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A study of margin width and local recurrence in breast conserving
therapy for invasive breast cancer.
J. Michael Dixon1, Jeremy Thomas1, Gillian R Kerr1, Linda J Williams1
Christine Dodds1, Ian H Kunkler1, E. Jane Macaskill2
1 Edinburgh
Breast Unit, Western General Hospital, Edinburgh
of Breast Surgery, Ninewells Hospital and Medical School,
Dundee, DD1 9SY
2 Department
Corresponding author:
Professor J. Michael Dixon,
Professor of Surgery and Consultant Surgeon,
Clinical Director, Breast Cancer Now Research Unit, Edinburgh,
Edinburgh Breast Unit,
Western General Hospital,
Edinburgh
EH4 2XU
Scotland, UK.
Tel: +44 131 537 2643,
Fax: +44 131 537 2653,
E-mail: [email protected].
1
ABSTRACT
Purpose
Debate continues on what is an adequate margin width to define a clear
margin and whether there is a need to excise pectoral fascia or remove skin in
breast conserving surgery. This study set out to provide answers to these
questions.
Patients and Methods
1411 patients with invasive breast cancer were treated by breast conserving
surgery and post- operative whole breast radiotherapy from January 2000 to
December 2005. Distance from each margin to any in situ or invasive cancer
was measured and recorded. If full thickness of breast tissue was removed no
re excision of anterior and posterior margins was performed even if disease
was <1mm from a margin. Patients ≤50 years of age and those with anterior
or posterior margins <1mm to invasive cancer had a radiation boost. Median
follow-up time was 6.4 years.
Results
Local in breast tumour relapse (IBTR) occurred in 50 patients. The overall
actuarial IBTR rate at 5 years was 2.2%. There was no difference in IBTR
when comparing patients with radial margins of 1-5mm or 5-10mm. Anterior
and posterior margins <1mm or with ink on tumour cells were not associated
with an increase in IBTR.
Conclusion
There is no justification for radial margins of greater than 1mm. If the anterior
or posterior margin is <1mm and full thickness of breast tissue has been
2
removed, then re excision of these margins is unnecessary if boost
radiotherapy is delivered.
3
INTRODUCTION
Numerous randomised controlled clinical trials have established the safety
and effectiveness of breast conserving therapy in the treatment of early
invasive breast cancer 1-5. Breast conserving therapy consists of complete
excision of all invasive and in situ breast cancer followed by radiation therapy.
The need for whole breast radiotherapy has been established by a series of
trials showing not only that radiation produces a significant reduction in local
recurrence following breast conserving surgery but provides a long term
survival benefit with an estimated 5.4% absolute reduction in breast cancer
deaths at 15 years 6. The breast after breast conserving surgery must look
satisfactory in terms of cosmetic appearance 7-8 if one is to maximise the
psychological benefits of breast preservation 9, 10. Numerous studies have
investigated patient, tumour and therapeutic factors that influence the risk of
in-breast local recurrence (IBTR) following breast conserving surgery for
invasive breast cancer 6-8, 11-24. Much of the literature has focused on the type
and extent of surgery and the status of the surgical margins.
The risk of local recurrence is increased significantly if the surgical margins
are positive (tumour cells are present at the resection margin) 8, 11, 13, 16, 18, 20,
23, 25-29. There
is huge variation in practice between individual clinicians,
centres and countries as to what constitutes an adequate margin width
following breast conserving surgery. This lack of agreement is evident in
surveys and consensus reports 13, 30-32. There is emerging evidence that
4
shows that increasing the negative margin width will not reduce local
recurrence rates11, 14, 33, 34.
Little attention in the literature has been paid to which margins matter most.
Many advocate removal of a cylinder of breast tissue from the subcutaneous
fat down to the pectoral fascia10, 35. Advocates argue that this controls the
front and back margins even if these margins are involved. There is however
no consensus on this issue because if disease is reported within one
millimetre of the anterior margin, 35% of surgeons would re-excise and if
disease is reported <1mm from the posterior margin 10% would re-excise. 30
Some surgeons take pectoral fascia routinely, while others do not.
The Edinburgh Breast Unit is the largest single Breast Unit in the United
Kingdom. A prospective database is kept of all patients treated by the team of
surgeons and oncologists in Edinburgh. The primary aim of the current study
was to investigate from a prospectively collected dataset whether local
recurrence rates vary in relation to margin width. The second aim was to
determine whether local recurrence rates are increased in patients who have
anterior and posterior margins <1mm but who have had full thickness of
breast tissue excised and were not subjected to re-excision of these margins.
