Intraoperative radiotherapy for breast cancer

Abstract

Intra-operative radiotherapy (IORT) as a treatment for breast cancer is a relatively new technique that is designed to be a replacement for whole breast external beam radiotherapy (EBRT) in selected women suitable for breast-conserving therapy. This article reviews twelve reasons for the use of the technique, with a particular emphasis on targeted intra-operative radiotherapy (TARGIT) which uses X-rays generated from a portable device within the operating theatre immediately after the breast tumour (and surrounding margin of healthy tissue) has been removed. The delivery of a single fraction of radiotherapy directly to the tumour bed at the time of surgery, with the capability of adding EBRT at a later date if required (risk-adaptive technique) is discussed in light of recent results from a large multinational randomised controlled trial comparing TARGIT with EBRT. The technique avoids irradiation of normal tissues such as skin, heart, lungs, ribs and spine, and has been shown to improve cosmetic outcome when compared with EBRT. Beneficial aspects to both institutional and societal economics are discussed, together with evidence demonstrating excellent patient satisfaction and quality of life. There is a discussion of the published evidence regarding the use of IORT twice in the same breast (for new primary cancers) and in patients who would never be considered for EBRT because of their special circumstances (such as the frail, the elderly, or those with collagen vascular disease). Finally, there is a discussion of the role of the TARGIT Academy in developing and sustaining high standards in the use of the technique.

Full text

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Introduction
Interest in the role of accelerated partial breast irradiation
(APBI) in the management of breast cancer has been
growing. The rationale behind this approach is that the
majority of local recurrences in the breast occur in the index
quadrant whether radiotherapy is given or not. Therefore,
“occult cancers” in other quadrants are probably not the
cause of local recurrence and radiotherapy to the index
quadrant alone maybe sufficient. The aim of APBI is to
decrease the volume of breast irradiated whilst increasing
the dose per fraction (hypofractionation).
A number of different techniques can be used for
partial breast irradiation, including linear accelerator
(LINAC)-based intensity modulated radiotherapy,
interstitial brachytherapy, MammoSite and intra-operative
radiotherapy (IORT). Although similar in principle, these
techniques have large difference in dose rate and dose
distribution, and are therefore not strictly comparable.
IORT as a treatment for breast cancer is a relatively new
method of delivering APBI that aims to replace whole
breast external beam radiotherapy (EBRT) in selected
women suitable for breast-conserving therapy.
IORT is possible because the development of mobile
radiotherapy systems provides clinicians with the ability to
readily provide treatment during the surgical intervention,
as these systems can be taken into the operating rooms
Review Article
Intraoperative radiotherapy for breast cancer
Norman R. Williams1, Katharine H. Pigott2, Chris Brew-Graves1, Mohammed R S Keshtgar3
1Clinical Trials Group, Division of Surgery & Interventional Science, Faculty of Medical Sciences, University College London, Charles Bell
House, 67-73 Riding House Street, London, W1W 7EJ, UK; 2Radiotherapy Department; 3The Breast Unit, Royal Free London Foundation Trust,
University College London, Pond Street, Hampstead NW3 2QG, UK
Correspondence to: Professor Mohammed Keshtgar, BSc, FRCSI, FRCS (Gen), PhD. Professor of Cancer Surgery and Surgical Oncology; Royal Free London
Foundation Trust, University College London, The Breast Unit, Pond Street, Hampstead, London, NW3 2QG, UK. Email: m.keshtgar@ucl.ac.uk.
Abstract: Intra-operative radiotherapy (IORT) as a treatment for breast cancer is a relatively new technique
that is designed to be a replacement for whole breast external beam radiotherapy (EBRT) in selected women
suitable for breast-conserving therapy. This article reviews twelve reasons for the use of the technique, with a
particular emphasis on targeted intra-operative radiotherapy (TARGIT) which uses X-rays generated from a
portable device within the operating theatre immediately after the breast tumour (and surrounding margin of
healthy tissue) has been removed. The delivery of a single fraction of radiotherapy directly to the tumour bed
at the time of surgery, with the capability of adding EBRT at a later date if required (risk-adaptive technique)
is discussed in light of recent results from a large multinational randomised controlled trial comparing
TARGIT with EBRT. The technique avoids irradiation of normal tissues such as skin, heart, lungs, ribs and
spine, and has been shown to improve cosmetic outcome when compared with EBRT. Beneficial aspects
to both institutional and societal economics are discussed, together with evidence demonstrating excellent
patient satisfaction and quality of life. There is a discussion of the published evidence regarding the use of
IORT twice in the same breast (for new primary cancers) and in patients who would never be considered for
EBRT because of their special circumstances (such as the frail, the elderly, or those with collagen vascular
disease). Finally, there is a discussion of the role of the TARGIT Academy in developing and sustaining high
standards in the use of the technique.
