British Journal of Cancer (2007) 97, 1211 – 1217
& 2007 Cancer Research UK All rights reserved 0007 – 0920/07 $30.00
www.bjcancer.com
BL Murthy*,1, CS Thomson2, D Dodwell3, H Shenoy1, JS Mikeljevic4, D Forman5 and K Horgan1
1
Department of Surgery, The General Inf irmary at Leeds, Leeds LS1 3EX, UK; 2West Midlands Cancer Intelligence Unit, Public Health Building, University
of Birmingham, Birmingham B15 2TT, UK; 3Department of Clinical Oncology, The General Inf irmary at Leeds, Leeds LS1 3EX, UK; 4Department of Acute
Medicine, St James’s University Hospital, Beckett’s Street, Leeds LS9 7TF, UK; 5Centre for Epidemiology and Biostatistics, University of Leeds, and the
Northern and Yorkshire Cancer Registry and Information Service, Leeds LS16 6QB, UK
Many factors involved in wound healing can stimulate tumour growth in the experimental setting. This study examined the relationship
between wound complications and the development of systemic recurrence after treatment of primary breast cancer. One thousand
and sixty-five patients diagnosed with operable primary invasive breast cancer between 1994 and 2001 were assessed for development
of systemic recurrence according to whether or not a wound complication occurred after surgery, with a median follow-up of 54
months (range 15–119). There were 93 wound complications (9%). There was a statistically significant greater risk of developing
systemic recurrence in patients with wound problems than those without (hazard ratio (HR) 2.87; 95% CI: 1.97, 4.18; Po0.0001). This
remained in a multivariate analysis after adjustment for case mix variables, including Nottingham Prognostic Index (NPI) and oestrogen–
progesterone receptor status (HR: 2.52; 95% CI: 1.69, 3.77; Po0.0001). In the good prognostic NPI group, 4 out of 27 patients (15%)
with wound problems vs 11 out of 334 (3%) without wound problems developed systemic recurrence. The corresponding figures were
10 out of 35 (29%) vs 48 out of 412 (12 %) in the moderate prognostic group and 18 out of 29 (62%) vs 75 out of 199 (38%) in the
poor prognostic group. In 29 patients NPI could not be calculated. Smokers at the time of diagnosis were more likely to develop
metastatic disease than the non-smokers (HR: 1.50; 95% CI: 1.04, 2.15; P ¼ 0.03) after adjustment for other factors. The results suggest
that patients with wound complications at primary surgery have increased rates of systemic recurrence of breast cancer.
British Journal of Cancer (2007) 97, 1211 – 1217. doi:10.1038/sj.bjc.6604004 www.bjcancer.com
Published online 30 October 2007
& 2007 Cancer Research UK
Keywords: breast cancer; wound healing; prognosis; breast surgery
Experimental work suggests that many factors involved in wound
healing can stimulate tumour growth. Factors studied in this
setting include TNFa, VEGF, epidermal growth factor, fibroblast
growth factor, PDGF and pro-inflammatory cytokines such as
interleukins 1 and 6 (Dvorak et al, 1995; Abramovich et al, 1999;
Balkwill and Mantovani, 2001; Coussens and Werb, 2002). Dvorak
(1986) described cancers as ‘wounds that do not heal’. As far as we
are aware, there is no published evidence on the influence of
delayed wound healing on the systemic recurrence rate in breast
cancer.
The incidence of wound complications after breast cancer
surgery ranges from 6 to 30% (Sorenson et al, 2002; Tran et al,
2003; Hall and Hall, 2004) and is increased if there is associated
axillary surgery. The aim of this study was to examine the
relationship between wound complications and systemic recurrence after excision of primary operable breast cancer.