PATIENTS AND METHODS
Patients diagnosed and treated with invasive breast cancer between 1 st
January 2000 to 31st December 2005 who were treated by breast conserving
5
surgery and had whole breast radiotherapy in the Edinburgh Cancer Centre
were identified from the South East of Scotland Cancer Area Network (SCAN)
prospective database. Patients had a core biopsy to establish a diagnosis of
invasive cancer. Following full imaging assessment of the primary cancer,
axillary nodes and appropriate scans to detect metastatic disease, all patients
were discussed at a multidisciplinary team meeting. Patients who underwent
breast conserving surgery by a team of specialist surgeons based in the
Edinburgh Breast Unit were identified from the data base. Patients having
breast conserving surgery after neoadjuvant chemo or hormonal therapy were
excluded. The aim was to excise the cancer with a 1cm macroscopic margin.
In almost all patients (>95%) full thickness of breast tissue from subcutaneous
fat down to pectoral fascia was removed. All specimens were orientated in a
standard fashion with metal clips and underwent intra-operative specimen
radiography and where appropriate further tissue was removed36. It was not
routine to take cavity shavings: the only margins that were re-excised were
those considered involved based on the routine specimen radiograph or on
palpation by the surgeon. It was not routine practice to remove skin overlying
the cancer or pectoral fascia. Only patients with cancers that were considered
very close to the overlying skin or were involving pectoral fascia before or
during surgery had these excised.
All excision samples were fixed immediately in formalin. They were processed
by specialist breast pathologists in a standard manner with specimens being
sliced parallel to the chest wall. Standard pathology reports were issued and
included the microscopically measured distance in mm to all six margins
6
(anterior, posterior and the radial margins: medial, lateral, superior and
inferior). The distance in mm from the surgical margin to the edge of both
invasive and in situ cancer was reported. All patients were then discussed at a
second multidisciplinary meeting after surgery when the full pathology report
was available. If a radial margin (medial, lateral, superior or inferior) was less
than 1mm clear of either invasive cancer or DCIS, then re-excision was
advised unless the surgeon reported in the operation note that he or she had
excised tissue to the limit of the breast at that margin. If the pathologist
reported disease <1mm from the anterior or posterior margin of the specimen
and full thickness of breast tissue had been taken and this had been recorded
by the operating surgeon, then no re-excision of these margins was
performed even if there was tumour on ink. Patients having a re-excision were
considered to have clear margins if the new radial margin was 1mm or greater
from both invasive and in situ disease. A small number of patients underwent
more than one re-excision to obtain clear margins.
All patients had adjuvant systemic therapy (see Table 1) and whole breast
radiotherapy and received a whole breast dose of 45 Gray in 20 fractions.
Patients aged 50 years of age or younger and patients who had an anterior or
posterior margin distance to invasive cancer of <1mm received a tumour bed
boost of 15 Gray delivered by external beam radiotherapy. Patients with DCIS
within 1mm of anterior or posterior margins did not receive a boost. All
patients had an annual review consisting of clinical examination and two view
mammography. Patients with suspicious abnormalities on clinical or
mammographic assessment were investigated further by ultrasound and/or
7
core biopsy to establish the presence or absence of any in-breast tumour
recurrence. The median follow-up time was 6.4 years. All patients with a
diagnosis of invasive or in situ disease which occurred anywhere in the
treated breast were considered to have in breast tumour relapse (IBTR).
Cross tabulation with other databases and clinical records confirmed the
validity and completeness of the data and allowed confirmation of all in breast
tumour recurrence events.
Statistical methods
Actuarial survival and relapse rates were calculated using the Kaplan-Meier
method37. The log rank test was used for statistical comparison between
curves38. A Cox proportional hazards regression model39 was used to assess
the independent prognostic significance of variables. All factors listed in Table
1 and all available clinical and histological factors including histological type
were included in the analysis. Not all patients could be included in the
proportional hazards analyses due to incomplete data for some variables.
RESULTS
We identified 1411 patients treated by breast conserving surgery and postoperative whole breast radiotherapy during the study period. Of these 1411,
only 57 patients (4.0%) had any skin or pectoral fascia excised. The median
age of patients was 58 years with an age range of 20-89 years and all were
female. One patient had no axillary surgery. An axillary node clearance was
carried out in 249 patients (18%) with the remaining 1161 having a sentinel
8
node biopsy and/or a 4 node axillary node sample. The clinical and pathology
details of the whole group are shown in Table 1.
