Targeted Intra-Operative Radiotherapy for the Management of Ductal Carcinoma In-Situ of the Breast (TARGIT-DCIS Trial): Use of Mammography and Breast MRI to Identify Candidates for IORT.
Phase: NA
Conditions: Breast Cancer
Sponsor: University of Southern California

 
 
Local Protocol #: 1B-06-9 
Protocol Title: Targeted Intra-Operative Radiotherapy for the 
Management of Ductal Carcinoma In-Situ of the Breast (TARGIT-
DCIS Trial): Use of Mammography and Breast MRI to Identify 
Candidates for IORT 
 
Protocol version date: 5/22/2010 
 
ClinicalTrialsgov #: NCT00556907 
 
 

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PROTOCOL NUMBER: 
1B-06-9 
 
TITLE:    
Targeted Intraoperative Radiotherapy for the 
Management of Ductal Carcinoma in Situ of the Breast 
(TARGIT-DCIS Trial):  Use of Mammography and 
Breast MRI to Identify Candidates for IORT 
 
STUDY PHASE:                            
Phase II 
 
STUDY ARMS: 
Single 
 
IND OR IDE #:                              
N/A 
 
PRINCIPAL INVESTIGATOR: 
Dennis R. Holmes, M.D. 
 
CO-INVESTIGATOR(S):               
Afshin Rastian, MD 
Heather Macdonald, 
MD 
Pulin Sheth, MD 
Linda Hovannesian-Larsen, MD 
Susan Groshen, PhD 
 
SPONSOR:                                    
None 
 
PARTICIPANTS/LOCATONS: 
USC/Norris Comprehensive Cancer Center 
 
AMENDMENTS/REVISIONS: 
3 
 
 
 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
 
SCHEMA, SYNOPSIS, OR STUDY SUMMARY 
 
 
PAGE 
1.0 
BACKGROUND AND HYPOTHESES 
4 
2.0 
OBJECTIVES AND PURPOSE 
7 
3.0 
STUDY DESIGN 
8 
4.0 
DRUG/DEVICE INFORMATION 
10 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
13 
6.0 
DESCRIPTIVE FACTORS/STRATIFICATION/RANDOMIZATION 
SCHEME 
15 
7.0 
STUDY AGENT ADMINISTRATION OR INTERVENTION AND 
TOXICITY     MANAGEMENT PLAN 
16 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
17 
9.0 
CLINICAL AND LABORATORY EVALUATIONS 
19 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
21 
11.0 
SPECIAL INSTRUCTIONS 
23 
12.0 
DATA COLLECTION AND MONITORING 
23 
13.0 
STATISTICAL CONSIDERATIONS 
23 
14.0 
REGISTRATION GUIDELINES 
28 
15.0 
BIOHAZARD CONTAINMENT 
28 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
28 
17.0 
REFERENCES 
28 
APPENDICES 
 
 
Appendix 1:  Philadelphia Consensus Guidelines for Classification 
of DCIS 
30 
 
Appendix 2:  The USC/Van Nuys Prognostic Index scoring system 
for DCIS 
30 
Data Collection Forms 
 
 

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Abstract 
 
The current standard of care for the management of ductal carcinoma in situ is total 
mastectomy or wide local excision followed by whole breast external beam radiotherapy when 
wide local excision can be achieved with acceptable cosmesis.  Whole breast external beam 
radiotherapy requires 6-week course of daily visits to a radiation oncology.  This protracted 
course of radiotherapy sometimes poses a barrier to the selection of breast conserving surgery 
for many women.  In addition, whole breast external beam radiotherapy may also be associated 
with local and systemic morbidity that increases its burden on patients.   Intraoperative 
radiotherapy (IORT) is a form of accelerated partial breast radiotherapy that focuses the 
radiotherapy dose on the tumor bed, allowing reduction in the total radiation dose as well as 
reduction of local and systemic side effects.  IORT is not currently the standard of care for the 
management of breast cancer.  However, as an approved treatment for the treatment of 
malignancy, IORT is currently being evaluated as an alternative to whole breast external beam 
radiotherapy for the treatment of breast cancer. The principal advantage of IORT is that the 
breast operation and the entire radiotherapy treatment can be completed while the patient is 
still under anesthesia.  Thus, the entire local therapy of the breast can be completed in one trip 
to the hospital.   The use of IORT as for the management of DCIS is limited by the fact that the 
IORT dose is delivered before the surgical margin status is known.  Consequently, IORT might 
be given prematurely or inappropriately, particularly when inadequate surgical margins 
necessitate re-excision or conversion to mastectomy.  Generally, surgeons and radiologists must 
rely on the presence and extent of microcalcifications on pre-operative mammograms to define 
the extent of DCIS and the portion of the breast requiring excision.  Unfortunately, not all 
DCIS lesions form microcalcifications and among those that do, the total span of 
microcalcifications may be smaller than the actual span of DCIS.   This size discrepancy can 
lead to underestimation of DCIS lesion size and increased risk of incomplete initial excision.  
Contrast-enhance breast magnetic resonance imaging (CE-MRI) has become an increasingly 
important adjunct to mammography for evaluating breast malignancy and has higher 
sensitivity in the detection of multifocal and multicentric disease.   For this reason, CE-MRI has 
a growing role in defining the extent of disease in patients with known breast malignancy.    We 
hypothesize that the combination of mammography and CE-MRI will improve the surgeon and 
radiologist’s ability to define extent of disease prior to surgical resection, improve the odds of 
obtaining clear surgical margins, and increase the efficacy of IORT delivered immediately after 
initial surgical resection.   In this investigation, we will determine whether or not patients 
deemed eligible for ‘immediate” IORT based on mammography and CE-MRI can be 
successfully treated without the need for re-excision or additional radiotherapy due to 
inadequate surgical margins. 

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1.0 
BACKGROUND AND HYPOTHESES 
 
1.1 
Ductal carcinoma in situ of the breast is a heterogeneous group of lesions 
characterized by proliferation of malignant cells within an intact basement 
membrane.  Ductal carcinoma in situ (DCIS) is a typically a clinically occult breast 
neoplasm that is usually diagnosed mammographically.  With advances in 
mammographic screening, the prevalence of DCIS has rapidly increased.  
Approximately 52,000 cases of DCIS were diagnosed in 20061, constituting 22% of 
all breast malignancies diagnosed that year.  DCIS is a non-obligate precursor of 
invasive breast malignancy.  If left untreated, most DCIS lesions are expected to 
progress to invasive breast cancer and create the potential for development of 
regional and systemic metastases. 
 
Similar to invasive breast cancer, the current standard of care for the management of 
DCIS is total mastectomy or wide local excision (WLE) followed by whole breast 
external beam radiotherapy when WLE can be achieved with acceptable cosmesis.  
Mastectomy is indicated for patients with extensive disease not amendable to WLE 
or in situations where breast radiotherapy is contraindicated.  In addition, 
approximately 1/3 of patients with low or intermediate grade DCIS may be treated 
without the use of radiotherapy.  
 
Until the early 1990’s, total mastectomy was the standard operation for patients with 
DCIS.  Surgical management began to change following the analysis of the landmark 
study, National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-
06, comparing breast conserving therapy to mastectomy for management of early 
stage invasive cancer2. A small group of women with pure DCIS had been 
inadvertently enrolled in the sample groups.  Subgroup analysis of these patients 
indicated that lumpectomy and radiation could be an acceptable alternative to 
mastectomy in terms of reducing local recurrence.  To validate the findings of the 
NSABP B-06, the NSABP undertook the B-17 trial, randomizing over 800 patients 
with DCIS to treatment with lumpectomy alone or lumpectomy plus whole breast 
external beam radiotherapy (WB-EBRT).   In 2001, the 12-year follow-up results 
demonstrated excellent local control rates for patients treated with lumpectomy plus 
WB-EBRT (local recurrence rate of 16%) compared to lumpectomy alone (local 
recurrence rate of 32%)3.  Similar benefits of radiotherapy were also demonstrated in 
the European Organization for Research and Treatment of Cancer (Protocol 19853) 
and the United Kingdom, Australia, New Zealand DCIS Trial4,5.  Collectively, these 
trials established radiation as a standard adjunct to wide local excision for women 
with 
DCIS. 
 
Currently, the standard of care for DCIS treated with wide local excision is WB-
EBRT (5000 rads divided over 25 treatment) with or without a radiation boost dose 
(1000 rads divided over 5 treatments) to the surgical scar and tumor bed.   Due to 
local radiation induced toxicity (skin injuring, breast fibrosis, breast edema, breast 
pain), inconvenience of daily therapy, and treatment non-compliance (20% of 
patients more than 10 miles from a radiotherapy treatment center never complete the 
prescribed course6), recent developments in breast radiotherapy have focused on 
accelerated partial breast irradiation (APBI) techniques designed to target the 
radiation dose to the tumor bed, reduce radiation injury to nearby breast and non-

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breast tissues, and reduce overall treatment time.  APBI is supported by numerous 
studies indicating that more than 85% of breast cancer recurrences occur at or near 
the original tumor site7,8. Therefore, limiting the radiation dose to the tumor site 
allows a therapeutic dose to be delivered to the portion of the breast where 
recurrences are most likely to occur, while minimizing exposure and collateral injury 
to more distant breast and non-breast tissues. 
 