PATIENTS AND METHODS
The records of all patients with primary invasive breast cancer
diagnosed under the care of a single surgeon (KH) in a specialist
*Correspondence: Dr BL Murthy; E-mail: kieran.horgan@leedsth.nhs.uk
Received 1 June 2007; revised 23 August 2007; accepted 31 August
2007; published online 30 October 2007
breast care unit from February 1994 to December 2001 were
retrospectively identified from cancer registry, pathology and
radiology databases. Information was extracted from case notes of
the patients by a single abstractor (BLM). An independent audit of
a random sample of 20 re-extracted notes was undertaken (HS)
and the quality of original data extraction examined. The audit
showed three minor disagreements on lymphovascular invasion
and total tumour size, including background in situ disease but
was otherwise in agreement with the main database. Patients with
bilateral tumours, with initial systemic metastases, and having
primary endocrine treatment for more than 1 year before palliative
surgical treatment were excluded from the study. However,
patients who had neo-adjuvant chemotherapy followed by surgical
treatment, were included. For the purpose of this study, a wound
complication was defined as any wound breakdown that occurred
before the completion of adjuvant chemotherapy and radiotherapy
and that needed surgical debridement, dressing, or packing or any
persistent discharge from the wound. Erythema alone of the
wound was not included.
The study comprises patients with primary operable breast
cancer admitted under the care of one NHS consultant
and managed by a team including consultants of different
disciplines, such as oncology, and also trainees and so represented
a typical NHS teaching hospital scenario. All surgeries
were performed by the consultant or by a trainee under
supervision.
Clinical Studies
Postoperative wound complications and systemic recurrence in
breast cancer
Wound complications and systemic recurrence in breast cancer
BL Murthy et al
1212
Clinical Studies
Patients were routinely followed up three-monthly for a year,
six-monthly for 5 years and then annually. Patients not seen in the
clinic during 2003 were followed up through their General
Practitioner, and their notes in the Oncology Centre were checked
for evidence of any recurrence. Systemic recurrence was defined as
any recurrence away from the breast, axillary or internal mammary
node regions. Data on deaths were extracted from the Northern
and Yorkshire Cancer Registry and Information Service in June
2004. The censoring date for data collection was 31 January 2004.
This was taken as the date the patients were last known to be alive
and without symptomatic disease, unless they were found to be
genuinely lost to follow-up. As this was a retrospective case note
audit, formal ethical approval was not required. The funding
source for this study was the Breast Cancer Research Action Group
and the Leeds Teaching Hospital NHS trust provided salary
support for the authors (KH, DD, BLM and HS); neither of them
had a role in study design, data collection, analyses, interpretation,
and writing of the report or on the decision to submit for
publication.
STATISTICS
Associations between factors of interest and whether or not a
patient had a wound complication were examined using the w2-test
of association.
Systemic recurrence-free survival analysis was performed with
the end point being the development of systemic disease. Patients
were censored at death for those who had not recurred
systemically, at the date last seen in the clinic, if this was during
2003, or at 31 January 2004 for those patients last seen in the clinic
before 2003, unless the patients had been lost to follow-up. The
starting point was taken as the date of first breast surgery.
Kaplan – Meier survival analysis was performed to plot survival
curves and to estimate point estimates of 5-year survival from the
date of the first operation. Equality of the survival curves was
assessed using the Log Rank test. The difference in 5-year systemic
recurrence-free survival between the patients having wound
complications and those who did not was calculated along with
an estimate of its standard error from the Kaplan – Meier analyses.
The s.e. for the difference was calculated by taking the square root
of the sum of the squared s.e.’s obtained for each of the 5-year
survival estimates for the two groups of patients under the
assumption of independence of the two groups. The numbers at
risk in both the ‘wound complication’ and ‘no wound complication’ groups are also presented.
Both univariate and multivariate hazard ratios of systemic
recurrence were obtained using Cox’s proportional hazards
models. The patient factors examined were age group at first
surgery, co-morbidity (diabetes, angina, hypertension, peripheral
vascular disease, renal, chronic skin problems), diabetes alone and
whether the patient was a smoker at the time of diagnosis. The
tumour factors were the Nottingham Prognostic Index (NPI)
(Elston and Ellis, 1991) calculated from histological grade 1, 2 or
3 þ Nodal status (no positive nodes ¼ 1, 1 – 3 nodes ¼ 2 and 43
nodes positive ¼ 3) þ 0.2 size of the tumour in cm, oestrogen –
progesterone receptor (ER/PR) positivity status and node positivity status. Finally, the treatment factors were type of initial
definitive breast surgery (wide local excision (WLE) or mastectomy), final primary breast cancer surgery, breast conservation or
mastectomy, use of radiotherapy, use of chemotherapy and use of
hormone therapy. Axillary node surgery does not include sentinel
node procedures during the time frame of the series. Additionally,
the occurrence of a wound complication following surgery was
examined.
