A Pilot Study of Four-Dimensional Conformal Image Guided Accelerated Partial Breast Irradiation In The Treatment Of Stage 0 and l Breast Cancer
Phase: NA
Conditions: Breast Cancer
Sponsor: Yale University

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
 
 
 
A Pilot Study of 
Four-Dimensional Conformal IMAGE GUIDED Accelerated Partial Breast Irradiation 
IN THE TREATMENT OF 
STAGE 0 and I BREAST CARCINOMA 
 
 
 
 
 
 
 
 
 
 
  
Principal Investigator 
 
Suzanne Evans, M.D., M.P.H. 
 
 
          Radiation Therapy  
 
Susan Higgins, M.D. 
Lynn Wilson, M.D., M.P.H. 
. 
         Surgery 
 
 
 
Don Lannin, M.D. 
 
 
 
 
 
 
Nina Horowitz, M.D. 
Anees Chagpar, M.D. MSc, MA, MPH,  
FRCS(C), FACS 
 
 
 
 
 
 
Brigid Killelea, M.D. 
 
 
         Physics 
 
 
 
Jay Chen, Ph.D. 
John Kim, C.M.D. 
 
 
Statistics 
 
 
 
Daniel Zelterman, Ph.D. 
 
 
Clinical Research Nurse 
 
Jeannie Kluytenaar, R.N., B.S.N. 
 
 
Clinical Research Assistant 
Kira Pavlik 
 
 
 
Version  
 
 
 
9 
 
Version Date  
 
 
September 5, 2014  
 
 
 
 
 
 
 
 
 
 
 
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Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
 
 
A Pilot Study OF 
Four-Dimensional Conformal IMAGE GUIDED Accelerated Partial Breast Irradiation 
IN THE TREATMENT OF 
STAGE 0 and I BREAST CARCINOMA 
SCHEMA 
 
 
 
 
 
 
 
 
 
Enrollment into Study 
 
 
 
 
 
 
     
 
 
4D treatment planning CT scan 
Generation of Four-Dimensional Conformal Partial Breast Plan 
Treatment with 4DCRT to 38.5 Gy in 3.85 Gy fractions delivered BID with daily image 
guidance and a minimum six hours between fractions 
 
 
 
 
 
 
      
 
 
 
Follow up evaluation of side effects and cosmesis ongoing for three years from 
completion of treatment 
 
 
Chemotherapy or Hormonal Therapy 
 
Chemotherapy or Hormonal Therapy may be given at the discretion of the treating 
physician, but cytotoxic chemotherapy is not to be started until at least 2 weeks post 
radiation. Hormonal therapy can be started at once. 
 
 
 
 
 
 
 
 
 
Patients with Stage 0, or I Breast Cancer Resected by Lumpectomy 
Tumor Size < 2.0 cm 
No Histologically Positive Nodes 
Cavity and cavity to breast ratio suitable to 4D CRTAPBI 
 
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Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
ELIGIBILITY:  
 
-Stage 0 or I breast cancer; if stage I tumor must be < 2cm and node negative (E.G. T0 
tumors not allowed)  
-The tumor can be histologically DCIS (also held to <2cm in size), or invasive ductal or 
lobular carcinoma of the breast.  In patients with both invasive and in situ carcinoma, 
they should be <2cm individually, but may be more than 2cm in aggregate  (i.e. a 
patient with a 1.5 cm infiltrating ductal carcinoma in a background of 1 cm of dcis would 
be eligible). 
-Patients with invasive cancer must have axillary staging by a) SNB alone (if SN is 
negative).  
-Unifocal breast cancer (single focus which can be encompassed by one lumpectomy). 
-Negative surgical margins greater than or equal to  2mm  
-No collagen vascular disease  
-No known unresected residual carcinoma; no suspicious microcalcifications. 
-No prior malignancy (≤ 2 years prior to enrollment in study) except nonmelanoma skin 
cancer, in situ melanomatic skin cancer, or CIS of the cervix or colon.   
-Negative pregnancy test for women of childbearing age. 
-Time interval from last breast surgical procedure to simulation is ≤ 8 weeks. 
-Signed study-specific consent form. 
-Patients who have undergone any oncoplastic resection involving significant 
manipulation of the tumor bed are not eligible. 
-Patient must have a well-defined seroma cavity (see Appendix VIII) with Cavity 
visualization score (CVS) of ≥3 or at least 4 surgical clips geometrically defining the 
cavity in order to be eligible.  NOTE: surgical clips are to be used to delineate the cavity 
as a primary function, whereas the gold fiducial markers can be used for cavity 
demarcation and also for daily set up with kilovoltage imaging. 
-Patient must not have received radiation to the same breast or in the thorax overlapping 
the treatment field.   
-Patients must be 50 years of age or older.  
-Patients must not have had neoadjuvant chemotherapy or hormonal therapy prior to 
surgery. 
-Patients must not have a post-operative seroma which, in the opinion of the treating 
radiation oncologist, is changing volume in a dynamic fashion as this will prevent 
accurate targeting. 
-Patients who are tested BRCA1/2 positive are ineligible due to the association with 
multifocality. 
 
 
 
 
 
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APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
 
INDEX 
 
Schema 
2 
 
1.0  Background 
6 
 
2.0  Study Aims 
 
 
 
 
 
 
 
 
13 
 
3.0  Endpoints 
 
 
 
 
 
 
 
 
14 
 
4.0  Eligibility Criteria  
 
 
 
 
 
 
 
15 
 
5.0  Pretreatment Evaluations  
 
 
 
 
 
 
16 
 
6.0 Four-Dimensional Conformal Accelerated Partial Breast Radiation  
18 
 
7.0 Quality Assurance of Dose Distribution 
 
 
 
 
22 
 
8.0 Assessment of Toxicity, Cosmesis Breast Pain, and Satisfaction 
22 
 
9.0 Surgery  
 
 
 
 
 
 
 
 
23 
 
10.0 Other Therapies 
 
 
 
 
 
 
 
24 
 
11.0 Pathology 
 
 
 
 
 
 
 
 
24 
 
12.0 Pre and Post Enrollment Patient Calendar  
 
 
 
25 
 
13.0 Statistical Considerations 
 
 
 
 
 
 
27 
 
14.0 Expected Side Effects and Adverse Events 
 
 
 
27 
 
15.0 Adverse Events Reporting, Safety Monitoring, and Compliance 
28 
 
16.0 Patient Termination 
 
 
 
 
 
 
 
31 
 
17.0 References 
 
 
 
 
 
 
 
 
33 
 
Appendix I 
 Karnofsky Performance Status   
 
 
 
38 
Appendix II  Staging System  
 
 
 
 
 
 
39 
Appendix III  RTOG Acute Toxicity Criteria 
 
 
 
 
42 
Appendix IV  RTOG/EORTC Late Toxicity Criteria 
 
 
 
47 
Appendix V  Harvard Criteria for Cosmesis 
 
 
 
 
51 
Appendix VI  Self Assessment Breast Cancer Treatment Outcomes Scale 52 
Appendix VII Cavity Visualization Score  
 
 
 
 
53 
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Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
Appendix VIII Contouring guidelines 
 
 
 
 
 
56 
Appendix IX  Radiation Quality Assurance 
 
 
 
 
60 
Appendix X  Radiation Dosimetry Worksheet  
 
 
 
61
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Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 and patient satisfaction with radiation treatment has been added to the 
protocol. 
 
2.0 
STUDY AIMS 
 
A.   
Primary Aim 
 
The purpose of this study is to evaluate the feasibility of using image guidance 
and four-dimensional computed tomography to reduce the volume of non target 
breast tissue that is treated with accelerated partial breast irradiation via the 
external beam technique.   
 
This is a pilot study to evaluate the feasibility of using 4DCT and daily image guidance 
in APBI to decrease set up error and individualize planning target volumes to limit the 
non-target breast tissue dose. The two specific breast constraints which shall be 
decreased are the V50 (percent volume of breast receiving 50% of the prescribed dose) 
and the V100 (percent volume of breast receiving 100% of the prescribed dose).  The 
goal will be to decrease these to 45% and 23.5%, respectively, which is down 33% from 
the NSABP B39 standard of 60% and 35%.  These are similar to the constraints which 
will be suggested by Dr. Jaroslaw Hepel (V50<40%, V100 <20%, to be presented at 
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Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
ASTRO 2011, Miami Beach, oral presentation-- via personal communication).  Patients 
in his series that followed these constraints have no grade 3 or higher subcutaneous 
toxicity. 
 
This study will be considered a success if >50% of patients enrolled are able to meet 
the dosimetric constraints on the breast (V50 <45% and V100 <23.5%).  If this occurs, a 
phase II study approval will be sought. 
 
 
 
B.   
Secondary Aims 
 
To track MD rated cosmesis and toxicity and patient rated cosmesis over time, with an 
expectation that less than 15% of patients starting at a good or excellent baseline will 
deteriorate to a poor cosmetic outcome. Individual dosimetric parameters will be 
correlated with cosmetic outcomes and any other toxicity outcome. 
 