Keywords: Early breast cancer; Intrabeam; intra-operative radiotherapy (IORT); radiotherapy; targeted intra-
operative radiotherapy (TARGIT)
Submitted Jan 27, 2014. Accepted for publication Mar 19, 2014.
doi: 10.3978/j.issn.2227-684X.2014.03.03
View this article at: http://www.glandsurgery.org/article/view/3783/4712

110 Williams et al. IORT for breast cancer
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and used to irradiate the tumour bed immediately after
the breast tumour (and surrounding margin of healthy
tissue) has been removed. Mobile instruments include
brachytherapy treatments using sealed sources (i.e., HDR),
electron units (Mobetron, Novac-7) and photon units
(Intrabeam™).
Targeted intraoperative radiotherapy (TARGIT) is a
simple and straightforward IORT technique, the success
of which depends on attention to detail and collaboration
between the multidisciplinary team of surgeons, radiation
oncologists, physicists, radiotherapy technicians and
operating theatre and nursing staff. In brief, after excision of
the tumour and a margin of healthy tissue, the tumour bed
is mobilised to ensure that there is at least 5 mm distance
between the surface of the applicator and the skin, in order
to reduce the risk of radionecrosis. The equipment used is
the Intrabeam™ system (Carl Zeiss Surgical, Oberkochen,
Germany) which is a mobile, miniature X-ray generator
where accelerated electrons strike a gold target at the tip
of a 10 cm long drift tube resulting in the emission of low
energy X-rays (50 kV) in an isotropic dose distribution. The
irradiated tissue is kept at a xed distance from the source by
a spherical applicator to ensure a uniform dose distribution.
A variety of sizes of applicators are available to t the size of
the surgical cavity; the dose rate depends on the diameter of
the applicator with larger applicators requiring more time to
deliver the dose of 20 Gy to the surface. Treatment times are
typically between 20 to 45 minutes depending on the size
of the applicator used. There is a steep attenuation of the
radiation which allows the treatment to be safely carried out
in unmodied operating theatres.
This article reviews twelve reasons for the use of IORT
as treatment for breast cancer, with a particular emphasis on
TARGIT.
Historical trends
EBRT is a safe and effective treatment after breast-
conserving surgery, which reduces the in-breast recurrence
rate by two-thirds (1) and the breast cancer death rate by
about a sixth (2). However, with few exceptions, EBRT
has been given to the entire breast. This is in contrast
to surgery which has moved from radical (mastectomy)
to minimal (lumpectomy) (3), but radiotherapy remains
radical (whole breast), even though the results of many
observational studies and clinical trials have demonstrated
that around 90% of recurrent disease in the breast after
breast conserving surgery is within the index quadrant,
whether or not whole-breast EBRT has been given (4).
Furthermore, after adjuvant endocrine therapy, the chance
of a local recurrence outside the index quadrant is no more
than the risk of a new contralateral tumour (5).
Timeliness of radiotherapy
Usually, EBRT is given several weeks after surgery, or
several months if chemotherapy is also given. Several
large population studies have shown that long intervals
between breast conserving surgery and EBRT could be
associated with inferior outcomes (6-8). By contrast, giving
radiotherapy during primary surgery avoids any delay and
may have benecial biochemical effects that are important
during the wound healing that occurs during recovery from
surgery.
Evidence from translational research has found that
treatment with TARGIT alters the molecular composition
and biological activity of wound fluid in the tumour bed,
which impairs the surgical trauma-stimulated proliferation
and invasiveness of cultured breast cancer cells (9). Further
work by the same group has found that treatment using the
TARGIT technique modulates expression of microRNA
that in turn modies the expression of two growth factors
known to be important in the regulation of cancer cell
growth and motility, which may help to prevent local
recurrences in early breast cancer (10).