The safety and efficacy of ABPI have been evaluated in several case control and 
cohort studies which have shown ABPI to be a safe and effective method of reducing 
local recurrence of breast cancer as well as the side effects associated with 
radiotherapy.  However, few of these studies have specifically examined the safety 
and efficacy of APBI for the management of DCIS.  One such trial is the Mammosite 
DCIS Trial, a multicenter study conducted at USC and 11 other centers, which 
showed minimal toxicity and effective control of local recurrences in patients 
receiving APBI following initial wide local excision.  The use of APBI is also 
currently being evaluated in the recently opened NSABP-39 study, comparing 
WBRT against several forms of ABPI (3D-Conformal Radiotherapy, Interstitial 
Multicatheter Brachytherapy, and Mammosite Balloon Catheter Brachytherapy) 
following initial WLE among patients with DCIS and invasive breast cancer.    
 
Currently, there are no clinical trials specifically designed to evaluate the use of 
IORT, or radiotherapy administered at the time of WLE, in the management of 
patients with DCIS.  However, promising preliminary findings have been reported at 
The European Institute of Oncology which has included DCIS among more than 
1,800 patients (primarily invasive breast cancer patients) undergoing immediate 
IORT.  Since 1999, the Institute reported only a 1.6% incidence of local recurrence 
and an 8.2% incidence of side effects (severe fibrosis 0.2%, mild fibrosis 2.6%, fat 
necrosis 4.1%, hematoma 1.3%) among all patients receiving immediate IORT 
following breast conserving surgery9.  These statistics are comparable to similar 
patients receiving WE-BRT following WLE. 
 
IORT is not currently the standard of care for the management of breast cancer.  
However, as an approved treatment for the treatment of malignancy, IORT is now 
being evaluated as an alternative to whole breast external beam radiotherapy for the 
treatment of DCIS.   One of the major barriers to the acceptance of ABPI, and 
particularly IORT, as an adjuvant therapy option for DCIS is the challenge of 
delineating the extent of DCIS prior to excision. Discrepancy between the 
mammographically measured lesion size (e.g., the span of microcalcifications) and 
the histologically measured lesion size may also lead to underestimation of lesion 
size and increased risk of incomplete initial excision.  To improve estimation of 
DCIS lesion size and to reduce the risk of incomplete excision, surgeon and 
radiologists have increasingly used contrast-enhanced magnetic resonance imaging 
(CE-MRI) to aid delineation of lesion size10-11.  CE-MRI relies on the presence and 
distribution of cancer-associated neovascularization to define the extent of disease.  
Whereas both benign and malignant lesions may experience neovascularization, the 
specific perfusion kinetics and morphologic patterns of cancer-associated 
microvasculature aid distinction between benign and malignant lesions. Indeed, in 
patients with biopsy-proven breast cancer, pre-operative CE-MRI has been shown to 
a change surgical therapy in up to 30% of breast cancer patients12-14.  Consequently, 

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CE-MRI may have important implications in treatment planning in patients 
considering lumpectomy, particularly in circumstances where a low re-excision rate 
is mandatory, such as with the use of intraoperative radiotherapy. 
 
1.2 
Intraoperative Radiotherapy.  Intraoperative radiotherapy is not currently standard 
treatment for breast cancer.  The purpose of this research study is to study the use of 
intraoperative radiotherapy for the treatment of ductal carcinoma in situ. IORT is 
emerging as an innovative alternative to WB-EBRT for the management of breast 
cancer.  Several treatment systems are currently in use internationally, including the 
Liac (Info&Tech, Roma, Italy) and Novac7 (Hitesys Srl, Latina, Italy) mobile linear 
accelerators in used at the European Institute of Oncology in Milan, Italy, the 
Mobetron (IntraOP, Stanford, CA) portable linear accelerator currently in use at 
Stanford University, and the Intrabeam Photon Radiosurgery System (PRS) (Carl 
Zeiss, Oberkochen, Germany) currently in use at the USC Norris Comprehensive 
Cancer Center as part of a multicenter, international prospective randomized 
controlled trial comparing targeted intraoperative radiotherapy to standard WB-
EBRT (The TARGIT Trial).  The Intrabeam PRS is similar to the other 
brachytherapy treatments in that it provides APBI to the tumor bed following 
removal of the tumor.  It differs from most others APBI techniques by the use of a 
low dose (50vK) energy source that, by design, does not require extensive shielding 
of the treatment area.  Therefore, the Intrabeam can be used in the standard operating 
theater without extensive radiation shielding.   
 
1.2.1 Advantages of the IORT approach include: 
 
a. Convenience and Efficiency.  IORT permits breast surgery and 
radiotherapy to be completed in one sitting while the patient is still under 
anesthesia.  Thus, the entire local therapy of the breast can be completed 
in one trip to the hospital. 
   
b. Accurate Delivery of Radiation Dose.  By permitting delivery of the 
radiation dose directly to the surgical margins, IORT avoids the problem 
of geographical miss in which the prescribed radiation dose is 
inaccurately and incompletely delivered to the tumor bed.  Geographic 
miss is estimated to occur in up to 80% of patients, and may result from 
patient movement, inconsistent patient set-up, and difficulty identifying 
the entire tumor site, particularly when radiotherapy is administered 
several months after surgery. 15.   
 
c. Protection of Adjacent Tissues.  Delivery of radiotherapy at the time of 
surgery allows the surgeon to protect adjacent tissues from exposure to 
excessive radiation, e.g., by placement of internal radiation barriers on 
the surface of the pectorals major muscle to protect the underlying heart 
and lung, and by retraction of the skin away from the radiation source to 
reduce skin toxicity. 
 
d. Lower Cost.  Since IORT allows the entire radiation therapy to be given 
in one dose rather than multiple doses, the cost of IORT is lower than 
other forms of radiotherapy.   For example, at the USC Kenneth Norris 

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Comprehensive Cancer Hospital, the cost of IORT using the Intrabeam 
PRS is approximately $7500 per patient compared to $9000 for WB-
EBRT and $28,000 for MammoSite balloon catheter brachytherapy16.  
 
1.2.2 While IORT for DCIS offers many advantages over alterative forms of breast 
radiotherapy, it also has several important limitations: 
 
a. Incomplete Pathology Results.  The IORT dose is delivered before the 
surgical pathology results (e.g., margin status) are fully known.  As a 
result, IORT might be given prematurely or inappropriately in patients 
who are later found to have more extensive disease than initially 
anticipated.  Inadequate surgical margins will necessitate re-excision or 
conversion to mastectomy, either of which will increase the cost and 
potential morbidity of breast cancer therapy.  These risks can be partially 
reduced with the use of Intraoperative margin assessment (e.g., frozen 
sections and specimen radiography) to aid identification of close or 
inadequate margins. 
 
b. Possible Need for Additional Radiotherapy. Patients found to have 
inadequate surgical margins after having received IORT may require the 
addition of WB-EBRT (with or without re-excision).  Generally, repeat 
IORT is not permitted. The addition of WB-EBRT not only increases the 
cost of radiotherapy, it may also, theoretically, increase the morbidity of 
radiotherapy.   However, based on several studies in invasive breast 
cancer patients evaluating IORT administered at a boost dose of 1000 
rads to the tumor bed, followed by routine WB-EBRT, there is good 
evidence to suggest that WB-EBRT given after IORT can be 
administered with good to excellent cosmesis and no grade 3 or 4 adverse 
effects17-19.  Currently, there are no published data specifically reporting 
the efficacy and safety of IORT (with or without combined WB-EBRT) 
for the treatment of DCIS.  
 
While appropriate candidates for IORT may be easily selected among patients 
receiving such treatment after analysis of the surgical specimen (hereafter referred to 
as “delayed IORT”), there are no established criteria for selecting which patients 
with DCIS are appropriate candidates for immediate IORT.  Consequently, the 
feasibility of administering IORT at the time of WLE (hereafter referred to as 
“immediate IORT”) of DCIS remains to be established.  
 
 
 
 
2.0 
OBJECTIVES AND PURPOSE 
 
In this investigation, we will determine whether or not patients with DCIS deemed eligible 
for ‘immediate” IORT based on pre-operative mammography and CE-MRI can be 
successfully treated with IORT without the need for additional therapy due to inadequate 
surgical margins or large tumor size.  To accomplish these objectives, this study has several 
specific aims:   

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2.1 
Specific Aim 1: To evaluate the ability of pre-operative mammography and CE-MRI 
to select suitable candidates for immediate IORT, without the need for re-excision.  
At USC, the re-excision rate for DCIS is about 20%, compared to published rates as 
high as 50%5-7.  In this study, with the use of CE-MRI, a re-excision rate of 15% or 
less will be acceptable and a rate of 30% or more will be unacceptable.  
 
