Targeted Intraoperative Radiotherapy United States (TARGIT-US) Phase IV Registry Trial: A Registry Trial of Targeted Intraoperative Radiation Therapy Following Breast-conserving Surgery
Phase: NA
Conditions: Stage IA Breast Cancer, Stage IIA Breast Cancer
Sponsor: University of California, San Francisco

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Targeted Intraoperative Radiotherapy United States (TARGIT-US) 
Phase IV Registry Trial:
A Registry Trial of Targeted Intraoperative Radiation Therapy 
Following Breast-conserving Surgery 
Version 9.0
Version Date:  April 23, 2018 
Co-Principal Investigators
Michael Alvarado, M.D.
University California San Francisco
Department of Surgery
1600 Divisadero St., Box 1710, 6th floor
San Francisco, CA 94109
(415) 885-7656
Michael.alvarado@ucsfmedctr.org
Eleanor Harris, M.D.
East Carolina University
Department of Radiation Oncology
600 Moye Boulevard
Greenville, NC  27834
ramsey@dca.net
Dennis Holmes, M.D., F.A.C.S.
Los Angeles Center for Women’s Health
at California Hospital Medical Center
1513 South Grand Avenue, Suite 400
Los Angeles, CA 90015 
213-742-6186
Dennis.holmes@chw.edu
drholmesmd@aol.com
William Small, Jr., MD 
Stritch School of Medicine Loyola University Chicago 
Cardinal Bernardin Cancer Center
2160 S 1st Ave
Maguire Center, Rm 2932
Maywood, IL 60153
Phone: (708) 216-2559
Fax: (708) 216-6076
wmsmall@lumc.edu
Dan Pavord
Assistant Vice President for Oncology Services and Chief Medical Physicist
NCT# 01570998

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Health Quest
45 Reade Place
Poughkeepsie, NY 12601
(845) 483-6229 (office)
(845) 224-6142 (cell)
(845) 437-3123 (fax)
Study Sponsor: University of California, San Francisco (UCSF)
Senior Advisors 
Professor Michael Baum
University College of London
The Clinical Trials Group, Dept. of Surgery
Clerkenwell Bldg, Whittington Campus
London, N19 5LW
Tel: 0207 288 3969
m.baum@ucl.ac.uk
Mr. Jay Vaidya
University College of London
Research Department of Surgery, 2nd Floor
Clerkenwell Building, University College London
Highgate Hill, London N19 5LW 
Tel: 0207 288 3970 or 0207 288 5831
jayant.vaidya@ucl.ac.uk
   
   
   
   
   
   
  
Frederik Wenz
Department of Radiation Oncology
University Centre Mannheim, University of Heidelberg
Mannheim  68167, Germany
+49 621 383 4960
Frederik.Wenz@medma.uni-heidelberg.de
Study Statistician
Max K. Bulsara, PhD, MSc, BSc(Hons)
Chair in Biostatistics
Institute of Health and Rehabilitation Research
University of Notre Dame
19 Mouat Street
P.O Box 1225, Fremantle, WA 6959
Tel: (08) 9433 0297
Fax: (08) 9433 0210
Email: max.bulsara@nd.edu.au  

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Revision History
Version 1.0 
04/02/2011
Version 2.0
06/01/2011
Version 3.0
07/18/2012
Version 4.0
02/05/2013
Version 5.0
01/16/2014
Version 6.0
07/21/2014
Version 7.0
09/17/2014
Version 8.0
08/21/2017
Version 9.0
04/23/2018
Table of Contents
SECTION 1:  BACKGROUND ......................................................................................................4
SECTION 2:  OBJECTIVES...........................................................................................................9
SECTION 3:  TRIAL DESIGN.......................................................................................................9
SECTION 4:  ENDPOINTS ..........................................................................................................12
SECTION 5:  SELECTION and ENTRY of PATIENTS .............................................................12
SECTION 6:  TREATMENTS......................................................................................................14
SECTION 7:  PATIENT FOLLOW-UP and RECORDING of EVENTS....................................18
SECTION 8:  DATA OWNERSHIP and PUBLICATION ..........................................................21
SECTION 9:  STATISTICAL CONSIDERATIONS ...................................................................24
SECTION 10:  ETHICAL CONSIDERATIONS..........................................................................25
SECTION 11:  QUALITY ASSURANCE....................................................................................26
SECTION 12:   REFERENCES ....................................................................................................28

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SECTION 1:  BACKGROUND
1.1 Accelerated Partial Breast Irradiation in Breast Conserving Therapy:
 
Over the past 30 years there has been a dramatic change in the local management of breast 
cancer. Radical mastectomy has been replaced by more conservative surgical procedures 
utilizing radiotherapy in conjunction with a wide local excision of the primary tumor. Breast 
conservation surgery has been supported by randomized clinical trials that clearly demonstrate its 
equivalence to the more radical procedures with regards to local control.1 In spite of surgical 
therapy moving towards “conservation", the current standard approach continues to be radical 
with regards to radiotherapy fields which treat virtually all the tissues previously excised by 
mastectomy. A recent paradigm shift now argues for avoiding unnecessary treatment to the 
whole breast and limiting radiotherapy to only a portion of the breast where the primary tumor 
was located, i.e. partial breast irradiation.
Trials that have included lumpectomy alone as a treatment arm have documented local 
recurrence rates of about 40%, which is reduced by a factor of two-thirds with the addition of 
whole breast irradiation.  The use of 45-50 Gy to the whole breast with or without a tumor bed 
boost achieves similar survivals as mastectomy with preservation of the breast, and achieves 
excellent or good cosmesis in the majority of patients. In the patients with local recurrence after 
irradiation, mastectomy has been demonstrated to be highly effective salvage therapy. While 
some patients do not have local recurrence with wide excision alone, no specific subset of 
patients with invasive cancer has been identified that does not benefit from breast radiotherapy in 
terms of local recurrence risk reduction.  The randomized trials of lumpectomy alone versus 
lumpectomy with breast irradiation show a reduction of 63-91% in local recurrence risk with 
radiation.  The Joint Center for Radiation Therapy conducted a trial in an attempt to identify 
patients with very limited cancer distribution who could be treated with wide excision alone and 
achieve similar outcomes as with breast irradiation.2  A highly selected cohort of women with 
stage T1 (<2 cm) invasive cancers, resected with wide margins of > 1 cm and with no nodal 
involvement or lymphatic invasion were enrolled and treated with surgery alone.  The overall 
local recurrence rate was 23%, and in patients with grade 3 tumors was 50%, therefore the local 
recurrence risk exceeded that expected with radiation, even in this very favorable subset.  In the 
CALGB C9343 randomized trial for women over 70 with favorable tumor biology, 636 women 
were randomized to post-lumpectomy tamoxifen alone compared to tamoxifen and whole breast 
irradiation.3  Even in this very low risk population, the 10 year local recurrence rate was 2% with 
radiation and 9% without radiation.  
The rationale for whole breast irradiation is based on the Halstedian principle of treating the 
entire breast, either through surgical extirpation or whole breast irradiation.  Pathologic studies 
of mastectomy specimens have documented rates of multicentricity (tumor present in more than 
one quadrant of the breast) in breast cancer from 10-75%,4,5 indicating the need for treatment 
beyond the region of the breast involved with gross disease.  Holland et al. examined 
mastectomy specimens with fine serial sections. In this series, 39% of specimens had no cancer 
beyond the index lesion, 20% had cancer confined to 2 cm beyond the index lesion, and 41% had 
residual cancer more than 2 cm from the index lesion6. Detailed examination of mastectomy 
specimens by Vaidya et al have shown small additional invasive or in situ cancer foci in over 
60% of patients, and in fact, 80% of these are located away from the index quadrant.7 The 
concept of partial breast irradiation is based on the long-standing observation that in large studies 