To track patient reported breast pain and patient satisfaction with the radiation treatment 
delivered. 
 
3.0 ENDPOINTS 
 
A.   
To achieve more rigid dose constraints on normal non-target breast tissue  
by using 4D CT and daily image guidance. 
 
B.   
Measure subcutaneous fibrosis toxicity, cosmesis, breast pain, and patient 
satisfaction the first 3 years following treatment with 4D conformal accelerated partial 
breast radiation with more rigid dose constraints. 
 
C.   
Collection of information of treatment parameters in order to define parameters 
most predictive of cosmesis, skin, subcutaneous, breast pain, or other toxicity. 
 
D.   
Duration of Study:  Until accrual and treatment of 60 patients is complete with 
three years follow-up after treatment completion, which is expected to take 4 to 7 years.  
 
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HIC 1110009173 
 
4.0   ELIGIBILITY CRITERIA 
 
4.1   Inclusion Criteria 
 
Women who satisfy all of the following conditions are the only patients who will be 
eligible for this study.   
 
1. The patient must consent to be in the study and must have a signed an approved 
consent form conforming with institutional guidelines.   
 
2. Patient must be > 50 years old. 
 
3. The patient should have a life expectancy of at least two years with a karnofsky 
performance status >70.  
 
4. The patient must have stage 0 or I breast cancer.   
 
5. On histological examination, the tumor must be DCIS or invasive adenocarcinoma of 
the breast. 
 
6. Surgical treatment of the breast must have been lumpectomy. The margins of the 
resected specimen must be histologically free of tumor (>2mm, DCIS and invasive). 
Re-excision of surgical margins is permitted.  
 
7. Gross disease must be unifocal with pathologic (invasive and/or DCIS) tumor size 2 
cm or less. (Patients with microscopic multifocality are eligible as long as total 
pathologic tumor size is 2 cm or less.)  Patients with both DCIS and invasive cancer 
may have more than 2 cm of disease in aggregate, provided they are both 
individually < 2cm. 
 
8. Patients with invasive breast cancer are required to have axillary staging which can 
include sentinel node biopsy alone (if negative), sentinel node biopsy followed by 
axillary dissection or sampling with a minimum total of 6 axillary nodes or axillary 
dissection alone (with a minimum of 6 axillary nodes). Axillary staging is NOT 
required for patients with DCIS. 
 
9. The patient must have simulation within 8 weeks/56 days of the final surgery for their 
breast cancer (lumpectomy, re-excision of margins, or axillary staging procedure).  
 
10. Patients with a history of non-ipsilateral breast malignancies are eligible if they have 
been disease-free for 2 or more years prior to enrollment. Patients with the following 
cancers are eligible even if diagnosed and treated within the past 2 years: carcinoma 
in situ of the cervix, colon, melanoma in situ, and basal cell and squamous cell 
carcinoma of the skin.   
 
11. Chemotherapy is permitted if planned for ≥ 2 weeks after radiation. 
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HIC 1110009173 
 
 
12. Urine pregnancy test must be performed and be negative on all women younger 
than 60 who have not had a tubal ligation, oophorectomy, or hysterectomy. 
 
13. Separate incisions for the lumpectomy and sentinel node biopsy should be present. 
Use of only one incision will typically result in a contiguous cavity with the tumor bed 
and the sentinel node sampling, and inability of the radiation oncologist to delineate 
the tumor bed from the sentinel node bed. 
 
14. The patient must have a cavity which is able to be targeted with external beam 
APBI, either through surgical clip placement, or CVS 3 or higher.  The cavity to 
whole breast ratio must be 30% or less. 
 
15. Eligible patients have not received prior thoracic radiation. 
 
16. Eligible patients have not received pre-operative hormonal or chemotherapy. 
 
4.2  
Exclusion Criteria 
 
1. Men are not eligible for this study as men are not breast conservation candidates. 
 
2. T0, T2 (>2.0 cm), T3, node positive, stage III or IV breast cancer. 
 
3. Any positive axillary nodes. 
 
4. Palpable or radiographically suspicious ipsilateral or contralateral axillary, 
supraclavicular, infraclavicular or internal mammary nodes, unless biopsy proven to 
be negative for tumor. 
 
5. Suspicious microcalcifications, densities or palpable abnormalities in either breast 
unless biopsy proven to be benign.   
 
6. Non-epithelial breast malignancies such as sarcoma or lymphoma. 
 
7. Proven multicentric carcinoma in more than one quadrant or separated by more than 
2 centimeters. 
 
8. Paget’s disease of the nipple. 
 
9. History of invasive breast cancer or DCIS in the same breast. 
 
10. Surgical margins that cannot be microscopically assessed or are less than 2 mm. 
 
11. Collagen vascular disease, specifically dermatomyositis with a CPK level above 
normal or with an active skin rash, systemic lupus erythematosis or scleroderma. 
 
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HIC 1110009173 
 
12. Pregnancy or lactation at the time of proposed radiation.  Women of reproductive 
potential must agree to use an effective non-hormonal method of contraception 
during therapy.   
 
13. Psychiatric or addictive disorders or other conditions that, in the opinion of the 
treating physician, would preclude the patient from meeting the study requirements.   
 
14. Patients with coexisting medical conditions in whom life expectancy is < 2 years. 
 
15. Patients with skin involvement, regardless of tumor size.   
 
16. Patients with a prior diagnosis of ipsilateral breast cancer are ineligible. 
 
17. Patients who are tested BRCA1/2 positive are ineligible due to the association with 
multifocality. 
 
5.0   PRETREATMENT EVALUATIONS 
 
1. History including family history of breast carcinoma and method of detection of the 
breast tumor (clinical, mammographic, or both). 
 
2. Physical examination with the location and palpable size of the tumor in cm. 
 
3. Mammogram of both breasts. 
 
4. CBC, platelets, alkaline phosphatase, SGOT, serum calcium within the past 6 
months. 
 
5. Bone scan if the alkaline phosphatase is elevated 1.5 times the upper limit of normal 
(ULN) and/or the patient complains of bone pain or has other symptoms possibly 
associated with skeletal metastasis. 
 
6. Evaluation of liver by CT if the liver function blood tests are elevated 1.5 times  
the ULN. 
 
7. Chest X ray if new or concerning pulmonary symptoms are present. 
 
8. An excision cavity amenable for 4D CRT PBI, defined as a CVS greater than or 
equal to 3 OR the presence of 4 or more surgical clips marking the cavity.  At the 
discretion of the treating physician, a pre-enrollment CT scan may be taken to 
determine the ability to visualize the cavity, as well as to calculate the cavity to whole 
breast ratio (≤30%).  This may be omitted in patients with surgical clip placement 
documented in the operative note or through personal communication with the 
surgeon, or in women who clinically have ample breast tissue. 
 
9. 4 dimensional CT scan for treatment planning.  
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6.0   4D CONFORMAL EXTERNAL BEAM PBI 
 
Please note: 
• Boosts are not permitted with delivery of PBI. 
• Electrons are not allowed. 
 
A.   
4D-CRT Treatment Planning 
 
The pre-enrollment CT data set (used to determine cavity visualization score for 
protocol eligibility, IF PERFORMED) cannot be used for 4D-CRT treatment 
planning.  A separate 4D CT scan is to be obtained. Treatment will be delivered only to 
the planning target volume (PTV) using 3-dimensional conformal fields. Field within a 
field technique to improve dosimetric coverage can be utilized; however, the use of 
dynamic multi-leaf collimator (MLC) to facilitate the delivery of intensity-modulated 
distributions derived from constraints-based computer optimization (i.e., inverse 
planning) is excluded. Field arrangements are at the discretion of the physician and will 
be determined by 4D-CRT treatment planning to produce the optimal conformal plan in 
accordance with volume definitions. The treatment plan used for each patient will be 
based on analysis of the volumetric dose including dose-volume histogram (DVH) 
analyses of the planning target volume for evaluation (PTV_EVAL) and critical normal 
tissues. Dose calculations with tissue inhomogeneity correction must be used. 
 
B.   
Imaging 
 
A treatment planning 4D CT scan with the patient in a supine position will be required. 
The CT should start at or above the mandible and extend several cm below the 
inframammary fold (including the entire lung). A CT scan thickness of ≤ 0.5 cm should 
be employed. Cases will only be acceptable if the following structures are contoured: 
excision cavity, clinical target volume (CTV), ITV, PTV, PTV_EVAL, skin, ipsilateral and 
contralateral breast reference volumes, thyroid, ipsilateral and contralateral lung, and 
heart. The chin, shoulders and contralateral breast should be included in the scan. The 
target structures and normal tissue structures must be outlined on all CT slices. The 
extent of normal tissue contouring is necessary with 4D-CRT to guide beam 
arrangement and normal tissue avoidance. 
 