2.2 
Specific Aim 2: To evaluate the ability of pre-operative mammography and CE-MRI 
to select suitable candidates for immediate IORT, without the need for additional 
WB-EBRT.  
 
2.3 
Specific Aim 3: To evaluate the safety and tolerability of IORT administered at the 
time of initial WLE (immediate IORT). 
 
2.4 
Specific Aim 4: To evaluate the safety and tolerability of IORT administered at the 
time of re-excision in a patient who has previously undergone a lumpectomy (e.g., a 
patient who has inadequate margins but is still believed to be an acceptable candidate 
for lumpectomy and radiotherapy, or a patient who has previously undergone 
successful lumpectomy but who desires IORT as adjuvant radiotherapy). 
 
2.5 
Specific Aim 5: To evaluate the safely and tolerability of post-operative WB-EBRT 
or mastectomy given after initial unsuccessful IORT (e.g., a patient who initially 
received immediate IORT but who was subsequently found to an unsuitable 
candidate for IORT). 
 
3.0 
STUDY DESIGN   
 
3.1 
Patients with biopsy proven-DCIS selecting WLE will undergo mammography and 
CE-MRI of the affected breast to evaluate the extent of disease.  Patients will be 
deemed eligible for immediate IORT if the DCIS lesion is estimated to measure 
≤4cm and is thought to be resectable with WLE and clear surgical margins.  The 
DCIS lesion size determined by imaging will be compared with lesion size and 
surgical margin status obtained from the surgical pathology specimen to evaluate the 
ability of mammography combined with CE-MRI to identify suitable candidates for 
immediate IORT.  For assessment of safety and tolerability of IORT (or other 
subsequent therapies), the study population will be divided into 3 cohorts: 
 
Cohort 1:  Patients who receive IORT at the time of initial WLE (the immediate 
IORT group). 
 
Cohort 2:  Patients who receive delayed IORT given at the time of a second 
operation, with or without re-excision of additional breast tissue (the delayed IORT 
group). 
 
Cohort 3:  This is the subset of patients in Cohort 1, who receive WLE and IORT, 
but who subsequently require WB-EBRT (with or without re-excision) or 
mastectomy.  
 
3.2 
Rationale for Inclusion of 3 Cohorts. 

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3.2.1 Rationale for Inclusion of Cohort 1.  Several randomized and numerous non-
randomized trials have been undertaken to evaluate the efficacy of APBI as 
an alternative to WB-EBRT to reduce recurrences after breast conserving 
surgery.  For the most part, DCIS has been excluded from these trials due to 
the perceived difficulty in estimating lesion size based on clinical and 
mammographic findings alone. Since IORT is optimally administered at the 
time of WLE, prior to complete assessment of the surgical specimen, patients 
undergoing immediate IORT have a theoretically elevated risk of requiring 
additional therapy, for example, repeat WLE for inadequate margins. The 
present study has been developed to evaluate the ability of mammography 
combined with CE-MRI to identify suitable candidates for IORT, i.e., those 
who would have a low risk of needing additional surgery or radiotherapy.   
 
3.2.2 Rationale for Inclusion of Cohort 2.  Although mammography is the standard 
imaging tool used for the detection and pre-operative staging of DCIS, the 
extent of the imaging abnormality may not always correspond exactly to the 
extent of DCIS within the breast.  CE-MRI may enhance the radiologist’s 
ability to evaluate the extent of disease within the breast.  However, since 
CE-MRI is typically performed after a core biopsy has already established 
the diagnosis of DCIS, post-biopsy artifact may lead to over-estimation of 
lesion size.  Given these limitations of imaging, one reason that Cohort 2 has 
been included is to preserve the option of IORT for patients who may have 
been excluded from immediate IORT based on imaging or clinical findings 
but who were ultimately found to be suitable candidates based on surgical 
pathology.  In addition, Cohort 2 also provides an opportunity to examine the 
safely and tolerability of administering delayed IORT after an initial WLE.  
Given the limited availability of IORT nationwide, establishing the safety 
and tolerability of delayed IORT as adjuvant therapy for DCIS is particularly 
important to referral centers interested in offering IORT to women who have 
already undergone successful or unsuccessful WLE at another facility, but 
who now present for definitive care.   
 
3.2.3 Rationale for Inclusion of Cohort 3.   Despite pre-operative mammograms 
and CE-MRI showing localized DCIS ≤4cm, it is expected that a minority of 
patients will be found to be unsuitable candidates for IORT on the basis of 
extensive multifocal or multicentric carcinoma.  The rationale for including 
these patients in the study is to examine the safety and tolerability of breast 
cancer treatment [e.g., WB-EBRT (with or without re-excision) or 
mastectomy] in patients who have previously received IORT.   Comparison 
of the preoperative imaging findings and surgical pathology results should 
ultimately improve our ability to identify pre-operatively these unsuitable 
candidates for immediate IORT.   
 
 
4.0 
DEVICE INFORMATION 
 
4.1 
Intrabeam Photon Radiosurgery System and Applicators.  The Intrabeam PRS is a 
miniature electron beam-driven X-ray source that provides a point source of low 

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energy X-rays (50kV maximum) at the tip of a 3.2mm diameter tube (Figure 1).  The 
radiation source can be inserted into the breast immediately after excision of the 
tumor (Figure 2) and switched on for 20-45 minutes to provide targeted IORT 
accurately to the surgical margins. 
 
Figure 1
 Figure 2. 
 
 
 
The physics, dosimetry and early clinical applications of this low energy x-ray 
device have been fully evaluated and in 1999 the device received FDA approval for 
use in any part of the body20.  Since then, the Intrabeam PRS has already been used 
for treatment of human malignant brain tumors, hepatic tumors, head and neck 
tumors, and urological tumors21-22.  Use of the Intrabeam PRS for treatment of breast 
cancer was piloted at the University College London Hospital, which treated 185 
patients with invasive breast cancer with IORT alone (n=25) or combined IORT and 
WB-EBRT (n=168) following wide local excision.  Excellent cosmesis was 
observed in both groups with no grade 3 or 4 side effects.  No recurrences were 
reported in the IORT alone group.  These studies laid the foundation for the 
TARGIT Trial, an international randomized trial comparing IORT alone to standard 
WB-EBRT as adjuvant therapy for invasive breast cancer23, 24.  To date, over 800 
patients have been accrued to the TARGIT Trial among 16 study sites.  With short-
term median follow-up of approximately 450 days, there appears to be no difference 
in the local recurrence rates between the two arms of the trials (personal 
communication).  
 
The Intrabeam PRS x-ray source is a small and lightweight (weight=1.8 Kg; 
dimensions: X-ray generator body 7 X 11 X 14 cm) device that is mounted on the 
surgical stand and balanced for ease of delivery and support during treatment.  For 
delivery of breast radiotherapy, the radiation source is covered by one of several 
spherical applicators ranging in size from 2 to 6 cm in diameter (Figure 3), 
depending on the dimensions of the cavity to be irradiated.  The pliable breast tissue 
can then be wrapped around the applicator using “purse-string” sutures, which allow 
the breast tissue to be conformed around the radiation source to facilitate delivery of 
a uniform field of radiation.  If necessary, the chest wall and skin can be protected by 
tungsten-impregnated silicone shields (providing >93% shielding), which can be cut 
to a desired size and shape.  

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Figure 3. 
 
Since the radiation consists of low energy x-rays, the radiation dose is rapidly 
attenuated as it passes through distant tissues.  The total radiation dose delivered is a 
function of time, which is set to administer a prescribed dose of 20 Gy in a single-
fraction to the surface of the tumor bed and 5 Gy at depth of 1cm from the surface of 
the tumor bed. Following dose delivery, the Intrabeam PRS device is switched off 
and transmission of radiation ends. Finally, the apparatus is removed and the wound 
is closed in the usual fashion. 
 
4.2 
Mammography.  Mammography will be completed prior to determining eligibility 
for IORT.  Mammograms of insufficient quality or those that were performed more 
than 60 days prior to determination of eligibility and will be repeated.  Standard 2-
view (MLO and CC views) mammograms will be obtained, in addition to any 
others projections requested by the radiologist, surgeon, or radiation oncologist. 
Mammographic lesion size will be measured in 3 perpendicular dimensions using a 
centimeter ruler, encompassing the entire span of suspicious or indeterminate 
microcalcifications, 
densities, 
or 
architectural 
distortions. 
Lesion 
size, 
multicentricity, multifocality, and/or evidence of invasive disease will be 
documented by a staff radiologist. 
 