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of breast conserving therapy, the majority of early in-breast recurrences occur near the site of the 
original primary tumor. This is true whether or not radiotherapy is given and whether or not the 
margins are involved. At 15 years after treatment, about half of all local recurrences occur in or 
near the original tumor, and half occur elsewhere in the breast.8  The rate of these “elsewhere” 
failures increases over time, becoming a larger percentage of the total number of local failures 
after longer periods of follow-up, and are likely to represent new breast cancers.  The rate of 
elsewhere failures is similar with or without whole breast irradiation.  Whole breast irradiation 
therefore does not necessarily prevent second ipsilateral primary cancers.  This suggests that 
occult cancer foci away from the index lesion do not generally give rise to local recurrence, 
unlike that which is developed from cells surrounding the primary tumor. Given these facts, 
numerous institutional studies have been reported using partial breast irradiation to the tumor bed 
alone, without whole breast irradiation, and several randomized trials comparing standard 
radiotherapy to partial breast irradiation are ongoing.9 
There are a variety of methods for delivering partial breast irradiation.  The only method reported 
on to date with outcome data at 5 years or more involves interstitial breast brachytherapy.  This 
method uses interstitial catheters placed in the breast either at the time of lumpectomy or at a 
later date.    Newer methods of delivering partial breast irradiation include balloon intracavitary 
brachytherapy, in which a catheter and inflatable balloon are placed into the tumor bed and a 
high dose rate source delivers the prescribed dose to the periphery of the balloon.  Also being 
investigated are partial breast external beam irradiation techniques which use multiple 
noncoplanar beams to target the tumor bed and margin based on 3D computer reconstruction 
with or without intensity modulated radiation therapy (IMRT).  Proton beam therapy can also be 
used to deliver partial breast treatment allowing more precisely localized dose deposition and 
selective normal tissue sparing. Intraoperative radiotherapy is an emerging technique to provide 
a single fraction to the vicinity of the tumor bed.
There are historical randomized trials comparing APBI to standard whole breast irradiation.  The 
Yorkshire Breast Cancer Group and Christie Hospital trials, both of which showed unacceptably 
high local recurrence rates with APBI, used staging, surgical and radiotherapy techniques that 
are not comparable to current standards, therefore their results are not applicable today.10,11  The 
other published randomized trial of APBI versus standard BCT was conducted at the National 
Institute of Oncology in Hungary.12  This trial enrolled 258 patients to receive partial breast high 
dose rate brachytherapy (4.33-5.2 Gy x 7) to the tumor bed alone using an interstitial implant 
technique versus standard whole breast irradiation.  At a median follow-up of 66 months, the 5 
year local recurrence was 4.7% with APBI and 3.4% with whole breast radiation, and the axillary 
recurrence rate was <2% in both arms.  
There are several institutional series from the United States that have reported outcomes after 
accelerated partial breast irradiation (APBI) employing LDR or HDR interstitial breast 
brachytherapy.  The Oschner Clinic reported a case control series including 51 patients treated 
with either LDR (45 Gy over 4 days) or HDR (8 Gy x 9 over 4 days) interstitial breast 
brachytherapy, and 94 case controls treated with standard whole breast irradiation.13  At a 
median follow-up of about 75 months in both groups, local recurrence was 8% after APBI 
compared to 5% after standard radiation, regional nodal recurrence was 6% versus 0%, 
respectively, cosmesis was excellent or good in 75% versus 84%, respectively, and grade 3 
complications were noted in 8% versus 5%, respectively. William Beaumont Hospital conducted 
a one-to-one matched pair analysis of 174 patients treated with LDR (50 Gy over 96 hours) or 

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HDR (4 Gy x 8 or 3.4 Gy x 10 twice daily) interstitial brachytherapy, compared to matched cases 
treated with standard whole breast irradiation.14  At a relatively short median follow-up of 36 
months for both groups, locoregional failure was 2% after APBI versus 1% after standard BCT, 
and overall, disease-free and cause-specific survivals were all similar between the two groups. 
Fat necrosis was seen in 8% after APBI and 4% after standard BCT.  A multi-institutional phase 
I-II study of HDR interstitial APBI also delivering 3.4 Gy x 10 in twice daily fractions reported 
6% 5 year local recurrence at a follow-up of 70 months.15  Fat necrosis was noted in 28%, and 
excellent or good cosmesis was found in 88%.  Few factors that predict the risk of local 
recurrence or complications are yet available from these studies, as events to date with limited 
follow-up have been rare.  
The Radiation Therapy Oncology Group (RTOG) conducted a phase I-II study of APBI using 
LDR (45 Gy in 3-5 days) or HDR (3.4 Gy x 10 twice daily).16  The study which enrolled 99 
women closed in 2000.  Outcome data from this trial showed a 5 year actuarial rate of breast 
local recurrence of 4%, and regional recurrence of 3%. The American Society of Breast 
Surgeons (ASBS) has published their 5 year outcomes from a registry trial for the Mammosite® 
system.  This study registered 1449 cases of Mammosite-based APBI, and noted an in-breast 
recurrence rate of 3.8%, identifying risk factors of negative estrogen receptor status, young age 
and positive margins 17  
The experience with partial breast irradiation in invasive breast cancer managed with breast 
conserving surgery (BCS) using this technique is receiving confirmation worldwide (Table 
1).
Table 1.
Author
Patients 
n
IORT 
device and 
dose
Local 
Recurrence 
Rate 
(median 
follow-up)
Long term 
Toxicity
Luini et 
al18
101
ELIOT:
70 cases 
single dose 
21 Gy
2.0% 
(42 months)
1% severe 
fibrosis
15% mild fibrosis
4% Liponecrosis
Veronesi 
U et al19
1822
ELIOT- 
single dose 
of 21 Gy
2.3% 
(36 months)
0.5% severe 
fibrosis
1.8% fibrosis,
4.2% 
Liponecrosis
Lemanski 
et al20
42
Saturne 
linac- single 
dose 21 Gy
4.7% 
(30 months)
No Grade 3 
fibrosis
9.5% Grade 2 
fibrosis
Vaidya et 
al21
1721
Intrabeam- 
single dose 
20 Gy
3.3%
(5 year 
actuarial)
Grade 3-4 
toxicity: 3.3%

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Since 1999, the European Institute of Oncology (EIO) in Milan has conducted a randomized 
trial comparing intraoperative radiotherapy with electrons (ELIOT) single dose with 
traditional external radiotherapy in patients with unifocal breast carcinoma up to 2.5 cm of 
diameter and treated with breast conserving surgery. The update on the results published in 
2005, with 101 cases treated with ELIOT, 70 of them treated with 21 Gy, reported a 2% 
incidence of local recurrence after a median follow-up of 42 months, Toxicity included of 
severe fibrosis (1%) , mild fibrosis, (15%)  and liponecrosis (4%). Liponecrosis was 
described as a localized collection of brown fluid with skin erythema, with no signs of 
infection. The EIO also reported a series of patients who either declined participation in the 
randomized trial or did not fulfill the eligibility criteria was published in 2010. One thousand 
eight hundred and twenty two patients were treated with 21 Gy dose of intraoperative 
radiotherapy with electrons (ELIOT) during breast conserving surgery. The mean follow-up 
was 26 months, with 2.4% local recurrence rate. The late toxicity was severe fibrosis in 0.5% 
patients and 3.2% with mild fibrosis. Liponecrosis was observed in 4.7% cases, 2-4 weeks 
after surgery.
 
The first randomized trial of partial breast irradiation using the Intrabeam system to deliver 
single-fraction intraoperative radiation (IORT) was recently reported.  The TARGIT trial 
enrolled more than 3400 patients in a randomized controlled trial comparing a single fraction of 
IORT to the periphery of the tumor bed to conventional whole breast irradiation over 5-6 weeks, 
and the early outcomes compare favorably to other forms of APBI.21 At five years median 
follow-up, the Kaplan Meier estimate of local recurrence in the conserved breast was 3.3% in the 
targeted intraoperative radiotherapy arm and 1.3% in external beam radiotherapy (EBRT) group. 
For patients who received IORT at the same time as surgery, the difference between the local 
recurrence rate for IORT and that of EBRT is even smaller, 1.1% for EBRT and 2.1% for IORT. 
The number of clinically relevant complications was not different between the two arms of the 
study. The annual hazard rate of local recurrence also showed a peak at three years, although 
longer follow up is needed to rule out a second peak at a later time point. The results, while 
somewhat preliminary, are encouraging for the use of intraoperative APBI in the study 
population, which represented a fairly low risk group overall, although 10-15% of patients had 
some higher risk features, such as negative estrogen receptors, age less than 45 years, tumor size 
larger than 2 cm, high grade histology, presence of lymphovascular space invasion or 1-3 
positive nodes. Continued follow-up of these patients is ongoing to ensure long-term results are 
reported. 
Overall, while there is a significant body of phase I-III data from studies including over 5000 
women worldwide looking at toxicity and short term outcomes after APBI, this radiation therapy 
approach is not considered standard of care for early stage breast cancer patients at this time.  
While randomized trials of various APBI techniques compared to standard BCT including whole 
breast irradiation are ongoing, it will be several years before any mature outcome data are 
available.  Accordingly, the current National Comprehensive Cancer Network (NCCN) practice 
guidelines state that partial breast irradiation “should only be performed as part of a prospective 
clinical trial”, and that “intraoperative radiation with photons or electrons with a single fraction 
(targeted intra-operative radiotherapy) can be used in institutions with that expertise and 
experience”.22  The main advantage of APBI is significantly shortened treatment time.  Potential 
advantages may be gained by treating smaller volumes of normal tissue, and in particular 