C.   
Target Volumes 
 
The excision cavity will be outlined based either on clear visualization on CT (defined as 
a CVS greater than or equal to 3) or, if placed, with the help of surgical clips. If the 
excision cavity cannot be clearly delineated, the patient is not eligible for study 
participation. This  score will be determined by the treating physician at the time of 
simulation.  A four dimensional CT will be used to capture the excision cavity throughout 
its full respiratory excursion, and this volume will be called the internal target volume 
(ITV).  The clinical target volume (CTV) will be defined by uniformly expanding the ITV 
by 15 mm. However, the CTV will be limited to 5 mm from the skin surface and by the 
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HIC 1110009173 
 
posterior breast tissue extent (chest wall and pectoralis muscles are not to be included).  
The CTV should never be smaller than the ITV (“Boolean operator” CTV OR ITV may 
be necessary).   Questions about the CTV should be addressed to Dr. Suzanne Evans.  
Treatment set up variation will be all but eliminated with cone beam CT/kv imaging, and 
as such, only 2mm additional margin is placed upon the CTV to form the planning target 
volume (PTV).  The PTV is saved and is used to generate the beam aperture with an 
additional margin to take penumbra into account.  
 
****In patients with a very posterior or very anterior cavity, it might be possible that the 
CTV is shaved off the pectoralis or skin such that the ptv becomes very close (2mm) to 
the ITV.  In all cases, the PTV should be no closer to the ITV than 5mm.  In eclipse, this 
can be achieved by creating a structure of ITV + 5mm margin, and performing a 
Boolean operator to PTV (“itv + 5mm or PTV”).  The PTV should never be less than 
5mm from the ITV.***** 
 
Since a substantial part of the PTV often extends outside the patient (especially for 
superficial cavities), the PTV is then copied to a PTV_EVAL, which is edited. This 
PTV_EVAL is limited to exclude the part outside the ipsilateral breast and the first 5 mm 
of tissue under the skin (in order to remove most of the build up region for the DVH 
analysis) and excluding (if applicable) the PTV expansion beyond the posterior extent of 
breast tissue (chest wall, pectoralis muscles and lung). This PTV_EVAL is the structure 
used for DVH constraints and analysis. This PTV_EVAL CANNOT be used for beam 
aperture generation.  
 
D.   
Beam Angles/Treatment Position 
 
The radiation oncologist may choose whatever beam arrangement and number of 
beams they desire, as long as the necessary dose volume constraints mentioned below 
can be met. Typically, a 3, 4, or 5-field non-coplanar beam arrangement utilizing high-
energy photons can be used. No plan will be considered acceptable if any of the beams 
are directed towards critical normal structures: heart, lung, contralateral breast.  
Patients should be treated in the supine position in most cases, although prone 
positioning is allowed at the discretion of the treating physician with the assent of Dr. 
Suzanne Evans. Bolus to improve anterior target coverage should not be used. 
 
 
E.   
Design of Beam Arrangements 
 
Suggested beam arrangements include noncoplanar 3-, 4- and 5-field beam 
arrangements using 6-MV photons. These arrangements use fields that approximate 
breast tangents within a 10°-20° steeper gantry angle for the medial beams to 
maximally spare breast tissue and couch angles of 15°-70°. The beam arrangement is 
arrived at in a similar manner for both. First, the isocenter is placed in the center of the 
PTV. The procedure used to set up the 4-field technique, consisting of a left anterior 
superior-to-inferior oblique (Lt ASIO), left anterior inferior-to-superior oblique (Lt AISO), 
right anterior inferior-to-superior oblique (Rt AISO), and right posterior superior-to-
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inferior oblique (Rt PSIO) for a right breast lesion is described. First, 3 medial tangents 
(couch angle of 0° for 2 beams and 180° for 1 beam) and 1 lateral tangent (couch angle 
of 0°) are constructed. Typically, the medial tangents have a 10°-20° steeper gantry 
angle than whole breast tangents to spare more breast tissue. The lateral tangent may 
also have a slightly shallower gantry angle to spare breast tissue, provided that it does 
not exit through the contralateral breast. Next, couch angles are applied to each beam. 
Typical couch angles for the 3 anterior oblique fields are 35°-45° from a transverse 
plane. However, for the Rt AISO beam, particular care should be taken to ensure that 
the field exited superior to the heart. The couch angle used for the posterior oblique field 
is usually only 10°-20° to avoid entering through the ipsilateral arm, as well as collision 
problems with the gantry head and treatment couch. The 5-field technique is usually 
used for left-sided lesions and consists of Rt ASIO, Rt lateral, Rt AISO, Lt PSIO, and Lt 
PISO beams. The primary difference that makes this technique better suited for left-
sided lesions is the elimination of the Lt AISO beam that would exit through the heart. 
The tradeoff is a larger volume of normal breast tissue irradiated. Each field typically 
has a universal 60° wedge in place for part of the treatment time. The heel of the wedge 
was directed anteriorly for all fields. The field edge is 5 mm beyond the PTV to account 
for penumbra. (Baglan KL, Sharpe SB, Jaffray D, et al. Accelerated partial breast 
irradiation using 3D conformal radiation therapy [3D-CRT]. Int J Radiat Oncol Biol Phys. 
55:302-311, 2003.) 
 
F.   
Dose Prescription and Delivery 
 
• 4D-CRT will begin within 56 days of lumpectomy or re-excision of margins and within 6 
weeks of study entry. 
• A total of 38.5 Gy will be prescribed to the ICRU 50 reference point dose (usually 
isocenter). Two fractions per day, each of 3.85 Gy, separated by at least 6 hours, given 
on 5 treatment days (over a period of 5 to 10 days), will sum to 10 fractions and 38.5 
Gy. 
G.   
Dose Limitations for Normal Tissues 
 
• Uninvolved normal breast: Ideally, < 45% of the whole breast reference volume 
should receive ≥ 50% of the prescribed dose and < 23.5% of the whole breast reference 
volume should receive the prescribed dose.  However, a treatment plan will be 
considered acceptable if <60% of the whole breast reference volume receives ≥ 50% of 
the prescribed dose and <35% of the whole breast reference volume receives the 
prescribed dose (as done in in NSABP B39).   Plans which exceed these parameters 
(V50 >60% or V100 >35%) must be evaluated by Dr. Suzanne Evans prior to approval 
by the treating physician.  For these calculations, the whole breast reference volume is 
defined as per Appendix VIII.  
 
• Contralateral breast: The contralateral breast reference volume, contoured using the 
same methods described for the ipsilateral breast reference volume, should receive < 
3% of the prescribed dose to any point. 
 
• Ipsilateral lung: < 15% of the lung can receive 30% of the prescribed dose. 
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HIC 1110009173 
 
• Contralateral lung: < 15% of the lung can receive 5% of the prescribed dose. 
 
• Heart (right-sided lesions): < 5% of the heart should receive 5% of the prescribed 
dose. 
 
• Heart (left-sided lesions): The volume of the heart receiving 5% of the prescribed 
dose (V5) should be less than 40%. 
 
Thyroid: maximum point dose of 3% of the prescribed dose. 
 
H.   
Treatment Verification 
 
Imaging dose for cone beam CT and kv imaging will be measured for the first 5 
patients, and reported to the clinical PI. 
 
• Before first treatment 
 
− For patients with fiducial markers placed:  
 
Portal images of each beam and a KV orthogonal pair (typically AP and lateral) must be 
obtained prior to initiation of treatment.  Shifts will be made based on the KV orthogonal 
pair. Cone Beam CT matching and kilovoltage imaging should plan to align seroma 
cavity and clips rather than bony structures if there is a conflict.  All shifts greater than 1 
mm will be made.  Any concerns about what structure is to be matched will be 
addressed to the supervising physician.  Cone beam CT will be performed at the first 
fraction to ensure stable clip geometry and seroma volume, and may be performed at 
the discretion of the supervising physician. 
 
− For patients without fiducial markers placed: 
 
Portal images of each beam and an orthogonal pair (typically AP and lateral) must be 
obtained prior to initiation of treatment.  Shifts can be made based on the orthogonal 
pair.  Following these films, cone Beam CT will be performed at the start of each 
treatment.  Cone Beam CT matching should plan to align seroma cavity and/or clips 
rather than bony structures if there is a conflict.  All shifts greater than 1 mm will be 
made.  Any concerns about what structure is to be matched will be addressed to the 
supervising physician.  Cone beam CT imaging is to be performed on the low dose 
setting whenever permitted by imaging quality, and the scan should encompass 
the breast region only with little to no additional scan performed superior or 
inferior to breast tissue.   Therapists are encouraged to clinically place 
radioopaque wires at the superior and inferior extent of breast to help plan the 
cone beam scan as breast tissue can be difficult to visualize on scout films.   
 
• Subsequent images or films 
 
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− Cone beam CT will be performed prior to each fraction in patients who do not have 
gold fiducial markers placed.  Those patients with gold fiducials may have kilovoltage 
imaging with fiducial alignment or cone beam CT.  Additional images may be obtained 
at the supervising physician’s discretion.   As is standard policy for all IGRT, therapists 
should notify the treating physician immediately with any difficulty in locating the target 
area. 
 