The univariate hazard ratios were obtained by including each
factor separately in a different Cox’s proportional hazards model.
A multivariate Cox model containing only the main effects for
British Journal of Cancer (2007) 97(9), 1211 – 1217
these factors was then obtained by forcing all of the factors into the
model. All analyses were performed using SPSS version 10.1.4. All
the analyses were considered statistically significant when the
P-value was less than 0.05.
RESULTS
General characteristics
A total of 1105 patients diagnosed with operable breast cancer
between February 1994 and December 2001 under the care of a
single surgeon were identified. Patients with bilateral tumours
(33), with initial systemic metastasis (1), those having only axillary
surgery (1) and those having primary endocrine treatment for
more than 1 year before palliative surgical treatment (5) were
excluded from the study. Thus, 1065 patients with operable
primary breast cancer were included and they received 1356
operations in total. Initially, 426 women underwent mastectomies,
478 women WLE and 161 women had open diagnostic biopsies. Of
these open biopsies, 81 women had a subsequent mastectomy, 76
had a subsequent WLE and 4 women no further surgery. Thus, the
initial definitive surgery was breast conservation in 558 (52%) and
mastectomy in 507 (48%) women. However, a total of 86 women
having WLE needed a completion mastectomy (10 of whom had
originally had an open biopsy), and so the final status of the breast
was conserved in 472 (44%) and 593 (56%) patients who had a
mastectomy. The minimum follow-up duration from the date of
first surgery was 15 months with a median follow-up of 54 months
(range 15 – 119 months). There were 13 (1%) patients who were
lost to follow-up (3 went abroad, 3 went out of region and 7 could
not be traced), with a median follow-up of 8 months (range 0 – 50).
The age at first surgery ranged from 22 to 98 years (median age
58 years). Of the 1065 patients, 228 (21%) had a poor NPI score,
447 (42%) had a moderate score and 361 (34%) were in the good
NPI group. There were 29 (3%) patients for whom the NPI could
not be calculated (10 patients underwent a mastectomy and 15 had
breast conservation but did not have any axillary surgery, 2 had
axillary surgery but the numbers of nodes removed/examined was
not known and the other 2 had neo-adjuvant treatment before
surgery for the residual tumour). The size of the tumour ranged
from 1 to 220 mm, with a median of 20 mm. There were 857
patients (81%) who were ER or PR positive, and 487 patients (46%)
had metastatic involvement of their axillary lymph nodes.
Ninety-three (9%) patients had wound complications (7% of the
total 1356 operations). Of these, 70 involved mastectomy wounds
(53 after initial mastectomy and 17 after initial breast surgery and
subsequent mastectomy), 12 involved WLE wounds and 11 the
separate axillary dissection wound associated with WLE to the
breast. There was a total of 73 breast reconstructions; 4 of these
patients had wound complications. The number of contralateral
breast cancers was 4 in the 93 patients having wound complications and 29 in the 972 patients without wound complications.
There was no significant delay in the administration of systemic
adjuvant treatment for the patients who developed wound
complications if they required such treatment.
Table 1 shows a significantly increased incidence of wound
problems in smokers than in non-smokers (15 vs 7%; P ¼ 0.001);
for diabetics compared to those without diabetes (20 vs 8%;
P ¼ 0.03) and for those patients having a mastectomy compared
with breast conservation (12 vs 5%; Po0.001) as the final breast
surgery.
