European Journal of Surgical Oncology xxx (xxxx) xxx

Contents lists available at ScienceDirect

European Journal of Surgical Oncology

journal homepage: www.ejso.com

Early complications in delayed breast reconstruction: A prospective,

randomized study comparing different reconstructive methods in
radiated and non-radiated patients
€lby , Anna Elander , Emma Hansson *
Fredrik Brorson , Andri Thorarinsson , Lars Ko
Department of Plastic Surgery, University of Gothenburg, The Sahlgrenska Academy, Institute of Clinical Sciences, Sahlgrenska University Hospital,
Gothenburg, Sweden

a r t i c l e i n f o a b s t r a c t

Article history: Background: There is little high-quality scientific evidence identifying the best and safest methods for
Received 8 May 2020 delayed breast reconstruction, with most previous studies retrospective in nature. The primary aim was
Accepted 8 July 2020 to compare early complication rates for two different breast-reconstructive methods in radiated and
Available online xxx
non-radiated patients, using a validated scale. The secondary aim was to identify predictors for
complications.
Keywords:
Materials and methods: This study represents a clinical, randomized, prospective trial (ClinicalTrials.Gov
Breast reconstruction
identifier: NCT03963427), where the patients were divided into two study arms: non-radiated and
Randomized controlled trial
Flap
radiated. In the non-radiated arm, patients were randomized to a one-stage lateral thoracodorsal flap
Implant with an implant or two-stage expander reconstruction. In the radiated arm, patients were randomized to
DIEP a latissimus dorsi reconstruction combined with an implant or deep inferior epigastric artery perforator
Latissimus dorsi flap (DIEP) reconstruction. All adverse events were classified according to ClavieneDindo and summarization
Expander of overall morbidity was performed by calculating the Comprehensive Complication Index score. The
Clavien-Dindo classification study was conducted from 2008 to 2020.
Comprehensive complication index Results: The complication frequencies were similar for the two surgical methods within each arm. In the
non-radiated arm, risk factors for any complication were any comorbidities, and in the radiated arm,
factors were a high body mass index and a contralateral operation.
Conclusions: The usage of the Clavien-Dindo scale in reconstructive surgery is feasible, but further
validation is needed. In non-radiated patients, the frequencies of short-term complications were similar
for lateral thoracodorsal flap and expander reconstruction, whereas in radiated patients, they were
similar for DIEP and latissimus dorsi. The complication profile of the methods varied.
© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).

Introduction yield the best results for delayed breast reconstruction.

Breast reconstruction is a fundamental aspect of modern breast
cancer treatment, and access to the procedure is stipulated in
documents, including The Women’s Health and Cancer Rights Act
[1] and The European Parliament resolution on breast cancer in the
European Union [2002/2279(INI)] [2]. There are multiple tech-
niques for breast reconstruction; however, to date, there is little
high-quality scientific evidence concerning the safest methods that
* Corresponding author. Department of Plastic Surgery, Sahlgrenska University
€na Stråket 8, SE-413 45, Gothenburg, Sweden.
Hospital, Gro
E-mail addresses: fredrik.brorson@vgregion.se (F. Brorson), emma.hansson.2@
gu.se (E. Hansson).
Most studies of outcomes of breast reconstructions have serious
methodological limitations [3e5], and the majority of studies of
morbidity and complications following breast reconstruction are
retrospective. Additionally, variability in the definitions of com-
plications and the use of subjective grading scales for complication
severity are common. Moreover, studies tend to focus on specific
complications at the surgical site or selected systemic complica-
tions rather than covering the entire span of adverse events. These
factors make the outcome data unreliable and comparison between
different surgical methods difficult. A prerequisite for an informed
decision [6] concerning breast reconstruction includes high-quality
and unbiased information regarding aspects that include compli-
cation risks, long-term consequences, and expected aesthetic and