7.0 
 Quality Assurance of Dose Distribution 
 
DVHs for the PTV_EVAL, designated critical structures, and unspecified tissues will be 
submitted. Each treatment plan shall be judged as: 
 
• Acceptable: 
− Dose volume histogram analysis of the target volume confirms 90% of the 
prescribed dose covers ≥ 90% of the PTV_EVAL. 
− Critical normal tissue DVHs within 5% specified value. 
− Maximum dose does not exceed 120% of prescribed dose. 
− Dose delivered twice a day for a total of 10 treatments over a period of 5 to 10 days. 
 
• Unacceptable: 
− Dose volume histogram analysis of the target volume will confirm < 90% of the 
prescribed dose covers < 90% of the PTV_EVAL. 
− Critical normal structure DVH exceeds 5% of the specified value  
− Maximum dose exceeds 120% of prescribed dose. 
− Dose delivered over a period of time extending greater than 10 days. 
 
8.0 
ASSESSMENT OF TOXICITY, COSMESIS, BREAST PAIN, AND 
SATISFACTION 
The purpose of this study is to evaluate the feasibility of using image guidance and four-
dimensional computed tomography to reduce the volumes of non target breast tissue 
that is treated with accelerated partial breast irradiation via the external beam 
technique.  However, toxicity will be assessed and a larger trial will be planned to 
formally assess the presence or absence of improved cosmesis with this technique. 
Some patients who were originally referred to Yale-New Haven Smilow from Lawrence 
& Memorial (L&M) Hospital for this trial will be followed beginning 1 month after 
treatment at L&M because it is closer to home for them.  Dr. Evans also works at 
Lawrence & Memorial. In these cases, Dr. Evans will be meeting with the patients for 
standard radiation therapy follow up and assessment of cosmesis.  No treatment 
procedures will occur there. 
 
A.   
The Breast Cancer Treatment Outcome Scale (BCTOS) will be used to assess 
cosmetic results using patient self-report. This brief self-report instrument has high 
reliability and validity, and has been used in a variety of previous studies on recovery 
from breast cancer treatment. The first patient-rated cosmetic evaluation will occur after 
informed consent but prior to completion of treatment (baseline). The BCTOS will be 
used to assess cosmesis at baseline, 1-year, and 3 year follow-up.   
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HIC 1110009173 
 
 
B.   
Treating radiation oncologist cosmesis assessment will occur at baseline, and 1 
year, and 3 years post Radiation Therapy, and will be graded according to the Harvard 
Cosmesis Scale (Appendix V).  Toxicity assessment will occur at 1 month, 3 months, 6 
months, 1 year, and 3 years post Radiation Therapy, and will be graded according to 
RTOG. 
 
C.   
Digital images (photographs) will be taken of the treated and untreated breasts, 
again using RTOG established protocol. For practical reasons, these digital images will 
only be taken at two points in time, at the 1-year and 3-year (final) assessment points. 
Two digital images will be taken at each of these assessment points. One will be a close 
up of the treated breast alone, in order to provide detailed information regarding the 
treatment effects, and should be taken at a 45° oblique with arms elevated over the 
patient's head. The second digital image will be a straight frontal view of both breasts 
taken in either a standing or seated position with the patient's hands symmetrically 
placed on her hips, taking care to exclude her face, jewelry, or tattoos and framing or 
focusing on both the treated and untreated breast to allow optimal comparison of the 
breasts for symmetry. These digital images will then be blinded and evaluated for 
cosmetic results by 2 separate investigators of a different specialty (IE medical 
oncology, surgery, radiation oncology) for cosmetic result according to the Harvard 
Cosmesis scale (Appendix V).  A placard with the first initial and the last 4 numbers of 
the medical record number and timepoint will be included in the photo (Example 
“A3456_1 year”). 
 
For patients who have already passed the year 1 time point, cosmetic photos will be 
taken at year 3 only. 
 
Patients enrolled prior to version 7 who decline photographs will still be followed on 
protocol.  Patients enrolled after the implementation of version 7 will also have the 
option to opt out of the photographs. 
 
D.   
Patients will be asked to complete a short questionnaire about breast pain and 
satisfaction with treatment at the 1-year and 3-year assessment points. All patients who 
have passed the 1-year assessment point will be mailed two copies of a consent 
addendum about the questionnaire as well as a copy of the questionnaire and be asked 
to return both documents via a pre-stamped envelope.  Patients will be able to opt out of 
completing the questionnaire.  Those who decline to complete the pain questionnaire 
will still be followed on protocol.  Because this questionnaire is being added after some 
patients have already passed the 1-year assessment point, those patients will be asked 
to complete the survey as soon as possible after receiving it.  Results will be compared 
to results of other studies which assessed pain in patients who had partial breast 
radiation. Findings will also be correlated to differences across patients in terms of 
radiation treatment plans and use of hormonal therapy. 
 
9.0   SURGERY 
 
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HIC 1110009173 
 
A.   
In the majority of instances, it is recommended that the incision for the 
lumpectomy and that for the SLNB be separate.  A single continuous incision for both 
the lumpectomy and the axillary sampling is to be avoided and will preclude inclusion on 
the protocol.  This is likely to allow lumpectomy and axillary node sampling cavities to 
communicate, prohibiting targeting of lumpectomy cavity alone. 
 
B.   
The cavity must be visible by CT .   Placement of 4-6 surgical clips is 
strongly encouraged.  The clips, if placed, are to be attached to the medial, 
lateral, anterior, posterior, superior and inferior walls of the resection cavity. 
Shaikh T, Chen T, Khan A, et al.  Improvement in interobserver accuracy in 
delineation of the lumpectomy cavity using fiducial markers. Int J Radiat 
Oncol Biol Phys. 2010 Nov 15;78(4):1127-34. Epub 2010 Mar 19.).  Closure of 
the resection cavity is encouraged to minimize the formation of large seromas 
which may make limiting non-target tissue exposure difficult.  
 
NOTE: gold fiducial markers may be used for both cavity delineation and 
daily kv imaging and image guidance, whereas surgical clips serve to 
delineate the cavity only.  Gold fiducial markers may be placed post-
operatively or intraoperatively for use in image guidance.  Closure of the 
resection cavity should be performed to limit seroma fluid accumulation 
and therefore minimize the target volume.  
 
C.   
Oncoplastic reconstruction is not allowed. 
 
D.   
If margins are positive, close (<2mm) or unknown, a re-excision is required prior 
to study entry.  
 
10.0   OTHER THERAPIES 
 
A.   
Hormonal therapy is allowed at any time after biopsy or lumpectomy, prior to, 
during or immediately after radiation, at the discretion of the patient's medical oncologist 
or other physicians. 
 
B.   
The use of chemotherapeutic agents prior to or during radiation is not allowed. 
 
C.   
Chemotherapy regimens should be started no earlier than 2 weeks after the 
completion of radiation. 
 
11.0   PATHOLOGY  
 
A.   
Pathology review at Yale of any specimen obtained from referring surgeons from 
outside institutions will be required for the purposes of this study.  
 
B.   
Otherwise standard pathologic assessment from Yale will be required. 
 
 
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APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

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Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
12.0 PRE AND POST ENROLLMENT PATIENT CALENDAR 
 
A.   
Study Parameters
 
Assessment 
Pre Rx 
During 
Radiation 
Therapy 
Post RX 
4 weeks 
(+/- 2 
weeks) 
Post 
RX 
3 mos. 
(+/- 2 
weeks) 
Post RX 
6 mos. 
(+/- 2 
weeks) 
Post RX 
1 year (+/- 6 
weeks) 
Post RX 3 
years (+/- 6 
weeks) 
H&P 
X 
X 
X 
X 
Xb 
Xb 
Breast exam 
X 
X 
X 
X 
Xb 
Xb 
Weight  
X 
 
 
X 
Xb 
Xb 
Height 
X 
 
 
 
 
 
Disease status 
X 
 
 
 
Xb 
Xb 
Toxicity 
Assessment 
X 
X 
X 
X 
X 
Xb 
Xb 
Bilateral 
Mammogram 
X 
Xc 
Xc 
Chest x-ray 
Xa 
Xa 
Xa 
CBC, platelets 
X 
 
 
SGOT, Alk Phos 
X 
 
 
Serum calcium 
X 
 
 
Bone scan, Abd. 
CT. 
Xa 
 
 
Patient Reported 
Cosmesis (BCTOS) 
X 
X 
X 
MD Reported 
Cosmesis 
X 
X 
X 
Digital images 
taken of treated and 
untreated breasts 
 
Xd 
Xd 
4D CT scan for 
planning  
X 
 
 
Urine Pregnancy 
Test (ages 10-60, 
and of childbearing 
potential) 
X 
 
 
Breast Pain 
Questionnaire 
 
Xd,e 
Xd 
X to be performed routinely 
Xa if clinical symptoms or lab values warrant 
Xb as per standard practice 
Xc  Bilateral mammograms will occur at least annually (+/- 6 weeks following the 
preceding bilateral mammogram), or as clinically indicated. 
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HIC 1110009173 
 
Xd If patient consents 
Xe Patients who have passed the 1-year assessment point will be asked to complete the 
questionnaire as soon as possible. 
 