The cost of any additional imaging and cost of resulting procedures, if any, will be 
performed as part of the patient’s routine preoperative evaluation and billed to her 
insurer. Alternatively, prospective participants may complete their imaging work-up 
by participating in an ongoing study at USC comparing bilateral breast CE-MRI, 
bilateral whole-breast ultrasound, and bilateral mammography (USC IRB Approved 
Protocol: Komen-06-01) which provides funding for these studies for uninsured or 
under-insured patients. 
 
The major limitations of mammographic imaging of DCIS is that not all DCIS 
lesion form microcalcifications and among those that do, the span of calcification 
may not exactly correlate to the span of DCIS.  High grade DCIS appear to show 
the best correlation between imaging findings and histological lesion size; low grade 
DCIS shows the worst correlation.  In addition, a variety of microcalcifications 
(malignant, indeterminate, and benign type microcalcifications) may co-exist within 

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the breast, which can lead to over-aggressive or inadequate excision of breast tissues 
if the span of DCIS is judged incorrectly.  
 
4.3 
Contrast-Enhanced Breast MRI.  CE-MRI of the breast will be required for all 
patients prior to determination of eligibility for IORT.  CE-MRI of insufficient 
quality or those that were performed more than 60 days prior to determination of 
eligibility will be repeated.  
 
Participants will undergo breast CE-MRI on a 1.5 or 3.0 Tesla MRI unit using a 
dedicated double breast coil.  CE-MRI performed at other institutions will be 
permitted if they are performed on similar equipment and judged to be of appropriate 
quality.  At USC, the following sequences will be obtained with the patient lying 
prone: (1) Scout-T1 FLASH—coronal/sagittal/axial (12 sec); (2) T2 TSE axial images 
of the breasts (3 min, 7 sec); and (3) T1 3d FLASH dynamic sequences (5 min, 30 sec 
including a pre-contrast sequence), contrast injection (15cc Gadolinium/20cc saline IV 
at 3cc/sec), a 20 second delay, and (4) pre-contrast images subtracted from last post-
contrast images (the subtraction images), and (5) maximum intensity projections 
(MIP) of the subtraction images.  Using the T2-weighted images and subtraction 
images, the area of maximal enhancement will be outlined and measured. 
 
CE-MRI will be interpreted by radiologists with expertise in breast CE-MRI. 
Morphologic and kinetic analysis for suspicious enhancing lesions will be performed 
using the American College of Radiology Breast Imaging Radiology and Diagnostic 
Imaging System lexicon.  Morphologic analysis of lesions (masses, foci, and 
regions) will be made by assessing the size, borders, and homogeneity of 
enhancement.  Lesions that are not round or oval, have irregular borders, and are 
heterogeneous will be considered suspicious.  Kinetic analysis will be performed for 
the lesion of interest in early enhancement (1-2 minutes after injection) and late 
enhancement (5-6 minutes after contrast injection). Masses (>5mm) that show at 
least 50% increase in signal intensity early will be considered suspicious unless there 
is a benign correlate at mammography or un-enhanced MRI.  Foci (<5mm) showing 
at least 50% increase in signal intensity early with late washout kinetics, and 
regional enhancement with at least 50% increase in signal intensity early, will also 
be considered suspicious. Segmental, linear, stippled or clumped enhancement will 
be considered suspicious for DCIS, regardless of kinetics.  Lesions not meeting any 
of these requirements will be considered benign or probably benign. Lesion size will 
be measured in 3 perpendicular dimensions by a staff radiologist using a centimeter 
ruler.  Measurement of lesion size, multicentricity, multifocality, or evidence of 
associated invasive disease will be documented. 
 
All discrete suspicious and indeterminate lesions seen on the CE-MRI will undergo a 
“second-look” or correlative ultrasound to determine if the lesion is also 
sonographically visible and amenable to ultrasound guided core needle biopsy if the 
results of the biopsy would significantly alter surgical management (e.g., conversion 
from breast conserving surgery to mastectomy or performance of a significantly wider 
local excision) or effect eligibility for this study.  If the lesion is not seen by 
ultrasound, MRI-guided core needle biopsy will be performed to establish a tissue 
diagnosis if the results of the biopsy would significantly alter surgical management or 
eligibility for this study.  

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13 
 
The major limitations of CE-MRI are the lack of standardized definitions of neoplasm 
on CE-MRI, which limits the inter-study specificity of CE-breast MRI 
(specificity=65-70%)25,26. In addition, when overall breast parenchymal density is 
high, there may be generalized mild parenchymal enhancement or multiple tiny foci of 
enhancement (e.g., hormonally influenced areas) that can be confused with the 
enhancement of a true lesion making it difficult to appreciate a smaller or lower grade 
lesion.  To minimize this normal physiologic enhancement of the breast, scheduling of 
the CE-MRI will be coordinated with the menstrual cycle of pre-menopausal patients, 
i.e., performed 7-10 after the start of menstrual flow.  Equally important, most patients 
will undergo MRI here at USC where their studies will be performed on the same MRI 
unit and interpreted by one of 2 experienced radiologists.  This should facilitate 
consistent performance and interpretation of breast MRIs. 
 
4.4 
Core needle biopsies.  Core needle biopsies will be performed of all additional 
suspicious lesions (excluding the index cancer) seen on mammography, ultrasound, or 
CE-MRI to obtain definitive information about the presence or absence of malignancy. 
Biopsies will be performed using either 14-gauge core biopsy or 11-gauge vacuum-
assisted needle biopsy guided by the imaging study that best depicts the lesion.   
 
Radiologists performing core biopsies will meet the Continuing Medical Education 
and experience requirements analogous to the American College of Radiology 
accreditation for breast biopsy.  For findings observed only on CE-MRI, MRI-
guided core needle biopsy will be performed using an 11-gauge vacuum-assisted 
breast biopsy instrument obtaining a minimum of 6 samples.  For calcifications seen 
only mammographically, 11-gauge vacuum-assisted biopsy will be performed under 
stereotactic guidance, obtaining a minimum of 6 core samples.  Lesions considered 
amenable to ultrasound-guided core biopsy will be biopsied with either a 14 or 18-
gauge core needle or an 11-gauge vacuum-assisted biopsy, obtaining a minimum of 
6 core samples.  Specimen radiography will be obtained on all biopsied lesions that 
contain microcalcifications.  A microclip or biopsy site marker will be placed to 
identify the biopsy site.   
 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
5.1 
Patients with biopsy-proven DCIS, mammographic and CE-MRI evidence of DCIS 
measuring ≤4cm, and a desire to receive breast conserving therapy, will be 
considered for participation in this study.  
 
5.2 
Patient history, physical examination findings, and demographics (sex, age, height, 
weight, bra size, etc.) will be performed and documented.  
 
5.3 
Inclusion Criteria for Initial Registration (all patients cohorts): 
 
5.3.1 All cohorts 
 
a. Signed informed consent and HIPAA documents 
b. Female sex  
c. Age ≥ 40 years  

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14 
d. Localized ductal carcinoma in situ  
e. Clinically and/or histologically negative axillary lymph nodes  
f. No imaging or clinical findings suggestive of invasive carcinoma. 
 
5.3.2 Cohort 1 (Immediate IORT group) 
 
a. Localized DCIS measuring ≤4 cm on preoperative imaging.  
 
5.3.3 Cohort 2 (Delayed IORT group)   
 
a. Localized DCIS measuring ≤4 cm or less on surgical pathology 
 
i. Delayed IORT could be performed for the explicit purpose of 
administering IORT or performed following re-excision of a previously 
operated breast to achieve clear surgical margins. 
ii. This cohort includes patients who were excluded from immediate 
IORT based on pre-operative imaging suggesting ineligibility for 
immediate IORT, but who are subsequently found to meet histological 
criteria (localized DCIS ≤4 cm and no invasive cancer) for IORT based 
on surgical pathology.    
iii. Unifocal microinvasive (T1mic or invasive focus ≤1mm in maximal 
diameter) is allowed following initial WLE if surgical pathology 
margins were ≥2 mm for both the invasive and non-invasive 
components.  
iv. Delayed IORT must be performed within 3 months of initial WLE. 
       
5.3.4 Cohort 3  
 
a. Subjects who received IORT at the time of initial WLE but whose surgical 
pathology indicates the need for further therapy: 
 
i. DCIS measuring greater than 5 cm on surgical pathology. 
 
b. Surgical margins width <2 mm. 
 