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significantly reducing the heart and lung volumes exposed to radiation.  The reduction in 
radiation exposure will likely lead to decreased treatment-related complications in this cancer 
population with an expectation of significant long-term survival.  The phase I-II and early phase 
III data strongly suggests that results of APBI when used in selected patients are comparable to 
standard whole breast irradiation at follow-up periods of 3 to 5 years.
As these data mature, it is extremely important to continue to offer APBI treatment as an option 
to women who fit the inclusion criteria of previously published studies. This should be done 
under an academic model and the patients should be treated and followed under an IRB-
approved protocol and informed consent process.  This approach ensures that appropriate 
eligibility, screening and work-up, and quality assurance are performed, and that toxicity and 
outcome data are collected prospectively and uniformly in a larger cohort of women. These are 
essential steps if any form of APBI is to be established as an appropriate standard of care in 
various early stage breast cancer populations.  A single arm registry trial is the perfect strategy to 
continue treatment with close follow-up as the data matures.  A TARGIT-US IORT registry trial 
can be modeled after the American Society of Breast Surgeons’ Mammosite Breast 
Brachytherapy Registry Trial, which has been very instrumental in establishing the long term 
outcomes and toxicity in balloon brachytherapy-based APBI.23  This protocol will accomplish a 
similar aim for targeted intraoperative APBI.  The TARGIT-US IORT registry would include 
patients for whom randomized data have already been collected during the original TARGIT 
study, essentially adopting the TARGIT trial eligibility criteria, for patients with otherwise 
favorable features.  
1.2 The Targeted Intra-operative Radiotherapy (TARGIT) Technique
The Intrabeam® Photon Radiosurgery System is a miniature electron beam-driven X-ray source 
which provides a point source of low energy X-rays (50 kV maximum) at the tip of a 3.2 mm 
diameter tube. The radiation source can be inserted into the area of interest immediately after 
excision of the tumor and switched on for 15-40 minutes to provide intraoperative radiotherapy 
accurately targeted to the tissues that are at the highest risk of local recurrence. The dosimetric 
characteristics and early clinical applications of this device have been well studied and this is the 
device which was utilized in the international TARGIT-A trial. 
The Intrabeam® device is FDA approved for use in any part of the body.  For breast irradiation, 
the radiation source is covered by a spherical applicator that is used to uniformly conform the 
lumpectomy cavity around the radiation source, enabling delivery of an accurately calculated 
dose to a prescribe depth.  Surgical sutures may also be used to maintain accurate conformance 
of the breast tissue to the application surface. With this approach, the surgical margins are 
wrapped around a radiotherapy source, i.e. the target is ‘conformed’ to the source and avoids the 
need for complex imaging to define the treatment target volume.  The spherical applicators range 
in diameter from 1.5 to 5 cm for optimal conformance to the surgical cavity.  If necessary, the 
chest wall and skin can be protected using sterile, radio-opaque tungsten-filled silicone shields 
that can be cut to size on the operation table.  
The X-ray source is small and lightweight and is mounted on a surgical arm and balanced for 
ease of delivery and support during treatment. With the use of soft X-rays, the radiation beam is 
rapidly attenuated as it passes through the breast tissue adjacent to the applicator. Thus, the 

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highest radiation dose is received by tissue nearest the primary tumor and a much lower dose at 
the skin, and significantly lower doses are received by more distant tissue.
  
The radiation received is proportional to the time the machine is switched on. The precise dose 
rate depends on the diameter of the applicator and the energy of the, both of which may be varied 
to optimize the radiation treatment. Low energy of the radiation allows for effective shielding by 
the sterile sheet shielding material applied around the irradiated area. In conjunction with 
distance, this is typically sufficient to reduce the dose below the regulatory limit for non-badged 
personnel outside of an unshielded operating room. Radiation workers remaining in the OR 
during the irradiation would typically use additional shielding such as leaded glass. Each facility 
would measure radiation levels inside and outside the OR, and ensure that they are below 
regulatory limits, as a part of routine license/registration application process.
SECTION 2:  OBJECTIVES
This is a pragmatic registry trial for women with breast cancers at low risk for local recurrence 
who will undergo breast IORT as sole radiation therapy post-lumpectomy (for whom equivalent 
local control outcomes have been published from the TARGIT randomized trial of IORT versus 
whole breast radiation).  It is recognized that some of these patients, because of unfavorable 
features found subsequently in the pathologic examination of the excised lesion, will still need to 
have external beam whole breast radiotherapy, but omitting any external beam tumor bed boost, 
which will have been provided by the IORT dose.  Whole breast radiation was required in 15% 
of cases in the international TARGIT-A trial.  
The objectives of this registry trial are to establish eligibility criteria based on previously 
published trials and studies in order to allow women who meet these criteria to receive IORT on 
an IRB-approved protocol and to systematically collect and assess acute and long-term toxicity 
and outcomes in larger cohort of patients.  This will add to the general fund of knowledge 
regarding this form of APBI and allow further assessment of risk groups. 
2.1 Primary Objectives:
To study the efficacy and toxicity of breast radiotherapy given intra-operatively as a single 
fraction after breast conserving surgery, with or without whole breast radiation as indicated by 
pathologic risk factors, in women with early stage breast cancer.
2.1.1 In-breast local failure and patterns of in-breast failure
2.1.2 Ipsilateral regional nodal failure
2.1.3 Toxicity and morbidity
2.1.4 Relapse-free survival
2.1.5 Overall survival
SECTION 3:  TRIAL DESIGN
3.1 Core Protocol
A pragmatic registry trial has been designed and modeled after the original successful TARGIT-
A protocol, to continue the use of IORT for a select population of women, and to follow 

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outcomes with regards to local and regional control, toxicity and morbidity. Within this 
pragmatic single arm registry trial is a more selective approach that may be employed in some 
centers for some or all patients.
Patients selected for breast conserving surgery who are considered to have a low risk of local 
recurrence are eligible for the registry trial once given their informed consent. Individual centers 
may decide on more strict inclusion criteria and management criteria than given herein. These 
are to be documented in advance of enrollment of any patients onto the trial by each participating 
center, who will submit a Treatment Policy Statement (see section 6.1 and Appendix) and all 
trial patients will be treated according to this pre-declared policy. Patients will be allowed to 
enter the trial in one of two cohorts; the rationale for each is given below. Investigators may 
determine in advance which data they wish to use for entry of patients from their center and 
stipulate this in the Treatment Policy Statement. If the center has agreed to enroll to both cohorts, 
the decision about which cohort needs to be made prior to enrollment, for each individual.
3.1.1 Cohort 1 — Pre-pathology Entry
This cohort allows entry of patients who have been diagnosed with early breast cancer and 
whose clinical stage is suitable for treating conservatively (small tumor and no gross nodal 
involvement). Tumors should not be more than 3.5 cm in size, as the largest IORT applicator 
size is 5 cm.  Patient informed consent is sought and enrollment is carried out prior to the 
surgical removal of the tumor (lumpectomy) with IORT delivered at the time of the lumpectomy. 
Postoperatively, some pathologic characteristics may be found that render the subject unsuitable 
for ABPI due to higher risk features for local recurrence (e.g., lobular carcinoma, positive 
margins at first excision, lymphovascular invasion, involved axillary nodes). According to the 
center's treatment policy, the patient will be recommended to have a full course of whole breast 
external beam radiotherapy with or without re-excision. The intraoperatively delivered 
radiotherapy replaces the tumor bed boost in these cases. In the international TARGIT trial, the 
organizers were well aware that this could provide a potential bias. The surgeon performing a 
local excision and placing the applicator will be aware that the patient is receiving IORT. 
Although the surgical excision should be similar to non-IORT standards, the surgeon may 
(consciously or unconsciously) remove a wider margin of normal tissue. This potential bias was 
studied in the randomized controlled TARGIT trial and the results showed that the excised tissue 
was equal in both arms.
3.1.2 Cohort 2 - Contralateral breast cancer  
Unfortunately most patients who require treatment for a metachronous breast cancer are 
excluded from entry to trials of local treatment. Later development of a contralateral breast 
cancer cannot be ascribed to the first breast tumor. These breast cancers are typically treated as if 
they were a first time occurrence. 
3.2
Trial Schema
3.2.1
Trial Schema - Cohort 1 – Pre-Pathology Trial Entry

