A Phase II Study of Preoperative Stereotactic Ablative Body Radiotherapy (SABR) for Early-Stage Breast Cancer: Introduction of a Novel Form of Accelerated Partial Breast Radiotherapy
Phase: NA
Conditions: Breast Cancer, Breast Cancer Female, Breast Adenocarcinoma
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

A Phase II Study of Preoperative Stereotactic Ablative Body Radiotherapy 
(SABR) for Early-Stage Breast Cancer: Introduction of a Novel Form of 
Accelerated Partial Breast Radiotherapy 
NCT03137693 
Version 6 
March 30, 2020 

1 
 
 
A Phase II Study of Preoperative Stereotactic Ablative Body Radiotherapy (SABR) for Early- 
Stage Breast Cancer: Introduction of a Novel Form of Accelerated Partial Breast Radiotherapy 
 
MCC 18596 
 
PRINCIPAL INVESTIGATOR 
Michael Montejo, M.D. 
 
CO-INVESTIGATORS 
Roberto Diaz, M.D., Ph.D. 
Sungjune Kim M.D., Ph.D. 
Marie Catherine Lee, M.D. 
Susan Hoover, M.D. 
Nazanin Khakpour, M.D. 
Christine Laronga, M.D. 
John Kiluk, M.D. 
Hatem Soliman, M.D. 
Jared Weinfurtner, M.D. 
Marilin Rosa, MD 
Youngchul Kim, Ph.D. 
Olya Stringfield, PhD 
Mahmoud Abdalah PhD 
 
 
 
 
 
CONTACT INFORMATION 
PRINCIPAL INVESTIGATOR 
Michael Montejo, M.D. Assistant Member 
Section Chief Gynecologic Radiation Oncology 
Section Chief Radiation Oncology at Moffitt International Plaza 
Department of Radiation Oncology 
Moffitt Cancer Center 
12902 Magnolia Dr. Tampa, FL 33612 
Office Phone: (813) 745-7030 
Office FAX: (813) 745-7231 
Email: Michael.montejo@moffitt.org 
 
 
Version 6 03/30/2020 

2 
 
 
TABLE OF CONTENTS 
SCHEMA 
4 
ELIGIBILITY CRITERIA 
5 
HYPOTHESIS 
7 
1.0 
BACKGROUND 
7 
1.1 
Study disease and rationale 
7 
1.2 
Pre-operative treatment 
9 
1.3 
Effects on surgical margins 
9 
1.4 
Study agent/technique: Stereotactic Ablative Body 
Radiotherapy (SABR) 
10 
1.4.1 
Prone-positioning during SABR 
10 
1.5 
Gender and age 
11 
2.0 
OBJECTIVES 
11 
2.1 
Primary Objective 
11 
3.0 
DIAGNOSIS/IMAGING/PATIENT    IDENTIFICATION 
11 
3.1 
Tissue Diagnosis/Pathology 
11 
3.2 
Patient Identification 
11 
3.3 
Magnetic Resonance Imaging (MRI) Considerations 
12 
4.0 
TREATMENT 
12 
4.1 
Simulation 
13 
4.2 
Dose Specifications 
14 
4.3 
Structures 
14 
4.3.1 Target Volumes 
14 
4.3.2 Normal Tissue Structures 
14 
4.4 
TREATMENT PLANNING PROCEDURE 
15 
4.5 
TREATMENT DELIVERY 
15 
5.0 
MANAGEMENT OF TOXICITY DUE TO SABR 
16 
6.0 
DURATION OF SABR 
16 
7.0 
CLINICAL AND LABORATORY EVALUATIONS (APPENDIX 1) 
16 
7.1 
Baseline/pre-treatment Evaluations 
16 
7.2 
Evaluations Before SABR 
16 
7.3 
Evaluation During SABR 
17 
7.4 
Evaluation After SABR 
17 
8.0 
EARLY DISCONTINUATION OF THERAPY 
17 

3 
 
9.0 
DOSING DELAYS/DOSE MODIFICATIONS 
17 
9.1 
Study Agents 
17 
9.2 
Other Agents 
17 
10.0 
AGENT FORMULATION AND PROCUREMENT 
17 
11.0 
ADVERSE EVENT (TOXICITY) REPORTING 
17 
12.0 
DEFINITIONS 
18 
12.1 
Adverse Events 
18 
12.2 
Serious Adverse Event 
18 
13.0 
PURPOSE 
18 
13.1 
Reporting Methods 
19 
13.2 
IRB Reporting 
19 
13.2.1  AEs and SAEs 
19 
13.3 
Follow-up Reporting 
19 
14.0 
CRITERIA FOR DISCONTINUATION OF THERAPY 
19 
15.0 
DATA REPORTING 
20 
16.0 
STATISTICAL CONSIDERATIONS 
20 
17.0 
INTERIM MONITORING 
20 
18.0 
REPORTING EXCLUSIONS 
20 
19.0 
INVESTIGATOR’S RESPONSIBILITIES 
20 
19.1 
Confidentiality/Monitoring 
21 
19.2 
Informed Consent and Permission to Use Protected 
Health Information 
21 
19.3 
Source Documentation and Investigator Files 
22 
19.4 
Non-Protocol Research 
22 
19.5 
Ethics 
22 
20.1 
REFERENCES 
22 
APPENDIX I 
27 
STUDY CALENDAR 
APPENDIX II 
28 
NATIONAL CANCER INSTITUTE (NCI) COMMON TOXICITY 
CRITERIA (CTC) 
APPENDIX III 
28 

4 
 
PERFORMANCE SCALE 
 
 
 
 
SCHEMA 
 
*IDC - Invasive ductal carcinoma 
 
**BCS - Breast-conserving surgery 
 
***SABR - Stereotactic Ablative Body Radiotherapy 

5 
 
 
ELIGIBILITY CRITERIA 
 
Inclusion Criteria: 
A. Understand and voluntarily sign an informed consent document prior to conducting any 
study related assessments or procedures. 
 
B. Histologically proven invasive adenocarcinoma of breast. 
 
C. Must have marker clip indicating location of target tumor in breast. 
 
D. Unifocal tumor ≤2 cm based on contrast-enhanced prone-breast MRI. 
 
E. The patient must be clinically and radiographically node negative (N0) to participate on this 
protocol. Clinically suspicious regional nodes by imaging or physical exam require biopsy 
evaluation to exclude disease involvement. 
 
F. Appropriate candidate for breast-conserving surgery based on multi-disciplinary 
assessment. 
 
G. Females age ≥ 50 years. 
 
H. Able to tolerate prone body positioning during radiation therapy. 
 
I. No prior ipsilateral-breast or thoracic radiotherapy. 
 
K. As defined on MRI, target lesion must be at least 10 mm distance from skin (defined as 
volume encompassing first 3 mm from breast surface). 
 
L. Subjects must be estrogen receptor (ER) positive . 
 
M. Must be negative for Her-2 amplification. (Either 1+ on semi-quantitative evaluation of 
immunostain or negative by fluorescent in-situ hybridization). 
 
N. No implanted hardware or other material that would prohibit appropriate treatment 
planning or treatment delivery in the investigator’s opinion. 
 
O. No history of an invasive malignancy (other than this breast cancer, or non-metastatic 
basal or squamous skin cancers) in the last 5 years. 
 
P. Must not have received nor be planned for neoadjuvant chemotherapy prior to SABR or 
surgery. 
 
Q. ECOG performance status <2 (see Appendix Ill). 

6 
 
R. Females of childbearing potential must have a negative urine pregnancy test prior 
to simulation and within seven days of SABR start as per section 7.2 of the protocol. 
A female of childbearing potential is a sexually mature woman who 1) has not undergone 
a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the 
surgical removal of both ovaries) or 2) has not been naturally postmenopausal for at  
least 24 consecutive months (ie, has had menses at any time during the preceding 
24 consecutive months). 
 