The overall actuarial 5 year survival for the whole group was 91.1% (95.0%
breast cancer specific survival). Local in breast relapse (IBTR) occurred in 50
patients. The overall actuarial IBTR rate at 5 years was 2.2% (95% CI 1.4% 3.0%). Patients were classified on the basis of final margin widths into four
groups <1mm (the majority of these patients had anterior or posterior margins
<1mm see Table 1), 1-5mm, >5mm and margins negative after re excision.
Two factors differed between these four groups [Table 1]. Patients who
required re-excision to achieve clear margins were on average 3 years
younger than the other three groups of patients. The mean ages of the groups
with margin widths of <1mm, 1-5mm and 5-10mm varied from 58.5 - 58.8
years; in comparison the mean age for the group with clear margins only after
re-excision was significantly younger at 55.9 years; this difference was
significant (t test p = 0.004).
Patients in the groups with margins < 1mm and those with clear margins after
re-excision were more likely to have multifocal disease (14.2%) compared
with those with a margin widths of 1-5mm or >5mm (6.9%), (both variables
available for 85.6% of the group) p < 0.001.
The in breast tumour recurrence rate (IBTR) at 5 years for each margin width
category is shown in Table 2 [Table 2]. The cumulative actuarial probability of
9
recurrence for each of the four groups is shown in figure 1 [Fig 1]. For all
distances the 5 year IBTR rate was no more than 0.5% per annum. For
patients with a distance to margin of less than 1mm, the number of IBTR was
small (7/218). There were no patients with a posterior margin width of <1mm
who developed an IBTR by 5 years (0/75). Three patients (2.7% at 5 years)
with an anterior margin width of <1mm developed IBTR. Few patients had
both anterior and posterior margin involvement and/or radial margin positivity.
Although numerically these patients appeared to have higher rates of IBTR
(3/45), no conclusions can be drawn because this group of patients was
small.
Multivariate analysis
In the proportional hazards analysis the distance to the nearest radial margin
was the first variable excluded from the model in the stepwise analysis. Grade
was the only significant variable related to IBTR. There were significantly
more local recurrences in Grade 3 cancers than Grade 1 or 2 cancers
(p=0.0004) [Fig 2].
DISCUSSION
For breast conserving surgery most units have protocols requiring a specific
distance between the edge of any invasive or in situ disease and the surgical
margin before they consider a cancer has been excised and the margins are
clear30. Negative margins are variably defined and definitions vary from no ink
on the cancer to greater than 10mm30, 34, 40. Despite major reviews and two
meta-analyses there remains no international consensus on what constitutes
an adequate negative surgical margin in breast conserving surgery14, 34, 40-42.
10
There is however agreement that leaving disease at the margin is
unacceptable as this significantly increases the risks of local recurrence14, 41.
Furthermore there is also now good evidence that close margins are also
associated with a higher rate of local recurrence compared to margins that are
≥1mm;15, 43 this indicates that previous definitions of no ink on cancer cells
may be insufficient as a definition of a negative margin2, 44. The logic of using
no ink on tumour is described by the consensus panel and is based in part on
the difficulties with analysing margins and the problems associated with inking
margins 42. These same issues would however have been present in all of the
studies that were included in the meta-analyses. A pairwise comparison
between distance categories for negative margins (in the adjusted models in
the second meta-analysis42) showed that the odds of local recurrence were
not different between 1 and 5 mm but were significantly higher for studies
using >0 mm relative to 5 mm (P = 0.021); this supports the 1mm margin used
in the series reported here.
The current study is unique in that not only have the data been collected
prospectively, but the distance of both DCIS and invasive cancer to each
margin recorded was measured microscopically and recorded. This has
allowed us to look separately at the radial margins (medial, lateral, superior
and inferior) and the anterior and posterior margins. The first aim of the study
was to determine whether there was any reduction of local recurrence with
wider radial margins. When comparing margin widths of 1-5mm with radial
margin widths of 5-10 mm, there was no significant difference in local
recurrence rates between the two groups. These groups were comparable in
11
terms of known risk factors for local recurrence6-8, 11-24. In the multivariate
analysis margin status was the first factor to drop out. The findings of our
study are thus clear and entirely in keeping with the recent meta-analyses of
21 studies that included 14,571 patients with invasive breast cancer14, 42. The
conclusion from the current study and the meta-analyses is that a 1mm
negative margin is as good as a wider margin, if patients receive optimal
adjuvant therapy. Margin width is important as a demand for wider margins
removes more normal breast tissue and results in a poorer cosmetic
outcome10, 45.