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3.2.2 Cohort 2 - Contralateral breast cancer  
Patients who meet the criteria for entry into the trial but have a history of contralateral breast 
cancer will be eligible for entry as described in Cohort 1.
SECTION 4:  ENDPOINTS
4.1 Local tumor control 
Local tumor control is defined as no recurrent tumor in the ipsilateral breast. Patients will be 
regularly monitored as per the individual center’s policy provided this meets the minimum trial 
criteria for follow-up with physical examination at least every 6 months for 3 years and yearly at 
4 and 5 years post-treatment. 
Confirmation of recurrence will follow clinical examination and cytology or biopsy.
See section 7.
4.2 Site of relapse within the breast will be recorded in order to assess whether the recurrence is 
at the site of initial tumor or at a new site and whether it has occurred within the treated field 
(IORT). The trial CRFs detail how to record the site of the initial tumor and any subsequent 
breast recurrence.
4.3 Local toxicity and morbidity will be recorded as adverse events related to the primary 
treatment of the breast cancer. These were recorded in the randomized trial and outcomes 
showed no significant difference in clinical complications for the IORT as compared to standard 
external beam radiation. However, all expected toxicities of hematoma, seroma, wound infection, 
wound breakdown and delayed wound healing will be assessed according to RTOG criteria. Late 
skin reactions, rash, telangiectasia and pain due to radiation and  all other toxicities will be 
recorded and graded according to standard NCI-CTCAE V. 4 criteria 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf).
4.4 Relapse-free survival will be recorded as the time interval between trial entry and the date of 
confirmation of any recurrence. The actual date to be used is the clinic day on which the 
investigations that led to a confirmed diagnosis of the recurrence were requested. Relapse-free 
survival would include any recurrence of breast cancer (local, regional or distant) or death 
without prior report a relapse. All patients will be analyzed under an “Intent to Treat” policy.
4.5 Overall survival will be the time interval between enrollment and death.
SECTION 5:  SELECTION and ENTRY of PATIENTS
5.1 Eligible patients:  Cohorts 1 and 2

Female

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
Age 45 years old or older with operable invasive breast cancer

T1 and T2 (<3.5 cm), N0, M0, confirmed by clinical, cytological or histological 
examination

Suitable for breast conserving surgery and radiotherapy

Ipsilateral diagnostic mammogram within 12 months of enrollment
Those with previously diagnosed and treated contralateral breast cancer may be entered. It is 
recommended that patients meet an ECOG performance status of 0-3, however, grade 4 patients 
can be treated at the discretion of the participating center.   
Individual centers may wish to restrict entry to a more exactly defined subset of patients in which 
case only patients with these characteristics may be entered by the particular center. For 
example, centers may decide at outset to recruit only women over the age of 50 or possibly only 
postmenopausal women. Such policies must be predefined in writing on the Treatment Policy 
Statement form, submitted and approved by the Steering Committee, and followed for all 
patients enrolled at that center. See section 6.1.
Before entering any patient into the trial, the local investigator should confirm that the patient 
would be available for regular follow-up for at least 5 years.
5.2 Exclusion criteria
5.2.1 All Cohorts:

Age < 45 years

Known axillary lymph node positive breast cancer (FNA not required)

Invasive lobular cancer 

Tumor size > 3.5 cm 

Multicentric cancer in the same breast as diagnosed by clinical examination, 
mammography, ultrasound. MRI or pathologic assessment, not amenable to excision 
with negative margins with a single lumpectomy.

Synchronous bilateral breast cancer at the time of diagnosis.

Ipsilateral breast had a previous cancer and/or prior in-field radiation.

Patients known to have BRCA1/2 gene mutations (testing for gene mutations is not 
required).

Patients undergoing primary systemic treatment (hormones or chemotherapy) as 
initial treatment with neoadjuvant intent of reducing tumor size. 
o
Patients who undergo a short course of anti-estrogen therapy (2-4 weeks) are 
NOT to be excluded because there is no neoadjuvant intent of reducing tumor size

Previous history of malignant disease does not preclude entry if the expectation of 
relapse-free survival at 10 years is 75% or greater

Any factor included as exclusion criteria in the participating center’s Treatment 
Policy Statement.
5.3 Patient entry to the trial

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Patients will be entered to the trial only after being given full information about the trial included 
in a written information sheet. Each patient should be given time to consider participation and 
ask questions before giving consent by signing the patient informed consent form. A patient 
deemed suitable for the trial will only be allowed enrollment once informed consent has been 
freely and voluntarily given. Once eligibility is confirmed and the informed consent form is 
signed, a patient will be enrolled into the trial and assigned a trial number.
If a patient chooses to withdraw, she can write a letter to the site PI or coordinator center PI 
expressing his or her desire to withdraw from the trial and provide a dated signature. 
5.3.1 Cohort 1 – Pre-pathology Entry
Those patients who will have intraoperative radiation therapy at the time of primary surgery will 
be enrolled in the cohort after giving consent but prior to the planned surgery.
5.3.2 Cohort 2 - Contralateral Entry
If the patient has a previous contralateral breast cancer then they will be entered as a separate 
stratum, with their other eligibility for cohort 1 as determined appropriate. 
5.3.3 Patient Consent
Sample consent forms are provided by the Steering Committee and may be modified to meet 
institutional criteria, but all changes must be approved by the Institutional Review Board, as well 
as by the Steering Committee prior to enrollment of any subjects onto the registry.
SECTION 6:  TREATMENTS
6.1 Treatment Policy Statements
Prior to entry of any patients each participating center will register with the Steering Committee 
and complete a Treatment Policy Statement which has been approved by the Steering 
Committee. The Treatment Policy Statement will define the categories of subjects to be entered 
in each cohort and details of the treatment policy (e.g. fractionation and dose of whole breast 
radiotherapy to be used).  The Steering Committee must be notified in writing prior to 
implementation of any change to practice during the course of the trial, in order to audit the 
patients entered and to confirm that treatment remains true to the core protocol.
Only clinical centers with the Intrabeam® device or those who are able to refer patients to such a 
center may participate in this trial. Centers with newly acquired equipment must consult the trial 
operation center prior to entering patients into the trial. The quality control of the Intrabeam 
system set up must be confirmed by the Coordinating Center before enrollment of patients can 
begin.
6.2 Surgery
All patients will have local excision of the primary tumor following appropriate clinical workup. 
No specific assessments prior to enrollment will be required although mammography and 