Follow-up
There were 172 patients with a systemic recurrence diagnosed by
31 January 2004, and of these 115 patients had died of metastatic
disease. There were also 45 non-cancer-related deaths in patients
& 2007 Cancer Research UK
Wound complications and systemic recurrence in breast cancer
BL Murthy et al
0.34
0.64
DISCUSSION
All patients Wound complication
Number
Number
%
Age group at surgery (years)
o50
50 – 64
65 – 74
75+
294
423
212
136
21
46
16
10
7.1
10.9
7.5
7.4
Any co-morbidity
Yes
No
287
778
31
62
10.8
8.0
Current smoker
Yes
No
230
835
34
59
14.8
7.1
35
1030
7
86
20.0
8.3
ER/PR status
Positive
Negative
857
208
70
23
8.2
11.1
Node status
Positive
Negative
Not known
487
550
28
49
42
2
10.1
7.6
7.1
NPI statusb
Good
Intermediate
Poor
Not known
Total
361
447
228
29
1065
27
35
29
2
93
7.5
7.8
12.7
6.9
8.7
Final breast surgery
Mastectomy
Wide-local excision
593
472
70
23
11.8
4.9
Use of radiotherapy
Given
Not given
748
317
61
32
8.2
10.1
Use of chemotherapy
Given
Not given
338
727
27
66
8.0
9.1
879
186
1065
76
17
93
8.6
9.1
8.7
Diabetes
Yes
No
Use of hormone therapy
Given
Not given
Total
P-valuea
0.25
0.18
0.001
0.03
0.22
0.37
0.12
o0.001
0.78
a 2
w -test for association. bWhen the 29 patients with NPI status unknown were
excluded from the analysis, the association between NPI status and wound
complication was marginally nonsignificant (P ¼ 0.06).
who had not developed metastatic disease. There were 21 patients
who had isolated local recurrence (2%), and of these 4 patients
later developed systemic metastases. The 5-year systemic recurrence-free survival estimate for all patients was 82.2% (95% CI:
79.6, 84.9), with corresponding figures for the NPI groups of 95.6%
(93.1, 98.2) for the good prognostic group, 85.9% (82.2, 89.6) in the
moderate prognostic group and 53.8% (46.3, 61.3) in the poor
prognostic group.
When univariate Cox regression models were fitted (Table 2),
the factors that significantly affected the chances of developing a
systemic recurrence in the univariate analyses were NPI score, ER/
& 2007 Cancer Research UK
Wound complications after excisional surgery for primary breast
cancer are not uncommon, particularly when surgery includes
axillary node dissection. This study demonstrates a statistically
significant relationship between the occurrence of a wound
complication and the subsequent rate of development of systemic
breast cancer recurrence. The magnitude of this deleterious effect
(three-fold increase risk in the risk of developing metastatic
disease) is of importance because it is similar to the size of benefit
seen by giving adjuvant treatment to women with early breast
cancer; for example, the effect of giving polychemotherapy after
surgery to those with ER poor tumours is 0.61 compared with
those not given it (Early Breast Cancer Trialist Collaborative
Group, 2005a) or giving radiotherapy after breast-conserving
surgery is 0.31 compared with those not given it (Early Breast
Cancer Trialist Collaborative Group, 2005b).
It is of interest that locoregional recurrence was not increased by
the occurrence of a wound complication and remained low for the
total patient cohort. The putative deleterious influence of a wound
complication appears to relate to systemic factors. The fact that
smokers were more likely to develop wound complications, but
also more likely to develop a systemic recurrence, does not explain
the observed effect of those patients having a wound complication
British Journal of Cancer (2007) 97(9), 1211 – 1217
Clinical Studies
1213
PR status, type of final breast surgery, use of radiotherapy, use of
chemotherapy and use of hormone treatment. Age at first surgery,
any co-morbidity and smoking were not significant in the
univariate analyses. However, there was also a statistically
significant relationship between the occurrence of wound complication after breast cancer surgery and the development of later
systemic recurrence (Po0.0001). There was a difference of 21.5%
(10.7, 32.3) in 5-year systemic recurrence-free survival figures for
those patients not having a wound complication (84.2%; 95% CI:
81.5, 86.8) compared with 62.7% (52.2, 73.1) for those who did
(Figure 1). The corresponding hazard ratio for developing a
systemic recurrence was 2.87 (95% CI: 1.97, 4.18) for those having
a wound complication (34 out of 93; 37%) relative to those who did
not have a wound complication (138 out of 972; 14%).