Supported by level-one evidence
The international multicentre TARGIT A randomised
controlled trial (ISRCTN34086741) was designed to
determine non-inferiority between the TARGIT technique
and conventional external beam radiotherapy (EBRT) in
women with early breast cancer. IORT is given as a single
dose of 20 Gy at the surface of the applicator (equivalent to
6 Gy at 1 cm) delivered directly to the tumour bed under
direct observation. The primary outcome measure is local
relapse within the treated breast; secondary endpoints are
site of relapse within the breast, relapse-free and overall
survival, and local toxicity/morbidity (11). The 5-year risk
for local recurrence in the conserved breast when TARGIT
was given concurrently with lumpectomy (n=2,298) had
much the same results as EBRT: 2.1% (1.1-4.2) vs. 1.1%
(0.5-2.5; P=0.31) (12).
A method of delivering IORT with electrons (instead
of photons) has also reported results from a randomised
controlled trial performed at the European Institute of

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Oncology (Milan, Italy). The results showed much poorer
local control with this type of IORT when compared with
EBRT: 35 patients in the IORT group and four patients in
the external radiotherapy group had an ipsilateral breast
tumour recurrence (P<0.0001). The 5-year event rate
for IBRT was 4.4% [95% confidence interval (CI), 2.7-
6.1] in the IOPT group and 0.4% (0-1.0) in the external
radiotherapy group [hazard ratio 9.3 (95% CI, 3.3-
26.3)] (13). This technique of delivering IORT, which
is superficially similar to TARGIT, is in fact different in
several important respects. Perhaps the most significant
drawback of electron beam therapy is the inability to
incorporate a risk-adjusted approach of giving EBRT after
IORT to patients with additional risk factors. In the ELIOT
trial, most of the local recurrences occurred in patients
with disease characteristics suggesting subsequent use of
whole breast irradiation (tumour >2.0 cm or ≥4 positive
nodes or grade 3 or triple negative); patients without these
characteristics had a much lower risk of local recurrence
(1.7% 5-year event rate). There may therefore be a role for
the Milan techniques of IORT using electrons during breast
conserving surgery in a carefully selected population at low
risk of local recurrence (14).
Regarding safety in the ELIOT study, information about
side-effects of radiotherapy was available for 464 and 412
patients in the IORT group and EBRT group, respectively.
Overall, skin side-effects showed a signicant difference in
favour of the IORT group (P=0.0002), with significantly
reduced rates of erythema (P<0.0001), dryness (P=0.04),
hyper-pigmentation (P=0.0004), and pruritus (P=0.002).
The rate of fat necrosis was worse in the IORT group
(P=0.04). In contrast, the TARGIT A trial reported that
the frequency of any complications and major toxicity was
similar in the IORT and EBRT groups [for major toxicity,
TARGIT, 37 (3.3%) of 1,113 vs. EBRT, 44 (3.9%) of
1,119; P=0.44]. Radiotherapy toxicity (Radiation Therapy
Oncology Group grade 3) was lower in the TARGIT group
[six patients (0.5%)] than in the EBRT group [23 patients
(2.1%); P=0.002] (15).
Two randomised trials of external partial breast
irradiation (16,17) have not shown this technique to be
an effective form of local control. A third trial (18), with a
strict selection of patients, reported non-inferiority between
partial and whole breast irradiation in terms of local
control and survival after a median follow up of 10 years.
A meta-analysis of partial breast irradiation (19) showed an
increased risk for both local and regional recurrence with
partial breast irradiation, with no survival difference, when
compared with whole breast irradiation.
Risk-adaptive technique
It should be pointed out that IORT cannot always be given,
even in women who meet the eligibility criteria. A study in
Germany of 297 women found that in 55 women (19%) the
planned IORT was not performed, mainly due to reasons
which became apparent during surgery, namely: insufcient
tumour-skin distance (n=20, 35.1%), an oversized wound
cavity (n=14, 24.6%), and a combination of both (n=8, 14%) (20).
In such cases, and in patients who have been given IORT,
it is always possible to treat with EBRT at a later date, with
omission of the tumour bed boost (if IORT has been given).