Exclusion Criteria: 
 
A. Subjects must not have invasive lobular carcinoma. 
 
B. Subjects must not have a Tumor > 2 cm as measured on prone contrast-enhanced breast 
MRI. 
 
C. Subjects must not have presence of histologically proven lymph node disease. 
 
D. Subjects are not a candidate for breast conserving surgery. 
 
E. Subjects must not have prior ipsilateral-breast or thoracic radiotherapy. 
 
F. Subjects must not have history of scleroderma or lupus erythematosus with either 
cutaneous manifestation or requiring active treatment. 
 
G. Subjects must not have an MRI defined target tumor that is within 10 mm of skin (defined 
as volume encompassing first 3 mm from skin surface). 
 
H. Subjects must not have amplification of Her-2 (Either 3+ by semi-quantitative immunostain 
or positive by Flourescent in-situ hybridization (FISH)). 
 
I. Subjects must not have implanted hardware or other material that would prohibit 
appropriate treatment planning or treatment delivery in the investigator’s opinion. 
 
J. Subjects must not have history of an invasive malignancy (other than this breast cancer, or 
non-metastatic basal or squamous skin cancers) in the last 5 years. 
 
K. Subjects must not have received or plan to receive neoadjuvant chemotherapy either 
before radiotherapy or before surgery. 
 
L. Subjects must not be a known carrier of BRCA1 or BRCA2 gene mutation. 
 
M. Subjects must not be pregnant or unwilling to undergo pregnancy screening. 

7 
 
HYPOTHESES 
Pre-operative breast SBRT will yield at least 10% probability of pathologic complete response. 
 
1.0 
BACKGROUND 
 
1.1 
Study Disease and Rationale 
More than 130,000 women undergo breast-conserving surgery (BCS) annually in the United States. [1] 
The current paradigm is to deliver post-operative radiotherapy to the retained whole or partial  
breast to maximize in-breast local control. 
 
Conventional post-operative whole breast radiotherapy is well studied and effective. It is, however, 
inconvenient consisting of 3-7 weeks of daily treatment. Also, due to its comprehensive coverage of 
all breast tissue, the radiation fields must extend posteriorly and typically include a portion of normal 
lung and in some cases heart. The unintended irradiation of these organs has been shown to cause 
late-term increase in cardiovascular mortality. [2, 3] 
Following the realization that most in-breast local recurrences occur near or at the previous tumor 
site, it becomes logical to irradiate only the post-operative lumpectomy cavity and spare the 
remaining breast. In properly selected patients, this approach has been shown to be effective in 
preventing tumor recurrence without excessive failures in remaining untreated breast. [4-17] 
 
The widespread adoption and interest for such partial breast irradiation (APBI) has been driven, in 
part, by its more patient-convenient shortened treatment schedules lasting one week to one day. 
Also, owing to reduced tissue volume that is irradiated, APBI generally results in reduced radiation 
exposure to heart and lung. 
 
Several methods of APBI have been developed. Frequently employed invasive techniques include 
intra- operative radiotherapy (IORT) and interstitial or intra-cavitary brachytherapy. The non-invasive 
category, which is our interest in this protocol, includes variations on 3D-conformal external beam 
radiotherapy. 
 
The invasive approaches typically treat a smaller volume of tissue more conformally although there 
remains operator dependence. [18] Aside from IORT, however, they have generally relied on twice- 
daily fractionation schedules which diminish convenience and cost benefits while also introducing 
complication risk from in-dwelling brachytherapy catheters which remain in place for the duration of 
treatment. [19] Published experiences have also indicated increased risk of conversion to mastectomy 
from brachytherapy-related soft tissue toxicity. [20, 21] 
 
In highly selected cases, IORT offers the convenience of single-treatment radiotherapy which is 
completed   at the time of surgery. Availability of IORT-equipped facilities is, however, limited and 
generally IORT  increases operating room and anesthesia time by 40-60 minutes--diminishing cost 
savings and increasing  anesthesia time for the typically elderly patients that are candidates for this 
treatment. 

8 
 
Conversely, external beam-based techniques are widely available, non-invasive, and less operator- 
dependent. Published experiences describe varied cosmetic outcomes with this approach as well, 
with  some reports of soft tissue toxicity. [22-23]  One potential explanation arises from the necessarily 
large breast  volume that is treated when employing conventional external beam APBI because one 
must account for  respiratory motion as well as uncertainty in delineation of the lumpectomy cavity 
which is often poorly defined on post-operative imaging. [24-26] 
 
In a dosimetric simulation of pre-operative stereotactic radiosurgery for prone-breast targets, Palta et 
al.  have shown significant reductions in volume of ipsilateral breast receiving 100% and 50% of 
prescription radiation dose from 18% to 3% and 53% to 13.3%, respectively, when compared to 
patients treated post- operatively. [27] 
 
In a phase 1 investigation of pre-operative stereotactic radiosurgery for breast carcinoma, Blitzbau et 
al similarly confirm the emergence of markedly smaller target volumes and ease of meeting normal 
tissue dose constraints. Moreover, no dose-limiting toxicities were encountered at the highest 
evaluated dose level of 21 Gray in a single fraction (personal communication with Dr. Blitzbau). [28] 
 
We therefore propose to build on this experience and evaluate pre-operative highly conformal 
stereotactic ablative body radiotherapy (SABR) in a phase 2 context. Our protocol will differ from the 
experience reported by Blitzbau et al. in an important way in that we will delay surgery for 6-8 weeks 
following radiotherapy as opposed to 10 days. We feel this is an important distinction because it is 
likely that 10 days is insufficient time for a pathologic complete response to become fully manifest. It 
is possible that if more time were allowed to elapse between radiation and tumor resection that 
more pathologic complete responses will perhaps be observed as has been shown to be the case in 
other disease sites where radiation is followed by surgical resection. [29] 
 
Another important difference will be the fractionation of treatment over three days as opposed to 
delivering a single fraction in one treatment session. While perhaps slightly less convenient than 
single-fraction treatment, it is possible that moderate fractionation will further reduce the risk of soft 
tissue toxicity in the treated breast. Of note, Blitzbau et al. reported fair/poor cosmetic outcome in all 
three patients who underwent pre-operative single-fraction breast radiosurgery who then also 
required post-operative whole breast radiotherapy for adverse findings noted on final surgical 
pathology. Conversely, Bondiau et al. reported only one grade 3 toxicity in a dose- finding study 
where patients received pre-operative SABR (maximum 31.5 Gy in 3 fractions of 10.5 Gy each) 
concurrent with chemotherapy than followed by conventional whole breast radiotherapy after 
surgery. Similarly, Formenti et al. have reported 2 cases of grade 3 toxicity and 1 local recurrence in 
one hundred patients treated with post-operative breast SABR at a median 64 month follow-up (30 
Gy in 5 fractions of 6 Gy each). These results suggest a toxicity sparing effect with only moderate 
fractionation of the radiation dose. [30, 31] 
 
Furthermore, historic dogma of radiobiology informs that fractionation of radiation promotes re- 
oxygenation of hypoxic tumor as well as redistribution of malignant cells into radiosensitive phases 
of cell cycle; both of which promote radiation mediated cell killing. It is therefore possible that the 
moderate fractionation proposed in this protocol will augment the probability of obtaining 
pathologic complete response. 

9 
 
 
Considering the low rates of toxicity and good patient tolerance reported by previous experiences 
delivering breast SABR in both pre- and post-operative settings, it is appropriate to conduct our trial 
as a phase 2 investigation aimed at establishing efficacy as measured by rates of pathologic complete 
response. We have selected our dose at 28.5 Gy in 3 fractions of 9.5 Gy per fraction for two reasons. 
 