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ultrasound are strongly recommended to facilitate identification and exclusion of multi-focal 
disease and to determine as accurately as possible the size of the tumor.
Surgery will be according to practice standards at each participating center. Complete 
macroscopic excision of the tumor is required. The aim of the local excision should be to achieve 
the widest margin of excision while maintaining a good cosmetic outcome. For superficial 
tumors, an ellipse of overlying skin can be excised. The depth of resection will depend on the 
position of the tumor within the breast and the size of the breast, but in most instances will 
extend to the pectoral fascia.
In all patients, but especially in those women with non-palpable tumors where pre-operative 
localization has been performed, the specimen should be well oriented with sutures or clips 
according to local protocols and x-rayed intraoperatively. The specimen x-ray should be 
examined in the operating room to ensure complete excision of the lesion and to assess the 
adequacy of the margins. Further tissue should be taken from a margin if intraoperative 
assessment indicates that tumor extends near the margin. Specimens must be processed in order 
to allow pathologic assessment microscopically of all margin widths.
Either a standard sentinel node biopsy or at least a level I axillary node dissection with removal 
of at least 6 axillary lymph nodes must be performed in all patients. Wound closure must be 
performed meticulously (air and water-tight) and sutures (if non-absorbable) should remain in 
place for 14 days.
6.2.1 Cohort 1:  Pre-pathology Stratum
6.2.1.1 Patients with Positive Margins
If final pathology shows involved or close margins (evidence of invasive or in-situ tumor at or 
within 1 mm of an excision margin), re-excision is strongly recommended, however, final 
margin width will be dependent on participating center’s institutional policy and will be stated in 
the Treatment Policy. In some cases margin status may necessitate a mastectomy.  If re-excision 
is not performed and the margin width does not meet that which is required by the Treatment 
Policy, the subject is no longer eligible for IORT alone, and should be treated with whole breast 
irradiation, omitting the external beam boost.  For subjects enrolled pre-pathology who have 
already received IORT, re-excision to negative margins must be followed by external beam 
radiotherapy with exclusion of a boost, or undergo mastectomy.
6.2.1.2 Patients with High Risk Features
Subjects selected for IORT alone whose surgical pathology specimens reveal higher risk with the 
following pathologic features: 

Axillary lymph node positive breast cancer 

Invasive lobular cancer 

Tumor size > 3.5 cm 

Extensive Intraductal Component (EIC= > 25% of the lumpectomy specimen 
involved with ductal carcinoma in situ, DCIS) as assessed on surgical pathologic 
lumpectomy specimen. 

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
Multicentric cancer in the same breast as diagnosed by pathologic assessment, not 
amenable to excision with negative margins with a single lumpectomy.

Inability to assess pathologic margin status

Any factor included as exclusion criteria in the participating center’s Treatment 
Policy Statement.
These subjects must be advised to receive external beam whole breast radiotherapy, since these 
subjects are at a higher risk of developing a local or regional recurrence, therefore are rendered 
unsuitable for IORT alone.  External beam radiotherapy will be administered in addition to the 
IORT that they have already received, and should not be followed by an external beam tumor 
bed boost.  These subjects should remain in the trial should continue to be followed according to 
the original enrollment cohort as per protocol.   
Alternatively, a mastectomy may be performed based on the histopathology findings, 
multidisciplinary consultation, or patient preference. The indication for mastectomy must be 
recorded on the patient's trial case report form. The patient should remain in the trial should 
continue to be followed according to the protocol.  If mastectomy is performed, the use of post-
mastectomy irradiation will be at the discretion of the radiation oncologist.  
6.2.1.3 Patients who do not receive IORT
A patient will no longer be followed and will be “Off Study” if he/she was not given IORT 
during surgery or was deemed clinically ineligible for IORT by the site investigators after 
signing consent.   No data needs to be reported for this patient. 
6.2.2 Cohort 2: Contralateral
Patients should be managed as described for Cohort 1 as indicated by their risk features. 
6.3 Pathological Examination
Data from the pathological examination should be recorded on the appropriate data collection 
forms in accordance with the T N M classification. Failure to assess and record all required 
pathologic criteria will necessitate pathologic re-review to achieve complete pathologic 
classification or this could result in protocol violation.  
6.4 Radiotherapy
The technique of the operation and the delivery of radiotherapy has been described and published 
previously. An instructional video produced by Carl Zeiss is also available from the Steering 
Committee.  All participating centers must be trained and submit required radiation quality 
assurance data according to Section 11.2.  
6.4.1 Preparation of the Intrabeam
Intraoperative radiotherapy will be delivered in the operating room immediately after the 
removal of the tumor. All patients should receive a prophylactic dose of antibiotic just before 
skin incision. The device and the arm of the stand are wrapped in a sterile clear plastic cover. 
The individual applicators are sterilized prior to the surgery session.

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The size of the applicator sphere is determined at surgery by the surgeon and/or the radiation 
oncologist. An appropriately sized in applicator fits comfortably without tension but allowing 
conformation of the surrounding tissue, and so that the skin and some subcutaneous tissues can 
be gathered with purse string suture over the sphere. Any other apparatus to assist this apposition 
may also be used.
It is essential to achieve complete hemostasis before insertion of the applicator sphere, because 
even a small amount of bleeding can distort the cavity around the sphere and significantly reduce 
the radiation dose to adjacent breast tissue. The applicator sphere is inserted into the surgical 
cavity and pursestrings suture may be inserted in the breast tissue to bring together the target 
breast tissue so that it conforms well to the surface of the spherical applicators and is held it in 
place during treatment. The skin, but not the breast tissue, should be retracted away from the 
radiation source device using surgical sutures to prevent direct contact with the applicator. It is 
important to keep the skin at a distance of at least 1cm from the applicator surface. 
  
If necessary, sterile protective tungsten sheets used according to the manufacturer’s instructions 
may be applied by the surgeon to protect deep structures (heart and lung) if the deep margin of 
the excision is at the chest wall.  The skin flap may also be protected by placement of moistened 
gauze between the skin and applicator shaft. Regardless of the shielding utilized, care must be 
taken to avoid inadvertent shielding of tissue that requires radiation treatment.
6.4.2 IORT dose prescription and delivery
The surgeon and radiation oncologist should choose the largest possible suitable applicator in 
order to ensure the optimal dose is delivered to the tumor bed tissue. 
The protocol allows for one dose prescription. A dose of 20 Gy at the surface of the applicator is 
prescribed by the radiation oncologist and delivered to the breast tissue. This takes 
approximately between 15-40 minutes depending on the size of the applicator.
During the radiation treatment, the anesthesiologist, clinician and physicist may remain within or 
adjacent to the operating room. To avoid unnecessary exposure of hospital personnel, it is 
recommended that as many people as possible vacate the operating room and those remaining 
either wear a lead apron or remain behind a shielded screen.
6.4.3 Completion of IORT
After completion of radiation the conforming sutures are removed. Strict hemostasis should be 
obtained following the removal of the Intrabeam device. The skin is sutured meticulously to 
achieve a watertight closure as per the surgeon’s usual technique. 
6.4.4 External beam irradiation
External beam techniques will be used uniformly in all patients who require whole breast 
irradiation regardless of the cohort into which they were enrolled.  It is recommended that the 
RTOG breast contouring atlas guidelines should be followed when target and normal tissue 

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volumes are contoured and dose-volumes evaluated.  A linear accelerator with a minimum 
energy of 6 MV should be used for treatments.  
Whole breast irradiation should be delivered to the entire ipsilateral clinical breast volume with 
an adequate margin (1.5 to 2 cm) and appropriate compensation to keep the maximum dose less 
than 15% above prescription dose.  A dose of 45 to 50.4 Gy in 1.8 to 2 Gy per fraction, or 42.56 
Gy in 2.66 Gy per fraction may be used. Dose calculations should use homogeneity corrections. 
It is strongly recommended that three dimensional CT-based treatment planning be used in all 
cases.  The lumpectomy cavity should be contoured on the planning CT and the treatment fields 
should cover this volume with adequate dose (at least 95% of the prescribed dose).  Intensity 
modulated radiotherapy (IMRT) is usually not appropriate for intact breast irradiation, but may 
be used in conjunction with appropriate image guidance if it provides a substantial reduction in 
normal tissue (heart or lung) doses, or significantly improved dose homogeneity in the target 
volume.  
No external beam boost should be delivered, as all patients will have already received an IORT 
boost.  
The following dose constraint guidelines as per ongoing RTOG breast trials are recommended:
Tumor bed: 100% to receive ≥ 95% prescribed dose
Ipsilateral lung:  < 15% to receive 30% prescribed dose
Contralateral lung:  < 15% to receive 5% prescribed dose
Heart (left sided tumor):  <5% to receive 40% prescribed dose
Heart (right sided tumor):  <5% to receive 5% prescribed dose
If the subject is not receiving chemotherapy, then whole breast irradiation should start within 9 
weeks of the final surgical procedure.   If the subject is to receive chemotherapy, then the 
radiation should begin within 6 weeks of the final dose of chemotherapy, not including 
trastuzumab or other biologic systemic therapies, or hormonal therapies, which may be 
administered concurrently with breast irradiation.  
6.5 Adjuvant Systemic Therapy
Following completion of intraoperative radiation therapy, patients may be advised to receive 
adjuvant systemic therapy according to local practice. The sequencing of adjuvant therapies is 
not governed by this protocol, but careful consideration should to be given to the timing of 
chemotherapy in patients who are scheduled to receive external beam radiotherapy after 
intraoperative therapy
SECTION 7:  PATIENT FOLLOW-UP and RECORDING of EVENTS
7.1 Follow-up and Notification of Recurrence, Adverse Events, and Death
Patients should be followed according to local guidelines and these should be noted on the policy 
statement prior to entry into the trial. However, submission of case report forms will be required 
for each patient at six-month intervals for the first three years and yearly for years four and five.  
Each patient should be seen within a six-week window of the planned visit date according to the 