5.4 
Exclusion Criteria for Initial Registration (all patient cohorts)  
5.4.1 Male sex  
5.4.2 Age <40  
5.4.3 DCIS associated with any evidence of microinvasion or invasive carcinoma on 
pre-operative imaging or core biopsy of the breast or axillary nodes.  
5.4.4 DCIS that is multicentric in the ipsilateral breast.  Multicentricity will be 
defined at 2 or more lesions separated by more than 3 cm in the same breast. 
5.4.5 Non-epithelial breast malignancies such as sarcoma or lymphoma  
5.4.6 DCIS associated with diffuse suspicious or indeterminate microcalcifications  
5.4.7 Pregnancy or lactation   
5.4.8 Collagen vascular diseases, including Systemic lupus erythematosus, Systemic 
sclerosis (scleroderma), CREST Syndrome (calcinosis, Raynaud phenomenon, 
esophageal dysfunction, sclerodactyly, telangiectasia, and the presence of 
anticentromere antibodies), polymyositis, dermatomyositis with a CPK level 

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15 
above normal or with an active skin rash, inclusion-body myositis, or 
amyloidosis  
5.4.9 Serious psychiatric or addictive disorders  
 
5.5 
Withdrawal from Study 
 
During the course of the study, it is possible that patients and/or device systems may 
be withdrawn from the study. Factors that may lead to a withdrawal from the study 
may include, but, are not limited to the following: 
 
5.5.1 Patient Withdrawal – At any time a patient may voluntarily withdraw from the 
study. This withdrawal will not affect her future medical treatment. 
 
5.5.2 Patient Lost to Follow-Up – Should a patient be classified as lost to follow-up, 
efforts to contact the patient will be made. 
 
5.5.3 Physician Decision – Should a physician decide that the constraints of the 
protocol are detrimental to the health and welfare of the patient, the patient 
may be withdrawn from the study. 
 
5.5.4 Medical Reason – Should the patient’s condition deteriorate, the patient may 
be withdrawn from the study to allow for proper medical care. 
 
 
 
 
6.0 
STRATIFICATION/DESCRIPTIVE FACTORS/RANDOMIZATION SCHEME 
 
Patient Selection. This is not a randomized study. The trial will be open to 3 cohorts of 
patients with a diagnosis of DCIS breast, as outlined in the inclusion criteria (Section 3.0). 
 
 
7.0 
STUDY AGENT ADMINISTRATIONS OR INTERVENTION AND TOXICITY 
MANAGEMENT PLAN 
 
7.1 
Patient Surgery and IORT 
 
7.1.1 Each patient will undergo WLE to remove DCIS and to create a cavity.  
Each of the following procedures qualifies as WLE: breast conserving 
surgery, lumpectomy, segmental mastectomy, segmental resection, and 
partial mastectomy. 
 
7.1.2 Recognizing the potential for DCIS to be larger than demonstrated on 
imaging, the surgeon will aim to excise the lesion with surgical margins of 10 
mm.  Multiple localizing wires will be placed pre-operatively to facilitate 
resection.  
 
7.1.3 Due to the potential for finding occult microinvasive carcinoma in the final 
surgical pathology, sentinel node biopsy will be allowed at the discretion of 

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16 
the surgeon. 
 
7.1.4 At the conclusion of IORT, surgical clips will be placed in the resection 
cavity to mark the surgical margins to facilitate re-excision, if indicated. 
 
7.2 
Criteria for Receiving Additional therapy after IORT (Cohort 3) 
 
7.2.1 Patients with DCIS >5 cm will be advised to undergo WB-EBRT (or 
mastectomy) despite having received IORT, even if surgical margins are 
clear (≥ 2mm).   
 
7.2.2 Patients with surgical margins width of <2 mm following local excision and 
immediate IORT will be advised to undergo re-excision.  If residual disease 
is found and new final margins are <2 mm, the patient will be advised to 
undergo WB-EBRT.  However, no addition therapy will be needed if no 
residual disease is found, or if final margins is ≥2mm.  
 
 
7.3 
Ancillary treatments.  
 
Neoadjuvant hormonal therapy (e.g., Tamoxifen or Fulvestrant) and 
chemopreventive therapy (e.g., green tea extract) will be allowed provided that the 
total duration of neoadjuvant hormonal or chemopreventive therapy does not 
exceed 30 days prior to WLE and immediate IORT. 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY   
 
8.1 
Side effects/Toxicities to be monitored.  These risks fall into four (4) general 
categories: 
 
8.1.1 Surgery.  Complications associated with the surgical implantation of the 
Intrabeam PRS are similar to any tumor removal surgery. These include, but 
are not limited to infection, loss or impairment of nerve function, breast 
edema, ecchymosis, hematoma formation, wound seroma, wound dehiscence, 
keloid formation, skin flap necrosis, and the need for re-excision if margins 
are inadequate. 
 
8.1.2 Intraoperative Radiotherapy Delivery.  Complications arising from the 
delivery of IORT include, but are not limited to infection, loss or 
impairment of nerve function, breast edema, fibrosis, and skin effects 
including dry/moist desquamation, hyperpigmentation, telangiectasia and 
radiation-induced skin necrosis.  
 
8.1.3 Whole-Breast External Beam Radiotherapy. Complications of WB-EBRT 
include, but are not limited to loss or impairment of nerve function, breast 
edema, fibrosis, superficial vein thrombosis, and skin effects including 
dry/moist desquamation, erythema, hyperpigmentation, telangiectasia and 
radiation-induced skin necrosis.  
 

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17 
8.1.4 Diagnostic Procedures.  As part of this clinical study, patients will undergo 
mammography, CE-MRI, and ultrasound (at the discretion of the radiologist) 
and will be subject to the associated risks: exposure to additional radiation, 
allergic reaction to MRI contrast (gadolinium), and the potential risks of 
additional minimally invasive breast biopsies (bleeding, hematoma, infection, 
and non-diagnostic or falsely negative results) that may result from the 
extensive imaging evaluation.  The risks associated with these procedures are 
minimal. 
 
8.1.5 Unanticipated Adverse Device Effects (UADEs) will be documented. 
UADEs are defined as any serious adverse effect on health or safety or any 
life-threatening problem or death caused by, or associated with a device if 
that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
 
8.1.6 Serious Adverse Event (SAE).  Serious adverse events are defined as 
follows: Death or threat to life; Permanent impairment of a body function 
or permanent damage to a body structure; or events that require medical or 
surgical intervention to preclude permanent impairment of a body function 
or permanent damage to a body structure.  
 
Events that are considered serious include skin necrosis, non-wound healing, moist 
desquamation (not resolving within 4 weeks), unresolved bleeding, infection 
requiring medical or surgical intervention, pneumothorax, seroma/hematoma 
(symptomatic and/or cosmetically deforming), rib fracture, severe pain (not 
resolving within the first month and requiring narcotics) and wound dehiscence. 
 
8.2 
Dosage change based on toxicity.  The prescribed dose is constant among all patients 
and will not be adjusted.  The only variable is the time period for which the dose will 
be delivered.  The treatment time will vary based on the lumpectomy cavity site, with 
total treatment time adjusted to deliver a prescribed dose of 20 Gy to the tumor 
surface or 5G at 1 cm depth from the tumor surface. 
  
8.3 
Adverse Event Reporting:  
 
8.3.1 All adverse events that occur during the study will be reported, except for 
observational events: cold, flu, headache, etc.  The CTC guideline will be 
used to grade the severity of all adverse events. Adverse events not included 
in the CTC, version 3, will be reported with common medical terminology 
and grading according to definitions in the CTC: 
 
8.3.2 A description of the nature, onset, duration, severity, attribution and 
outcome of the occurrence will be recorded.  Any treatment employed to 
alleviate the adverse event(s) will also be recorded. 
 
CTC Grading of Adverse Events:  

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18 
Grade 1 = 
Mild adverse event 
Grade 2 = 
Moderate adverse event 
 
Grade 3 = 
Severe and undesirable adverse event 
Grade 4 = 
Life-threatening or disabling adverse event 
Grade 5 = 
Death related to adverse event 
 
8.3.3 All serious adverse events will be recorded on the study data forms 
throughout the duration of the study. 
 
8.3.4 The physician will document his/her opinion of the relationship of the event 
to the device as follows: 
 
Unrelated = the event is clearly not related to the device 
Unlikely = the event is doubtfully related to the device 
Possible = the event may be related to the device 
Probable = the event is likely to be related to the device 
Definite = the event is clearly related to the device 
 
8.3.5 Any serious adverse device effect, including death due to any cause, which 
occurs during this treatment, will be reported within 5 working days of 
learning of the event to Carl Zeiss, Inc. and to the IRB per the IRB 
requirements. 
 
8.3.6 Serious unanticipated adverse device effects will be reported within 24 hours 
of learning of the event to Carl Zeiss, Inc. and to the IRB per the IRB 
requirements. 
 
8.3.7 Patients who are removed from the protocol due to adverse events will be 
followed until the adverse event has resolved or stabilized and will continue 
to be followed in the intent-to-treat population.  Copies of relevant 
documentation will be kept with the patient’s protocol records.  
 