This is why the technique is called “risk-adaptive”. Note
that in such cases the patients do not “lose” anything, apart
from a few more minutes under anaesthesia.
The replacement of the EBRT boost to the tumour bed
by a TARGIT boost given during surgery is being tested in
TARGIT-B (for boost, ISRCTN43138042), a multicentre
randomised controlled trial that began accrual in 2013 (21). All
patients will receive EBRT. The target population is patients
with breast cancer who have a high risk of local recurrence.
Specifically, patients should be either younger than 45 or, if
older, need to have pathological features that confer a high risk
of local recurrence of breast cancer, such as lymphovascular
invasion, gross nodal involvement (not micrometastasis), more
than one tumour in the breast but still suitable for breast-
conserving surgery through a single specimen, ER negative,
grade 3 histology or positive margins at first excision. This
trial is based on results from a phase II non-randomised study
in 299 unselected patients who had breast-conserving surgery
and TARGIT as a boost to the tumour bed as a single dose
of 20 Gy delivered intraoperatively. Postoperative external
beam whole-breast radiotherapy excluded the usual boost.
The treatment was well tolerated. After a median follow up of
60.5 months, eight patients had an ipsilateral recurrence,
which gave a 5-year Kaplan-Meier estimate for ipsilateral
recurrence of 1.73% (SE 0.77) (22). This therefore justies the
“risk adaptive” approach.
Reduced irradiation of normal tissues
In addition to the avoidance of irradiation of skin, the
rapid attenuation of IORT X-rays means there is much
less radiation exposure to normal tissues. An estimate was
made of secondary cancer risks after IORT compared to
APBI and EBRT by using computer-tomography scans of

112 Williams et al. IORT for breast cancer
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an anthropomorphic phantom with an Intrabeam™ IORT
applicator in the outer quadrant of the breast; the scans
were then transferred to a treatment planning system.
For normal tissues, the maximal doses were calculated
and lifetime risk for secondary cancers estimated. IORT
delivered the lowest maximal doses to contralateral breast
(<0.3 Gy), ipsilateral (1.8 Gy) and contralateral lung (<0.3 Gy),
heart (1 Gy) and spine (<0.3 Gy). In comparison, maximal
doses for APBI were 2-5 times higher. EBRT delivered
a maximal dose of 10.4 Gy to the contralateral breast
and 53 Gy to the ipsilateral lung. The estimated risk for
secondary cancer was considerably lower after IORT and/or
APBI as compared to EBRT (23).
Darby et al. (24) recently conducted a population-
based case–control study of major coronary events (such
as myocardial infarction, coronary revascularization, or
death from ischemic heart disease) in women who received
radiotherapy for breast cancer between 1958 and 2001.
For each woman, the mean radiation dose to the heart was
estimated. The overall average of the mean dose to the
whole heart was 4.9 Gy; rates of major coronary events
increased by 7.4% per gray (95% CI, 2.9 to 14.5; P<0.001),
with no apparent threshold. It was concluded that exposure
of the heart to ionizing radiation during radiotherapy
increased the subsequent rate of ischemic heart disease.
Brenner et al. (25) then performed a similar study on
women exposed to contemporary (2005 and later) EBRT,
and found a mean cardiac dose of 1.37 (95% CI, 1.12-1.61) Gy,
less than one-third that found by Darby et al. However,
the highest estimated radiotherapy-induced lifetime risks
were still significant [3.52% (95% CI, 1.47-5.85%)]. It
therefore seems that, even with modern radiotherapy
planning techniques, EBRT can deliver an undesirable dose
of radiation to the heart.
There is no question that TARGIT delivers less
radiation to normal tissues. This has been demonstrated
using a biological marker of radiation dose (gamma-H2AX
in circulating lymphocytes) where it was shown that the
DNA damage caused by X-radiation was significantly less
with TARGIT compared with EBRT (26).