https://doi.org/10.1016/j.ejso.2020.07.010
0748-7983/© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Please cite this article as: Brorson F et al., Early complications in delayed breast reconstruction: A prospective, randomized study comparing
different reconstructive methods in radiated and non-radiated patients, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2020.07.010
2 F. Brorson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx
Abbreviations
ASA American Society of Anesthesiologists class
BCS Breast conserving surgery
BMI Body Mass Index
CCI Comprehensive Complication Index
CDC Clavien-Dindo Classification
CI Confidence interval
DIEP Deep Inferior Epigastric Artery Perforator flap
EXP Expander reconstruction
LD Latissimus dorsi flap
mITT Modified intention-to-treat
OR Odds ratio
PONV Postoperative nausea and vomiting
PP Per protocol
TD Thoracodorsal flap
functional results. This requires randomized controlled trials,
which have thus far been a rare commodity in reconstructive sur-
gery [3].
In Sweden, delayed breast reconstruction after mastectomy is
provided within the public health care system and is considered an
integrated part of breast cancer care. Guidelines [7] for patient
selection and choice of methods are provided by a national
consensus document since the early 2000’s; women with no his-
tory of radiotherapy are offered implant-based reconstructions
while those who have received radiotherapy are offered autologous
reconstructions. Higher rates of reconstructive failures in implant-
based reconstructions for irradiated patients and public resource
optimization were the main reasons for this degree of limited pa-
tient choice at the time of publication of the guidelines [7].
This randomized, prospective study of complications following
delayed breast reconstruction aimed to overcome the described
methodological limitations by using a validated system for classi-
fication of complications and accounting for a complete range of
both local and general adverse events. Specifically, the primary aim
of this study was to compare early complication rates for two
different breast-reconstructive methods in radiated and non-
radiated patients. The secondary aim was to identify predictive
factors for complications associated with the different methods.
Methods
Study design and protocol
This study is a clinical, randomized, prospective trial and one of
the studies described in the Go Breast Prospective study protocol
(ClinicalTrials.Gov identifier: NCT03963427).
Ethics
The Regional Ethical Committee of Gothenburg reviewed and
approved the study (043e08). Procedures were conducted in
accordance with the Helsinki Declaration of 1964 and Good Clinical
Practice guidelines.
Participants, recruitment, and informed consent
All referrals to our department for breast reconstruction were
assessed for inclusion, and invitation letters were sent to all eligible
patients. The department is located in one of seven university
hospitals in Sweden, has a catchment area of ~2 million people, and
Please cite this article as: Brorson F et al., Early complications in delayed breast reconstruction: A prospective, randomized study comparing
different reconstructive methods in radiated and non-radiated patients, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2020.07.010
performs ~350 breast reconstructions annually.
Eligibility assessment was performed during the initial consul-
tation, and all patients meeting the inclusion criteria were asked to
participate. The plastic surgeon described the study (risks/benefits,
participation principles, and procedures), and the patient was given
adequate time to reflect on the information and receive answers to
any questions. Participants provided written informed consent to
participate in the study.
Inclusion and exclusion criteria
The inclusion criteria were women aged >18 years with a uni-
lateral mastectomy defect. Exclusion criteria were inability to give
informed consent, status as a current smoker, and a body mass
index (BMI) > 30 kg/m2. For the radiated participants, additional
exclusion criteria were previous abdominal liposuction or surgery
rendering a deep inferior epigastric artery perforator (DIEP) flap
inappropriate and age >60 years. For the non-radiated participants,
additional exclusion criteria were extensive scarring on the thorax,
making a lateral thoracodorsal flap inappropriate.
Sample size
The sample size was calculated according to the power calcu-
lation described by the Go Breast Prospective study protocol
(ClinicalTrials.Gov identifier: NCT03963427) and based on aesthetic
outcomes.
Randomization
According to Swedish guidelines, autologous delayed recon-
struction is offered to patients who have received radiotherapy [7].
Briefly, radiated patients are offered a choice of different but pri-
marily autologous techniques, and non-irradiated patients are
offered different but primarily implant-based techniques [7].
Therefore, the patients were divided into two study arms
comprising non-radiated and radiated patients. In each arm, two
techniques were used for the reconstruction. The design was par-
allel, and the intended allocation ratio in the four groups was
1:1:1:1. The allocation sequence was concealed in a sealed-
envelope process.
Interventions: surgical techniques
In the non-radiated arm, patients were operated for either a
one-stage lateral thoracodorsal flap with a permanent implant (TD)
[8] (later referred to as a lateral intercostal artery perforator flap)
[9] or two-stage expander reconstruction (EXP) [10]. In the radiated
arm, patients were operated for either latissimus dorsi-flap
reconstruction (LD) combined with a permanent implant [11] or a
DIEP flap [12]. All contralateral, symmetrizing procedures were
performed at the time of the breast reconstruction. Our department
has significant and well-documented experience with applications
of the four reconstructive methods [13e16].
Clinical data collection
Information concerning demographics and patient characteris-
tics, comorbidities, breast cancer stage, and treatment, as well as
data for operating time, surgeon experience, blood loss, and the
length of hospital stay, was recorded. Adverse events from the time
of preparation for anesthesia until 3-months postoperation were
registered. All events were recorded, even when they were related,
in order to prevent subjective underreporting [17].
 F. Brorson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx
Outcomes: complication classification
All adverse events were classified according to the five grades
described by the ClavieneDindo Classification (CDC) of surgical
complications [18]. The system is based on ranking the severity of
the intervention required to treat a given complication, as follows:
grade I includes deviations from the postoperative course without