This relationship remained after adjustment for case mix
variables, including NPI status and ER/PR status in the multivariate model (hazard ratio 2.52; 95% CI: 1.69, 3.77; Po0.0001;
Table 2). Figure 2A – C shows that this relationship is generally
maintained across all the NPI groups, with those patients not
having postoperative wound complications having better systemic
recurrence-free survival times than those who did have wound
complications, for each of the NPI groups. The corresponding
5-year systemic recurrence-free survival estimates are also shown
in Figure 2. Despite there appearing to be differences in the
proportions of patients having a systemic recurrence with and
without postoperative wound complications for the different NPI
groups (Table 3), the interaction between the NPI status factor and
the wound complication factor was not statistically significant in
the multivariate model (P ¼ 0.78) when the 29 cases with NPI
status unknown were excluded from the analyses, showing that the
factors acted independently on the hazards of developing a
systemic recurrence.
Multivariate modelling revealed that NPI status and ER/PR
status both independently and significantly affected the chances of
developing metastatic disease in addition to the deleterious effect
seen for patients having a wound complication (Table 2). There
was also a borderline significant effect for type of final breast
surgery (P ¼ 0.03), with patients who had a mastectomy being at
higher risk of developing a systemic recurrence than those who
had breast conservation. Similarly, those patients who smoked at
diagnosis also had a slightly higher risk of developing metastatic
disease (P ¼ 0.03).
Table 1 Number and percentage of patients with wound complications
according to different factors
Wound complications and systemic recurrence in breast cancer
BL Murthy et al
1214
Table 2
Unadjusteda and adjustedb hazard ratios of a systemic recurrence with a median of 54 months follow-up, based on all cases (n ¼ 1065)
No. of cases
Unadjusted hazard of systemic
recurrence (95% CI)
Wound complication occurred
Yes
No
93
972
2.87 (1.97, 4.18)
1.0
Age group (years)
o50
50 – 64
65 – 74
75+
294
423
212
136
1.0
0.75 (0.52, 1.07)
0.73 (0.47, 1.13)
0.78 (0.47, 1.31)
Any co-morbidity
Yes
No
287
778
0.92 (0.65, 1.30)
1.0
Smoker
Yes
No
230
835
1.29 (0.92, 1.81)
1.0
ER/PR status
Positive
Negative
857
208
1.0
2.97 (2.18, 4.04)
NPI statuse
Good
Intermediate
Poor
361
447
228
1.0
3.32 (1.89, 5.87)
13.35 (7.73, 23.04)
Factor
Clinical Studies
Final breast surgery
Mastectomy
Wide-local excision
P-valuec
Adjusted hazard of systemic
recurrence (95% CI)
o0.0001
o0.0001
2.52 (1.69, 3.77)
1.0
0.35
0.78
1.0
0.94 (0.63, 1.41)
1.18 (0.67, 2.08)
1.21 (0.59, 2.49)
0.62
0.58
0.89 (0.60, 1.34)
1.0
0.14
0.03
1.50 (1.04, 2.15)
1.0
o0.0001
o0.0001
1.0
2.22 (1.45, 3.40)
o0.0001
o0.0001
1.0
2.59 (1.42, 4.72)
8.30 (4.28, 16.09)
0.03
o0.0001
593
472
1.0
0.41 (0.29, 0.58)
Use of radiotherapy
Given
Not given
748
317
1.77 (1.23, 2.54)
1.0
Use of chemotherapy
Given
Not given
338
727
2.79 (2.07, 3.77)
1.0
Use of hormone therapy
Given
Not given
879
186
0.62 (0.43, 0.88)
1.0
P-valued
1.0
0.63 (0.42, 0.96)
0.002
0.07
1.50 (0.96, 2.34)
1.0
0.73
o0.0001
1.09 (0.68, 1.73)
1.0
0.008
0.96
1.01 (0.63, 1.63)
1.0
a
Derived from univariate Cox’s proportional hazards models. bDerived from a multivariate Cox’s proportional hazards model. cP-values for the factors are the Wald statistics for
the estimates in each univariate model. dP-values for the factors are the Wald statistics for the estimates in the model, conditional on the other factors being present. eTwentynine patients with NPI status not known were excluded.
being more likely to recur systemically, given that both factors
were significant in the multivariate model. This suggests that they
both increase the likelihood of getting metastatic disease in the
presence of the other factors. The interaction between the two
factors was not significant (P ¼ 0.72), indicating that the effect of
developing a systemic recurrence for those patients having a
wound complication compared to those who did not was the same
whether or not the patient smoked at the time of diagnosis.
