Editorial
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A new approach to treating breast cancer
combining tumor removal and
intraoperative radiotherapy: is it viable?
...we could possibly complete all the treatment at the time of surgery by
irradiating the tumor bed after the removal of the primary disease.
The development of the classical radical mas-
tectomy in the latter part of the 19th Century
is credited to William S Halsted, of the Johns
Hopkins Hospital, Baltimore (MD, USA) [1] .
In 1922, Geoffrey Keynes, a surgeon at St
Bartholomews Hospital London (UK) began
experimenting with the use of radium enclosed
in hollow platinum needles in the treatment
of advanced breast cancer. Following on from
his experience with advanced disease, he took
a courageous leap of faith and started treat-
ing women with early-stage breast cancer with
local excision (lumpectomy) and radium nee-
dles inserted into the unaffected quadrants of
the breast and the axillary plus supraclavicular
lymphatic fields [2] .
Over the last 30years, the major change in
surgical treatment of early breast cancer has
been the shift towards breast conservation
surgery (BCS). BCS was introduced to reduce
the physical and psychological consequences of
removing the whole breast. Trials performed
in the 1970s demonstrated equivalent survival
when comparing BCS plus radiotherapy with
mastectomy [3] .
Over the last 30years, the major
change in surgical treatment of early
breast cancer has been the shift
towards breast conservation surgery.
The meta-analysis conducted by the Early
Breast Cancer Trialists Collaborative Group
comparing BCS with BCS plus radiotherapy
demonstrated that the addition of radiotherapy
reduced the risk of local recurrence by 75% and
resulted in a disease-free survival advantage, with
a decrease in the 15year risk of dying of breast
cancer from 31 to 26% in node negative patients,
and from 55 to 48% in node positive patients [4] .
Postoperative radiotherapy is therefore
regarded as an integral component of BCS and
cannot be safely omitted. There is evidence to
10.2217/WHE.09.74 2010 Future Medicine Ltd
suggest that this approach decreases the risk
of local recurrence and, more importantly,
improves survival [5] . Mohammed
Keshtgar
How does radiotherapy work?
The aim of radiation is to kill tumor cells selec-
tively without damaging normal cells. It works
by generating free radicals, which cause single-
or double-stranded breaks in cellular DNA. This
affects tumor cells more than normal cells because
tumor cells are less able to repair DNA damage Michael
than normal cells, and are more frequently in the Baum
radiosensitive part of the cell cycle.
If external beam radiotherapy works,
why change?
We cannot underestimate the achievements of
the last 100years in shifting the paradigm of
Author for correspondence
breast cancer treatment from the mutilation of
Department of Surgery, University
the classical radical mastectomy to the modern College London Medical School,
default treatment of breast conserving treat- UCL, London, UK
ment, sentinel node biopsy and whole breast Tel.: +44 207 830 2966
irradiation (WBI). However, many problems Fax: +44 207 317 7608
related to WBI cannot be ignored, which m.keshtgar@ucl.ac.uk
limits the availability and convenience of the
treatment:
WBI takes between 3 and 7weeks to deliver,
which is a great inconvenience for working
women or the elderly who find the daily
journeys exhausting;
In the UK, the treatment of breast cancer
accounts for approximately a third of all the
workload of radiotherapy departments;
Women in the developing world or those in
wealthy countries who live in rural areas more
than 100miles from a center are denied the
chance of BCS or are at great hazard of local
recurrence if the treatment is omitted [6,7] ;
part of
Geographic misses are commonplace in post-
operative attempts to target the tumor bed [8] ;
Women's Health (2010) 6(1), 912 ISSN 1745-5057 9
editorial Keshtgar & Baum
Cosmesis is often impaired by the short- or
long-term radiotoxicity, especially in women
with collagen disease or those who have been
treated by mantle radiotherapy for lymphoma
in the past;
Delays in the start of chemotherapy or delays
in the start of radiotherapy in order to accom-
modate chemotherapy might compromise
either modality [9] .
The paradox of local recurrence
After BCS, the results of most observational stud-
ies and clinical trials have demonstrated that 90%
of recurrent disease in the breast is within the
index quadrant in the presence or absence of WBI
[1012] . Furthermore, following the adoption of
adjuvant endocrine therapy, the chance of a local
recurrence outside the index quadrant is no more
than the risk of a new contralateral tumor [13] .