the need for pharmacological treatment or surgical/endoscopic/
radiological intervention; grade II complications require pharma-
cological treatment, blood transfusion, or total parental nutrition;
grade III complications require surgical/endoscopic/radiological
intervention; grade IV includes life-threatening complications,
including those involving the central nervous system, that require
intensive care treatment; and grade V includes complications that
result in death [18]. The CDC has been tested and validated [17,18],
as well as used in previous studies concerning breast surgery and
reconstruction [19e21].
To summarize overall morbidity, CDC outcomes were converted
to Comprehensive Complication Index (CCI) [22,23] scores ac-
cording to AssesSurgery [24]. The CCI gives a single score [range:
0 (uneventful course) to 100 (death)] [22], and although the CCI is
based on the CDC, their simultaneous recording is recommended
[22]. To facilitate interpretation of the results and future quality
improvement [25], complications were also classified separately as
systemic and/or surgical site-specific complications.
A limited number of previous studies on breast reconstruction
has used CDC [21,27,28]. They have focused on surgical-site com-
plications in the reconstructed breast or the donor site and not all
systemic complications [21,27,28]. In the previous studies it has
been noted that the complication frequencies become higher when
a systematic system, such as CDC, is used. Hence, it can be expected
that complication frequencies according to CDC cannot be
compared with frequencies reported according to in-house
definitions.
Statistical analyses
Statistical analysis of drop outs, demographics, and post-
operative variables was performed using Fisher’s exact test for
dichotomous variables, the ManteleHaenszel chi-squared exact
test for ordered categorical variables, and Fisher’s nonparametric
permutation test for continuous variables. For the CDC, univariable
logistic regression was used to identify factors predictive of com-
plications within 30 days of surgery. Predictive factors were
calculated using data from all registered complications. For the CCI,
linear regression was used for the same purpose. Analyses were
performed both per protocol (PP) and according to a modified
intention-to-treat (mITT; all participants who underwent the
assigned procedure). Analyses were performed for each method
(e.g., the two-stage EXP procedure was counted as one method).
Significance was determined at a p < 0.05.
Results
Participants, recruitment, and randomization
Patients were recruited for the study from 2008 to 2015, and the
reconstructive procedures were performed from 2009 to 2016. A
total of 150 patients were randomized into the non-radiated arm
(Fig. 1.1) and 83 into the radiated arm (Fig. 1.2).
Interventions: surgical techniques
In the non-radiated arm, 125 of 150 patients underwent the
procedure for which they were originally randomized (mITT), with
Please cite this article as: Brorson F et al., Early complications in delayed breast reconstruction: A prospective, randomized study comparing
different reconstructive methods in radiated and non-radiated patients, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2020.07.010
3
119 of these performed according to all of the inclusion criteria (PP)
(Fig. 1.1). In the radiated arm, 66 of 83 patients underwent the
procedure for which they were originally randomized (mITT), with
57 of these performed according to all of the inclusion criteria (PP)
(Fig. 1.2).
Drop-out analysis
In the non-radiated arm, drop-out analysis revealed that the PP
population had a lower BMI (24.9 vs. 27.3; p ¼ 0.0006) and a lower
frequency of tobacco consumption (14.6% vs. 39.4%; p ¼ 0.004)
relative to the drop outs. There were no differences in age,
comorbidities, initial tumor stage, or adjuvant cancer treatment
received between the non-radiated mITT and PP populations or
between the TD and EXP groups (Table 1).
In the radiated arm, drop-out analysis revealed that the PP
population was younger than the drop outs (49.7 vs. 54.0 years;
p ¼ 0.012), and there were no differences in BMI, tobacco con-
sumption, comorbidities, initial tumor stage, or adjuvant cancer
treatment received between the radiated mITT and PP populations
or between the LD and DIEP groups (Table 1).
Complications in the non-radiated arm
In the non-radiated arm, 57% of patients in the TD group and
53% in the EXP group experienced a complication, although there
were no differences in the total number of complications between
the reconstructive methods used in each of the groups (Table 2).
The number of patients who did not experience any complication at
all were 43% (22/51) in the TD group and 47% (31/66) in the EXP
group. In the mITT population, the TD and EXP groups showed
median CCI scores of 8.7 (range: 0e40.6) and 8.7 (range: 0e60.4),
respectively (p ¼ 0.50), with the same median CCI scores and
ranges determined for the PP population (p ¼ 0.56). In addition to
the complications classified by the CDC, there were two hospital
readmissions in the TD group and seven in the EXP group (3 after
stage I and 4 after stage II), as well as one implant loss in both
groups (after stage II). The majority of the complications in both
groups was CDC grade I and included surgical-site wound infection,
dehiscence, and seroma occurring at the reconstructed site
(Table 3) and systemic complications, such as postoperative nausea
and vomiting (PONV) and constipation (Table 4).
Complications in the radiated arm
In the radiated arm, 78% of patients in the DIEP group and 75% in
the LD group experienced a complication, although there were no
differences in the total number of complications between the
reconstructive methods used in each of the groups (Table 2). The
number of patients who did not experience any complication at all
were 22% (7/37) in the DIEP group and 25% (6/24) in the LD group.
In the mITT population, the DIEP and LD groups showed median CCI
scores of 22.6 (range: 0e85.1) and 18 (range: 0e49.1), respectively
(p ¼ 0.25), and in the PP population, the DIEP and LD groups
showed median CCI scores of 21.8 (range: 0e85.1) and 22.6 (range:
0e43.4), respectively (p ¼ 0.32). In addition to the complications
classified by the CDC, there were two hospital readmissions in the
DIEP group and one in the LD group, and one reconstructive failure
occurred in each group within 30 days [LD: an implant loss due to
infection; and DIEP: one major flap failure (loss of >50% of the
flap)].
Most complications were CDC grades I and II, with similar fre-
quencies in both groups (Tables 2e4). However, there were more
grade IIIb complications, particularly tissue necrosis requiring
revision under general anesthesia (Table 3), in the DIEP group as
4 F. Brorson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx

Le er of invita on and ques onnaires

(n=456)

Eligible a er consulta on

(n=274)

Decline

(n=124)

Randomiza on by sealed envelope (n=150)

Randomized to thoracodorsal flap (n=70) Randomized to expander (n=80)

Opt-out = 13 Opt-out = 9
Recurrence = 1 Recurrence = 1
Gene carrier =1

Reconstructed with thoracodorsal flap (n=55) Reconstructed with expander (n=70)

Analysed per modified inten on to treat Analysed per modified inten on to treat

4 excluded 4 excluded

Reconstructed with thoracodorsal flap (n=51) Reconstructed with expander (n=66)

Analysed per protocol Analysed per protocol

Follow up for early complica ons (n=55) Follow up for early complica ons (n=70)

Fig. 1. Consort diagram for the non-radiated arm.

compared with the LD group (PP: p ¼ 0.026; and mITT: p ¼ 0.022)
(Table 2). Additionally, most of the surgical-site complications were
in the reconstructed breast or at the donor site (Table 3).
Predictors of complications in the non-radiated arm
Risk factors for any complication (CDC  grade I) were an
American Society of Anesthesiologists (ASA) class 3 and comor-
bidities, such as autoimmune, psychiatric, and pulmonary diseases
(Table 5). Sub-analyses specifically for CDC grade II revealed that a
long operating time (>2 h) was a predictor [PP: odds ratio
(OR) ¼ 2.11, confidence interval (CI): 1.11e4.03, p ¼ 0.024; and
mITT: OR ¼ 2.07, CI: 1.12e3.83, p ¼ 0.020] and for CDC grade III,
adjuvant chemotherapy (PP: OR ¼ 5.80, CI: 0.92e36.80, p ¼ 0.062;
and mITT: OR ¼ 6.33, CI: 1.00e40.07, p ¼ 0.051) and previous
breast-conserving surgery (PP: OR ¼ 8.58, CI: 1.25e59.04,
p ¼ 0.029; and mITT: OR ¼ 9.25, CI: 1.35e63.58) constituted risk
factors.
Predictors of complications in the radiated arm
Risk factors for any complication (CDC  grade I) were a high
BMI and a contralateral operation (Table 5). Sub-analyses revealed
that comorbidities, particularly psychiatric morbidity and an ASA
class 2, were also risk factors specifically for CDC grades II (PP:
OR ¼ 2.99, CI: 0.99e9-07, p ¼ 0.053; and mITT: OR ¼ 2.97, CI:
1.08e8.18, p ¼ 0.035) and III (PP: OR ¼ 6.43, CI: 1.50e27.46,
p ¼ 0.012; and mITT: OR ¼ 4.03, CI: 1.09e14.84, p ¼ 0.036). Addi-
tionally, a long operating time (>7 h) was a specific risk factor for
CDC grade IIIb (PP: OR ¼ 1.52, CI: 1.06e2.19, p ¼ 0.024; and mITT:
OR ¼ 1.38, CI: 1.02e1.87, p ¼ 0.035).
Discussion
This study is one of few prospective, randomized studies
comparing complication rates after delayed breast reconstruction
in two different groups: radiated and non-radiated patients.

Please cite this article as: Brorson F et al., Early complications in delayed breast reconstruction: A prospective, randomized study comparing
different reconstructive methods in radiated and non-radiated patients, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2020.07.010
 F. Brorson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx 5

Fig. 2. Consort diagram for the radiated arm.

Complications were classified according to the validated CDC
[17,18] and the CCI [22,23], with the results suggesting that the
complication frequencies were similar for the two surgical methods
within each arm (Table 2).
Considerations regarding the results
The primary scope of the study was to compare early compli-
cation rates for two different breast-reconstructive methods in
radiated patients and two methods in non-radiated patients,
respectively. Such a comparison can be made as long as complica-
tions are identically defined in all groups, which they were in this
study. Our findings of few differences between TD and EXP groups
of non-radiated patients and between DIEP and LD groups of
radiated patients are valid. The secondary aim was to identify
predictive factors for complications associated with the different
methods. The identified risk factors, including ASA class 2 and
comorbidities, a high BMI, and a long operating time (>2 h)
(Table 5), are well-known risk factors for complications in breast
reconstruction [13,15,26]. Nevertheless, this study is among the few
prospective, randomized studies verifying these risks.
Considering specific complications in the present study
(Tables 3 and 4), the frequencies were similar to those previously
reported [16,26]; however, the frequencies appear high according
to the CDC. It is possible that the CDC might overestimate the
overall postoperative morbidity when all complications rather than

Please cite this article as: Brorson F et al., Early complications in delayed breast reconstruction: A prospective, randomized study comparing
different reconstructive methods in radiated and non-radiated patients, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2020.07.010
6 F. Brorson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx

Table 1
Demography and per-operative details of study participants.