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follow-up calendar. At each visit the patient should be offered a physical examination and asked 
whether she has experienced any adverse events. Below is a list of suggested patient interactions. 
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9 
Visit 10
 Visit 11
Initial 
screaning 
by 
surgeon
Rad-onc 
consult to 
consent 
patient 
and 
discuss 
trial and 
radiation 
therapy.
Six-
week 
follow 
up with 
Surgeon
6 mo 
f/u. 
Breast 
exam 
and/ or 
mammo
1-year 
f/u 
Breast 
exam 
and/ or 
mammo
1.5-year 
f/u 
Breast 
exam 
and/ or 
mammo
2-year 
f/u 
Breast 
exam 
and/ or 
mammo
2.5-year 
f/u 
Breast 
exam 
and/ or 
mammo
3-year 
f/u 
Breast 
exam 
and/ or 
mammo
4-year 
f/u 
Breast 
exam 
and/ or 
mammo
5-year 
f/u 
Breast 
exam 
and/ or 
mammo
It is recommended that mammography of the ipsilateral breast occur at six month intervals post-
treatment for the ipsilateral breast for the first three years then yearly thereafter. Any other 
radiological examination is at the discretion of the local clinicians.
For patients enrolled on the new contract starting 9/15/2017, submission of follow-up case report 
forms will only be required for the second and fifth year follow-up. The initial case report form 
is required as usual.
Patient follow-up may extend beyond the 5 year follow-up period specified in this protocol. An 
optional 10 year follow-up telephone questionnaire may be added as a sub-protocol and patients 
will be consented to be contacted at this later time point. 
7.2 Recording of Recurrence Events
Local recurrence includes any ipsilateral invasive or non-invasive breast tumor recurrence. 
Location of local recurrence, for the purpose of this protocol, is defined as “true” recurrence in 
the index quadrant of the breast versus “elsewhere” if in another quadrant of the ipsilateral 
breast. Regional recurrence is defined as recurrence in the ipsilateral axillary, infraclavicular, 
supraclavicular or internal mammary lymph nodes. 
Confirmation of ipsilateral recurrence must be by histology or unequivocal cytology. Clinical 
examination and imaging are not sufficient. Careful recording of the site of the recurrence is 
required to determine whether it is at the site of the original tumor and/or within the treatment 
field to determine whether the disease is true or elsewhere. 
Recurrence at any other site, including contralateral breast or contralateral regional nodes, must 
be confirmed by appropriate imaging and/or biopsy. Details of both first local or regional and 
first distant recurrence are required to be submitted as well as the status of the patient with regard 
to active disease when treatment for local disease has been completed.
Development of recurrence or new malignancy, including in the contralateral breast, must be 
reported on the case report forms once a diagnosis has been confirmed.
7.3 Guidelines for the Management of Recurrence

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The management of recurrent disease will be left to the discretion of the participating institution. 
If appropriate, patients having had intraoperative radiation therapy alone are able to have 
conventional radiation as part of the management of a recurrence, according to institutional 
standards.
7.4 Adverse Events
For purposes of this study, only those adverse events (AEs) related to the surgery or radiation 
will be reported, as this study includes no guidelines or requirements regarding any systemic 
therapy. Patients on this trial will be assessed for acute and late radiation morbidity, according to 
NCI CTCAE criteria, version 4. Adverse events may be recorded at any time following the 
surgery for the 5 year observation period.
7.4.1 Adverse Event Reporting Requirements
7.4.1.1 Expected Adverse Events
Expected adverse events are adverse reactions or events that are thought to be related to the 
research procedure. For the purpose of this trial the following is a list of potential expected AEs.
Fibrosis
Wound complication
Wound infection
Wound dehiscence
Hematoma in breast or axilla 
Seroma 
Dermatitis radiation
Telangiectasia
Pain in the radiated field
Localized edema in the breast
Expected AEs will be recorded in the complication form and will be completed per Standard 
Operating Procedure manual.
7.4.1.2
Unexpected adverse reactions are adverse reactions or events that are thought to be related to the 
research procedure but do not appear on the list as mentioned above. These are recorded in the 
complication form if grade 3 or more according to CTCAE criteria. Unexpected AEs should also 
be reported to the coordinating center within 5 days of being brought to the attention of the 
investigator and reported to the site’s Institutional Review Board per its requirements.
7.4.2 Serious Adverse Events (SAEs)
A serious adverse event is defined as any event that is fatal, life-threatening, causes or prolongs 
hospitalization, causes disability or incapacity, or requires medical intervention to prevent 
permanent impairment or damage,  
7.4.3 Serious Adverse Events Reporting Requirements

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Only SAEs related to surgery or radiation need to be reported to the coordinating center. These 
related SAEs must be reported directly to the coordinating center as soon as possible and at least 
within five working days of the investigator becoming aware of the adverse event. An early 
report can then be followed up by a more detailed report.
All serious adverse events that occurred during the period of observation must be documented on 
the serious adverse event form and complication form. Any complications following surgery 
with intraoperative radiation therapy must be reported on the complication form.  It is also the 
investigator's responsibility to report them to the local institutional IRB as required by local 
regulations.
The clinical course of the serious adverse event should be managed according to accepted 
standards of medical practice until a satisfactory explanation is found or the investigator 
considers it medically justified to terminate follow-up of this event. Should the adverse event 
result in death, a full pathological report should be supplied if possible. 
7.4.4 Period of Observation
For the purpose of this trial, the period of serious adverse event observation extends from the 
time of registration onto the trial until 5 years after the completion of the intraoperative radiation 
therapy. Trial follow up should continue according to schedule once the SAE is resolved. 
7.5 Deaths
All deaths with date and cause must be reported as soon as possible to the coordinating center on 
the appropriate case report form. Deaths which also meet SAE criteria should additionally be 
reported as described in 7.4.3.
7.6 Withdrawal of Consent
Patients may opt out of the trial at any time by signing a letter of intent to withdraw. At this 
point, the patient will be censored and no further data will be collected. Such cases should be 
reported to the coordinating center immediately so that no further data are entered onto the 
database.
SECTION 8:  DATA OWNERSHIP and PUBLICATION
The management of this trial is the responsibility of the Steering Committee, which also owns 
the rights to all data collected on the trial. Individual centers own the rights to the data collected 
on patients entered from their own center.  However, by agreeing to participate in this trial, 
investigators also must agree not to present or publish any analysis of their institutional data on 
trial patients until after the first publication of the overall result for the whole trial. The policy for 
publication of the trial has been agreed by the Steering Committee. 
The Steering Committee will meet regularly and review all matters of trial conduct and will also 
address any questions relating to the trial.  Responsibility for any decisions on the management 