Better cosmetic outcome
The use of IORT has been shown to result in better cosmetic
outcome when compared with EBRT (27) using an objective
evaluation of aesthetic outcome. Frontal digital photographs
were taken at baseline (before TARGIT or EBRT) and
annually thereafter for up to 5 years. The photographs were
analysed by a validated, specialised software application that
produces a composite score (Excellent, Good, Fair, Poor)
based on symmetry, colour and scar. There was a statistically
significant increases in the odds of having an outcome of
Excellent or Good for patients in the TARGIT group relative
to the EBRT group at year 1 [odds rate (OR) 2.07, 95% CI,
1.12-3.85, P=0.021] and year 2 (OR 2.11, 95% CI, 1.0-4.45,
P=0.05). This study demonstrated that women treated with
TARGIT had a superior cosmetic result compared with
patients who received conventional EBRT.
The cosmetic effects of breast conservation therapy have
been studied for decades, but the usual methods for evaluating
cosmetic outcome are assessments made by the clinical care
team, including the surgeon who performed the operation.
Although this is an important source of feedback, such
information is obviously biased and cannot be used reliably
to compare techniques carried out by different clinicians,
perhaps at different centres, using different techniques. Some
researchers utilise a blinded assessment of outcome, usually by
an independent panel examining photographs, but this is time
consuming and too cumbersome to be used in routine practice.
There are few published studies on the measurement of
cosmesis after IORT. In the MSKCC Series (28), where
quadrant IORT of 18-20 Gy was given, the cosmetic
outcome was acceptable. In the Montpellier phase II
trial (29) IORT was given as electrons (21 Gy); at a median
follow-up of 30 months of 94 patients, all showed excellent
or good cosmesis. In a study of IORT using Axxent, a
balloon-based electronic brachytherapy (20 Gy), at median
follow-up of 12 months there was excellent cosmesis in 10
of the 11 patients (30). However, an interim report from a
large randomised controlled trial found that APBI increased
rates of adverse cosmesis (and late radiation toxicity)
compared with EBRT (31).
Economically viable
The institutional perspective
An economic evaluation of new treatments is a key part
of a health technology assessment, as resources are finite.
Appleby has shown that, in the past 30 years, total national
expenditures on healthcare as a percentage of gross
domestic product (GDP) have increased. In the UK this
gure rose from 3.9% in 1960 to 9.4% in 2010, in Germany
it rose from 6.0% in 1970 to 11.6% in 2010 and in the US
from 5.1% in 1960 to 17.6% in 2010 (32).
The population is ageing; the demand on LINAC units

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for treatment of breast cancer is approximately a third of
the workload in the UK, and rising, putting an increasing
burden on radiotherapy infrastructure. For IORT, one
consideration is the capital cost to purchase the required
equipment, which is at least one-tenth of that required for a
LINAC capable of delivering EBRT. This is without taking
into account the requirements for shielding the LINAC
(which usually requires significant amounts of shielding,
often in the form of a “concrete bunker”); with TARGIT,
minimal shielding is required in the operating theatre (33). It
might be argued that as the institution has already invested
in the LINAC, it might as well use it. However, workload
on radiotherapy departments is increasing, so alternative
methods of delivering radiotherapy should be considered,
particularly those that are safe, efficacious, and cost-
effective.
A Markov decision-analytic model developed in the USA
has shown that significant cost savings are possible when
using TARGIT even if only a small proportion of women
with early breast cancer are offered IORT as opposed to
EBRT (34). IORT single-dose intraoperative radiation
therapy was the more cost-effective strategy, providing
greater quality-adjusted life years at a decreased cost. The
authors concluded that IORT offers a unique example of new
technology that is less costly than the current standard of
care option but offers similar efcacy; the capital investment
for the equipment could be recouped after 3-4 years.
However, Shah et al. (35), using cost-minimization
analyses, compared intra-operative radiation therapy
(IORT) with whole-breast irradiation (WBI) and
accelerated partial-breast irradiation (APBI) and concluded
that APBI and WBI are cost-effective compared with IORT.
This was partially due to the level of reimbursement paid in
the USA for these treatments.
Another economic consideration is the additional
time required in the operating theatre for delivery of the
radiation. In some circumstances, this can be offset by using
this time for the intraoperative testing of the histological
status of the sentinel lymph nodes, as most patients who
undergo IORT also require sentinel node biopsy. An
example is the one stage nucleic acid (OSNA) test. During
administration of the IORT the sentinel lymph node is
processed; by the end of treatment, the result of the OSNA
test has been received and further surgery can be performed
if required. It is therefore possible for a woman to have
complete removal of the tumour, clearance of the axilla (if
necessary), and radiotherapy all in a single session.