8.4 
Minimization of Risks  
 
8.4.1 Although the risks outlined in Section 8.1 may occur, the likelihood of 
serious events occurring is considered minimal.  Carl Zeiss, Inc. has reduced 
the potential of the above risks by: 
 
a. Performing complete validation testing of the Intrabeam PRS 
b. Implementing quality assurance measures each day prior to using the   
Intrabeam PRS 
c. Providing adequate directions for use in device labeling. 
 
Clinical investigators who are involved in the study are knowledgeable and 
experienced in the field of surgical oncology and radiation oncology, which 
will help to minimize risks to the patients involved.  Inclusion/Exclusion 
criteria are intended to reduce the potential of including patients who might 
be prone to injury or who might be inappropriate candidates of IORT for 
other reasons. 

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19 
 
8.4.2 Potential Patient Benefits 
 
a. The potential benefits of IORT are: 
b. Decreased likelihood of tumor recurrence 
c. More accurate delivery of radiation dose to targeted tissue 
d. Reduced radiation delivered to normal breast and surrounding tissues 
e. Reduced delays in systemic/local therapy 
f. Reduced risk of infection and skin toxicity compared to standard external 
beam or other partial breast irradiation techniques 
g. Reduced treatment time  Improved patient compliance 
h. Possibly increased feasibility of breast conserving therapy 
 
9.0 
CLINICAL AND LABORATORY EVALUATIONS AND STUDY CALENDAR 
 
9.1 
Histological Evaluation of Specimen.  The surgical specimen will undergo   
histological evaluation to determine the following features:  DCIS histology, lesion 
size, surgical margin width, and the presence or absence of invasive carcinoma.   The 
surgical margin width will be measured as distance from the nearest tumor cell to the 
cut or inked edge of the WLE surgical specimen. 
 
9.2 
DCIS histology [histologic type, grade (nuclear, histologic, mitotic), and the   
presence or absence of comedonecrosis] will be determined using the Philadelphia 
consensus guidelines (Appendix 1) and assessed in the core biopsy and/or WLE 
specimen prior to administration of IORT.  In addition, The Van Nuys Prognostic 
Index (VNPI) score will be calculated and reported in the final WLE specimen 
(Appendix 2). 
 
9.3 
Surgical margin width will be measured in all directions (i.e., superior, inferior, 
medial, lateral, anterior and posterior) in the WLE specimen.  The anterior and 
posterior margins will be considered widely clear if the involved margin(s) 
approximate the skin (anterior) or pectoralis fascia (posterior) AND these margins 
have been removed with the surgical specimen. 
 
9.4 
DCIS lesion diameter will be measured in the three widest dimensions (e.g., anterior-
posterior diameter, medial-lateral diameter, superior-inferior diameter) in the WLE 
specimen.   Specimen weight will also be recorded. 
 
 
 
 
 
 
 
 
 
 
 
 

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20 
 
 
 
 
 
 
 
 
 
 
9.5 
Study Calendar.    
 
Data Required 
Pre- 
Entry 
Surgery/ 
Applicator 
Placement 
Post 
Surgery 
Follow up 
Demographics/Medical History  
X 
 
 
 
  Inclusion/Exclusion (Eligibility) 
     (TT01*) 
X 
 
X 
 
 Mammography (TT02) 
Xb 
 
 
Xb, 
 CE-MRI (TT02) 
Xd 
 
 
Xd 
 Pathology (TT06) 
X 
 
X 
 
Intrabeam PRS Placement, Brachytherapy 
 & Removal (TT04, TT10, TT07) 
 
X 
 
 
 Follow-Up Visit (TT11, TT12, TT05, TT13) 
 
 
 
Xa, 
  Quality of Life Questionnaires 
 (EORTC QLQ-BR23 & QLQ-C30 version 3.)   
 
 
Xf 
  Photographs 
 
 
 
X c 
  Cosmesis 
 
 
 
Xe 
 Adverse Event Reporting at each visit (TT09)  
X 
X 
X 
*TT refers to the respective data collection form (see Section 12.0). 
 
a. 
The patient will be evaluated at 3 months, 6 months, 1 year, and 2 years post-
IORT. 
b. 
Mammograms of the treated breast will be performed at baseline within 60 days 
of accrual and repeated semiannually post_IORT X 2 years  
Suspected recurrences and new cancers detected using imaging and/or physical 
examination will be confirmed histologically.  
c. 
Photos of both breasts will be obtained at 3 months, 6 months, 1 year, and 2 
years post-IORT.  The first photo will be taken of both breasts with the patient 
standing with both arms at her side.  The second photo will be taken of both 

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21 
breasts with the patient standing with her hands on her hips.  Care will be taken 
to exclude the patient's face from the photo.   
 
d. 
MRI will be performed at baseline within 60 days of accrual.  MRI may also be 
performed at any time to evaluate a clinical or mammographic finding or to 
follow-up on an earlier MRI finding. 
e. 
Cosmesis will be reported at 3 months, 6 months, 1 year, and 2 years post-IORT. 
f. 
Quality of life will be evaluated at baseline (preoperatively), 3 months, 6 months, 
1 year, and 2 years post-IORT. 
 
10.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 Feasibility Endpoint.  The primary efficacy endpoint of the treatment will be re-
operation (re-excision or mastectomy) rates following WLE and IORT. 
 
Re-excision (or mastectomy) will be indicated for patients with microscopic surgical 
margins measuring <1 mm following WLE and immediate IORT.   
 
Additionally, the following data will also be reported and analyzed:  
 
10.1.1 Indications for WB-EBRT.  Patients with margins that are margins < 2 mm 
after reexcision for <2 mm margins, or, DCIS > 5 cm. 
   
10.1.2 Extent of disease.  Extent of disease will be determined by measuring the 
dimensions of the DCIS lesion as demonstrated by pre-operative 
mammography and CE-MRI and the dimensions of the DCIS lesion 
contained within the surgical resection specimen 
 
10.1.3 Surgical Margins.  Surgical margins will be defined as the distance from the 
closest tumor cells to the cut or inked edge of the surgical specimen. 
 
10.1.4 DCIS histopathology.  DCIS histopathology will be determined by evaluating 
the histopathological type, grade (histological, nuclear, and mitotic), the 
presence or absence of comedonecrosis or invasive carcinoma in the pre-
operative biopsy and the surgical specimen. 
 
10.2 Safety Endpoint  
 
10.2.1 The overall serious adverse event rate will be assessed for all patients at the 
stated follow-up periods.  Complications associated with each of the 
following setting will be documented and reported separately: 
 
10.2.2 Complications resulting from immediate IORT 
 
10.2.3 Complications resulting from delayed IORT with or without reexcision 
 
10.2.4 Complications resulting from WB-ERBT following WLE and immediate 
IORT (e.g., if lesion is > 5 cm) 
 

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10.2.5 Complications of mastectomy after initial WLE and IORT  
 
10.3 Cosmesis Endpoint  
 
The surgeons or radiation oncologists will evaluate cosmetic results at stated follow-up 
periods.  Cosmetic results will be assessed using the Harvard Scale:  
 
Excellent - The treated breast looks essentially the same as or better than the 
opposite breast. 
 
Good – There are minimal but identifiable effects of radiation on the treated 
breast 
 
Fair – There are significant effects of radiation on the treated breast 
 
Poor – There are severe tissue sequelae secondary to irradiation 
 
The appearance of the breast will be described in detail, including the presence of skin 
telangiectasia, skin atrophy, scarring, pigment change, erythema, fat necrosis, fibrosis, 
retraction or contour defect, volume loss, and other significant treatment effects.  Each 
of these features will be documented as “none”, “present but does not affect cosmesis”, 
or “present and affects cosmesis”. 
 
Digital photos of both breasts will be taken pre-treatment and at each stated follow-up 
period.  
 
10.4 Quality of Life Endpoint 
 
Patients will be asked to complete Quality of Life (QOL) questionnaires at baseline, 
and at the 3 month, 6 month, 1 year and 2 year follow-up point using validate QOL 
instruments published by the EORTC (EORTC QLQ-BR23 & QLQ-C30 version 3.).  Quality 
of life will evaluate physical appearance and symptoms.  Patients will be asked to 
assess differences between the treated and untreated breast and to provide an overall 
assessment of the appearance of the treated breast.  They will also be asked to rate their 
breast and non-breast symptoms during the 4-week period prior to completion of each 
QOL questionnaire. 
 
11.0 SPECIAL INSTRUCTIONS: 
 
11.1 None  
 
12.0 DATA COLLECTION AND MONITORING 
 
FORMS TO BE USED IN THE STUDY (TO BE CREATED): 
 
Enrollment Form (TT00) 
Eligibility Worksheet Form (TT01) 
Entry Form 1 (TT02) 
Entry Form 2 (TT03) 

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23 
Surgery Form (TT04) 
Pathology On-Study Form (TT05) 
Pathology Form (TT06) 
Intraoperative Radiotherapy Form (TT07) 
Complication Form (TT09) 
Additional Procedure Form (TT10) 
Photography Form (TT16) 
Lost To Follow Up Form (TT17) 
Cosmesis Evaluation (TT18) 
Quality of Life Questionnaires EORTC QLQ-BR23 & QLQ-C30 version 3. 
 