First, it has been experimentally suggested that moderately fractionated SABR is efficient at inducing 
immune activation which is a focus of planned correlative biomarker studies. [32, 33] 
 
Secondly, Bondiau et al. showed no further correlation with pathologic complete response in 
evaluated doses higher than 25.5 Gy in 3 fractions of 8.5 Gy/fraction and they actually proposed that 
this be the dose evaluated in a phase 2 trial. An important distinction, however, to our proposed trial 
is that our patients will not receive concurrent chemotherapy as was done by Bondiau et al. We have 
therefore chosen the next higher dose cohort to off-set loss of anti-tumor effect resulting from not 
giving concurrent chemotherapy. 
 
1.2 
Pre-operative Treatment 
 
Generally all forms of APBI, invasive and non-invasive, have followed the paradigm of treating post- 
operatively to the lumpectomy cavity to reduce in-breast recurrence risk. External beam APBI is 
unique, however, in that it can theoretically be applied pre-operatively. Because other forms of APBI 
require surgical creation of a cavity for placement of a treatment applicator, they are innately 
incompatible with pre-operative treatment. 
 
Pre-operative treatment may be advantageous to reduce soft tissue toxicity and optimize breast 
cosmesis because, generally speaking, an intact breast tumor is smaller than its corresponding 
lumpectomy cavity following surgery and is also easier to distinguish on treatment-planning images. 
Therefore delivering APBI pre-operatively is likely to result in smaller and more accurately delineated 
target volumes, which is expected to reduce normal tissue exposure and attendant risk of soft tissue 
toxicity. [27, 34-36]    Also, because treatment is delivered pre-operatively, subsequent surgery will 
remove the most heavily irradiated tissue and hopefully reduce risk of fibrosis. 
 
Pre-operative treatment may also overcome theoretical losses in radiotherapy efficacy associated 
with delays in treatment arising from post-operative recovery time and/or delivery of chemotherapy 
which typically delays radiotherapy by several months. [37] 
Lastly, evaluation of excised tumor following delivery of ablative radiotherapy provides a unique 
opportunity to study the, as yet, incompletely characterized effects on gene expression and immune 
system activation of high dose radiation. 

10 
 
1.3 
Effect on Surgical Margins 
 
In patients undergoing breast-conserving surgery, it is generally preferred to begin radiotherapy only 
after negative surgical margins have been achieved because positive margins increase the risk of in- 
breast local recurrence. [38-40]    Typically, 25% of women undergoing breast-conserving surgery will 
require surgical re-excision for close or positive margins. Between 8-12% of patients requiring re- 
operation will be converted to mastectomy and, critically, 11% of positive margins will never be re- 
excised. The challenge of obtaining appropriate margins results in additional surgical procedures that 
lead to increased patient morbidity and healthcare costs while diminishing cosmesis and, in some 
cases, optimal treatment. [1, 41-43] 
 
It is unclear if pre-operative SABR would reduce the incidence of re-operation for inadequate surgical 
margins because the significance of close or positive margins after radiotherapy is unknown and we 
are unlikely to abandon our entrenched belief that negative surgical margins must be achieved. 
 
Considering, however, that breast tumor excisions do not always result with the target lesion 
precisely in the center of the excised specimen, it may hold that inducing tumor regression with 
uniform pre-operative irradiation of the tumor and its peripheral margin may facilitate obtaining 
sufficient clear margins. [44, 45] 
 
Any reduction in need for re-operation to address margins would constitute an immediate benefit to 
patients and the payor system. [46] 
 
1.4 
Study Agent/Technique: Stereotactic Ablative Body Radiotherapy (SABR) 
 
Stereotactic ablative body radiotherapy (SABR) is an established technique utilized successfully in the 
non-operative management of brain, spinal, liver, adrenal, nodal, and lung metastases as well as in 
definitive management of prostate carcinoma, pancreatic carcinoma, and early-stage medically 
inoperable lung carcinoma with local control rates in excess of 90%. [47-51] 
SABR distinguishes itself from conventional fractionated radiotherapy in that significantly larger 
radiation dose is delivered with each treatment fraction with intent to ablate tissue within the target 
volume. Owing to this potent biologic effect it is necessary that the treatment planning be 
undertaken with a high degree of targeting accuracy and dose conformity. This treatment frequently 
utilizes image guidance, target motion management, and tight immobilization to ensure targeting 
accuracy. 
 
Therefore all treatment on this protocol will be delivered on a Moffitt linear accelerator with 
appropriate stereotactic and image-guidance capabilities. 
 
1.4.1 
Prone positioning during SABR 
 
Prone patient-positioning equipment is established and widely available for breast radiotherapy. 
Commercially available prone breast boards can be indexed to the treatment table and enable 

11 
 
comfortable and reproducible patient set-ups. Modern breast boards allow un-obstructed access to 
nearly 360 degrees of beam direction for treatment planning. 
 
The primary advantage of prone-breast radiotherapy is to displace the breast away from the chest 
wall, lung, and heart which further enhances sparing of these structures from radiation exposure. [52] 
Prone positioning attenuates motion of the breast associated with normal respiration thereby 
simplifying the process for accurate targeting during treatment. [53, 54] Lastly, prone positioning 
during treatment facilitates image-registration of the diagnostic breast MRI (usually imaged prone) 
to the treatment planning CT- simulation which will be used to enhance accuracy of target 
delineation. 
 
1.5 
Gender and Age 
 
Breast cancer is a disease diagnosed typically in women over 40 years of age. In keeping with our 
intent to select patients of lower risk and restrict our patient population to those defined as 
‘suitable’ or ‘cautionary’ by American Society of Therapeutic Radiation Oncology (ASTRO) consensus 
for accelerated partial breast radiotherapy, only women ≥50 years of age will be enrolled and men 
will not be candidates for this protocol. 
 
2.1 
OBJECTIVES 
2.2 
Primary objective 
Primary objective: 
Assess rate of pathologic complete response following pre-operative 
SABR for early-stage breast carcinoma. 
 
Secondary objective: 
Assess incidence of re-operation for inadequate surgical margin. 
 
Tertiary objective: 
Characterize imaging response following SABR (and before surgery) and 
correlate to observed pathologic responses. 
 
3.1 
DIAGNOSIS, IMAGING and PATIENT IDENTIFICATION 
 
3.2 
Tissue Diagnosis/Pathology 
Whenever possible, patients will undergo diagnostic breast core biopsy at Moffitt facility for tissue 
diagnosis and storage. Slides/blocks from pre-treatment diagnostic breast core biopsies performed 
at an outside facility will be obtained to confirm the diagnosis. Outside pathology slides must be 
reviewed by a Moffitt pathologist. Standard histopathologic features, including the histologic grade 
and hormone receptor and Her-2 expression will be recorded. Margin status and degree of 
pathologic response following breast- conserving excision will also be assessed and reported, as per 
standard of care. All extirpated specimens will be preserved as archived tissue so that additional 
future analysis can be performed. Currently planned studies include comparative gene expression 
analysis of matched pre-radiation, post-radiation and germline tissue. Also planned is multiplex 
immunofluorescence (CD68, CD8, CD4, CD3, FOXP3, PCK, DAPI) in order to highlight specific 
immune cell types within matched pre-radiation and post-radiation tumor tissue. 
 

12 
 
3.3 
Patient Identification 
Patient referrals to the Moffitt Comprehensive Breast Program as well as patients seen in the Moffitt 
Screening and Prevention program will be screened for participation on this protocol chiefly by 

13 
 
surgical and radiation oncology providers during regular clinical encounters. Potential candidates will 
also be identified and discussed at our weekly breast treatment planning conference. 
 