Another economic argument is that the IORT equipment
can be used for applications other than breast cancer, such as
treatment during kyphoplasty for vertebral metastases (36),
or to deliver intravaginal radiotherapy (37).
Societal perspective
This perspective is wide and explores costs and benefits
borne by all. The IORT equipment does not need to
be based in a radiotherapy centre; it can be used in any
operating theatre. Also, IORT is given as a single fraction,
and does not require daily visits over three to five weeks.
These factors mean that patients may have reduced travel
time for treatment, and reduced time off work (or as
primary carers for family). A large study in the USA found
that women traveling over 75 km for treatment are about
1.4 times more likely to receive a mastectomy than those
traveling under 15 km (38).
These factors need to be further explored to tease out not
only costs saved by patients due to reduced travel time and
reduced time off work, but also to interrogate the effects
of shifting radiotherapy burden away from radiotherapy
centres and into surgical theatres, effects on income tax,
works and pensions, savings to families and employers, and
effects on private insurance premiums and claims. A full
assessment would yield a “treasure trove” of information.
Excellent patient preference and satisfaction
A study in the USA (39) used a trade-off technique to vary
the risk of local recurrence for IORT and quantify any
additional hypothetical 10-year local recurrence risk that
patients would accept to receive either IORT or EBRT.
Data from 81 patients showed that the median additional
accepted risk to have IORT was 2.3% (from 9% to 39%),
mean 3.2%. These results demonstrate that the majority of
women with breast cancer will accept a small increment of
local risk for a simpler delivery of radiation.
A study in Australia compared preferences of women
after they had received either IORT or EBRT. There was
discordance in the willingness of patients to accept additional
risk; the patients who had received EBRT were risk-
averse, whilst patients who had received IORT valued the
convenience of this treatment: 60% of them would accept an
additional risk of recurrence as high as 4% to 6% (40).
Better quality of life
It should be noted that although patient-reported outcome

114 Williams et al. IORT for breast cancer
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measures are increasingly used and quality of life is a key
measure of clinical effectiveness, the measures used fall short
of those required for evidence-based medicine. A review of
227 outcome studies for aesthetic and reconstructive breast
surgery found only one study that was validated, specic and
reproducible (41). The use of objective measurement of the
patient’s perception and expectations is needed to assist in
the development of accurate predictive tools to better enable
clinicians and patients to choose the optimal treatment.
It has been demonstrated in Germany that women who
received IORT had superior radiation-related quality of
life parameters compared with those who have EBRT (42).
A single-centre subgroup of 87 women from the two arms
of the randomized controlled TARGIT-A trial found that
patients receiving IORT alone reported less general pain,
fewer breast and arm symptoms, and better role functioning
than patients receiving EBRT (P<0.01).
Quality of life has also been reported to be high during/
after MammoSite breast brachytherapy (43).
IORT can be given to a previously irradiated breast
It is possible to apply IORT to a breast that has already been
exposed to whole-breast EBRT, provided that the woman
is suitable for a second breast-conserving procedure (44).
This means that such women can be given an alternative to
salvage mastectomy.
Furthermore, there is limited but encouraging
experience of giving IORT twice within the same breast, for
the primary cancer and a subsequent new primary cancer in
another quadrant that developed some years later (H Flyger,
Denmark, personal communication).
IORT can be given to women who would not be
given EBRT
There are women who present with special circumstances
who would never be considered for EBRT and for whom
mastectomy is the only option; such as those who are frail
and elderly, or who have Parkinson’s Disease, or who have
a cardiac pacemaker, or have collagen vascular disease. A
study performed on a group of such patients has shown
that IORT is an option that should be considered in
such patients (45). Thirty-one patients were treated with
TARGIT due to clinical reasons for not receiving EBRT
such as systemic lupus erythematosus, motor neuron
disease, Parkinson’s disease, ankylosing spondylitis, morbid
obesity, and cardiovascular or severe respiratory disease. A
further 28 patients were included for compelling personal
reasons, usually on compassionate grounds. After a median
follow-up of 38 months, only two local recurrences were
observed, an annual local recurrence rate of 0.75% (95%
CI, 0.09-2.70%). This evidence suggests that TARGIT is an
acceptable option in highly selected cases in whose EBRT is
not feasible or possible.