As is standard for evaluation of radiation toxicity, patients will be followed for three 
years. For the first 90 days post-treatment, the RTOG acute toxicity scale will be used, 
and for up to three years the RTOG/EORTC late toxicity scale will be used. Any 
additional toxicities that do not meet the criteria for RTOG scoring will be recorded 
according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
guidelines.  
 
B.   
Patient Enrollment Sheet 
 
C.   
Complete History and Physical Examination 
 
D.   
Mammographic Report(s) 
 
E.   
Pathology Reports 
 
F.   
Initial Radiation Therapy Consult Note 
 
G.   
Patient Treatment Data 
 
H.   
Toxicity Reports 
 
Skin reaction(s) to radiation, including erythema, desquamation, etc. and any radiation 
complications or unusual or severe side effects of treatment will be recorded using 
RTOG acute and RTOG/ECOG late toxicity scoring. All toxicity from radiation is 
described in both acute and late terms, and this is often grouped together, because 
radiation delivery can lead to either side effect for normal tissue. Specifically, RTOG 
acute and RTOG/ECOG late radiation toxicity scoring parameters were originally 
described for breast conservation treatment, and will be used in this study.33 Acute 
toxicity includes any side-effects during treatment or within three months following 
treatment and late toxicity includes side-effects from three months up to three years in 
this study (see Appendix III and IV). Both acute and late toxicity use scores from 0-5. 
Toxicity is not expected for other tissues but will be documented. Excess toxicity will be 
reported as detailed below (Section 14 and Section 15).  
 
I.   
Copies of Dosimetry Calculations (see Appendix VI). 
 
J.   
Patient Follow Up 
 
Patient follow up will occur 4 weeks, 3 months, 6 months, 1 year, and three years post 
Radiation Therapy. Some patients will be followed beginning 4 weeks after treatment at 
L&M because it is closer to home for them.  In these cases, Dr. Evans will be meeting 
with the patients. 
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HIC 1110009173 
 
 
-  Vital status. If patient has expired, a data form must be submitted. 
 
-  Disease status, classified local, elsewhere, contralateral, regional, or distant.  A local 
failure is defined as an ipsilateral breast tumor recurrence within the same quadrant of 
the breast as the original lumpectomy.  An elsewhere failure is defined as an ipsilateral 
breast tumor recurrence not inside the same quadrant as the original lumpectomy.  A 
contralateral breast cancer is defined as a breast cancer in the opposite breast.  A 
regional failure is a recurrence in the axilla, internal mammary nodal chain, or 
supraclavicular lymph node basins.  A distant failure is any metastasis to distant organs 
(i.e. bone, lung, liver, brain). 
 
-  Toxicity evaluation. 
 
-  Follow-up physical examination and mammographic results. 
 
13.0  STATISTICAL CONSIDERATIONS 
 
A.   
Primary Endpoint 
 
The purpose of this study is to evaluate the feasibility of using image guidance 
and four-dimensional computed tomography to reduce the volume of non target 
breast tissue that is treated with accelerated partial breast irradiation via the 
external beam technique.   
 
Therefore, the primary focus will be to evaluate the utility of 4DCT and daily image 
guidance in APBI to decrease non target breast tissue constraints.  The novelty of this 
protocol lies in the use of four dimensional CT and daily image guidance to minimize 
planning target volume, and thereby reduce incidental breast radiation (V50, V100 
breast doses), which have been linked to poor cosmetic outcomes.34,35  
 
This study will be considered a success if 50% or more of patients enrolled are able to 
meet the dosimetric constraints on the breast (V50 <45% and V100 <23.5%).  If this 
occurs, a phase II study approval will be sought. 
 
B.   
Secondary Endpoints 
· 
To study cosmesis rates and toxicity with improved dose constraints, and to assess 
whether this technique warrants further study in a larger trial designed to show 
improvement in cosmesis through this technique. 
 
 
C.   
Patient Accrual 
 
Patient accrual is expected to be 70 patients. 
 
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HIC 1110009173 
 
14.0 EXPECTED SIDE-EFFECTS AND ADVERSE EVENTS 
 
A.   
Expected side effects 
The side effects expected in this trial are not predicted to be significant, and should be 
similar to those experienced in the previously reported trials. Expected toxicities and 
relative incidences over time are given from Berrang et al.  It is important to note that in 
addition to this list, Hepel et al reported 5/60 grade 3 toxicities, 4 of which were 
subcutaneous fibrosis, and one which was rib fracture and pericarditis.  This group also 
reported one grade 4 subcutaneous toxicity, which was a patient who required wide 
local excision for severe breast pain at the site of APBI, and later underwent 
mastectomy for non-healing ulceration at the same site.  This is the only toxicity higher 
than grade 3 reported in the literature (1 of a combined 3D CRT PBI PUBLISHED 
experience of 348, or 0.2%).  If unexpected severe toxicities arise then we will follow 
early stopping and reporting guidelines as detailed in Section 15.   
 
 
 
B.   
Assessing Adverse Events 
 
All toxicities possibly, probably or definitely related to Radiation Therapy will be scored 
using RTOG acute and RTOG/EORTC late toxicity guidelines (see Appendix III and IV). 
Adverse events will be described and reported as described in Section 15.  
 
Any additional toxicities will be recorded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 guidelines.  
 
15.0   ADVERSE EVENTS REPORTING, SAFETY MONITORING, AND 
COMPLIANCE  
 
A.   
Reporting Safety Information 
 
An Adverse Experience or Event (AE) is any undesirable medical event occurring during 
the course of a clinical study, whether considered treatment-related or not, whether 
expected or not, whether it is serious or not.  All AEs are to be reported. 
 
B.   
Adverse Events 
 
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Following questioning and evaluation of the subject, all adverse clinical events, whether 
believed to be related or unrelated to the study treatment will be recorded and 
described.  The subject will be followed until the AE has resolved or, if a chronic 
condition, stabilized. 
 
Grading: 
 
The maximum intensity of the AEs possibly, probably or definitely related to Radiation 
Therapy will be recorded using the current version of the RTOG acute and 
RTOG/EORTC late toxicity criteria (appendix III and IV). If a certain event or symptom is 
not described in the RTOG and EORTC toxicity criteria, it will be recorded according to 
the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 guidelines.  
 
Attribution: 
 
Assessment of attribution is made by consideration of all clinically relevant data prior to, 
during, and after the occurrence of the event, including diagnostic tests to assess the 
cause of the event.  Clinically relevant data include, but is not limited to; underlying 
disease, past and present medical history (all concurrent non-malignant disease), 
concurrent medications, and timing between event and drug administration.  The 
mechanism of action and prior toxicology of the study treatment should be considered. 
• Certain: An AE that occurred in a reasonable time after study treatment 
administration, and cannot be explained by concurrent disease or drugs.  
• Probable: An AE that occurred in a reasonable time after study treatment 
administration is unlikely to be attributed to concurrent disease or drugs. 
• Possible: An AE that occurred in a reasonable time after study treatment 
administration but could be related to concurrent disease or drugs.  
• Unlikely: An AE where the clinical picture is highly consistent with a cause other than 
the study treatment, but attribution cannot be made with absolute certainty and a 
relationship between study treatment and AE cannot be excluded with complete 
confidence. 
• Unrelated: An AE that is unrelated to the study treatment, for instance, one that is 
plausibly related to other drugs or the underlying disease.  If the relationship is 
assessed as “Unrelated”, the cause is provided if known. 
• Unassessable: Available information is insufficient, contradictory, and cannot be 
supplemented or verified at this point in time. 
 
C.   
Unexpected Adverse Event 
 
An unexpected AE may require expedited reporting if the nature and severity of the 
event is not consistent with information in the agent’s Toxicity List. The first occurrence 
of a previously unknown toxicity (regardless of RTOG/EORTC toxicity grade) is 
considered unexpected. A list of known toxicities, based on clinical events, will be 
updated and obtained from published outcomes of the treatment. Adverse events that 
are ‘expected’ based on toxicology or mechanism of action are still considered 
‘unexpected’ if not previously observed (regardless of RTOG/EORTC Toxicity Grade 
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HIC 1110009173 
 
criteria) following the administration of the treatment in this trial.  Expected adverse 
events are those that have been observed and attributed to the treatment in a clinical 
trial, and are listed on the agent’s toxicity list. 
 