Upon identification of a candidate, the patient will be referred to a breast radiation oncologist for 
patient evaluation and confirmation of participation eligibility, protocol consent and enrollment. 
(Due to utilization of a novel radiotherapy application in this protocol, all patients’ eligibility 
confirmation, consent, and protocol enrollment will be conducted by a radiation oncologist or 
radiation oncology research support staff.) 
 
3.4 
Magnetic Resonance Imaging (MRI) considerations 
Contrast-enhanced MRI of the breast will be performed at baseline and at least 5 weeks but no more 
than 6 weeks after SABR but prior to breast conserving surgery. When MRI is performed at Moffitt 
facility, the gadolinium based contrast agent gadobutrol (Gadavist, Bayer HealthCare 
Pharmaceuticals) will be used at a concentration of 0.1 mmol/kg. The breast MRI technique at our 
institution is performed at 1.5 T and includes axial dynamic 3D T1-weighted fat-suppressed gradient- 
recalled echo pulse sequences obtained before and after contrast administration. Dynamic images 
are obtained every 90-110 seconds adjusted for breast thickness for a total of five acquisition times. 
Slice thickness is 2 mm. Subtraction images are obtained from the dynamic series. Fluid-sensitive 
T2-weighted images are also obtained. Diffusion-weighted and ADC map images are also obtained 
 
All data sets are reviewed on a PACS workstation (DynaCAD, Aegis, Hologic) with computer aided 
diagnosis for review of lesion enhancement kinetics, multiplanar reconstructions, and maximum 
intensity projections. Examinations are interpreted with available prior breast imaging and clinical 
history. 
 
For the purposes of this study, imaging parameters to be analyzed will include change in tumor size 
using the longest diameter measurement, overall evaluation of tumor enhancement kinetics, mass vs 
non-mass enhancement, and any change in tumor margin description for baseline vs follow-up 
evaluation as determined by the reading radiologist. 
 
In addition to the qualitative analysis of MRI images described above, quantitative analysis will also be performed. 
Multiparametric MRI (mpMRI) scans will be pre-processed to match voxel dimensions across patients, scans and scan 
dates, co-registering pre- and post- SABR images in each patient, computing DCE-MRI parameter maps, computing ADC 
maps, and calibrating T2W intensities using reference normal tissues. Next, we will develop a response predictor for 
pathologic complete response and MRI complete response using multispectral (habitats) analysis (primarily through 
multispectral cluster analysis of habitats) and machine learning (primarily through analysis of tumor voxels using Self-
Organizing Maps). 
 
4.1 
TREATMENT 
 
4.2 
Simulation 
A prone-breast immobilization device will be used. 
 
CT simulation will be performed at a minimum of one week after any invasive breast procedure to 
allow edema to settle. CT slices will be 3 mm. The imaging set will be downloaded to the treatment 
planning system for contouring and dosimetry. 

14 
 
 
During simulation external markers may be placed on the target breast skin to facilitate localization 
during treatment. The simulation CT will encompass the thyroid gland and both lungs in their 
entirety in addition to both whole breasts. Respiratory gating is not permitted. 

15 
 
Previously obtained prone-breast diagnostic MRI with marker clip in place will be co-registered to   
the planning CT to aid with accurate delineation of the intact breast tumor. The MRI and CT should  
be fused based on soft tissue using the visualized breast tumor, breast contour and breast biopsy  
clip. If there is discrepancy between the MRI and CT, and the fusion is not considered representative 
then at the discretion of the treating radiation oncologist the patient will either be removed from the 
protocol or alternatively an image- deformation registration technique may be used to facilitate 
fusion of diagnostic breast MRI to the planning CT. The final registration must be reviewed by the 
radiation oncologist for accuracy. 
 
4.3 
Dose Specifications 
All patients will undergo pre-operative stereotactic ablative body radiotherapy (SABR) to 28.5 Gy in 3 
fractions of 9.5 Gy on different days separated by no more than 48 hours. 
 
All specified doses are for the entire treatment course. All volume percentages are rounded to the 
nearest tenth of a percent for consistency, e.g., a volume of 0.02% shall be recorded as 0.0%. 
 
4.3.1 PTV: 
D95 = 100%, Dose maximum (Dmax) 130% 
 
Minor variations: D95<100%, ≥97% 
Major variations: D95<97% 
CTV: D95 = 100% 
Major variation: D95<100% 
4.3.2 THYROID: Per Protocol: Dose maximum 1.2Gy (4% prescription). 
Minor variation: Dose maximum >1.2Gy, <2Gy. 
Major variation: Dose maximum >2Gy 
 
4.3.3 CHEST-WALL: Per Protocol: V28.5Gy ≤30cc. 
 
Minor variation: V28.5 Gy >30cc, ≤35cc. 
Major variation: V28.5 Gy >35cc 
. 
4.3.4 IPSILATERAL LUNG: Per Protocol: V9Gy < 5%. 
 
Minor variation: V9Gy ≥5%, ≤10%. 
Major variation: V9Gy >10%. 
 
4.3.5 CONTRALATERAL LUNG: Per Protocol: V9 <3% 
 
Minor variation: V9Gy ≥3%, ≤5%. 
Major variation: V9Gy >5%. 

16 
 
 
4.3.6 IPSILATERAL BREAST: Per Protocol: V15Gy ≤25%; V25 Gy ≤10%. 
 
Minor variation: V15 Gy >25%,≤30%; V25 Gy >10%, ≤15% 
Major variation: V15 Gy >30%, V25 Gy >15% 
 
4.3.7 CONTRALATERAL BREAST Per Protocol: V10 Gy < 7%, V5 Gy <10% 
 
Minor variation: V10 Gy >7%,≤9%; V5 Gy >10%, ≤13% 
Major variation: V10 Gy >9%, V5 Gy >13% 
 
4.3.8 HEART Per Protocol: Mean ≤ 2Gy, ≤10cc to get 3Gy. 
 
Minor variation: Mean >2Gy, ≤3 Gy; >10cc getting 3Gy but ≤15cc 
Major variation: Mean >3Gy, >15 cc getting 3 Gy 
 
4.3.9 SKIN Per Protocol: D10cc ≤15Gy 
 
Minor variation: D10cc >15Gy, ≤18Gy 
Major variation: D10cc >18Gy 
 
***If all the above “Per Protocol” dose-volume criteria cannot be met on a given patient, then 
normal tissue constraints and target prescriptions may be relaxed to the “minor variation” range.*** 
 
4.4 
Structures 
 
4.4.1 Target Volumes 
 
GTV: The gross tumor volume (GTV) will consist of the intact breast tumor as defined on 
contrast-enhanced MRI and simulation CT. CTV: Clinical target volume 
 
CTV: Clinical target volume (CTV) will constitute the GTV + 15 mm uniform expansion to or subclinical 
extent of tumor. The CTV will exclude areas not expected to contain tumor including skin, muscle and bone. 
 
PTV: The planning target volume (PTV) will constitute the CTV + 3 mm uniform expansion to 
account for patient set-up error. The PTV is the volume to which the prescription dose is prescribed. 
 
While the static targeting accuracy of the eligible treatment delivery platform is between 1- 
2 mm, deformation of the breast, and target movement occurring after imaging but before dose 
delivery could contribute to targeting uncertainty. Generally, movement of breast tumor in the 
prone position is minimal. Although the cumulative targeting uncertainty has not been accurately 
quantified, a 3 mm CTV to PTV expansion will be employed in all cases. 