Fentiman et al (2005) reported that in a series of 166 women with
stage 1 or 2 invasive breast cancer, smoking was the third most
important predictor of distant relapse-free breast cancer-specific
and overall survival after stage and age at diagnosis. A large
overview of 53 epidemiological studies (Collaborative Group on
Hormonal Factors in Breast Cancer, 2002) found that smoking had
little or no effect on the risk of initially developing breast cancer.
The data in our study demonstrated a marginally significant
association between mastectomy as the final breast status and the
occurrence of systemic metastases. Most of the reasons for such an
association should be linked to tumour variables such as size,
grade and nodal involvement. The association after we had taken
British Journal of Cancer (2007) 97(9), 1211 – 1217
into account the influence of those tumour variables is not obviously
explained, although it is possible that it is linked with socioeconomic deprivation. The area serving the Leeds Teaching
Hospitals Trust has a population with relatively high levels of
deprivation, and previous work in both Scotland (Thomson et al,
2001, 2004) and Yorkshire (Downing et al, 2007) has shown that
deprived women are, especially those aged under 65 years at
diagnosis, more likely to undergo a mastectomy than WLE. These
studies also showed that deprivation was associated with poorer
survival, so it is reasonable to assume an association with the
occurrence of systemic recurrences, although we have not specifically
examined this in our study. It is also possible that the association
between final breast surgery and the occurrence of systemic
recurrences is associated with other tumour-associated characters
not adjusted for, or is in some other way related to the greater
magnitude of surgery involved in a mastectomy than WLE. Other
studies have shown increased rates of wound complication rates with
axillary surgery, however our study did not demonstrate this.
While these data do represent a hospital series for a single
surgeon within an NHS Teaching Hospitals Trust, the mastectomy
& 2007 Cancer Research UK
Wound complications and systemic recurrence in breast cancer
BL Murthy et al
1215
Systemic recurrence-free survival curves
1.0
0.9
NWC=no wound comp
0.7
0.6
0.5
WC = wound comp
0.4
Log-rank, P < 0.0001
0.3
0.2
0.1
0.0
0
10
20
30
40
0
93
972
10
84
938
20
70
863
30
55
722
40
49
578
50
60
70
80
90
100
110
120
80 90
14
9
185 128
100
7
79
110
4
36
120
0
0
Time in months
WC
NWC
50
44
441
60 70
35 22
336 245
Figure 1 Systemic recurrence-free survival curves (Kaplan – Meier by occurrence of wound complication).
and breast conservation rates are similar to other regional data
presented at the annual audit by The Association of Breast Surgery
at BASO 2006 (Breast Cancer Clinical Outcome Measures Newsletter, 2006, 1(1)). It is difficult to obtain comparative published
data of total series of patients, which are just not related to patients
involved in clinical trials. The data for the study were obtained by
retrospective case note review. Patients were followed closely
subsequent to their surgery, and all were seen at clinics within a
short time of hospital discharge to discuss their tumour histology
and plan adjuvant therapy. It is unlikely, therefore, that there is
significant inaccuracy in the recording of whether patients had
wound complications. Indeed, data retrieval was independently
checked using a random sample of cases, which were re-examined,
and it was found to be consistent.
The literature on the influence of wound complications on
cancers at other anatomical sites is sparse and inconsistent.
Improved survival associated with postoperative wound infection
was reported in laryngeal cancer by Schantz et al (1980) and
Ramadan and Witmore (1992).
In contrast Jackson and Rice (1990), Grandis et al (1992) and
Rodrigo and Suarez (1998) reported adverse effects on survival.