This is the first study to look in detail at local recurrence rates in patients who
have had full thickness of breast tissue excised. It has been our practice for
many years not to excise skin or pectoral fascia routinely. If the anterior or
posterior margin is reported as being <1mm from invasive cancer and even if
the pathologists reports tumour on ink and full thickness of breast tissue has
been excised then we do not re-excise these margins but give patients a
boost of external beam radiation to the tumour bed. Patients with DCIS <1mm
from margins do not have a re-excision or boost. There is huge variation in
practice as to how surgeons and oncologists manage anterior and posterior
margins and when they will re-excise or boost these margins as demonstrated
in a survey we conducted30. One can conclude from this study that if the
anterior or posterior margins are reported as <1mm and even if there is ink on
invasive cancer and full thickness of breast tissue has been taken, then
satisfactory rates of local control can be obtained with a tumour bed boost
without the need for re-excision. It also shows that neither boost nor re
excision is necessary if DCIS is <1mm from the anterior and posterior margins
12
and full thickness of breast tissue has been excised. These observations have
important implications for clinical practice. In this study it was not routine to
remove the pectoral fascia and no patient with an isolated posterior margin
distance of <1mm including a small number with ink on tumour cells
developed recurrence at 5 years [Table 1]. This study thus questions whether
there is ever a need to remove pectoral fascia in breast conserving surgery
that is not directly involved by cancer. Given the lack of evidence that excision
of pectoral fascia provides any benefit, it is now time for breast surgeons to
stop taking this fascia routinely.
There was a satisfactory rate of local control in patients with initially involved
margins who underwent re-excision and then had clear margins. This mirrors
the findings in other studies27. There is a huge variation between centres in
the percentage of women who have re-excision or mastectomy after an initial
wide excision with positive margins30, 46, 47. Some women in the past in the UK
have undergone re-excision or mastectomy even though radial margins are
>1mm because they have been classified as having ‘involved margins’ as
defined by local protocols. It is no surprise that the overwhelming majority of
these women have no residual disease at re-excision or mastectomy48. The
residual rate of disease in re-excisions in this series was 38%.
In the current study the only factor that was significantly related to IBTR was
tumour grade, with grade 3 cancers having an increased rate of local
recurrence compared to grade 1 and 2 cancers. Other studies have also
noted grade is a factor that relates to local recurrence. Although many studies
have found a higher rate of IBTR in grade 3 cancers, this is by no means
13
universal49. In the PRIME II study of older women undergoing breast
conserving surgery, patients with grade 3 cancers that were not treated with
radiotherapy had a much higher rate of local recurrence than grade 1 or 2
cancers. However in the multivariate analysis of the whole study grade was of
borderline significance (p=0.06)50.
A potential weakness of this study is that this is a single centre study, but it
did include multiple surgeons of different grades. This study includes both
screen detected and symptomatic breast cancer and as a regional centre the
Edinburgh Breast Unit manages all patients in the region so this set of
patients is representative of the whole population. A strength is the consistent
method of data collection and the completeness of follow up. The findings of
this study and those of the meta-analyses are also consistent and could not
be clearer in their conclusions. In terms of radial margins for breast
conserving surgery for invasive cancer a clear radial margin is essential. The
time has come for surgeons to follow the evidence. Surgeons should abandon
local protocols and unite behind a defined margin which in the US is no
tumour on ink and in the UK is a 1mm margin. The inconsistency in translating
the current knowledge base on margin width into clinical practice has to
change.
ACKNOWLEDGEMENTS
The authors would like to thank all the surgeons, radiologists, oncologists and
pathologists in the Edinburgh Breast Unit for their cooperation and
collaboration. This manuscript was typed and edited by Miss Rosalee Ross.
14
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TABLES AND FIGURES
Table 1.
Patient, Treatment and Tumour details (NK = Not known)
Table 2.
IBTR by distance to margin and site of involved margin
Figure 1.
In breast local recurrence (LR) for patients subdivided on the
excision margin into 4 groups.
a. Survival Function
b. Case Processing Summary
c. Overall comparisons
Figure 2.
In breast local recurrence (LR) for patients subdivided on the
grade of the invasive cancer
a. Survival Function
b. Case Processing Summary
c. Overall comparisons
20