If that is the case, why do we not demand pro-
phylactic treatment of the contralateral breast at
the same time? This counterintuitive observation
has both biological and clinical consequences.
Biologically, this tells us that not all that looks
like cancer under the microscope will behave like
cancer if left to nature. The evidence to support
the notion of latency amongst microscopic foci
of breast cancer has been well documented in
much of the contemporary scientific literature
on the natural history of breast cancer [14,15] . The
clinical consequences of this observation suggest
that perhaps we do not have to treat the whole
breast but only the immediate area around the
tumor bed after removal of the primary disease
or the index quadrant. If that is the case, then
we could possibly complete all the treatment at
the time of surgery by irradiating the tumor bed
after the removal of the primary disease. This can
be achieved by accelerated partial breast irradia-
tion (APBI) over a period of 1week, or by intra
operative radiotherapy (IORT) during surgery
as a single fraction, which is the main focus of
this article.
Accelerated partial breast irradiation
A number of different techniques of APBI are
available that aim to decrease the volume of
treatment and increase the daily fraction size of
radiation that can be completed within 1week
(instead of 37weeks). These include linac-based
intensity-modulated radiotherapy, multicatheter
interstitial brachytherapy, balloon-based APBI
using the MammoSite brachytherapy appli-
cator (Hologic, Inc., MA, USA) and a newly
developed, modified form of balloon-based
10 www.futuremedicine.com
brachytherapy called Xoft Axxent Electronic
Brachytherapy (Xoft, Inc., CA, USA)
At present, there is a lack of level1 evidence
in support of the efficacy of this approach; how-
ever, despite this, the technique of MammoSite
brachytherapy is widely used in the USA [16,17] .
There are a number of ongoing prospective, ran-
domized, PhaseIII trials of APBI. However, they
are not comparable since they vary in inclusion
criteria, total dose, fractionation, volume and
timing related to chemotherapy and hormone
treatment. The National Surgical Adjuvant
Breast and Bowel ProjectB and the Radiation
Therapy Oncology Group have noted this short-
coming and are conducting an intergroup study,
randomizing patients with early-stage breast
cancer to WBI versus APBI. At present, APBI
should be considered as under investigation only.
Intraoperative radiotherapy
The technique of IORT, which was pioneered
by our group [18] , allows the patient to receive
all required radiation in a single fraction before
they awake from surgery. The potential advan-
tage of this approach includes delivering the
radiation before tumor cells have a chance to
proliferate, performing the radiation treatment
under direct visualization at the time of surgery
and decreasing costs to the healthcare providers.
At present, accelerated partial breast
irradiation should be considered as
under investigation only.
This is achieved by using the INTRABEAM
(Carl Zeiss Surgical, Oberkochen, Germany)
machine, which is a mobile, miniature xray gen-
erator powered by a 12volt supply. Accelerated
electrons strike a gold target at the tip of a 10cm
long drift tube with a diameter of 3 mm, result-
ing in the emission of low-energy xrays (50kV)
in an isotropic dose distribution around the tip.
The irradiated tissue is kept at a distance from
the source by spherical applicators to ensure a
more uniform dose distribution. The tip of the
electron drift tube sits precisely at the epicen-
ter of a spherical plastic applicator, the size of
which is chosen to fit the cavity after the tumor
is excised. Using this method, the walls of the
tumor cavity are irradiated to a biologically
effective dose (20Gy to the tissue in contact
with the applicator) that rapidly attenuates over
a distance of a few centimeters. As a result, the
vital organs are spared and the device can be
used in any operating theater without the need
of lead shielding [18] .
future science group
 Breast cancer: a new approach combining tumor removal & intraoperative radiotherapy
The other IORT approach is electron intraoper-
ative therapy, pioneered at the European Institute
of Oncology in Milan, Italy. In this technique,
a portable linear accelerator is used to deliver a
single dose of 21Gy radiations during the surgery
[19] . With this approach it is necessary to perform
the procedure in a specially shielded operating
theater for radiation safety considerations.
Evidence
We have established the safety and tolerability of
the technique in PhaseII studies [20,21] . In 1998,
we conducted a pilot study (targeted intraopera-
tive radiotherapy [TARGIT]) on 299patients
(with 300cancers) who underwent BCS for their
breast cancer management. They all received a
single dose of 20Gy radiotherapy during surgery.