Fucini et al (1985), Sauven et al (1989) and Kressner et al (2002)
reported increased local recurrence in colorectal cancers after
perineal wound infection similar to the report of Varty et al (1994).
They found no difference in overall survival and concluded that
there was no overall survival difference for patients with or without
postoperative sepsis following excision of colorectal cancer. This is
in contrast to Fujita et al (1993), who report an increased incidence
of local recurrence as well as poor prognosis. In malignant
melanoma, wound infection at the site of nodal dissection was
associated with fewer nodal recurrences but no change in survival
(Papachristou and Fortner, 1979). Chang et al (2005) recently
reported further studies on wound healing characteristics of
fibroblasts and the link to cancer progression. They found an
association between a ‘wound response signature’ and increased
metastases in a series of early breast cancer patients.
Many cytokines and chemokines are released during wound
healing and inflammation: TNFa, interleukin 6, PDGF and VEGF to
cite a few. Activated macrophages, fibroblasts, smooth muscle cells
and keratinocytes release them along with other inflammatory
& 2007 Cancer Research UK
cytokines. In the experimental setting, TNFa acts as a tumourigenic agent and tumour promoter (Coffey et al, 2003). Various
other mechanisms explain how other factors like VEGF, PDGF and
interleukins influence tumour growth (Dvorak, 1986; Dvorak et al,
1995; Abramovich et al, 1999; Balkwill and Mantovani, 2001;
Coussens and Werb, 2002; Chang et al, 2005). There is also
evidence to suggest that cell-mediated immunity and natural killer
cell function is suppressed by the effect of anaesthesia and the
post-surgical stress response (Bogden et al, 1997). If this ‘window
period’ of decreased immunity is prolonged by wound complications like flap necrosis and breakdown, there may be increased
growth of occult micro metastases. It is not possible to state from
this study if those influences are due to altered immun response or
active promotion of circulating or micrometastatic tumour cells or
some other mechanisms. Retsky et al (2005) suggest ‘surgeryinduced angiogenesis’ as an important cause of the frequently
noted early peak in recurrence rates after breast cancer excision.
They suggest that therapeutic strategies might allow for this effect
by the introduction of anti-angiogenetic drugs at the time of
surgery.
It is of interest that the increase in systemic recurrence rate
subsequent to wound complication was seen across all three
prognostic NPI groups and was of a similar magnitude (Table 3).
This would suggest that intrinsic tumour characteristics reflecting
tumour aggression are not those most influenced by wound
factors.
CONCLUSIONS
The results of this study suggest that delayed wound healing is
associated with an increased rate of systemic recurrence after
primary breast cancer excisional surgery. As this study is only
hypothesis generating and falls short of proving any cause and
effect relationship, the statistically significant effect of having a
wound complication in the multivariate analysis after adjustment
for case mix does suggest that further studies, including
prospective evaluation at more than one centre, are required to
confirm the findings. If the relationship showing the considerable
increase in systemic recurrence rates in patients who have wound
British Journal of Cancer (2007) 97(9), 1211 – 1217
Clinical Studies
Cumulative survival
0.8
Wound complications and systemic recurrence in breast cancer
BL Murthy et al
1216
Systemic recurrence-free survival curves
Cumulative survival
NPI = good
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Systemic recurrence-free
survival at 5 years (95% CI)
NWC=no wound comp
WC = wound comp
Wound complication:
Log-rank, P = 0.02
88.9% (77.0, 100.0)
No wound complication:
96.2% (93.6, 98.8)
0
10
20
30
40
50
60
70
80
90
100
110
120
Clinical Studies
Time in months
WC
NWC
0 10 20 30 40 50 60
27 27 26 25 24 22 16
334 330 315 272 228 177 132
70
13
88
80
9
63
90 100 110 120
4
3
3
0
42 26 13
0
Difference at 5 years
7.3% (0.0, 19.5)
