A Comparison of Intra-operative Radiotherapy Boost With External Beam Radiotherapy Boost in Early Breast Cancer.

DESIGN: A pragmatic multi-centre randomised clinical trial to test whether TARGeted
Intraoperative radioTherapy as a tumour bed Boost (TARGIT-B) is superior in terms of local
relapse within the treated breast compared with standard post-operative external beam
radiotherapy boost in women undergoing breast conserving therapy who have a higher risk of
local recurrence. Patients can be entered before the primary surgery or in a smaller
proportion of cases, post-pathology. SETTING: Specialist breast units in UK, USA, Canada,
Australia and Europe; 31 centres currently recruiting in the TARGIT-A trial and several are
ready to join. TARGET POPULATION: Breast cancer patients suitable for breast conserving
surgery, but with a high risk of local recurrence. Details of inclusion and exclusion are
given in part 2. Briefly the patients should be either younger than 45 or if older, need to
have certain pathological features that confer a high risk of local recurrence of breast
cancer. HEALTH TECHNOLOGIES BEING ASSESSED. The TARGIT Technique: The Intrabeam® (Carl Zeiss,
FDA approved and CE marked) is a miniature electron beam-driven source which provides a point
source of low energy X-rays (50kV maximum) at the tip of a 3.2mm diameter tube. The radiation
source is inserted into the tumour bed immediately after excision of the tumour and switched
on for 20-35 minutes to provide intra-operative radiotherapy accurately targeted to the
tissues that are at highest risk of local recurrence. The physics, dosimetry and early
clinical applications of this soft x-ray device have been well studied. For use in the
breast, the technique was first developed and piloted at University College London. The
radiation source is surrounded by a spherical applicator, specially designed (and available
in various sizes) to produce a uniform field of radiation at its surface, enabling delivery
of an accurately calculated dose to a prescribed depth. It is inserted in the tumour bed and
apposed to it with surgical sutures and/or other means. As the x-rays rapidly attenuate the
dose to more distant tissues is reduced; this also allows it to be used in standard operating
theatres. 20 Gy is delivered to the tumour bed surface in 20-35 minutes, after which the
radiation is switched off, the applicator removed, and the wound closed in the normal way.
This simple technique has potentially several advantages over convential external beam
radiotherapy, interstitial implantation of radioactive wires or conformal external beam
radiotherapy. The first pilot of twenty-five cases was at performed at UCL using TARGIT
technique as a replacement for the boost dose of radiotherapy; full dose external beam
treatment was subsequently given. The phase II study of 300 patients was published and
recently updated with long term data along with favourable toxicity and cosmetic outcome
results of individual cohorts. A mathematical model of TARGIT developed recently (funded by
Cancer Research UK) suggests that it could be superior to conventional radiotherapy.
Translational research has found that TARGIT impairs the surgical-trauma-stimulated
proliferation and invasiveness of breast cancer cells. This effect of radiotherapy may act
synergistically with its tumouricidal effect yielding a superior result. MEASUREMENT OF COST
AND OUTCOME: Patient assessments will be clinical examination (6 monthly x 3 years then
yearly x 10 years) and mammography (yearly). with ulstrasound (if needed) . Primary outcome:
histologically/cytologically proven local recurrence. Secondary: site of relapse in the
breast, overall survival, local toxicity (RTOG and LENT SOMA criteria), cosmesis, quality of
life, patient satisfaction and health economics. The cost and cost-effectiveness of TARGIT
versus EBRT, both as boost, will be calculated from a NHS and personal social services (PSS)
perspective. Costs directly incurred by patients will also be assesed, since EBRT as a boost
is likely to impose additional time and travel expense to patients and families.

Inclusion Criteria:

At least one of these criteria must be satisfied:

1. Less than 46 years of age

2. More than 45 years of age, but with one of the following poor prognostic factors:

1. lymphovascular invasion

2. gross nodal involvement (not micrometastasis)

3. more than one tumour in the breast but still suitable for breast conserving
surgery through a single specimen

3. More than 45 years of age, but with at least two of the following poor prognostic
factors

1. ER and/or PgR negative

2. Grade 3 histology

3. Positive margins at first excision

4. Those patients with large tumours which have responded to neo-adjuvant chemo- or
hormone therapy in an attempt to shrink the tumour and are suitable for breast
conserving surgery as a result.

5. Lobular carcinoma or Extensive Intraductal Component (EIC)

6. A list (one to many) of high risk factors are present (as predefined in the policy
document) that give a high risk of local recurrence.

7. Patients with either HER2 positive or HER2 negative can be included.

Exclusion Criteria:

1. Bilateral breast cancer at the time of diagnosis.

2. Patients with any severe concomitant disease that may limit their life expectancy

3. Previous history of malignant disease does not preclude entry if the expectation of
relapse-free survival at 10 years is 90% or greater (e.g., non-melanoma skin cancer,
CIN, etc).

4. No more than 30 days can have elapsed between last breast cancer surgery (not
axillary) and randomisation for patients in the post-pathology stratification unless
part of a specific clinical trial that addresses the question of timing or tumour bed
can be reliably identified, e.g., by ultrasound.