13.0 STATISTICAL CONSIDERATIONS 
 
This is a pilot study to evaluate the feasibility of IORT for the treatment of patients with 
DCIS who undergo WLE of the breast lesion.  Currently at USC, about 20% of patients who 
elect WLE for the treatment of DCIS are found to have surgical margins that measure less 
than 1mm.  For these patients, reexcision (or mastectomy) is recommended unless the small 
distance occurs at the anterior and posterior margins if the skin has been removed anteriorly 
or the pectoralis muscle fascia has been removed posteriorly.  Among patients requiring re-
operation, it can be argued that the decision to undergo IORT was not optimal.  Careful use 
of mammography and CE-MRI should reduce the likelihood that, based on inadequate 
margins, a re-operation would be necessary.  In addition, for tumors that are found to be 5 
cm or greater, or that have multicentric or extensive multifocal disease, in the surgical 
specimens, WB-EBRT is recommended.   While there are studies indicating that WB-EBRT 
can be given safely following IORT, in this setting, the decision to treat these patients with 
immediate IORT was not optimal.  
 
The primary aim (Section 2.1) of this study is to estimate the likelihood that CE-MRI and 
mammography were not able to identify patients for whom IORT is not optimal – because a 
re-operation (re-excision or mastectomy) was required.  The secondary aim (Section 2.2) is 
to estimate the likelihood that CE-MRI and mammography were not able to identify patients 
for whom WB-EBRT was indicated.   In addition, the safety of IORT administered at the 
time of initial WLE will be evaluated (Section 2.3). 
 
An additional secondary aims, but also very important, will be to document the treatment 
course and complications of those patients who received delayed IORT (after initial WLE) 
(Section 2.4) or who received immediate IORT but subsequently required mastectomy or 
WB-ERT (Section 2.5).     
 
13.1 Study Design and Sample Size Justification 
 
The study design was selected based on the primary aim: to evaluate the ability of 
CE-MRI and mammography to identify patients for whom IORT is not optimal 
because of the inability to achieve sufficiently wide surgical margins.  If 15% or 
fewer patients require re-excision, this would be considered acceptable and 
encouraging for further study; however, a reexcision rate of 30% or higher would not 
be acceptable.   
 

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24 
13.1.1 Accrual to Cohort 1 (Specific Aims 1-3 in Sections 2.1 – 2.3).   
 
Patients will be enrolled in Cohort 1 until 79 patients have received 
immediate IORT.  All patients who are deemed eligible for IORT based on 
mammography and CE-MRI results will be considered in the decision to stop 
or continue the trial.  There will be one interim analysis when 25 patients 
have completed WLE and immediate IORT, whether or not additional 
therapy is needed.  
 
After 25 patients have been evaluated, if 19 or more did NOT require re-
excision (based on the surgical specimen), then accrual will continue until 79 
patients undergo WLE and immediate IORT.  If 7 or more of the initial 25 
needed re-excision, then the study will terminate and investigators will 
conclude that the current method for staging is not sufficiently accurate.  
 
After 79 patients have been evaluated, if 62 or more did NOT need re-
excision (based on surgical specimen), investigators will conclude that the 
chance of correctly identifying a tumor that is suitable for IORT is greater 
than 70% and that further study of the approach would be justified.  If 18 or 
more of the initial 79 needed re-excision, then investigators will conclude 
that the chances of correctly identifying a tumor that is suitable for IORT is 
less than 85%.  In this instance, investigators would aim to improve the 
staging procedures before continuing with this approach. 
 
With this Simon optimal 2-stage design, there will be a 5% chance (alpha) of 
incorrectly deciding that that approach warrants further study, when the true 
chance of correctly staging is less than 85%; and there will be a 10% chance 
(beta) of correctly deciding that this approach warrants further study, when 
the true chance of correctly staging is greater than 70%. 
 
To evaluate the safety and tolerability of immediate IORT, the following side 
effects or complications will be taken as evidence that IORT was not well 
tolerated: 
 
a. any Grade 2 or greater toxicity  
b. failure for the surgical incision to heal as evidenced by wound 
dehiscence, wound infection, or skin ulceration. 
 
If 25% or more of Cohort 1 patients experience the above side effects or 
complications, this will be considered clear evidence that IORT is not well 
tolerated and will lead to suspension of accrual to this cohort.  The decision 
to continue unchanged, modify the regimen, or terminate the trial will be 
based on a careful review of all patients treated to date, and all toxicities and 
complications experienced.  The rules given below will trigger such a review 
(and are based on the sequential probability ratio test with the theoretical 
parameters set to α=0.10, β=0.10, po=0.05, pa=0.25).  At the completion of 
the study, all complications and toxicities will be summarized and reported.   
During the conduct of the trial, when an unacceptable toxicity or 
complication (as defined above) is observed, the number of patients (X) who 

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25 
have experienced any unacceptable toxicity or complication will be 
compared to the number of patients (N) who have begun IORT in this 
Cohort.  If the number of patients, N, is greater than NX, the number given in 
the bottom row of the Table 1, then accrual will continue.  If N is less than or 
equal to NX, then accrual will be suspended for review of the data. 
 
Table 1:  Criteria for Suspending Accrual to Evaluate Tolerability 
X: # pts with 
unacceptable toxicity 
or a complication 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Nx:  Suspend trial if # 
patients (N) is ≤ Nx 
≤6 
≤1
4 
≤2
1 
≤2
9 
≤3
7 
≤4
5 
≤5
3 
≤6
0 
≤6
8 
≤7
6 
≤7
9 
 
These rules were selected to ensure a reasonable chance that the trial would not be 
suspended if the true chance of unacceptable toxicity were less than 5% and a reasonable 
chance that it would be suspended if the true chance were 25% to 30% (Table 2).  The table 
below summarizes these probabilities.  The values in the table below are based on 10,000 
simulations and are accurate to ±0.01 (based on a 95% confidence interval. 
 
Table 2. 
 
 
 
 
 
 
True Chance of Unacceptable Toxicity or 
Complication 
5% 
10% 15% 20% 25% 30% 
Probability of Suspending Accrual to Review 
Tolerability 
0.07 0.37 0.78 0.96 0.99 0.99 
 
 
13.1.2 Accrual to Cohort 2 (Specific Aim 4 in Section 2.4) 
 
While Cohort 1 is open to accrual, as part of this trial, IORT will be offered 
to patients who have previously (within 3 months) undergone WLE and, 
based on the surgical specimen, are now considered to be eligible for IORT.  
Our estimate is that approximately 20 such patients will be enrolled.   These 
patients will be enrolled and treated to document the safety and feasibility of 
IORT when given in the delayed setting,   
 
For this component of the trial, the following side effects or complications 
will be taken as evidence that IORT was not well tolerated: 
 
a. any Grade 2 or greater toxicity  
b. failure for the surgical incision to heal as evidenced by wound 
dehiscence, wound infection, or skin ulceration. 
 
If 25% or more of Cohort 2 patients experience the above side effects or 
complications, this will be considered clear evidence that IORT is not well 
tolerated and will lead to suspension of accrual to this cohort.  As above, the 
decision to continue unchanged, modify the regimen, or terminate the trial 
will be based on a careful review of all patients treated to date, and all 

1b069_TARGIT-DCIS   
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26 
toxicities and complications experienced.  The rules given below will trigger 
such a review (and are based on the sequential probability ratio test with the 
theoretical parameters set to α=0.10, β=0.10, po=0.05, pa=0.25).  At the 
completion of the study, all complications and toxicities will be summarized 
and reported.   During the conduct of the trial, when an unacceptable toxicity 
or complication (as defined above) is observed, the number of patients (X) 
who have experienced any unacceptable toxicity or complication will be 
compared to the number of patients (N) who have begun IORT in this 
Cohort.  If the number of patients, N, is greater than NX, the number given in 
the bottom row of the Table 3 then accrual will continue.  If N is less than or 
equal to NX, then accrual will be suspended for review of the data. 
 
 
Table 3:  Criteria for Suspending Accrual to Evaluate Tolerability 
X: # pts with unacceptable toxicity or a complication 
2 
3 
4 
Nx:  Suspend trial if # patients (N) is ≤ Nx 
≤6 
≤14 
≤20 
 
These rules were selected to ensure a reasonable chance that the trial would not be 
suspended if the true chance of unacceptable toxicity were less than 5% and a reasonable 
chance that it would be suspended if the true chance were 25% to 30% (Table 4).  The table 
below summarizes these probabilities.  The values in the table below are based on 10,000 
simulations and are accurate to ±0.01 (based on a 95% confidence interval. 
 