17 
 
4.4.2 Normal Tissue Structures: CONTOURING REQUIRED 
 
The structures listed below will be contoured and evaluated using dose-volume histogram (DVH) 
analysis. The normal tissues should be defined based on CT. The MRI is chiefly used in delineating the 
intact breast tumor. 
THYROID: Defined as both lobes of thyroid gland, contoured in their entirety 
CHESTWALL: Defined at muscle/bone interface with breast soft-tissue. 
SKIN: Defined as volume occupying first 3 mm of tissue from soft-tissue/air interface. 
IPSILATERAL LUNG: Defined as entire ipsilateral lung. 
CONTRALATERAL LUNG: Defined as entire contralateral lung. 
CONTRALATERAL BREAST: Defined as entire contralateral breast (see below). 
IPSILATERAL BREAST: Defined as entire ipsilateral breast minus the PTV. The whole breast volume  
for this protocol approximates the volume that is bounded by conventional tangent fields: anteriorly 
bounded by skin, posteriorly bounded by chestwall, medially bounded by ipsilateral border of 
sternum, laterally bounded by anterior edge of latissimus dorsi muscle or mid-axillary line, superiorly 
bounded by inferior border of clavicular head, inferiorly bounded 1-2 inferior to inframammary fold. 
HEART: Defined as heart structure extending from level where pulmonary trunk branches into left 
and right pulmonary arteries through ventricles and including visualized great vessels and coronary 
arteries. 
 
4.4 
Treatment Planning Procedure 
 
Inverse or forward planning may be employed. Volumetric modulated arc therapy (VMAT, ie 
RapidArc or SmartArc) or any form of static-field intensity modulated radiotherapy (IMRT) is 
permissible. The treatment plan used for each treatment will be based on the volumetric dose 
requirement of the protocol as described in section 4.2. Any beams entering through contra-lateral 
breast, heart or lungs on their way to the planning target volume should be avoided as much as 
possible. Tissue density heterogeneity correction is required for all beams. 
 
4.5 
Treatment Delivery 
 
4.5.1 Delivery System 
 
Conventional linear accelerators (linacs) with photon energies from 6 MV to 15 MV are allowed. 
Linacs should be equipped with stereotactic image-guidance system capable of delivering image- 
guided IMRT/3D-conformal RT and SABR/SRS. 
 
A kV-orthogonal or cone-beam CT based stereotactic image-guidance system is mandatory for linac- 
based treatment delivery. An on-board imager (OBI) or equivalent, or the BrainLab ExacTrack system, 
is required. At treatment, the implanted marker clip and any breast-surface markers (which will be 
marked for image guidance) will be imaged and used to determine final shifts to the location of the 
breast target. 

18 
 
 
The image-guidance procedure may be repeated during treatment at the discretion of the radiation 
oncologist. 
 
 
5.0 
Management of Toxicity due to SABR 
 
Management of toxicity due to SABR will be provided during the study period at the discretion of the 
treating physician(s) within the parameters of the protocol and documented. Most patients have 
grade 2 or lower skin, soft-tissue, or chestwall adverse effects during and after treatment. Symptoms 
and their management will be documented per routine clinic visit. In very rare cases, patients may 
experience extreme symptoms including high-grade soft-tissue fibrosis, dermatitis, fatigue, or breast 
pain. Supportive measures, skin care and medication will be instituted as needed. Common 
supportive medications include: 
• 
Topical antimicrobials: Antimicrobials such as silver sulfadiazine may be used in areas of skin 
desquamation. The amounts of the drug(s) used should be documented. 
• 
Topical skin moisturizers: Moisturizing lotions are used routinely in patients undergoing 
breast radiotherapy and is permitted on this protocol. The use of these products should be 
documented. 
• 
Hydrocolloid/Hydrogel dressings: Topical hydrocolloid/hydrogel dressings may be used in 
cases of confluent moist desquamation when deemed appropriate by the supervising 
radiation oncologist. The use of this product will be documented. 
• 
Analgesics: Analgesics is a broad category, including non-narcotic and narcotic agents. The 
use of non-narcotic agents, such as acetaminophen, non-steroidal anti-inflammatory agents 
for radiotherapy treatment-related pain should be documented. Narcotic use as a 
consequence of treatment should also be recorded. 
• 
Topical steroid: Topical 1% cortisone lotion is often used for radiotherapy related dermatitis 
and pruritus and is permitted on this protocol. The use of this drug should be documented. 
 
6.0 
Duration of SABR 
 
SABR will be completed in 3 treatment sessions (separated by no more than 48 hours) and will be 
scheduled to begin within 2 weeks of simulation and at least 6 weeks prior to breast- conserving 
tumor excision. 
 
7.1 
CLINICAL AND LABORATORY EVALUATIONS (APPENDIX I) 
 
7.2 
Baseline/pretreatment evaluations 
• History and physical/ECOG performance status. 
• Diagnostic core biopsy with placement of marker clip. 
• Post-biopsy contrast-enhanced prone-breast MRI (with marker clip in place). 

19 
 
7.3 Evaluations Before SABR 
 
• Females of childbearing potential, must have a urine pregnancy test (in menstruating 
women) prior to CT simulation. (A female of childbearing potential is a sexually mature woman who 
1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy 
(the surgical removal of both ovaries) or 2) has not been naturally postmenopausal for at least 24 
consecutive months (ie, has had menses at any time during the preceding 24 consecutive months). 
CT simulation for treatment planning 
 
7.4 Evaluations During SABR 
 
• History and physical. 
• ECOG performance status. 
• NCI Common Terminology Criteria for Adverse Events (CTCAE) v4 toxicity scoring 
system. 
• Urine pregnancy test will be repeated on first day of SABR before beginning treatment 
if last result is greater than 7 days old. 
 
7.5 
Evaluations After SABR 
• History and Physical (4-5 weeks after SABR) 
• ECOG performance status (4-5 weeks after SABR) 
• NCI Common Terminology Criteria for Adverse Events (CTCAE) v4 toxicity scoring 
system. (4-5 weeks after SABR) 
• Pre-operative diagnostic breast MRI (5-6 weeks following SABR) 
 
8.0 
Early Discontinuation of Therapy 
 
Patients who experience excessive adverse events as evaluated by their treating physician will be 
recorded. All attempts should be made to manage adverse events adequately. Because radiation 
related toxicity typically manifests weeks or months after treatment delivery, it is expected to be low 
probability that any high grade toxicity will surface before treatment is completed (3-fraction SABR 
delivered over 3-5 days) and so there will be minimal opportunity for early discontinuation of  
therapy due to toxicity. 
 
9.1 
DOSING DELAYS/DOSE MODIFICATIONS 
 
9.2 
Study Agent 
 
N/A 
 
9.3 
Other Agent(s) 
 
N/A 

20 
 
10.0 
AGENT FORMULATION AND PROCUREMENT 
 
N/A 
 
11.0 
ADVERSE EVENT (TOXICITY) REPORTING 
 
The descriptions and grading scales found in the revised National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v4 will be used for adverse event reporting. A copy 
of the CTCAE v4 can be downloaded from the CTEP web site  
http://ctep.cancer.gov/reporting/ctc.html. 
 
Adverse events monitoring will begin following initiation of SABR and continue for 28-35 days 
following completion of SABR. For purposes of this protocol, we will record any grade 2 or greater 
adverse events. Grade 1 adverse events will be omitted from toxicity reporting. 
 
12.1 Definitions 
 
12.2 
Adverse events (AE’s) will use the descriptions and grading scales found in the NCI Common 
Toxicity Criteria in Appendix II. 
 
Adverse events: Any unfavorable and unintended sign (including abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure, 
regardless of whether it is considered related to the medical treatment or procedure (attribution of 
unrelated, unlikely, possible, probable, or definite). Each AE is a unique representation of a specific 
event used for medical documentation and scientific analysis. 
 
