not be included.
Post-mastectomy radiation, irrespective of the method of reconstruction,
increases the incidence of postoperative complications however, this study
has demonstrated that in this setting, an autologous flap offers a more
favourable outcome in terms of morbidity than expander/implant
reconstruction. There is a paucity of high quality conclusive data regarding the
correct sequencing of breast reconstruction and radiotherapy. The majority of
studies involve small numbers of patients in single centres with retrospective
anaylsis. Multicenter randomised controlled trials with longer follow-up times and
better specified parameters are necessary to validate any future strategies
regarding the optimum timing of radiotherapy and breast reconstruction.
Unfortunately, these studies are difficult to perform, as it is difficult to ethically
justify demanding that patients undergo an immediate versus a delayed
reconstructive procedure due to a randomisation process. Therefore, in the
absence of level I evidence, the current data suggests that immediate breast
reconstruction with PMRT may be undertaken though morbidity is higher with
either immediate or delayed technique. The timing and effect of radiotherapy on
breast reconstruction must be discussed to ensure informed opinion and consent
of the patient. The patient’s expectations, preferences, motivations as well as
their level of understanding should be explored to enhance postoperative
satisfaction and quality of life .
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Figure 1. Quorom diagram: Consort flow of study selection.
20 studies of BR +
9 studies excluded
due to insufficient
11 studies of BR +
4 studies of BR +
7 studies of BR
flaps + RT
4 studies of implant
flaps + RT.
3 studies comparing
flap recon + RT.