D.   
Serious Adverse Events (SAEs) 
 
A Serious Adverse Experience or Event (SAE) is any AE that occurring at any dose 
results in any of the following outcomes: death, life-threatening adverse toxicity 
experience, inpatient hospitalization or prolongation of existing hospitalization 
(excluding hospitalization for elective procedures or transfusions), a persistent or 
significant disability/incapacity, or a congenital anomaly/birth defect.  Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be 
considered a serious adverse treatment experience, when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition.  In 
general an important medical event is grade Grade 4-5 by the RTOG or RTOG/EORTC 
criteria. 
 
The term “life threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.  Medical and scientific 
judgment should be exercised in deciding whether an important medical event is 
serious.  Although the event may not be immediately life-threatening, fatal, or result in 
hospitalization, it should be considered serious when it jeopardizes the patient or 
requires intervention to prevent a serious outcome as defined above. 
 
Examples of serious important medical events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasia or convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse. 
 
E.   
Expedited Reporting of Unexpected SAEs 
 
AEs classified as “serious” and “unexpected” that are possibly, probably, or definitely 
attributed to treatment administration, or SAEs whose frequency exceeds expectations, 
require expeditious handling and reporting to the Human Investigations Committee 
(HIC) to comply with regulatory requirements as well as to the FDA using the Medwatch 
form and the device maker.  Deaths within 30 days of treatment administration will be 
reported to HIC, as well as any unexpected SAE that occurs more than 30 days after 
treatment administration but is possibly, probably, or definitely attributed to treatment 
administration.  
 
All AEs meeting the criteria for expedited reporting will be reported to the Yale HIC 
within 48 hours of the PI`s initial receipt of the information. The PI will promptly 
investigate all safety information related to an adverse experience. Full written reports 
using the Yale Cancer Center Expedited SAE Report Form will be submitted to the HIC  
no later than 15 calendar days following the PI`s receipt of complete information on the 
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SAE. Follow-up information to a safety report shall be submitted as soon as the relevant 
information is available.  
 
If the results of the PI`s investigation shows that an adverse treatment experience not 
initially determined to be reportable (based on whether the event is serious, 
unexpected, and associated with treatment administration) is so reportable, the PI will 
report such experience in a written safety report as soon as possible, but in no event 
later than 15 calendar days after the determination is made. 
 
Results of the PI`s investigation of other safety information will be submitted, as 
appropriate, in an information amendment or annual report. 
 
F.   
Yale Safety Monitoring and Reporting  
 
The PI will monitor the clinical trial for safety. The PI will assess all expedited adverse 
events and will periodically review all adverse events observed on the trial.  Yale 
Cancer Center standard operating procedures (SOPs) for assessment and reporting of 
adverse events are followed which are in compliance with FDA 21 Code of Federal 
Regulations Part 312.32 and 312.33.  
 
The clinical trial data consisting of all required observations, AEs, and laboratory data 
are entered into a computerized database (OnCore) in a timely manner. The accuracy 
and completeness of the database, and compliance with the protocol, is assured by 
periodic auditing conducted by the Yale Cancer Center Office of Quality Assurance and 
Training, which reports to the Yale QUACS Committee. On a regular interval basis 
(approximately every 1-2 weeks), status reports of all laboratory parameters, AEs and 
SAEs are reviewed by the PI to view composite data across subjects. Weekly meetings 
are held to discuss ongoing patient treatment and adverse events. The Yale QUACS 
Committee also reviews safety data for the trial at least annually. 
 
Possible actions taken by the PI or the Yale QUACS if a new unexpected toxicity is 
identified from the above safety review, or if the periodic review of all adverse events 
and laboratory data indicates a pattern of incidence or severity of toxicity that raises a 
safety concern, can be to: 
·Revise consent form 
·Amend the protocol 
·Suspend the protocol 
 
All AEs found to be expected or non-serious, will be included in the Annual Report. 
 
G.   
Stopping Rules 
The trial will be discontinued if we experience 2 serious adverse events within the study 
cohort.  Serious adverse events resulting in protocol discontinuation would include 
grade 3 pneumonitis, grade 3 pericarditis, or severe breast pain requiring excision of the 
area. 
 
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Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
This trial will be discontinued if we are unable to achieve the more rigid dose constraints 
on breast reference volume (V50<45%, V100<23.5%) on 15 patients, as this would 
make the primary endpoint impossible. 
 
16.0   PATIENT TERMINATION 
 
Patients will be removed from the study at the patient’s request.  If a patient is unable to 
lie still for treatment or complete 4D CT, the patient may be removed from the trial.  In 
the event that the patient does not tolerate treatment, at the discretion of the treating 
radiation oncologist, the patient will be removed from the trial.  Patients will be removed 
from protocol therapy if the target area is not visible by cone beam CT scan or 
kilovoltage imaging at any point during the treatment.
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Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
17.0  REFERENCES 
 
1.   
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 347:1233-1241, 2002. 
   
2.  
Veronesi U, Cascinelli N, Mariani L, Greco M, et al.  Twenty-year follow-up of a 
randomized study comparing breast-conserving surgery with radical mastectomy for 
early breast cancer.  N Engl J. Med 347:1227-1232, 2002. 
 
3.   
Morrow M, White J, Moughan J, et al.  Factors predicting the use of breast-
conserving therapy in stage I and II breast carcinoma.  J Clin Oncol 19:2254-2262, 
2001. 
 
4. 
Bartelink H, Horiot JC, Poortmans P, et al.  Recurrence rates after treatment of 
breast cancer with standard radiotherapy with or without additional radiation.  N Engl J 
Med 345:1378-1387, 2001.   
 
5.  
Rosen PP, Fracchia AA, Urban JA, et al.   “Residual” mammary carcinoma 
following simulated partial mastectomy.  
Cancer 35:739747, 1975. 
 
6. 
Veronesi U, Marubini, E, Mariani L, et al.  Radiotherapy after breast-conserving 
surgery in small breast carcinoma: long-term results of a randomized trial. Ann Oncol 
12:997-1003, 2001. 
 
7. 
Clark RM, Whelan T, Levine 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 Natl Cancer Inst 88:1659-1664, 1996. 
 
8. 
Holli K, Saaristo R, Isola J, et al.  Lumpectomy with or without postoperative 
radiotherapy for breast cancer with favourable prognostic features: results of a 
randomized study.  Br J Cancer 84:164-169, 2001. 
 
9. 
Lijegren G, Holmberg L, Bergh J, et al.  10-Year results after sector resection 
with or without postoperative radiotherapy for Stage I breast cancer: a randomized trial.  
J Clin Oncol 17:2326-2333, 1999. 
 
10. 
Morrow M.  Rational local therapy for breast cancer.  N Engl J Med 347:1270-
1271, 2002. 
 
11. 
Smith TE, Lee D, Turner BC, et al.  True recurrence vs. new primary ipsilateral 
breast tumor relapse: an analysis of clinical and pathologic differences and their 
implications in natural history, prognoses, and therapeutic management.  Int J Radiat 
Oncol Biol Phys 48:1281-1289, 2000. 
 
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HIC 1110009173 
 
12. 
Obedian E, Fischer DB, Haffty BG.  Second malignancies after treatment of 
early-stage breast cancer: lumpectomy and radiation therapy versus mastectomy.  J 
Clin Oncol 18:2406-2012, 2000. 
 
13.  
Fisher ER, Dignam J, Tan-Chiu E, et al.  Pathologic findings from the National 
Surgical Adjuvant Breast and Bowel Project (NSABP) eight-year update of Protocol B-
17: intraductal carcinoma.  Cancer 86:429-438, 1999. 
 
14. 
Faverly DR, Burgers L, Bult P, Holland R.  Three dimensional imaging of 
mammary ductal carcinoma in situ: clinical implications.  Semin Diagn Pathol 11:193-
198, 1994. 
 
15. 
King TA, Bolton JS, Kuske RR, et al.  Long-term results of wide-field 
brachytherapy as the sole method of radiation therapy after segmental mastectomy for 
T(is,1,2) breast cancer.  Am J Surg 180:299-304, 2000. 
 
16.   Park SS, Grills IS, Chen PY, et al.  Accelerated Partial Breast Irradiation for Pure 
Ductal Carcinoma in Situ. Int J Radiat Oncol Biol Phys. 2010 Aug 26. [Epub ahead of 
print] 
 
17.  
Vicini F, Baglan K, Kestin L, et al.  The emerging role of brachytherapy in the 
management of patients with breast cancer.  Semin Radiat Oncol 12:31-39, 2002. 
 
18.  
Kuske RR Jr.  Breast brachytherapy.  Hematol Oncol Clin North Am 13:543-558, 
1999. 
 
19.  
Vicini F, Winter K, Wong J, et al.  Initial Efficacy Results of RTOG 0319: Three-
Dimensional Conformal Radiation Therapy (3D-CRT) Confined to the Region of the 
Lumpectomy Cavity for Stage I/ II Breast Carcinoma.  Int J Radiat Oncol Biol Phys. 
2010 Jul 15;77(4):1120-7. Epub 2009 Nov 10. 
 