Non -radiated arm Radiated arm

PP mITT PP mITT

TD Expander n ¼ 66 p TD Expander n ¼ 70 p DIEP LD p DIEP LD p

n ¼ 51 n ¼ 55 n ¼ 32 n ¼ 24 n ¼ 34 n ¼ 32

Age (years)a 54.9 (7.0) 56.0 (9.0) 0.49 55.1 (7.0) 55.7 (9.0) 0.70 49.3 (6.4) 50.1 0.67 49.3 (6.4) 51.9 0.15
Mean (SD) (6.9) (8.3)
BMIa (kg/mb) 24.8 (2.5) 25.0 (2.8) 0.76 25.2 (3.2) 25.6 (3.9) 0.52 25.5 (2.6) 25.1 0.65 25.3 (3.2) 25.8 0.47
(2.9) (2.9)
BMI > 25a (kg/mb) 54.9% 45.4% 0.31 58.2% 48.6% 0.29 46.9% 50.0% 0.82 50.0% 53.1% 0.80
Tobaccob 15.7% 13.6% 0.59 18.2% 15.7% 0.57 12.5% 8.3% 1.00 11.7% 15.6% 1.00
Any comorbidityb 49.0% 58.5% 0.41 50.9% 59.4% 0.44 40.6% 41.7% 1.00 41.2% 43.8% 1.00
ASA classb 0.10 0.17 0.69 0.18
1 86.3% 74.2% 83.6% 74.3% 90.6% 83.3% 88.2% 78.1
2 13.7% 22.7% 16.4% 22.9% 9.4% 16.7% 11.8% 21.9%
3 0 3.0% 0 2.9% 0 0 0 0
Tumor stageb,c
0 11.8% 18.8% 14.5% 19.1% 0 0 0 0
1 27.5% 35.9% 25.5% 36.8% 3.1% 4.3% 2.9% 6.5%
2 60.8% 43.8% 60% 42.6% 31.3% 43.5% 32.4% 45.2%
3 0 1.6% 0 1.5% 65.6% 52.2% 64.7% 48.4%
Previous BCSb 12.0% 6.1% 0.43 11.1% 5.7% 0.44 12.5% 12.5% 1.00 11.8% 12.5% 1.00
Chemotherapy 25.5% 19.7% 0.46 23.6% 18.6% 0.50 90.6% 75.0% 0.12 91.2% 75.0% 0.08
Operating time 112 Stage 1:74 (33.4) <0.01 111 Stage 1:76 (34.4) Stage 2: 54 <0.01 432 (84.9) 232 <0.01 438 (85.5) 231 <0.01
(minutes)a (36.5) Stage 2: 54 (28.0) (35.6) (28.8) (49.8) (56.5)
Total 128 Total 130
Any contralateral 78.4% 1: 84.8% 0.44 78.2% Stage 1: 80.0% 0.81 65.6% 75.0% 0.45 67.6% 71.9% 0.71
procedureb 2: 25.8% Stage 2: 24.3%
Length of stay (days)a 1.25 Stage 1: 0.89 0.95 1.24 Stage 1:0.91 (0.67) 0.97 6.6 (3.8) 2.4 <0.01 6.6 (3.7) 2.6 <0.01
(0.69) (0.68) (0.69) Stage 2:0.35 (0.63) (0.76) (0.77)
Stage 2:0.35
(0.64)
Surgical experience (max)d
>10 years 39.2% Sage 1: 25.8% 0.15 36.4% Stage 1: 25.7% 0.31 21.9% 50.0% 0.11 26.5% 53.1% 0.03
Stage 2: 27.3% Stage 2: 30.0%
5e10 years 56.9% Stage 1: 56.1% 0.62 60.0% Stage 1: 58.6% 0.38 78.1% 33.3% <0.01 73.5% 34.4% <0.01
Stage 2: 48.5% Stage 2: 45.7%
<5 years 3.9% Stage 1: 16.7% <0.01 3.6% Stage 1: 15.7% <0.01 0 16.7% 0.02 0 12.5% 0.03
Stage 2: 24.2% Stage 2: 22.8%

PP: per protocol analysis.

mITT: modified intention to treat analysis.
TD: thoracodorsal flap.
EXP: expander.
LD: latissimus dorsi flap.
DIEP: deep inferior epigastric flap.
ASA: American Society of Anesthesiologists classification of physical status.
BCS: breast conserving surgery.
a
Mean (standard deviation).
b
Percentage of total in group. The patients in the non-radiated group were operated on with an additional mastectomy before radiation was given. Hence, none of the
patients in the non-radiated group have had any form of radiation to the breasts.
c
Tumor stage according to the TNM (Tumor, Node, Metastasis) classification.
d
Experience of most senior surgeon.

only the most severe are recorded [18]. This is especially relevant
for complications, such as wound dehiscence [20], a common
complication in breast reconstruction. In some cases, wound
dehiscence heals without intervention and is registered as CDC
grade I or as grade II if antibiotics are administered (Tables 2 and 3).
In other cases, wound dehiscence develops into a more severe
complication that requires surgical intervention, at which time it is
registered as both CDC grade I/II and III (Tables 2 and 3). Therefore,
the strategy of recording all events, even when they are related [17],
might explain our high frequencies of CDC grade I and II compli-
cations (Table 2). Moreover, this study was prospective, which
allowed us to register all complications as they occurred and use
predefined definitions of the different complications [18]. This
eliminated the obvious risk of underestimation that can occur upon
use of retrospective chart data and subjective definitions for com-
plications. Therefore, the prospective nature of this study might
have contributed to higher complication frequencies. Additionally,
the limited number of previous studies [21,27,28] focused on breast
reconstruction using the CDC registered only surgical-site compli-
cations in the reconstructed breast or the donor site and not all
systemic complications [21,27,28]. In fact, studies of breast recon-
struction rarely report grade I systemic complications, such as
PONV, despite the frequent occurrence of PONV in association with
breast surgery [29]. Indeed, it was the most common grade I sys-
temic complication in the present study (Table 4). It should be
mentioned that the modern use of local anesthetics, that has
become more common since the present study was performed,
might reduce the frequency of PONV.
Moreover, previous studies do not state whether only the most
severe or all complications were registered [21,27,28], which con-
stitutes a clear risk for underestimation of complication fre-
quencies. These findings suggest that comparisons of complication
rates between studies are often unreliable.
In a study concerning breast reduction [20], classifying all

Please cite this article as: Brorson F et al., Early complications in delayed breast reconstruction: A prospective, randomized study comparing
different reconstructive methods in radiated and non-radiated patients, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2020.07.010
 F. Brorson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx 7

Table 2
Clavien-Dindo Classification of adverse events.