12.3 
A serious adverse event (SAE) is defined in the FDA CFR 312 as any adverse drug experience 
occurring at any dose that results in any of the following outcomes: death, a life-threatening adverse 
drug experience, inpatient hospitalization, or prolongation of existing hospitalization, a persistent or 
significant disability/incapacity, or a congenital anomaly/birth defect. 
 
SAEs are defined by FDA and therefore seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations for patient/subject safety. Serious is based on patient/event 
outcome or action criteria usually associated with events that pose a threat to a patient’s life or 
functioning. 
 
13.1 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents. Adverse events are reported in a routine manner at scheduled times 
during a trial (please follow directions for routine reporting provided in the Data Reporting Section). 
Additionally, certain adverse events must be reported in an expedited manner for timelier 
monitoring of patient safety and care. The following sections provide information about expedited 
reporting. 

21 
 
 
Events resulting from concurrent illnesses and reactions to concurrent medications must be reported 
as adverse events. (grade 1 adverse events will not be collected) 
 
Any worsening of the patient’s clinical condition while the patient is on study will be considered to 
be an adverse event unless it is within the normal range of disease fluctuation for that patient. 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 
 
1) 
whether the patient has received an investigational or commercial agent; 
2) 
the characteristics of the adverse event including the grade (severity), the relationship 
to the study therapy (attribution), and the prior experience (expectedness) of the 
adverse event; 
3) 
the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization or prolongation 
of hospitalization was associated with the event. 
 
Steps to determine if an adverse event is to be reported in an expedited manner: 
Step 1: Identify the type of event using the NCI Common Toxicity Criteria (CTC). 
The CTC provides descriptive terminology and a grading scale for each adverse event listed. A copy 
of the CTC can be downloaded from the CTEP home page (http://ctep.cancer.gov). Additionally, if 
assistance is needed, the NCl has an Index to the CTC that provides help for classifying and locating 
terms. All appropriate treatment locations should have access to a copy of the CTC. 
 
Step 2: Grade the event using the NCI CTC. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy (investigational or 
commercial). 
 
Attribution categories are as follows: Unrelated, Unlikely, Possible, Probable, and Definite. 
 
13.2 
Reporting Methods 
 
All serious, unusual life-threatening or lethal adverse which may be study related will be reported 
within 24 hours. For all fatal events (Grade 5) while on study or within 30 days of treatment, the IRB 
must be notified within 24 hours of site notification. 
 
13.3 
IRB Reporting 
 
13.2.1  Report of AEs and SAEs must be reported according to IRB policy and procedures. 

20 
 
13.3 
Follow-up Reporting 
 
For all SAEs, the investigator is obligated to pursue and provide follow-up reporting information until 
the event has resolved to < grade 3 or until an acceptable medical endpoint, per treating physician, 
has been reached or the patient is lost to follow-up. 
 
14.0 
CRITERIA FOR DISCONTINUATION OF THERAPY 
 
The patient may elect to withdrawal from this protocol at any time prior to SABR. During SABR the 
patient will be maintained under audio and video observation and so can indicate discontinuation at 
any time during treatment. 
 
Patients who are enrolled on the study but not treated will be excluded from the analysis. 
15.0 
DATA REPORTING 
 
Data will be submitted according to the protocol requirements for ALL patients treated with SABR. 
Patients for whom documentation is inadequate to determine eligibility will generally be deemed 
ineligible. 
 
16.0 
STATISTICAL CONSIDERATIONS 
 
Under the assumption that the true pCR rate following pre-operative SABR is 25%, compared with 
the null hypothesis that pCR is 10%, a two stage design with total 40 subjects will give us 80% power 
at 5% 1- sided significance level. In particular, the study will enroll 22 patients in the first stage, and if 
2 or less subjects achieve pCR, the study will be terminated for futility; and, if 3 or more patients 
achieve pCR, then additional 18 patients will be enrolled for a total 40 patients. The null hypothesis 
will be rejected if 8 or more patients achieve pCR out of the 40 total subjects enrolled in the study. 
 
Descriptive statistics will be summarized for patient demographics and patient characteristics, which 
include patient age, tumor grade, tumor size, tumor histology, timing after surgery, minor variations 
on target coverage or not, lymphatic-vascular space invasion, presence of ductal carcinoma in situ, 
and ASTRO consensus risk group. Fisher’s exact test will be performed to examine the association 
between pCR and each of the patient characteristics, as well as the association between surgical 
margins and the patient characteristics. Multivariate logistic regression and linear regression will be 
conducted to explore the association between pCR and surgical margins with these patient 
characteristics. 
 
17.0 
Interim monitoring 
 
The Research Team will continuously monitor study accruals, toxicities and clinical outcome. The 
Moffitt Cancer Center Data and Safety Monitoring Committee (DSMC) will meet on a monthly basis 
and will continually assess for subject safety and recommend changes to protocol and study as 
required to preserve subject safety and to prevent any untoward toxicity. DSMC oversight of the 

21 
 
conduct of this trial includes ongoing review of adverse event data and periodic review of trial 
outcomes. 
 
18.0 
Reporting Exclusions 
 
N/A 
 
19.1 
Investigator Responsibilities 
 
The investigator will ensure that this study is conducted in accordance with all regulations governing 
the protection of human subjects and Good Clinical Practices (GCP) guidelines. The investigator will 
ensure that all work and services described in or associated with this protocol will be conducted in 
accordance with the investigational plan, applicable regulations, and the highest standards of 
medical and clinical research practice. 
19.2 
Confidentiality/Monitoring 
 
The investigator must ensure that each subject’s anonymity will be maintained and each subject’s 
identity will be protected from unauthorized parties. A number will be assigned to each subject  
upon study enrollment and the number and the subject’s initials will be used to identify the subject 
for the duration of the study. The investigator will maintain all documents related to this study in 
strict confidence. All electronic documents will be kept under password protection known only to the 
principal investigator. 
 
The PI of this study is ultimately responsible for every aspect of the design, conduct and actions of all 
members of the research team. This includes the final analysis of the protocol. 
 
The PI will ensure that the monitoring plan is followed, that all data required for oversight of 
monitoring are accurately reported to the DSMC and/or to the Protocol Monitoring Committee 
(PMC) and IRB as required, that all adverse events are reported according to protocol guidelines, and 
that any adverse actions reflecting patient safety concerns are appropriately reported. 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. Regulatory documents and case 
report forms will be monitored internally according to Moffitt Cancer Center Monitoring Policies. 
Internal monitoring will be performed regularly to verify data is accurate, complete, and verifiable 
from source documents; and the conduct of the trial is in compliance with the currently approved 
protocol/amendments, Good Clinical Practice (GCP), and applicable regulatory requirements. 
The PMC monitors provide monthly review for: adverse event reporting, data and safety 
monitoring, and internal audit findings. The PMC upon review of any agenda item may approve the 
study for continuation, require revisions, suspend or close a protocol. 
 
Investigators of studies shall provide a statistical report of the study’s progress and summary of 
adverse events and deviations based on the phase of the study and the associated risk of the study 
or more often if applicable. 

22 
 
The DSMC will meet on a monthly basis and will continually assess for subject safety and recommend 
changes to protocol and study as required to preserve subject safety and to prevent any untoward 
toxicity. 
 
19.3 
Informed Consent and Permission to Use Protected Health Information 
 
It is the responsibility of the investigator or designee to obtain written informed consent from each 
subject participating in this study after adequate explanation, in lay language, of the methods, 
objectives, anticipated benefits, and potential hazards of the study. The investigator or designee 
must also explain that the subject is completely free to refuse to enter the study or to discontinue 
participation at any time (for any reason) and receive alternative conventional therapy as indicated. 
Prior to study participation, each subject will sign an IRB approved informed consent form and 
receive a copy of same. 
 