Pr ot oc ol Versi o n: 9. 0
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4/ 2 3/ 2 0 1 8
2 2
of t he trial a n d its p u blicati o ns is i n veste d i n t he cli nical a n d scie ntific aca de mic me m bers of t he 
c o m mittee.
8. 1 Trial A d mi nistrati o n
Si nce t his is a m ultice nter trial, it has bee n a gree d t hat eac h ce nter ta kes res p o nsi bilit y f or t he 
c ollecti o n a n d ma na ge me nt of its o w n data. A n y ot her arra n ge me nt re q uires a p pr o val b y t he 
Steeri n g C o m mittee.  Eac h partici pati n g ce nter will be re q uire d t o pr o vi de na mes of staff 
c o m pleti n g case re p ort f or ms, a n d c o nfir mi n g t hat t he staff has c o m plete d G o o d Cli nical Practice 
trai ni n g. I n a d diti o n, eac h site c o or di nat or m ust c o m plete a data e ntr y trai ni n g we bi nar wit h t he 
c o or di nati n g ce nter. T he data will be e ntere d i nt o a n electr o nic C R F s yste m, w hic h e ver y 
c o or di nat or will gai n access t o o nl y after c o m pleti n g t he re q uire d trai ni n g. A maj or c o m p o ne nt 
of t his trai ni n g is t o strea mli ne data e ntr y a n d pre ve nt t he s u b missi o n of i nacc urate a n d 
i nc o m plete data.
Eac h partici pati n g ce nter m ust s u b mit t he re q uire d data f or ms a n d case re p ort f or ms t o t he 
c o or di nati n g data ce nter wit hi n re q uire d ti me li mits. T he Steeri n g C o m mittee will m o nit or a n d 
ha ve access t o all t he data. Re g ular electr o nic re p orts will be pr o d uce d a n d passe d t o eac h ce nter 
f or a u dit a n d m o nit ori n g p ur p oses.
Data s u b missi o n fr o m eac h site will be m o nit ore d cl osel y b y t he c o or di nati n g ce nter. T he first 
fi ve patie nts fr o m eac h site will ha ve all C R F’s verifie d b y c o or di nati n g ce nter. De pe n di n g o n 
t he res ults of t his i nitial data a u dit, a mi ni m u m of 2 0 % of all C R F’s will be a u dite d f or t he 
d urati o n of t he st u d y. 
T he f oll o wi n g s o urce d oc u me nts are re q uire d t o be u pl oa de d t o verif y C R F data. Please n ote, all 
d oc u me nts s h o ul d be re dacte d of patie nt na mes a n d me dical rec or d n u m bers, a n d s h o ul d ha ve 
t heir T A R Gi T- U S st u d y i de ntifier o nl y. T hese pr ocesses will be i ncl u de d i n t he re q uire d data 
trai ni n g sessi o n. 
1.
Cli nic n ote, w hic h i ncl u des d oc u me ntati o n of eli gi bilit y i ncl u di n g patie nt a ge, size of 
t u m or b y cli nical or i ma gi n g e val uati o n, a n d c o nfir mati o n of i n vasi ve ca ncer s uita ble f or 
breast-c o nser vi n g s ur ger y.
2.
S ur gical Pat h ol o g y re p ort(s) f or all s ur gical pr oce d ures, i ncl u di n g t he I O R T pr oce d ure
3.
P ost-s ur ger y cli nic n ote d oc u me nti n g a dj u va nt t hera p y, c o m plicati o ns, rec urre nces, or 
a n y ot her si g nifica nt e ve nts i n t he f oll o w- u p peri o d ( o nl y i ncl u de d if a p plica ble)
Partici pati n g sites will be rei m b urse d f or eac h patie nt e ntere d o nt o t he trial, b ut o nl y after 
c o nfir mati o n t hat t he re q uire d C R F’s ha ve bee n vali date d f or acc urac y a n d c o m plete ness. T he 
f oll o wi n g ta ble o utli nes t he case re p ort f or ms re q uire d i n or der t o recei ve rei m b urse me nt:
Rei m b urse me nt Sc he d ule f or P artici p ati n g Ce nters
D at e
It e m
A m o u nt
Y e ar 1: A n n u al p ati e nt r e cr uit m e nt 
p a y m e nt s
A c cr u al p a y m e nt s: 
P ati e nt r ei m b ur s e m e nt p a y m e nt s d u e u p o n 
v erifi c ati o n of c o m pl eti o n of t h e f oll o wi n g: 

U pl o a d e d C o n s e nt
$ 5 0 0 p er 
p ati e nt

Pr ot oc ol Versi o n: 9. 0
Pr ot oc ol N u m ber: 1 1 7 5 1 5
4/ 2 3/ 2 0 1 8
2 3

Eli gi bilit y Crit eri a

D e m o gr a p hi c I nf or m ati o n

O n St u d y I nf or m ati o n

Tr e at m e nt I nf or m ati o n

S eri o u s A d v er s e E v e nt F or m( s) 
(if a p pli c a bl e)

E ntr y F or m 

S ur g er y F or m

P at h ol o g y F or m

I O R T F or m

E B R T F or m (if a p pli c a bl e)

A dj u v a nt T h er a p y F or m

A d diti o n al Pr o c e d ur e F or m 
     (if a p pli c a bl e)

C o m pli c ati o n F or m( s) 

F oll o w- u p F or m s ( 1 m o nt h, 6 
m o nt h s, a n d 1 y e ar)
C o n c o mit a nt m e di c ati o n s F or m s ( D a y 1, 1 m o nt h, 
6 m o nt h s, a n d 1 y e ar
E n d of y e ar 3:  A n n u al p ati e nt 
r ei m b ur s e m e nt p a y m e nt s f or f oll o w-
u p
F oll o w- u p p a y m e nt s: P ati e nt r ei m b ur s e m e nt 
p a y m e nt s d u e u p o n v erifi c ati o n of c o m pl eti o n of 
t h e f oll o wi n g C a s e R e p ort F or m s:

F oll o w- u p F or m s ( 1. 5 y e ar s, 2 
y e ar s, 2. 5 y e ar s, 3 y e ar s)

S eri o u s A d v er s e E v e nt F or m( s) 
(if a p pli c a bl e)

C o m pli c ati o n F or m( s) (if 
a p pli c a bl e)

C o n c o mit a nt m e di c ati o n s F or m s 
( 1. 5 y e ar s, 2 y e ar s, 2. 5 y e ar s, 3 
y e ar s)

L o c al/ Di st a n c e R e c urr e n c e 
F or m s (if a p pli c a bl e)
$ 3 0 0 p er 
p ati e nt
E n d of y e ar 5:  A n n u al p ati e nt 
r ei m b ur s e m e nt p a y m e nt s f or f oll o w-
u p
F oll o w- u p p a y m e nt s: P ati e nt r ei m b ur s e m e nt 
p a y m e nt s d u e u p o n v erifi c ati o n of c o m pl eti o n of 
t h e f oll o wi n g C a s e R e p ort F or m s:

F oll o w- u p F or m s ( 4 y e ar s, 5 
y e ar s)

S eri o u s A d v er s e E v e nt F or m( s) 
(if a p pli c a bl e)

C o m pli c ati o n F or m( s) (if 
a p pli c a bl e)

C o n c o mit a nt m e di c ati o n s F or m s 
( 4 y e ar s, 5 y e ar s)

L o c al/ Di st a n c e R e c urr e n c e 
F or m s (if a p pli c a bl e)
$ 2 0 0 p er 
p ati e nt
T ot al:
$ 1 0 0 0 p er 
p ati e nt

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NOTE: Collaborating sites will not be reimbursed for patients enrolled on the new 9/15/2017 
contract.
Any data management or clinical queries should be addressed in the first instance to the principal 
investigator at the local center. If the investigator cannot adequately address the question it 
should be passed to the coordinating center, which will either deal with the query directly or pass 
it on to the Steering Committee.
In addition to the initial data audits, ongoing data quality monitoring, with appropriate feedback 
to each participating center, will be conducted by the coordinating center at six-month intervals 
under the oversight of the Steering Committee.  Participating centers who do not abide by the 
Standard Operating Procedures and Good Clinical Practice guidelines will have patient 
reimbursement withheld and their continued participation will be at the discretion of the Steering 
Committee. Data monitoring reports will be reviewed by the Steering Committee as outlined in 
Section 11.3. 
SECTION 9:  STATISTICAL CONSIDERATIONS
9.1 Patient Numbers and Power Calculations
The objective of this trial is to enroll patients in a single arm protocol and monitor local tumor 
control. 
The sample size calculation for the TARGIT US Registry Trial (a prospective observational 
cohort study with no comparator group) assumes a background rate for local recurrence and 
utilizes the following calculation. 
If λ0 = background rate
δ is the difference between background rate and current recurrence rate
For a given level of α and β, the sample size is calculated using method by Machin et al24:
𝑛=
[𝑧1 ‒ 𝛼𝜆0 + 𝑧1 ‒ 𝛽(𝜆0 + 𝛿)]
2
𝛿2
For TARGIT US Registry trial, the background recurrence rate is assumed to be 4.5% and the 
current rate of recurrence is set at 2.00%. Delta is the difference between background rate and 
current recurrence rate. Sample size has been calculated using the following: Alpha=5% and 
Power=90%, resulting in a required 755 patients. An excess of 5% will be added as a rule for 
anticipated ineligible subjects, increasing the total sample size to 793. The two patient cohorts 
will not be separated for the analysis regarding local control. 
Background 
Rate
Current
Rate
Delta
Alpha
Power
Sample 
size
4.50%
2.00%
0.025
5%
90%
755