The influence of age on short-term complications in
women undergoing IORT for early breast cancer was
investigated in a retrospective study of 188 women who
underwent IORT during breast-conserving surgery and
found that acute toxicity after IORT in women aged 70 years
and older was not higher compared to younger patients (46).
TARGIT-E (for elderly) is a single-arm trial on use
of TARGIT in elderly patients being run in Mannheim
by Professor Frederik Wenz. The protocol is based on
the international TARGIT-A study. The purpose is to
investigate the efcacy of a single IORT treatment within
elderly low-risk patients (≥70 years, cT1, cN0, cM0,
invasive ductal carcinoma) which is followed by EBRT only
when adverse risk factors are present (47).
TARGIT Academy
Although the TARGIT IORT technique is relatively
straightforward, the success of this technology requires
adequate training and attention to detail. The lessons
learned from the introduction of new surgical techniques in
surgery in the past have been appreciated and incorporated
into a unique training scheme.
The TARGIT Academy was established in 2010 and
is co-directed by Professor Mo Keshtgar from the Royal
Free and University College London, UK and Professor
Frederik Wenz from the University Medical Centre
Mannheim & University of Heidelberg. The remit of the
TARGIT Academy is to offer high quality training together
with the opportunity to gain access to a broad academic
network. The faculty are from a variety of disciplines, many
of whom have been involved with this technology from
the outset. Some of the trainers have extensive experience
in performing the procedure and can provide “first hand”
advice for difcult cases that are seen occasionally. Regular
training courses are run in London and Mannheim and are
sponsored by the manufacturer of the Intrabeam™ (Carl
Zeiss Surgical, Oberkochen, Germany).
The foundation of the TARGIT Academy is a
networking platform, which enables interaction and
cooperation between surgeons, radiation oncologists,

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medical physicists and other members of the
multidisciplinary team. As the success of this technique
depends on multidisciplinary team working harmoniously
with each other, the training is available only to teams and
not individuals. At the outset it was felt important that the
entire team should listen to some of the detailed specialist
instructions so that they can appreciate the roles of their
colleagues more fully. For example, many of the surgeons
will be unfamiliar in the use and handling of the IORT
device, selection of an appropriate applicator and adequate
placement in the tumour bed; it is important that the entire
team are aware of these “surgical” details, as they can have a
bearing on other aspects of patient management.
The UK Newstart sentinel node biopsy training
programme (48) has been used as a model for the TARGIT
Academy. The training involves three phases: theory
and hands on experience in a skills laboratory; proctored
training; and an audit phase.
Theory and hands-on training
The TARGIT Academy offers participants a unique first
hand education and intensive hands-on training, which
accelerates the learning curve to the optimum level within
shortest time. An extensive training course is run over two
days, and is intended to provide peer-led training about
proper selection of patients, current clinical trial results, the
safe use of Intrabeam™ and the precise use of the TARGIT
technique. There is also emphasis on the radiobiology and
radiation safety aspects of this procedure to ensure correct
guidelines are followed. As the indications for the use of
TARGIT is expanding to other tumour sites, these new
developments are also covered. At the end there is a group
discussion, incorporating troubleshooting and presentations
of interesting cases in a mock multidisciplinary meeting
setting.
Educational material
The educational material comprises of full slide set of the
training programme, a video recording of the procedure
performed in the operating theatre, and a comprehensive
reference list with copies of key publications. All participants
receive a copy of a comprehensive textbook edited by the
course organisers (49), which has recently been revised and
updated (50).
The TARGIT training simulator
In order for the surgeons and the interdisciplinary team to
be equipped with the appropriate practical skills required
to perform the procedure, a bespoke training simulator,
conceived by one of the authors (MK), has been designed
and built, and is commercially available (51). This simulator
accelerates the learning curve to the optimum level within
the shortest time, as it is realistic anatomically, and is
constructed from a hot-melt thermoplastic polymer with
similar physical characteristics and radiation attenuation
qualities to the human breast, which therefore allows an
accurate demonstration of the technical aspects of TARGIT.