The investigator or designee must explain to the subject before enrollment into the study that for 
evaluation of study results, the subject’s protected health information obtained during the study 
may be shared with the study sponsor, regulatory agencies, and the IRB. 
 
19.4 
Source Documentation and Investigator Files 
 
The research team will maintain adequate and accurate records to fully document the conduct of the 
study and to ensure that study data can be subsequently verified. Subject clinical source documents 
will corroborate data collected on any CRF’s. Subject clinical source documents would include 
hospital/clinic patient records; physician's and nurse's notes; original laboratory, radiology, 
pathology, and signed informed consent forms. 
 
At a minimum the following source documents will be collected: 
• Medical history/physical condition and diagnosis of the subject before involvement in 
the study sufficient to verify protocol randomization criteria. 
• Study number, assigned subject number, and verification that written informed consent 
were obtained (each recorded in dated and signed notes on the day of randomization 
into the study). 
• Progress notes for each subject visit, including treatment toxicity. 
• Documentation of treatment. 
• Adverse events (action taken and resolution). 
• Condition and response of subject upon completion of or early termination from the 
study. 
• Radiation treatment Dose Volume Histograms. 
 
19.5 
Non-Protocol Research 
No investigative procedures other than those described in this protocol will be undertaken on the 
enrolled subjects without the agreement of the IRB. 

23 
 
19.6 
Ethics 
 
The investigator agrees to conduct the study in compliance with the protocol, current good clinical 
practices, and all applicable (local, FDA, local ethics committee) regulatory guidelines and  
standard of ethics. 

24 
 
20.1 References 
 
1. 
McCahill, L.E., et al., Variability in reexcision following breast conservation surgery. JAMA, 2012. 
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2. 
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breast  hypofractionated radiotherapy. Semin Radiat Oncol, 2011. 21(1): p. 55-65. 
 
3. 
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4. 
Fisher, B., et al., Twenty-year follow-up of a randomized trial comparing total 
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5. 
Veronesi, U., et al., Radiotherapy after breast-conserving surgery in small breast carcinoma: 
long- term results of a randomized trial. Ann Oncol, 2001. 12(7): p. 997-1003. 
 
6. 
Clark, R.M., et al., Randomized clinical trial of breast irradiation following lumpectomy and 
axillary dissection for node-negative breast cancer: an update. Ontario Clinical Oncology Group. J 
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7. 
Holli, K., et al., Lumpectomy with or without postoperative radiotherapy for breast cancer with 
favourable prognostic features: results of a randomized study. Br J Cancer, 2001. 84(2): p. 164-9. 
8. 
Liljegren,  G.,  et  al.,  10-Year  results  after  sector  resection  with  or  without 
postoperative  radiotherapy for stage I breast cancer: a randomized trial. J Clin Oncol, 1999. 17(8): 
p. 2326-33. 
 
9. Shah, C., et al., Twelve-year clinical outcomes and patterns of failure with accelerated partial 
breast irradiation versus whole-breast irradiation: results of a matched-pair analysis. Radiother 
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10. Clark, R.M., et al., Breast cancer: a 21 year experience with conservative surgery and radiation. 
Int J Radiat Oncol Biol Phys, 1982. 8(6): p. 967-79. 
 
11. Schnitt, S.J., et al., Pathologic predictors of early local recurrence in Stage I and II breast cancer 
treated by primary radiation therapy. Cancer, 1984. 53(5): p. 1049-57. 
 
12. Boyages, J., et al., Early breast cancer: predictors of breast recurrence for patients treated with 
conservative surgery and radiation therapy. Radiother Oncol, 1990. 19(1): p. 29-41. 
 
13. Kurtz, J.M., et al., Conservation therapy for breast cancers other than infiltrating ductal 
carcinoma. Cancer, 1989. 63(8): p. 1630-5. 

25 
 
14. Fisher, E.R., et al., Ipsilateral breast tumor recurrence and survival following lumpectomy and 
irradiation: pathological findings from NSABP protocol B-06. Semin Surg Oncol, 1992. 8(3): p. 161- 
6. 
 
15. Clark, R.M., et al., Randomized clinical trial to assess the effectiveness of breast irradiation 
following lumpectomy and axillary dissection for node-negative breast cancer. J Natl Cancer Inst, 
1992. 84(9): p. 683-9. 
 
16. Veronesi, U., et al., Radiotherapy after breast-preserving surgery in women with localized 
cancer of the breast. N Engl J Med, 1993. 328(22): p. 1587-91. 
 
17. Vaidya, J.S., et al., Targeted intraoperative radiotherapy versus whole breast radiotherapy 
for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority 
phase 3 trial. Lancet, 2010. 376(9735): p. 91-102. 
 
18. Tang, J.I., et al., Multi-catheter interstitial accelerated partial breast irradiation - tips and 
tricks for a good insertion. J Contemp Brachytherapy, 2014. 6(1): p. 85-90. 
 
19. Haynes, A.B., et al., Timing of infectious complications following breast-conserving 
therapy with catheter-based accelerated partial breast irradiation. Ann Surg Oncol, 2014. 
21(8): p. 2512-6. 
 
20. Rosenkranz, K.M., et al., Increased rates of long-term complications after MammoSite 
brachytherapy compared with whole breast radiation therapy. J Am Coll Surg, 2013. 
217(3): p. 497-502. 
 
21. Smith, G.L., et al., Association between treatment with brachytherapy vs whole-breast 
irradiation and subsequent mastectomy, complications, and survival among older women 
with invasive breast cancer. JAMA, 2012. 307(17): p. 1827-37. 
 
22. Hepel, J.T., et al., Toxicity of three-dimensional conformal radiotherapy for accelerated 
partial breast irradiation. Int J Radiat Oncol Biol Phys, 2009. 75(5): p. 1290-6. 
 
23. Jagsi, R., et al., Unacceptable cosmesis in a protocol investigating intensity-modulated 
radiotherapy with active breathing control for accelerated partial-breast irradiation. Int J 
Radiat Oncol Biol Phys, 2010. 76(1): p. 71-8. 
24. van Mourik, A.M., et al., Multiinstitutional study on target volume delineation variation in 
breast radiotherapy in the presence of guidelines. Radiother Oncol, 2010. 94(3): p. 286-91. 
 
25. Petersen, R.P., et al., Target volume delineation for partial breast radiotherapy planning: 
clinical characteristics associated with low interobserver concordance. Int J Radiat Oncol 
Biol Phys, 2007. 69(1): p. 41-8. 
 
26. Landis, D.M., et al., Variability among breast radiation oncologists in delineation of the 
postsurgical lumpectomy cavity. Int J Radiat Oncol Biol Phys, 2007. 67(5): p. 1299-308. 

26 
 
 
27. Palta, M., et al., Preoperative single fraction partial breast radiotherapy for early-stage 
breast cancer. Int J Radiat Oncol Biol Phys, 2012. 82(1): p. 37-42. 
 
28. Blitzblau, R.C., et al., A phase 1 trial of preoperative partial breast radiation therapy: 
Patient selection, target delineation, and dose delivery. Pract Radiat Oncol, 2015. 
 
29. Francois, Y., et al., Influence of the interval between preoperative radiation therapy and 
surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the 
Lyon R90-01 randomized trial. J Clin Oncol, 1999. 17(8): p. 2396. 
 
30. Bondiau, P.Y., et al., Phase 1 clinical trial of stereotactic body radiation therapy 
concomitant with neoadjuvant chemotherapy for breast cancer. Int J Radiat Oncol Biol 
Phys, 2013. 85(5): p. 1193-9. 
 