 
Table 4. 
 
 
 
 
 
 
True Chance of Unacceptable Toxicity or 
Complication 
5% 
10% 15% 20% 25% 30% 
Probability of Suspending Accrual to Review 
Tolerability 
0.05 0.23 0.46 0.67 0.83 0.93 
 
13.1.3 Accrual to Cohort 3 (Specific Aim 5 in Section 2.5)  
 
Cohort 3 will be a subset of patients who begin in Cohort 1 (i.e. are deemed 
candidates for immediate IORT and who receive immediate IORT) but who 
subsequently are found to require a mastectomy, re-excision alone, re-
excision followed by WB-EBRT, or WB-EBRT alone.  This cohort will be 
followed to monitor and document the complications of the mastectomy and 
WB-EBRT (with or without re-excision) which are performed following 
IORT. If all 79 patients are enrolled in Cohort 1 (i.e. the study is not stopped 
early), then we would expect between 8 and 17 patients requiring an 
additional surgical procedure (mastectomy or re-excision); as soon as 18 
patients require an additional surgical procedure, the study will be 
terminated.   
 
Using the same definition of unacceptable toxicity as above in 13.1.1 for 
Cohort 1 and in 13.1.2 for Cohort 2 (any Grade 2 or greater toxicity, or 
failure for the surgical incision to heal as evidenced by wound dehiscence, 

1b069_TARGIT-DCIS   
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27 
wound infection, or skin ulceration), the rules in Table 3 will also be applied 
to the patients undergoing an additional surgical procedure in Cohort 3.  
Separately, we will evaluate the tolerability of WB-EBRT following IORT, 
in the same manner (using Table 3).  Unacceptable toxicity of WB-EBRT 
include any Grade 2 or greater toxicity, skin flap necrosis, skin ulceration, 
wound dehiscence, or brachial plexopathy. 
 
13.2 Analysis of Results 
 
The outcome of all patients who are registered onto this study will be reported.  The 
results of patients in Cohorts 1, 2, and 3, will be summarized separately.  
 
For those patients whose CE-MRI and mammography results suggested that they 
would be candidates for IORT (i.e. Cohort 1), the surgery results will be summarized 
in terms of whether or not a re-operation was indicated (because of inadequate 
margins or for any other reason) or whether or not WB-EBRT was recommended 
(because of small margin size or large tumor size, or another reason).  For those 
patients who subsequently underwent re-excision +/- WB-EBRT or who 
subsequently received WB-EBRT alone (or mastectomy), all complications and side 
effects will be summarized. 
 
For all patients, the size of the lesion as estimated by the imaging modalities will be 
compared to the size measured in the surgical specimen. 
 
 
14.0 REGISTRATION GUIDELINE 
 
Registration will be done with the Clinical Investigations Support Office into the Cancer 
Center database.  
 
15.0 BIOHAZARD CONTAINMENT 
 
No radioactive elements are used in the delivery of IORT.   Background radioactively will be 
actively monitored by the radiation physicist during the delivery of IORT to ensure patient 
and staff safety.  WB-EBRT, if indicated, will be delivered per usual radiation oncology 
protocols established by the Radiation Safety Committee.  
 
16.0 ETHICAL AND REGULATORY CONSIDERATIONS 
 
All institutional and Federal regulations concerning the Informed Consent form will be 
fulfilled.  The study will be conducted in adherence to ICH Good Clinical Practice. 
 
 
 
 
 
 
 
17.0 REFERENCES 

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28 
 
1. American Cancer Society, Cancer Facts and Figures 2006. Atlanta: American Cancer 
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2. Fisher B, Anderson S, Bryant J et al.  Twenty-year follow-up of a randomized trial 
comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the 
treatment of invasive breast cancer.  N Engl J Med 2002;347(16):1233-41. 
3. Fisher B, Land S, Mamounas E.  Prevention of invasive breast cancer in women with ductal 
carcinoma in situ: an update of the National Surgical Adjuvant Breast Project experience.  
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4. Bijker N, Meijnen P, Peterse JL.  Breast-conserving treatment with or without radiotherapy 
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5. UK Coordinating Committee on Cancer Research (UKCCCR) Ductal carcinoma in situ 
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6. Athas WF, Adams-Cameron M, Hunt WC et al. Travel distance to radiation therapy and 
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7. Fisher ER, Dignam J, Tan-Chiu E et al. Pathologic findings from the National Surgical 
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8. Holli K, Saaristo R, Isola J et al. Lumpectomy with or without postoperative radiotherapy 
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9. Personal communication.  Umberto Veronesi. 
10. Chung A, Saouaf R, Scharrew K, Phillips E. The impact of MRI on the treatment of DCIS.  
Am Surg 2005;71(9):750-710.  
11. Menell JH, Morris EA, Dershaw DD et al.  Determination of the presence and extent of pure 
ductal carcinoma in situ by mammography and magnetic resonance imaging.  Breast J 
2005;11(6):382-90. 
12. Hata T, Takahashi H, Watanabe K et al.  Magnetic resonace imaging for preoperative 
evaluation of breast cancer: a comparative study with mammography and ultrasonography.  
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13. Bedrosian I, Mick R, Orel SG. Changes in Surgical Management of patients with breast 
carcinoma based on preoperative magnetic resonance imaging.  Cancer 2003;98(3):468-73. 
14. Schelfout K, Van Goethem M, Kersschot E, et al.  Contrast-enhanced MR imaging of breast 
lesions and effect on treatment.  Eur J Surg Oncol 2004;30(5):501-7. 
15. Benda RK, Yasuda G, Sethi A et al.  Breast boost: are we missing the target? Cancer 
2003;97(4):905-9. 
16. Personal Communication 
17. Kraus-Tiefenbacher U, Bauer L, Kehrer T et al.  Intraoperative radiotherapy (IORT) as a 
boost in patients with early-stage breast cancer – acute toxicity.  Onkologie 2006;29(3):77-
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18. Kraus-Tiefenbacher U, Bauer L, Scheda A.  Long-term toxicity of an intraoperative 
radiotherapy boost using low energy x-rays during breast-conserving surgery.  Int J Radiat 
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19. Reitsamer R, Peintinger F, Kopp M et al.  Local recurrence rates in breast cancer patients 
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20. Vaidya J. Intraoperative radiotherapy for breast cancer.  Lancet Oncology. 2004;5(3):165-
73. 
21. Kalapurakal JA, Goldman S, Stellpflug W et al.  Phase I study of intraoperative 
radiotherapy with photon radiosurgery system in children with recurrent brain tumors: 
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8. 
22. Koniaris LG, Chan DY, Magee C et al. Focal hepatic ablation using interstitial photon 
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23. Vaidya JS, Baum M, Tobias JS et al.  The novel technique of delivering targeted 
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24. Kraus-Tiefenbacher U, Bauer L, Scheda A.  Intraoperative radiotherapy for breast cancer 
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25. Bazzocchi M, Zuiani C, Panizza P et al.  Contrast-enhanced breast MRI in patients with 
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APPENDICES 
 
Appendix I  Philadelphia Consensus Guidelines for Classification of DCIS 

1b069_TARGIT-DCIS   
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30 
 
A. Low grade nuclei (NG 1) 
 
Appearance: Monotonous (monomorphic) 
Size: 1.5-2.0 normal RBC or duct epithelial cell nucleus dimensions 
Features: Usually exhibit diffuse, finely dispersed chromatin, only occasional nucleoli and 
mitotic figures. Usually associated with polarization of constituent cells. 
Caveat: The presence of nuclei that are of similar size but are pleomorphic precludes a low 
grade classification. 
 
B. High-grade nuclei (NG 3)  
 
Appearance: Markedly pleomorphic 
Size: Nuclei usually >2.5 RBC or duct epithelial cell nuclear dimensions 
Features: Usually vesicular and exhibit irregular chromatin distribution and prominent, often 
multiple nucleoli. Mitosis may be conspicuous. 
 
C. Intermediate grade nuclei (NG 2)  
 
Nuclei that are neither NG 1 nor NG 3 
 
Necrosis Quantification  
 
Comedonecrosis: Any central zone necrosis within a duct, usually exhibiting a linear pattern 
within ducts if sectioned longitudinally. 
 
Punctate: Non-zonal type necrosis (foci of individual cells necrosis visible under 10X, 40X is 
not needed) 
 
Appendix 2   The USC/Van Nuys Prognostic Index scoring system for DCIS 
 
Score 
1 
2 
3 
Size (mm) 
≤15 
16-40 
>40 
Margins width (mm) ≥10 
1-9 
<1 
Pathologic 
Classification 
Non-high grade 
Without necrosis 
(Nuclear grades 1 or 
2) 
Non-high grade with 
necrosis 
(Nuclear grades 1 or 
2) 
High grade with or 
without necrosis 
(nuclear grade 3) 
Age 
>60 
40-60 
<40