Non-radiated arm Radiated arm

PP mITT PP mITT

TD (n ¼ 51) EXP p TD (n ¼ 55) EXP (sum) n ¼ 70) P DIEP (n ¼ 32) LD (n ¼ 24) p DIEP (n ¼ 34) LD (n ¼ 32) p
(sum)
(n ¼ 66)

CDC Ia
1 16 18 17 21 11 8 12 11
2 4 7 6 7 3 3 4 6
3 0 1 0 1 0 1 0 2
4 0 0 0 0 1 0 1
Total number of CDC I 24 35 0.69 29 38 1.00 17 24 0.17 18 33 0.058
Number of patients with CDC I 20 (39%) 26 (39%) 23 29 (41%) 14 (44%) 13 (54%) 16 (47%) 20 (63%)
(42%)
CDC II
1 10 11 12 13 7 9 8 14
2 2 2 2 2 3 2 4 2
3 0 2 0 2 2 0 2 0
4 0 1 0 1 0 0 0 0
Total number of CDC II 14 25 0.52 16 27 0.53 19 13 0.87 24 18 0.76
Number of patients with CDC II 12 (24%) 16 (24%) 14 (25%) 18 (26%) 12 (38%) 11 (46%) 14 (41%) 16 (50%)
CDC IIIa
1 1 1 1 1 6 4 6 5
2 0 0 0 0 0 1 0 1
3 0 0 0 0 1 0 1 0
Total number of CDC IIIa 1 1 1.0 1 1 9 6 1.00 9 7 0.83

Number of patients with CDC 1 (2%) 1 (1.5%) 1 (18%) 1 (14%) 7 (22%) 5 (21%) 9 (26%) 7 (22%)
IIIa
CDC IIIb
1 1 3 1 3 8 1 9 3
2 0 1 0.32 0 1 1 0 1 0
3 0 0 0 0 0 0 0 0
4 0 0 0 0 0 0 0 0
5 0 0 0 0 1 0 1 0
Total number of CDC IIIb 1 5 0.32 1 5 0.32 15 1 0.026 16 3 0.022

Number of patients with CDC 1 (2.0%) 4 (6.0%) 1 (1.8%) 4 (5.7%) 10 (31%) 1 (4%) 11 (32%) 3 (9%)
IIIb
CDC IV 0 0 0 0 0 0 0 0
CDC V 0 0 0 0 0 0 0 0

PP: per protocol analysis.

mITT: modified intention to treat analysis.
TD: thoracodorsal flap.
EXP: expander.
LD: latissimus dorsi flap.
DIEP: deep inferior epigastric flap.
CDC: Clavien Dindo Classification.
a
Number of patients with 1 complication, 2 complications, 3 complications etc in each category.

wound-healing problems and not just the most severe cases ac-
cording to the CDC resulted in a grade I complication rate of 48%,
which is similar to the frequencies reported in the present study
(Table 3). Indeed, Winter et al. [20] argue that wound-healing
problems not requiring intervention might be so common in
breast plastic surgery that they should not be considered an un-
expected complication but rather a side effect of the operation. The
results of the present study support this argument. These findings
indicate that use of the CDC for comparisons related to studies of
reconstructive breast surgery, benchmarking, and quality control
requires its validation in a plastic surgery setting. Furthermore,
complication frequencies for larger cohorts need to be determined.
Methodological aspects
Although this study has the advantage of being prospective and
randomized, there were a few methodological aspects. First, this
study was part of a larger randomized prospective study, and the
sample size was not calculated specifically using the CDC or CCI as a
primary end-point, which could have resulted in the study being
underpowered. The risk was most notable in the radiated arm,
where tendencies toward differences in complication frequencies
were registered. For example, 32% of DIEP patients and 9% of LD
patients demonstrated grade IIIb complications (Table 2). However,
the differences could also be explained by the small number of
patients included in the radiated arm (Fig. 1.2). When the study was
conducted, our department performed ~50 DIEP/LD procedures and
300 EXP/TD procedures annually. Because LD and DIEP are offered
mainly to radiated patients [7], these procedures are less common;
therefore, the recruitment of patients was considerably slower in
the radiated arm. This suggests that the small sample sizes could
have affected the results. The problems could be solved with
multicentric data collection in future studies. Still, such an
approach could have introduced more confounding factors, such as
differences in patient, tumor and surgeon dependent factors.
Second, the relatively high frequency of patients not undergoing
the operation for which they were randomized (17% in the non-
radiated arm and 20% in the radiated arm) might indicate

Please cite this article as: Brorson F et al., Early complications in delayed breast reconstruction: A prospective, randomized study comparing
different reconstructive methods in radiated and non-radiated patients, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2020.07.010
8 F. Brorson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx

Table 3
Clavien-Dindo Classification of adverse events.

Non-radiated arm

PP mITT PP mITT

TD (n ¼ 51) EXP p TD (n ¼ 55) EXP (sum) n ¼ 70) P DIEP (n ¼ 32) LD (n ¼ 24) p DIEP (n ¼ 34) LD (n ¼ 32) p
(sum)
(n ¼ 66)

CDC Ia
1 16 18 17 21 11 8 12 11
2 4 7 6 7 3 3 4 6
3 0 1 0 1 0 1 0 2
4 0 0 0 0 1 0 1
Total number of CDC I 24 35 0.69 29 38 1.00 17 24 0.17 18 33 0.058
Number of patients with CDC I 20 (39%) 26 (39%) 23 29 (41%) 14 (44%) 13 (54%) 16 (47%) 20 (63%)
(42%)
CDC II
1 10 11 12 13 7 9 8 14
2 2 2 2 2 3 2 4 2
3 0 2 0 2 2 0 2 0
4 0 1 0 1 0 0 0 0
Total number of CDC II 14 25 0.52 16 27 0.53 19 13 0.87 24 18 0.76
Number of patients with CDC II 12 (24%) 16 (24%) 14 (25%) 18 (26%) 12 (38%) 11 (46%) 14 (41%) 16 (50%)
CDC IIIa
1 1 1 1 1 6 4 6 5
2 0 0 0 0 0 1 0 1
3 0 0 0 0 1 0 1 0
Total number of CDC IIIa 1 1 1.0 1 1 9 6 1.00 9 7 0.83