31. Formenti, S.C., et al., Prone accelerated partial breast irradiation after breast-conserving 
surgery: five-year results of 100 patients. Int J Radiat Oncol Biol Phys, 2012. 84(3): 
p. 606-11. 
 
32. Dewan, M.Z., et al., Fractionated but not single-dose radiotherapy induces an immune- 
mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res, 2009. 
15(17): p. 5379-88. 
 
33. Schaue, D., et al., Maximizing tumor immunity with fractionated radiation. Int J Radiat 
Oncol Biol Phys, 2012. 83(4): p. 1306-10. 
 
34. Nichols, E.M., et al., Preoperative radiation therapy significantly increases patient eligibility 
for accelerated partial breast irradiation using 3D-conformal radiotherapy. Am J Clin Oncol, 
2013. 36(3): p. 232-8. 
 
35. van der Leij, F., et al., Target volume delineation in external beam partial breast irradiation: 
less inter-observer variation with preoperative- compared to postoperative delineation. 
Radiother Oncol, 2014. 110(3): p. 467-70. 
 
36. Kim, L. and S. Shaitelman, What is the target volume for preoperative accelerated partial 
breast irradiation (APBI)? In regards to Nichols et al. (Int J Radiat Oncol Biol Phys 2010;77:197-202) 
and Palta et al. (Int J Radiat Oncol Biol Phys 2010, in Press). Int J Radiat Oncol Biol Phys, 2011. 
80(1): p. 314-5; author reply 315-6. 
37. Mikeljevic, J.S., et al., Trends in postoperative radiotherapy delay and the effect on survival in 
breast cancer patients treated with conservation surgery. Br J Cancer, 2004. 90(7): p. 1343-8. 
 
38. Houssami, N., et al., The association of surgical margins and local recurrence in women with 
early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann 
Surg Oncol, 2014. 21(3): p. 717-30. 

27 
 
 
39. Wazer, D.E., et al., Factors determining outcome for breast-conserving irradiation with 
margin- directed dose escalation to the tumor bed. Int J Radiat Oncol Biol Phys, 1998. 40(4): p. 
851-8. 
 
40. Mansfield, C.M., et al., Ten-year results in 1070 patients with stages I and II breast cancer 
treated by conservative surgery and radiation therapy. Cancer, 1995. 75(9): p. 2328-36. 
 
41. Morrow, M., et al., Surgeon recommendations and receipt of mastectomy for treatment of 
breast cancer. JAMA, 2009. 302(14): p. 1551-6. 
 
42. King, T.A., et al., Clinical management factors contribute to the decision for contralateral 
prophylactic mastectomy. J Clin Oncol, 2011. 29(16): p. 2158-64. 
 
43. Heil, J., et al., Do reexcisions impair aesthetic outcome in breast conservation surgery? 
Exploratory analysis of a prospective cohort study. Ann Surg Oncol, 2012. 19(2): p. 541-7. 
 
44. Stroom, J., et al., Using histopathology breast cancer data to reduce clinical target volume 
margins at radiotherapy. Int J Radiat Oncol Biol Phys, 2009. 74(3): p. 898-905. 
 
45. Bartelink, H., C. Bourgier, and P. Elkhuizen, Has partial breast irradiation by IORT or 
brachytherapy been prematurely introduced into the clinic? Radiother Oncol, 2012. 104(2): p. 
139-42. 
 
46. Greenup, R.A., et al., Cost implications of the SSO-ASTRO consensus guideline on margins for 
breast-conserving surgery with whole breast irradiation in stage I and II invasive breast cancer. 
Ann Surg Oncol, 2014. 21(5): p. 1512-4. 
 
47. Yang, T.J., et al., Outcomes and prognostic factors in women with 1 to 3 breast cancer brain 
metastases treated with definitive stereotactic radiosurgery. Int J Radiat Oncol Biol Phys, 2014. 
90(3): p. 518-25. 
 
48. Smith, T.R., et al., Survival after surgery and stereotactic radiosurgery for patients with 
multiple intracranial metastases: results of a single-center retrospective study. J Neurosurg, 2014. 
121(4): p. 839-45. 
 
49. Matsunaga, S., et al., Gamma Knife surgery for metastatic brain tumors from primary breast 
cancer: treatment indication based on number of tumors and breast cancer phenotype. J 
Neurosurg, 2010. 113 Suppl: p. 65-72. 
 
50. Varlotto, J.M., et al., Analysis of tumor control and toxicity in patients who have survived at 
least one year after radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys, 2003. 57(2): p. 
452- 64. 

28 
 
51. Gerszten, P.C., et al., Single-fraction radiosurgery for the treatment of spinal breast 
metastases. Cancer, 2005. 104(10): p. 2244-54. 
 
52. Formenti, S.C., et al., Phase I-II trial of prone accelerated intensity modulated radiation 
therapy to the breast to optimally spare normal tissue. J Clin Oncol, 2007. 25(16): p. 2236-42. 
 
53. Morrow, N.V., et al., Intra- and interfractional variations for prone breast irradiation: an 
indication for image-guided radiotherapy. Int J Radiat Oncol Biol Phys, 2007. 69(3): p. 910-7. 
 
54. Lakosi, F., et al., Respiratory Motion, Anterior Heart Displacement and Heart Dosimetry: 
Comparison Between Prone (Pr) and Supine (Su) Whole Breast Irradiation. Pathol Oncol Res, 2015. 

29 
 
APPENDIX I STUDY CALENDAR 
 
Baseline Evaluation 
Prior to 
SABR 
Day of 
SABR 
4-5 
weeks 
post 
SABR 
5-6 
weeks 
post 
SABR 
6-8 
weeks 
post 
SABR 
Medical 
History 1 
X¹ 
X¹ 
X¹ 
Physical Exam 1 
X¹ 
X¹ 
X¹ 
ECOG 1 
X¹ 
X¹ 
X¹ 
Diagnostic core 
biopsy 2 
X 
Post biopsy 
breast MRI 3 
X 
X 
Record 
Adverse Events 
4 
 
X 
X 
Urine 
pregnancy test 
(menstruating 
women only) 
X 5 
X 5 
CT Simulation 
X 6 
Tumor Excision 
and submission 
for 
pathological 
evaluation 
X 7 
 
(1)+/- 28 day window 
(2) Moffitt facility preferred. Non-Moffitt pathology must be over-read by Moffitt breast pathologist. 
During the biopsy procedure, a marker clip will be placed indicating location of biopsied tumor. 
Placement and location of marker clip will be confirmed on post-biopsy MRI that follows. 
(3) Moffitt facility preferred. Non-Moffitt diagnostic MRI must be over-read by breast radiologist. 
This MRI occurs following biopsy and placement of marker clip. 
(4) NCI CTCAE v4 
(5) Urine pregnancy test will be performed in all females of childbearing potential prior to any 
radiation exposure for purpose of this protocol. The results of urine pregnancy test will remain valid 
for seven days. 
(6) CT simulation will be performed no less than 1 week following any invasive procedure to the 
target breast (ie biopsy) in order to allow procedure related edema to settle. 
(7) Patient will undergo breast conserving tumor excision by Moffitt breast surgeon 6-8 weeks 
following SABR. Specimen will be delivered for pathologic evaluation as per standard practice. 

30 
 
APPENDIX II 
 
NATIONAL CANCER INSTITUTE (NCI) COMMON TOXICITY CRITERIA (CTC) 
The NCI CTCAE criteria v4 may be viewed on-line at the following NCI web site:  
http://ctep.cancer.gov/reporting/ctc.html 

31 
 
 
APPENDIX Ill 
PERFORMANCE SCALES 
ECOG SCALE 
0 
Fully active, able to carry on all pre-disease activities without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry work of 
a light or sedentary nature. For example, light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair 50% or more of waking 
hours 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed 
5 
Death