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The original international TARGIT trial was written as a non-inferiority trial. Its recent 
publication in the Lancet shows that the intraoperative radiation therapy is not inferior to 
standard external beam radiation therapy at a median follow-up of four years. As that data 
continues to mature, this registry trial will enroll patients for the purpose of both verifying those 
results and collecting additional outcome and toxicity data.
ASTRO, the governing body for radiation oncology, recently changed their guidelines for IORT. 
Although the published data has been promising, the group's recommendation is that IORT with 
lower-energy X-ray should only be used for prospective registry trials. In order to continue 
offering this radiation treatment in accordance with the ASTRO guidelines the accrual has been 
increased to 1500 patients. In discussion with the other collaborating sites on the study, we've 
expressed a mutual desire to continue the study in order to continue offering IORT and to 
continue looking at toxicity data, local recurrence numbers, etc. 
9.1.1 Early Stopping
Early stopping of this trial is within the power of the Steering Committee.  Reasons for early 
stopping include: 

Any grade V toxicity

More than 5 grade IV toxicities within the first 50 patients reported at the 6 month 
follow-up

More than 10 grade IV toxicities within the first 100 patients reported at the 6 month 
follow-up

More than 5% local recurrences after the first safety report

Skin breakdown and wound dehiscence (reported at 6 weeks of after procedure), which 
after detailed review of the Steering Committee as to time course and severity, were 
considered clinically significant
There will be one formal interim analysis for efficacy of this single arm therapy once half the 
expected number of patients has been enrolled or once half of the expected events has occurred, 
whichever happens first. If at this time local recurrence is noted to be significantly different then 
the parent TARGIT trial (outside the initial 2.5% non-inferiority boundary; in which local 
recurrence is more than 5%) then early stopping will be undertaken.
9.1.2 Additional Sub-protocols
Additional sub-protocols will be written to address questions such as quality of life, patient 
preference, and health economics. Each sub-protocol will have its own statistical considerations 
and will be funded independently of this protocol.
9.2 Statistical Analysis
The major endpoint is the incidence of local recurrence. This will be calculated on the basis of 
intention-to-treat. All three cohorts will be combined for the local recurrence analysis.
In addition, exploratory subgroup analyses will be performed on the main endpoint including 
variables such as timing of IORT with respect to surgery, tumor size, grade and axillary node 
involvement. 

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SECTION 10:  ETHICAL CONSIDERATIONS
This registry trial uses a well-established technology with FDA approval to deliver intraoperative 
radiation therapy. The recent results of the analysis with four years median follow-up showed 
that the TARGIT is equal in efficacy as compared to external beam radiation therapy for selected 
patients. Although the median follow-up is less than five years, the annual hazard rates are very 
promising with a peak incidence of local recurrence at 3 years. This is supported by other large 
randomized trials, which show a similar peak incidence of local recurrence within the first 2-3 
years. However, these results should be interpreted with caution and the Intrabeam technology 
for delivering radiation therapy whether as sole therapy or as a boost should continue to be 
monitored within a well-organized clinical trial. Until sufficient follow-up time has elapsed to 
establish this modality as an alternative standard of care and the appropriate patient selection 
determined. All suitable patients will be informed of the trial and given the opportunity to 
participate. Patients will be given a period of time to consider entry and to complete the consent 
form. Entry into the trial will only proceed once signed consent form has been received at the 
clinic.
SECTION 11:  QUALITY ASSURANCE
11.1 Quality Assurance Procedures:
All the evidence to date supports the description of the Intrabeam as delivering an accurate and 
reliable dose. Physicists on site at each participating center are responsible for verifying the 
miniature x-ray source is operational prior to use and setting up the parameters within the control 
console software for treatment delivery. During the procedure, the control console monitors the 
system for safe and accurate dose delivery.
The Intrabeam System includes a full set of quality assurance tools. These combined with the 
operator interface of the control console allow complete verification of all of the performance 
functions in minutes and constant monitoring of critical treatment parameters throughout the 
treatment. The participating centers are responsible for Q/A according to the manufacturer's 
instructions detailed in the User Manual and these data must be submitted to the coordinating 
center. 
The set of dosimetric QA procedures described in the User Manual is at its core a set of relative 
calibration verification tests based on the absolute calibration performed at the factory. Each 
participating site shall submit documentation about the site’s device for review before enrolling 
patients in the study. This documentation will include ion chamber calibration certificate, 
independent absolute dose measurement for the bare probe showing agreement with 5% of the 
factory measured value (in which the charge measured and all of the factors used to convert the 
reading to absolute dose should be included; a measurement at a distance of 2cm is 
recommended), description of the depth dose measurement setup, factory measured depth doses 
for the bare probe and each applicator,  Analysis of site measured depth dose showing agreement 
within 5% of the factory measured depth dose for at least 1 applicator, where the depths 
measured should range from the closest possible distance to the applicator to at least 2cm from 
the surface of the applicator. This should be done at acceptance, annually, and following major 
repairs/replacement of the accelerator unit.

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Recalibration of the output of the X-ray source must be performed at least annually and a report 
must be submitted to the coordinating center. Carl Zeiss-Meditec, Inc. offers contracts for annual 
manufacturer service. For quality assurance purposes, the operations office will request from 
each site annually or after every 50th patient (whichever is earlier) a printout of the system 
parameters.
11.2 IORT Physics and Quality Assurance
Prior to entering any patient into the trial, participating centers will submit data for each X-ray 
source probe and applicator set in use. Each participating center will be responsible for 
measuring data for the probe and applicator set and shall submit the data supplied by the 
manufacturer for comparison with measured data together with a copy of the letter of acceptance 
supplied by Carl Zeiss-Meditec, Inc. In the event that a new applicator that has demonstrated 
equal effectiveness is developed, it can be used in this protocol. The same information for the 
applicator must be collected as described below. Information regarding the new applicator must 
be submitted to the IRB as a minor modification to the protocol.
In addition, if a center was not previously a member of the international TARGIT randomized 
controlled trial, it is strongly suggested that five pilot cases be performed prior to enrollment of 
any study subjects (followed by an audit by a member of the steering committee), a case be 
proctored on site by a surgeon designated by the Steering Committee, or investigators attend 
TARGIT Academy (a training program covering all aspects of the TARGIT technique) to ensure 
that the investigators and medical team is familiar with the device.  Dose prescription and 
planning protocols for the conventional radiotherapy will vary among centers, but for each 
center, the Treatment Policy Statement approved by the Steering Committee must specify the 
techniques that will be used for all enrolled subjects.  All patients that receive whole breast 
external beam radiotherapy in addition to intraoperative radiation therapy must be treated in 
accordance with this policy. 
The following will be collected for each treatment delivered: applicator serial number, applicator 
size, prescribed dose, treatment time, kilovolts and microamps.
11.3 Data and Safety Monitoring 
The Steering Committee will be responsible for both data and safety monitoring oversight. All 
data collected for this trial is compliant with Good Clinical Practice guidelines, as outlined by the 
IHC-GCP guidelines. The data monitoring process will be conducted by the coordinating center.  
Each participating center must submit the required documentation and complete the required 
training and certification process prior to entering any subjects on study.  Each participating 
center must submit all required documentation on all enrolled subjects during the five-year 
follow-up period. Ongoing data quality monitoring, with appropriate feedback to each 
participating center, will be conducted by the coordinating center at six-month intervals under 
the oversight of the Steering Committee.  Each participating center may be required to undergo a 
monitoring site visit as needed.
Currently there is an independent, international Data Safety Monitoring Committee for the 
International TARGIT-A Trial. All patient safety concerns from the International Trial will be 

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communicated directly to the TARGIT-US Steering Committee, and any early stopping will be 
implemented simultaneously in both the U.S. and international trials. The TARGIT-US 
coordinating center will conduct six-month evaluations of complication rates and local 
recurrence rates for the entire cohort.  If safety issues are identified from either a single 
institution or multiple institutions, the U.S. Steering Committee will take appropriate action. 

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SECTION 12:   REFERENCES
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Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for 
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Clinical Studies” (1997) Second Edition, Blackwell Science