Number of patients with CDC 1 (2%) 1 (1.5%) 1 (18%) 1 (14%) 7 (22%) 5 (21%) 9 (26%) 7 (22%)
IIIa
CDC IIIb
1 1 3 1 3 8 1 9 3
2 0 1 0.32 0 1 1 0 1 0
3 0 0 0 0 0 0 0 0
4 0 0 0 0 0 0 0 0
5 0 0 0 0 1 0 1 0
Total number of CDC IIIb 1 5 0.32 1 5 0.32 15 1 0.026 16 3 0.022

Number of patients with CDC 1 (2.0%) 4 (6.0%) 1 (1.8%) 4 (5.7%) 10 (31%) 1 (4%) 11 (32%) 3 (9%)
IIIb
CDC IV 0 0 0 0 0 0 0 0
CDC V 0 0 0 0 0 0 0 0

PP: per protocol analysis.

mITT: modified intention to treat analysis.
TD: thoracodorsal flap.
EXP: expander.
LD: latissimus dorsi flap.
DIEP: deep inferior epigastric flap.
CDC: Clavien Dindo Classification.
a
Number of patients with 1 complication, 2 complications, 3 complications etc in each category.

performance bias. It is impossible to blind both the patient and the
surgeon in a study such as this. Indeed, the most common cause for
a patient not receiving the randomized procedure was the patient
not wanting a reconstruction at all or desiring a different procedure
from that originally randomized (Fig. 1). This is common in normal
clinical practice; however, the frequency of patients not receiving
the randomized procedure was uniform (~20% in arms), suggesting
that the effect of drop outs likely did not significantly affect the
results. Moreover, drop-out analysis revealed few differences be-
tween the PP and mITT populations, with statistical analyses
revealing no clear variations (Table 2). In brief, the risk for perfor-
mance bias is considered low in the study.
Third, although standardized systems for reporting complica-
tions allow for comparison between studies and reduce the risks of
underreporting and subjective interpretation [18], there remain
methodological limitations. For example, the CDC and CCI do not
account for the role of oncologic factors in complication suscepti-
bility [23]. However, in the present study, comorbidities, ASA
classification, tumor stage, and adjuvant treatment were similar
within the arms. Therefore, accounting for such factors might not
be relevant for comparing complication frequencies. Nevertheless,
the effect of oncologic factors on complication susceptibility is
important to consider in studies not separately analyzing radiated
and non-radiated patients. Patients receiving radiation are gener-
ally considered to have a worse therapeutic starting position, as
many of them harbor a more advanced tumor and/or exhibit
migration of cancer cells to axillary lymph nodes. In the present
study, this was demonstrated by a higher occurrence of relapse in
radiated patients (Fig. 1). Moreover, radiation complicates and in-
creases the risk of reconstructive surgery, which is reflected by
higher complication frequencies (Tables 2e4). Ideally, a classifica-
tion system for complications in breast reconstruction would
include the effect(s) of oncologic factors on susceptibility to com-
plications in order to allow comparison of a particular reconstruc-
tive technique across different types and stages of breast cancer.
However, as radiated and non-radiate patients were analyzed
separately in the present study, such background factors are not an
issue in this particular study, which is a clear methodological

Please cite this article as: Brorson F et al., Early complications in delayed breast reconstruction: A prospective, randomized study comparing
different reconstructive methods in radiated and non-radiated patients, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2020.07.010
 F. Brorson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx 9

Table 4
Detailed number of systemic complications.

Complication (CDC) Non-radiated arm PP Radiated arm PP

TD (n ¼ 51) EXP Stage I (n ¼ 66) EXP Stage II (n ¼ 66) LD (n ¼ 32) DIEP (n ¼ 24)

PONV (I) 12 17 5 6 8
Constipation (I) 1 0 0 2 4
Allergic reaction (II) 2 1 2 1 1
Cardiovascular event (II) 1 1 0 0 0
Pneumonia (II) 0 1 1 0 0
Pulmonary embolism (II) 0 1 0 0 0
Deep venous thrombosis (II) 0 0 0 0 0
Asthmatic episode (II) 0 2 0 0 0
Transfusion (II) 0 0 0 2 7

Total 16 23 8 11 20

PONV:Postoperative nausea and vomiting.

CDC: Clavien Dindo Classification.
PP: per protocol analysis.
mITT: modified intention to treat analysis.
TD: thoracodorsal flap.
EXP: expander.
LD: latissimus dorsi flap.
DIEP: deep inferior epigastric flap.

Table 5
Predictors for any complication.