This was instead of 1week of radiation to the
tumor bed (boost radiation); however, patients
received standard external beam radiotherapy
(EBRT) to the whole breast. A total of 32% of
the patients were younger than 51years; 57% of
cancers were between 1 and 2cm (21%>2cm);
29% had a grade3 tumor; and 27% were node
positive. The treatment was well tolerated by
all patients, and with median follow-up of
60.5 months (range: 10120 months), eight for staging of patients to a minimally invasive
patients had developed ipsilateral recurrence:
the 5year Kaplan Meier estimate for ipsilateral
recurrence is 1.74% (standard error:0.77).
...the time has come to question
the radical approach of radiotherapy
in early breast cancer.
Subsequently, a pilot study in August 2008, con-
ducted by our colleagues in Milan on 101patients,
also confirmed low recurrence rate after a median
follow-up of 36 months (five patients [0.5%]
developed a local recurrence and three (0.3%)
developed ipsilateral breast cancer) [1922] .
In March 2000, we launched an international,
randomized trial comparing TARGIT versus
EBRT as a non-inferiority study with the primary
outcome of local recurrence, currently involving
31centers across the world [23] . The recruitment
goal of 2232 (powered to test noninferiority; haz-
ard ratio:<1.25) is expected to be completed in the
second quarter of 2010. The results of this study
will provide level1 evidence for this approach in
the management of breast cancer patients. A sub-
protocol analysis of cosmesis indicates a superior
cosmetic outcome in the first year for the patients
receiving IORT, and equivalent cosmetic outcome
has been achieved for the second and third year of
follow-up between the two groups [24] .
future science group Women's Health (2010) 6(1)
editorial
During this period, we offered IORT within
three major centers in the UK, Germany
and Australia, to a highly selected group of
80 patients with exceptional circumstances
who were not suitable for randomization into
a TARGIT trial and who also could not receive
standard EBRT. This included patients who had
received previous radiation (e.g., patients with
recurrent cancer in the same breast or those who
have been treated with mantle radiotherapy for
Hodgkins disease) or because of comorbidities,
such as severe respiratory or cardiac problems,
collagen or autoimmune disorders, or painful
arthritis (which might prevent adequate abduc-
tion of the shoulder). After a median follow-up
of 38months, only two local recurrences were
observed, an actuarial annual local recurrence
rate of 0.75% (95%CI:0.092.70%), suggest-
ing that this approach may be considered in
special ci rcumstances in which EBRT is not
feasible [25,26] .
Concluding remarks
Over the years, we have moved from radical
surgery for breast cancer treatment to BCS,
and more recently from radical axillary surgery
approach of sentinel node biopsy. Surely the time
has come to question the radical approach of
radiotherapy in early breast cancer. The implica-
tions of this leap into the dark are profound. If
it proves beneficial, then many women will be
spared up to 7weeks of treatment and travel-
ing back and forth to the radiotherapy center.
Furthermore, tens of thousands of women in
the developing world who live hundreds of miles
from a radiotherapy unit, or in countries that
cannot afford the multimillion pound invest-
ment, will be able to enjoy the advantages of
breast conservation by bringing the radiotherapy
units to the patient. In countries such as the UK,
the waiting list for postoperative radiotherapy
would vanish at a stroke, and we estimate the
NHS would be saved 15,000,000 per year. We
will have to watch this space; however, in our
view, the future is bright.
Financial & competing interests disclosure
Michael Baum has received consultancy fees from Carl
Zeiss. The authors have no other relevant affiliations or
financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from
those disclosed.
No writing assistance was utilized in the production of
this manuscript.
11
editorial Keshtgar & Baum
Bibliography
Papers of special note have been highlighted as:
of interest
of considerable interest
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12
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Affiliations
Mohammed Keshtgar
Department of Surgery, University College
London Medical School, UCL, London, UK
Tel.: +44 207 830 2966
Fax: +44 207 317 7608
m.keshtgar@ucl.ac.uk
Michael Baum
University College London Medical School,
UCL, London, UK
Tel.: +44 207 288 3970
Fax: +44 207 288 3969
michael@mbaum.freeserve.co.uk
future science group