Simulated tumours of different sizes and locations
are implanted within the model to simulate a real life
experience as far as possible. The polymer can be cut with
a scalpel, and stitches applied. The design of the simulator
is such that participants get an opportunity to practice the
implementation of the entire treatment workflow. This is
accompanied by an in-depth demonstration of the practical
aspects by reviewing the recorded operative procedure on
an actual patient (see Figures 1 and 2).
Proctored training
The Academy also facilitates proctored training for
TARGIT naïve centres that have recently acquired the
equipment. This is done by an experienced trainer and
provides an opportunity for the extended multidisciplinary
team including the operating theatre staff to familiarize
Figure 1 Simulator for training in the TARGIT Academy. The
Intrabeam with applicator has been placed into the tumour bed of
the simulator, and a purse-stitch applied. TARGIT, targeted intra-
operative radiotherapy.

116 Williams et al. IORT for breast cancer
© Gland Surgery. All rights reserved. Gland Surgery 2014;3(2):109-119www.glandsurgery.org
themselves with the technical aspects of the procedure.
In order to ensure that adequate numbers of trainers are
available, a “training the trainer” programme is being
designed and will commence soon.
Audit phase
Centres that intend to participate in one or more of the
international TARGIT trials need to complete an audit
phase by successfully performing ve TARGIT procedures,
followed by review and approval by the trial steering group.
This ensures uniformity of practice within the participating
centres in the trial.
TARGIT Academy website
A TARGIT Academy website (52) is an interactive, up-to-
date portal with both “open” and “closed sections which
can only be accessed by the members of the academy.
The intention is to develop a group discussion forum so
that staff from centres all over the world can look up new
information, or refresh their memories of information that
they may have forgotten. All the educational materials and
latest developments on TARGIT will be posted on the
website for access by Intrabeam™ users.
There has been a significant interest in the TARGIT
technique since the first publication of the results of the
randomized controlled trial confirming its safety and
efficacy. It is essential that as new centres take up this
innovative technology worldwide, there is an adequate
quality assurance and training program in place to ensure
that this powerful technology is implemented appropriately.
The establishment of the TARGIT Academy is a step
towards achieving this objective.
Conclusions
Finally, it should be mentioned that TARGIT is the only
IORT technique that is capable of delivering X-rays
within the operating theatre, and is supported by level-
one evidence. In addition to the trials already mentioned,
the following studies will continue to gather high-quality
evidence for the effectiveness of the technique.
TARGIT-US (for United States) is a Phase IV Registry
Trial being run in the USA through the University of
California, San Francisco to study the efcacy and toxicity
of breast radiotherapy given intraoperatively as a single
dose after breast-conserving surgery, with or without whole
breast radiation as indicated by pathological risk factors, in
women with early stage breast cancer (53).
TARGIT-R (for registry, ISRCTN91179875) will be
an open registry study with very wide inclusion criteria,
enabling clinicians to treat patients with the TARGIT
technique provided they have the support of their
institution and colleagues. Data collection will be as per the
existing TARGIT-A trial and is ideal for centres involved
in this trial who wish to continue to treat patients now that
randomisations have ceased (54).
Acknowledgments
All authors made substantial contributions to the conception,
design and interpretation of data for this article; AND drafted
the article and revised it critically for important intellectual
A B
Figure 2 (A) Hands-on training in progress demonstrating the steps involved to trainees; (B) A close-up view of the simulator with the
Intrabeam applicator in place.

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Gland Surgery, Vol 3, No 2 March 2014
© Gland Surgery. All rights reserved. Gland Surgery 2014;3(2):109-119www.glandsurgery.org
content; AND gave final approval of the version to be
published; AND agree to be accountable for all aspects of the
article and will ensure that questions related to the accuracy
or integrity of any part of the article are appropriately
investigated and resolved.
Funding: The authors wish to acknowledge the TARGIT
International Steering Committee, NIHR HTA (for
funding the TARGIT A and B trials), and David Bishop (for
medical photography).
Disclosure: The authors declare no conict of interest.
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Cite this article as: Williams NR, Pigott KH, Brew-Graves
C, Keshtgar MR. Intraoperative radiotherapy for breast cancer.
Gland Surgery 2014;3(2):109-119. doi: 10.3978/j.issn.2227-
684X.2014.03.03