Non-radiated arm: TD vs. EXP Radiated arm: DIEP vs. LD

PP mITT PP mITT
a
Odds ratio p-value Odds ratio p-value Odds ratio p-value Odds ratio p-value

Age (years) 1.07 (0.68e1.68) 0.76 1.09 (0.70e1.69) 0.78 0.56 (0.20e1.56) 0.27 0.81 (0.35e1.186) 0.62
BMI (kg/mb) 0.85 (0.43e1.67) 0.63 1.40 (0.83e2.36) 0.21 2.41 (0.67e8.59) 0.18 2.46 (0.75e8.03) 0.14
BMI > 25a (kg/mb) 0.75 (0.36e1.58) 0.45 0.78 (0.38e1.64) 0.52 6.42 (1.25e32.84) 0.026* 5.26 (1.05e26.48) 0.044*
Tobacco 0.65 (0.25e1.69) 0.38 0.90 (0.38e2.18) 0.82 0.79 (0.17e3.60) 0.76 1.09 (0.27e4.41) 0.91
Any comorbidity 1.85 (0.87e3.82) 0.11 2.09 (1.01e4.32) 0.046* 1.78 (0.47e6.69) 0.39 1.86 (0.51e6.81) 0.35
ASA 2.41 (0.97e5.98) 0.059 2.63 (1.07e6.49) 0.035* 1.95 (0.21e17.83) 0.56 2.79 (0.32e24.02) 0.35
Operating time 1.58 (0.89e2.79) 0.12 1.63 (0.94e2.81) 0.080 1.32 (0.94e1.84) 0.11 1.21 (0.87e1.67) 0.25
Contralateral procedure 1.42 (0.51e4.01) 0.49 1.39 (0.53e3.62) 0.50 3.85 (1.05e14.12) 0.042* 3.59 (1.02e12.62) 0.046*
Surgical experienceb 0.99 (0.55e1.79) 0.97 1.05 (0.59e1.85) 0.87 0.64 (0.22e1.89) 0.42 0.52 (0.18e1.29) 0.22
Previous BCS 1.24 (0.33e4.65) 0.75 1.13 (0.30e4.23) 0.86 þ infinity 0.28 þ infinity 0.31
Tumor stagec 1.03 (0.63e1.68) 0.91 1.03 (0.65e1.64) 0.90 1.11 (0.37e3.29) 0.85 0.94 (0.33e2.69) 0.92
Chemotherapy 0.96 (0.40e2.29) 0.92 0.86 (0.36e2.05) 0.87 0.36 (0.004e3.22) 0.36 0.32 (0.04e2.72) 0.30

PP: per protocol analysis.

mITT: modified intention to treat analysis.
TD: thoracodorsal flap.
EXP: expander.
LD: latissimus dorsi flap.
DIEP: deep inferior epigastric flap.
ASA: American Society of Anesthesiologists classification of physical status.
BCS: breast conserving surgery.
a
Median (range).
b
Experience of most senior surgeon.
c
Tumor stage according to the TNM (Tumor, Node, Metastasis) classification.

strength. hematoma and complete flap failure, we described specific com-

The CDC and CCI have not been validated for plastic surgery,
thereby limiting their utility for application in such a setting. For
example, evacuation of a hematoma is assigned the same grade as
complete flap failure [25], even though the long-term conse-
quences of the former are relatively mild for the patient. In fact,
association of the CCI with long-term disability has not been
investigated [30]. However, such considerations are not important
for comparisons between groups in the same study, because the
same conditions apply for all of the groups. Our results suggest that
the additional value of the use CCI can be questioned and the
recommendation [22] that CDC and CCI should be used together
disputed. We suggest that further studies comparing CDC and CCI
should be conducted. To allow for distinctions that are particularly
relevant in plastic surgery, such as the difference between a
plications in addition to using the CDC and CCI. Therefore, sys-
tematic classification of the complications, as well as the
prospective nature of the study, likely increased the reliability of
the reported complication frequencies. In summary, we consider
the CDC and CCI accurate enough for plastic surgery, but the sys-
tems could be finetuned to better capture complications of partic-
ular relevance in a reconstructive setting.
Conclusion
This represents a prospective, randomized study of complica-
tions following delayed breast reconstruction according to Clavien-
Dindo. It is the first study that reports complications in a way that
allows for comparison between studies and reduce the risks of

Please cite this article as: Brorson F et al., Early complications in delayed breast reconstruction: A prospective, randomized study comparing
different reconstructive methods in radiated and non-radiated patients, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2020.07.010
10 F. Brorson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx
underreporting and subjective interpretation. This is a prerequisite
for high evidence information on complication rates. The usage of
the Clavien-Dindo scale in reconstructive surgery is feasible, but
further validation is needed. The study shows that, in non-radiated
patients, the frequencies of short-term complications were similar
for the TD and EXP groups, whereas in radiated patients, they were
similar for the DIEP and LD groups. Nonetheless, the complication
profile of the different methods varied. Although the frequency of
short-term complications is important to consider when choosing a
surgical method, other factors, including long-term consequences,
costs, and patient satisfaction, also need to be analyzed to provide a
more comprehensive picture.
Source of funding
The study was funded by grants from the federal government
under the ALF agreement (ALFGBG-724171) and The Percy Falk
Foundation for research into prostate cancer and breast cancer.
Role of the funding sources
The funding sources had no role in the design, conduct, analysis,
and reporting of the study.
CRediT authorship contribution statement
Fredrik Brorson: Conceptualization, Methodology, Formal
analysis, Investigation, Data curation, Writing - review & editing.
Andri Thorarinsson: Conceptualization, Methodology, Investiga-
tion, Writing - review & editing. Lars Ko € lby: Conceptualization,
Methodology, Investigation, Writing - review & editing. Anna
Elander: Conceptualization, Methodology, Investigation, Writing -
review & editing. Emma Hansson: Conceptualization, Methodol-
ogy, Investigation, Writing - review & editing, Supervision, Funding
acquisition.
Declaration of competing interest
None.
Acknowledgements
We would like to express our gratitude to our former colleagues,
Dr. Jonas Lundberg and Dr. Richard Lewin, for participating in the
planning stages of the study.
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