Systemic recurrence-free survival curves
Cumulative survival
NPI = intermediate
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Systemic recurrence-free
NWC = no wound comp
Wound complication:
WC = wound comp
70.5% (53.9, 87.1)
Log-rank, P = 0.002
No wound complication:
87.3% (83.6, 91.0)
0
10
20
30
40
50
60
70
80
90
100
110
120
Time in months
WC
NWC
survival at 5 years (95% CI)
0 10 20 30 40 50 60 70
35 33 28 21 19 18 16
7
412 400 371 316 254 194 154 117
80
3
93
90 100 110 120
3
2
0
0
64 44 20
0
Difference at 5 years
16.8% (0.0, 33.8)
Cumulative survival
Systemic recurrence-free survival curves
NPI = poor
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Systemic recurrence-free
survival at 5 years (95% CI)
Log-rank, P < 0.001
NWC = no wound comp
29.3% (9.6, 49.0)
No wound complication:
W C = wound comp
57.3% (49.3, 65.3)
0
10
20
30
40
0 10 20 30
29 23 16
9
199 184 157 120
40
6
87
50
60
70
80
90
100
110
120
Difference at 5 years
Time in months
WC
NWC
Wound complication:
50
4
64
60
3
46
70
2
37
80
2
26
90 100 110 120
2
2
1
0
8
19
3
0
28.0% (6.7, 49.3)
Figure 2 (A) Systemic recurrence-free survival curves (Kaplan – Meier by occurrence of wound complication) for good NPI. (B) Systemic recurrence-free
survival curves (Kaplan – Meier by occurrence of wound complication) for intermediate NPI. (C) Systemic recurrence-free survival curves (Kaplan – Meier by
occurrence of wound complication) for poor NPI.
Table 3 Numbers having systemic recurrence, with adjusteda hazard ratios of a systemic recurrence with a median of 54 months follow-up, based on all
cases with a known NPI status (n ¼ 1036)
Patients not having a wound complication
No systemic recurrence/
total number
%
NPI status
Good
Intermediate
Poor
11/334
48/412
75/199
Adjusted hazard of systemic
recurrence (95% CI)
3
12
38
1.0
2.8 (1.4, 5.5)
9.1 (4.4, 18.8)
Patients having a wound complication
No systemic recurrence/
total number
%
4/27
10/35
18/29
15
29
62
Adjusted hazard of systemic
recurrence (95% CI)
3.5 (1.1, 11.3)
7.1 (2.9, 17.1)
21.3 (8.9, 50.8)
a
Derived from a multivariate Cox’s proportional hazards model.
British Journal of Cancer (2007) 97(9), 1211 – 1217
& 2007 Cancer Research UK
Wound complications and systemic recurrence in breast cancer
BL Murthy et al
ACKNOWLEDGEMENTS
We thank Cheryl Craigs, NYCRIS, for help with the initial
organisation of the data and preliminary analyses and the Breast
Cancer Research Action Group (BCRAG) for their support for
research salaries.
Declaration
I hereby certify on behalf of all the authors that we accept
responsibility for the conduct of this study and for the analysis and
interpretation of the data. I helped write this manuscript and agree
with the decisions about it. We all meet the definition of an author
as stated by the International Committee of Medical Journal
Editors, and I have seen and approved the final manuscript.
Neither the article nor any essential part of it, including tables and
figures, will be published or submitted elsewhere before appearing
in the journal. The initial findings and analyses of results of this
study were presented in the Association of Surgeons of Great
Britain and Ireland meeting at Harrogate, United Kingdom, in
April 2004, and at the San Antonio Breast Cancer Symposium,
USA, in December 2004, and the abstract was published in Br J
Surg, 2004, 91(41) (Suppl1).
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British Journal of Cancer (2007) 97(9), 1211 – 1217
Clinical Studies
1217
complications at the time of their primary breast cancer surgery
can be supported, then the implications on the surgical process are
substantial. This is because the benefits to systemic recurrence
rates and, ultimately, death, which could be achieved by reducing
wound complications, are of similar magnitude to the known
benefits seen for giving appropriate adjuvant treatment to women
with early breast cancer. Therefore, there is an increased onus on
the surgeon to minimise wound complication by attention to
technique and choice of less risk-associated interventions in a
multi-disciplinary environment, which may include preoperative
anti-angiogenic therapies.