20.   T.B. Julian, J. P. Costantino, F. A. Vicini, et al.  Early toxicity results with 3D 
conformal external beam therapy (CEBT) from the NSABP B-39/RTOG 0413 
accelerated partial-breast irradiation (APBI) trial.  ASCO 2010 Breast Cancer 
Symposium, National Harbor, Maryland, October 1-3, 2010. 
 
21.  
Keisch M, Vicini F, Kuske RR, et al.  Initial clinical experience with the 
MammoSite breast brachytherapy applicator in women with early-stage breast cancer 
treated with breast-conserving therapy.  Int J Radiat Oncol Biol Phys 55:289-293, 2003. 
 
22.   Clark.  High dose rate brachytherapy for breast cancer.  In: Nag S, editor.  High 
dose rate brachytherapy:  A textbook.  Futura Publishing 321-329, 1994. 
 
23.  
Polgar C, Sulyok Z, Fodor J, et al.  Sole brachytherapy of the tumor bed after 
conservative surgery for T1 breast cancer: Five-year results of a Phase I-II study and 
initial findings of a randomized Phase III Trial.  J Surg Oncol 80:121-128, 2002. 
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HIC 1110009173 
 
 
24.  
 Polgár C, Major T, Lövey K, et al. Hungarian experience on partial breast 
irradiation versus whole breast irradiation: 12-year results of a phase II trial and updated 
results of a randomized study. Brachytherapy 2008;7:91–2 
 
25. 
Perera F, Engel J, Holliday R, et al.  Local resection and brachytherapy confined 
to the lumpectomy site for early breast cancer: a pilot study.  J Surg Oncol 65:263-267, 
1997. 
 
26. 
Perera F, Chisela F, Engel J, et al.  Method of localization and implantation of the 
lumpectomy site for high dose rate brachytherapy after conservative surgery for T1 and 
T2 breast cancer.  Int J Radiat Oncol Biol Phys 31:959-965, 1995. 
 
27. 
Vicini FA, Baglan KL, Kestin LL, et al.  Accelerated treatment of breast cancer.  J 
Clin Oncol 19:1993-2001, 2001. 
 
28. 
Baglan KL, Martinez AA, Frazier RC, et al.  The use of high-dose-rate 
brachytherapy alone after lumpectomy in patients with early-stage breast cancer treated 
with breast- conserving therapy.  Int J Radiat Oncol Biol Phys 50:1003-1011, 2001. 
 
29. 
Kuske RR, Martin B, Hanson W, et al.  Quality assurance and reproducibility on 
RTOG 95-17: A Phase II trial of brachytherapy alone for select breast cancers.  
Personal Communication.  2001. 
 
30.   Benitez PR, Keisch ME, Vicini F, et al.  Five-year results: the initial clinical trial of 
MammoSite balloon brachytherapy for partial breast irradiation in early-stage breast 
cancer. Am J Surg. 2007 Oct;194(4):456-62. 
 
31. 
Wazer DE, Berle L, Graham R, et al.  Preliminary results of a Phase I/II study of 
HDR brachytherapy alone for T1/T2 breast cancer.  Int J Radiat Oncol Biol Phys 
53:889-897, 2002.   
 
32.   Chen PY, Wallace M, Mitchell C, et al.  Four-year efficacy, cosmesis, and toxicity 
using three-dimensional conformal external beam radiation therapy to deliver 
accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2010 Mar 
15;76(4):991-7. Epub 2009 Jun 8. 
 
33. 
Berrang TS, Olivotto I, Kim DH, et al.  Three-Year Outcomes of a Canadian 
Multicenter Study of Accelerated Partial Breast Irradiation Using Conformal Radiation 
Therapy. Int J Radiat Oncol Biol Phys. 2010 Oct 23. [Epub ahead of print] 
 
34.   Hepel JT, Tokita M, MacAusland SG, Evans et al.  Toxicity of three-dimensional 
conformal radiotherapy for accelerated partial breast irradiation.  Int J Radiat Oncol Biol 
Phys. 2009 Dec 1;75(5):1290-6. Epub 2009 Apr 22. 
 
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HIC 1110009173 
 
35. 
Jagsi R, Ben-David MA, Moran JM, 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 Jan 1;76(1):71-
8. 
 
36.   Yue NJ, Goyal S, Zhou J, Khan AJ, Haffty BG.  Intrafractional target motions and 
uncertainties of treatment setup reference systems in accelerated partial breast 
irradiation. Int J Radiat Oncol Biol Phys. 2011 Apr 1;79(5):1549-56. Epub 2010 Aug 26. 
 
37.   Leonard CE, Tallhamer M, Johnson T, et al.  Clinical experience with image-
guided radiotherapy in an accelerated partial breast intensity-modulated radiotherapy 
protocol. Int J Radiat Oncol Biol Phys. 2010 Feb 1;76(2):528-34. Epub 2009 May 19. 
 
38. 
Fatunase T, Wang Z, Yoo S, et al.  Assessment of the residual error in soft tissue 
setup in patients undergoing partial breast irradiation: results of a prospective study 
using cone-beam computed tomography. Int J Radiat Oncol Biol Phys. 2008 Mar 
15;70(4):1025-34. Epub 2007 Sep 24. 
 
39.   Liao ZW, Guan XX, Li FY, et al.  Accelerated partial breast irradiation: Use of 
four-dimensional CT for target localization and assessment of intrafractional motion. 
Oncol Res. 2010;18(10):503-7. 
 
40.   Hasan Y, Kim L, Wloch J, Chi Y, Liang et al. Comparison of Planned Versus 
Actual Dose Delivered for External Beam Accelerated Partial Breast Irradiation Using 
Cone-Beam CT and Deformable Registration. Int J Radiat Oncol Biol Phys. 2010 Jul 23. 
[Epub ahead of print] 
 
41.   Ahunbay EE, Robbins J, Christian R, et al.  Interfractional Target Variations for 
Partial Breast Irradiation. Int Radiat Oncol Biol Phys. 2011 May 11. [Epub ahead of 
print] 
 
 
42.   Kan MW, Leung LH, Wong W, Lam N.  Radiation dose from cone beam 
computed tomography for image-guided radiation therapy. Int J Radiat Oncol Biol Phys. 
2008 Jan 1;70(1):272-9. Epub 2007 Nov 5. 
 
43.   Song WY, Kamath S, Ozawa S, Ani SA, Chvetsov A, Bhandare N, Palta JR, Liu 
C, Li JG.  A dose comparison study between XVI and OBI CBCT systems. Med Phys. 
2008 Feb;35(2):480-6. 
 
44.   Hyer DE, Serago CF, Kim S, Li JG, Hintenlang DE.  An organ and effective dose 
study of XVI and OBI cone-beam CT systems.  J Appl Clin Med Phys. 2010 Apr 
17;11(2):3183 
 
45. 
Lewin AA, Derhagopian R, Saigal K, et al.  Accelerated Partial Breast Irradiation 
is Safe and Effective Using Intensity-Modulated Radiation Therapy in Selected Early-
Stage Breast Cancer. Int J Radiat Oncol Biol Phys. 2011 Jun 1. [Epub ahead of print] 
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APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
 
46. 
Olivotto IA, Whelan TJ, Parpia S, et al.  Interim Cosmetic and Toxicity Results 
From RAPID:A Randomized Trial of Accelerated Partial Breast Irradiation Using Three-
Dimensional Conformal External Beam Radiation Therapy. J Clin Oncol. 2013 Jul 8. 
[Epub ahead of print] 
 
47.  Mak KS, Chen YH, Catalano PJ, Punglia RS, Wong JS, Truong L, Bellon JR. 
Dosimetric Inhomogeneity Predicts for Long-Term Breast Pain After Breast-Conserving 
Therapy. Int J Radiat Oncol Biol Phys. 2014 Jul 29. pii: S0360-3016(14)00621-X. doi: 
10.1016/j.ijrobp.2014.05.021. [Epub ahead of print]) 
 
48.  Galland-Girodet S, Pashtan I, MacDonald SM, Ancukiewicz M, Hirsch AE, Kachnic 
LA, Specht M, Gadd M, Smith BL, Powell SN1, Recht A, Taghian AG. 
Long-Term Cosmetic Outcomes and Toxicities of Proton Beam Therapy Compared With 
Photon-Based 3-Dimensional Conformal Accelerated Partial-Breast Irradiation: A Phase 
1 Trial. Int J Radiat Oncol Biol Phys. 2014 May 28. pii: S0360-3016(14)00446-5. doi: 
10.1016/j.ijrobp.2014.04.008. [Epub ahead of print] 
 
 
 
 
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APPENDIX I 
 
KARNOFSKY PERFORMANCE SCALE   
 
100 
Normal; no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some sign or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most personal needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization is indicated, although death not imminent 
20 
Very sick, hospitalization necessary, active support treatment is necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
 
 
 
 
 
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APPENDIX II 
 
BREAST STAGING, AJCC 7th Edition 
 
DEFINITION OF TNM 
 
Primary Tumor (T) 
 
Definitions for classifying the primary tumor (T) are the same for clinical and for 
pathologic classification. The telescoping method of classification can be applied.  If the 
measurement is made by physical examination, the examiner will use the major 
headings (T1, T2, or T3).   If other measurements, such as mammographic or 
pathologic, are used, the examiner can use the telescoped subsets of T1. 
 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ: intraductal carcinoma, lobular carcinoma in situ, or Paget's 
disease of the nipple with 
 
no tumor. 
T1 
Tumor 2 cm or less in greatest dimension 
 
T1mic Microinvasion 0.1 cm or less in greatest dimension 
 
Tla      Tumor more than 0.1 cm but not more than 0.5 cm in greatest dimension 
 
T1b     More than 0.5 cm but not more than 1 cm in greatest dimension 
 
T1c    More than 1 cm but not more than 2 cm in greatest dimension 
T2 
Tumor more than 2 cm but not more than 5 cm in greatest dimension 
T3 
Tumor more than 5 cm in greatest dimension 
T4 
Tumor of any sizes with direct extension to chest wall or skin 
 
T4a  Extension to chest wall, not including pectoralis muscle 
T4b  Edema (including peau d' orange) or ulceration of the skin of the breast or 
satellite skin nodules 
 
confined to the same breast 
 
T4c  Both (T4a and T4b) 
 
T4d  Inflammatory carcinoma 
 
 
Note:  Paget's disease associated with a tumor is classified according to the size 
of the tumor. 
 
Regional Lymph Nodes (N) 
 
NX 
Regional lymph nodes cannot be assessed (e.g., previously removed) 
N0 
No regional lymph node metastasis 
NI 
Metastasis to movable ipsilateral lymph node(s) 
N2 
Metastasis to ipsilateral axillary lymph node(s) fixed to one another or to other 
structures 
N3 
Metastasis to ipsilateral internal mammary lymph node(s) 
  
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Pathologic Classification(pN) 
 
pNX Regional lymph nodes cannot be assessed (for example, previously removed, or 
not removed for pathologic study) 
pN0 No regional lymph node metastasis identified histologically 
 
Note: Isolated tumor cell clusters (ITC) are defined as small clusters of cells not greater 
than 0.2 mm, or single tumor cells, or a cluster of fewer than 200 cells in a single 
histologic cross-section. ITCs may be detected by routine histology or by 
immunohistochemical (IHC) methods. Nodes containing only ITCs are excluded from 
the total positive node count for purposes of N classification but should be included in 
the total number of nodes evaluated. 
 
pN0(i−) No regional lymph node metastases histologically, negative IHC 
pN0(i+) Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by 
H&E or 
IHC including ITC) 
pN0(mol−) No regional lymph node metastases histologically, negative molecular 
findings (RT-PCR) 
pN0(mol+) Positive molecular findings (RT-PCR)**, but no regional lymph node 
metastases detected by histology or IHC 
pN1 Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or in internal 
mammary nodes with metastases detected by sentinel lymph node biopsy but not 
clinically detected 
pN1mi Micrometastases (greater than 0.2 mm and/or more than 200 cells, but none 
greater than 2.0 mm) 
pN1a Metastases in 1–3 axillary lymph nodes, at least one metastasis greater than 2.0 
mm 
pN1b Metastases in internal mammary nodes with micrometastases or 
macrometastases detected by sentinel lymph node biopsy but not clinically detected 
pN1c Metastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes 
with micrometastases or macrometastases detected by sentinel lymph node biopsy but 
not clinically detected 
pN2 Metastases in 4–9 axillary lymph nodes; or in clinically detected  internal mammary 
lymph nodes in the absence of axillary lymph node metastases 
pN2a Metastases in 4–9 axillary lymph nodes (at least one tumor deposit greater than 
2.0 mm) 
pN2b Metastases in clinically detected internal mammary lymph nodes in the absence 
of axillary lymph node metastases 
pN3 Metastases in 10 or more axillary lymph nodes; or in infraclavicular (level III 
axillary) lymph nodes; or in clinically detected  ipsilateral internal mammary lymph 
nodes in the presence of one or more positive level I, II axillary lymph nodes; or in more 
than three axillary lymph nodes and in internal mammary lymph nodes with 
micrometastases or macrometastases detected by sentinel lymph node biopsy but not 
clinically detected; or in ipsilateral supraclavicular lymph nodes 
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pN3a Metastases in 10 or more axillary lymph nodes (at least one tumor deposit greater 
than 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes 
pN3b Metastases in clinically detected  ipsilateral internal mammary lymph nodes in the 
presence of one or more positive axillary lymph nodes; or in more than three axillary 
lymph nodes and in internal mammary lymph nodes with micrometastases or 
macrometastases detected by sentinel lymph node biopsy but not clinically detected 
pN3c Metastases in ipsilateral supraclavicular lymph nodes 
 
Distant Metastasis (M) 
 
MX 
Presence of distant metastasis cannot be assessed 
M0 
No distant metastasis 
M1 
Distant metastasis (includes metastasis to ipsilateral supraclavicular lymph 
node[(s)]) 
 
STAGE GROUPING 
 
Stage 0 
Tis 
    N0         M0 
Stage IA 
 
T1        N0         M0 
Stage IB        T0       N1mi      M0 
                      T1       N1mi      M0 
Stage IIA 
T0         N1         M0 
 
T1 
   N1*       M0  
 
T2        N0         M0 
 
Stage IIB 
T2 
   N1        M0  
 
T3 
   N0        M0  
Stage IIIA 
T0 
   N2        M0  
 
T1 
   N2        M0  
 
T2 
   N2        M0  
 
T3 
   N1        M0  
 
T3 
   N2        M0  
Stage IIIB 
T4 
   N0-2    M0  
Stage IIIC 
Any T   N3        M0  
Stage IV 
Any T   Any N  M1  
 
* Note: The prognosis of patients with N1a is similar to that of patients with pN0. 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX III 
 
RTOG Acute Radiation Morbidity Scoring Criteria          
[0] 
[1] 
[2] 
[3] 
[4] 
SKIN 
No change 
over 
baseline 
Follicular, faint or 
dull 
erythema/epilatio
n/dry 
desquamation/de
creased sweating 
Tender or bright 
erythema, patchy 
moist 
desquamation/mo
derate edema 
Confluent, moist 
desquamation other
than skin folds, 
pitting edema 
Ulceration, 
hemorrhage, 
necrosis 
MUCOUS 
MEMBRANE 
No change 
over 
baseline 
Injection/may 
experience mild 
pain not requiring 
analgesic 
Patchy mucositis 
which may 
produce an 
inflammatory 
serosanguinous 
discharge. May 
experience 
moderate 
Pain requiring 
analgesia 
Confluent fibrinous 
mucositis/may 
include severe pain 
requiring narcotic 
Ulceration, 
hemorrhage or 
necrosis 
EYE 
No change Mild conjunctivitis 
with or without 
scleral 
injection/increase
d tearing 
Moderate 
conjunctivitis with 
or without keratitis 
requiring steroids 
&/or antibiotics/ 
dry eye requiring 
artificial tears / 
iritis with 
photophobia 
Severe keratitis 
with corneal 
ulceration/objective 
decrease in visual 
acuity or in visual 
fields/acute 
glaucoma/panoptha
lmitis 
Loss of vision 
(unilateral or 
bilateral 
EAR 
No change 
over 
baseline 
Mild external otitis 
with erythema, 
pruritus, 
secondary to dry 
desquamation not 
requiring 
medication.  
Audiogram 
unchanged from 
baseline 
Moderate external 
otitis requiring 
topical 
medication/serous 
otitis 
medius/hypoacusi
s on testing only 
Severe external 
otitis with discharge 
or moist 
desquamation/sym
ptomatic 
hypoacusis/tinnitus, 
not drug related 
Deafness 
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SALIVARY 
GLAND 
No change 
over 
baseline 
Mild mouth 
dryness/slightly 
thickened 
saliva/may have 
slightly altered 
taste such as 
metallic 
taste/these 
changes not 
reflected in 
alteration in 
baseline feeding 
behavior, such as 
increased use of 
liquids with meals 
Moderate to 
complete 
dryness/thick, 
sticky 
saliva/markedly 
altered taste 
Acute salivary 
gland necrosis 
PHARYNX & 
ESOPHAGUS 
No change 
over 
baseline 
Mild dysphagia or 
odynophagia/may 
require topical 
anesthetic or non-
narcotic 
analgesics/may 
require soft diet 
Moderate 
dysphagia or 
odynophagia/may 
require narcotic 
analgesics/may 
require puree or 
liquid diet 
Severe dysphagia 
or odynophagia 
with dehydration or 
weight loss > 15% 
from pre-treatment 
baseline) requiring 
N-G feeding tube, 
I.V. fluids or 
hyperalimentation 
Complete 
obstruction, 
ulceration, 
perforation, 
fistula 
LARYNX 
No change 
over 
baseline 
Mild or 
intermittent 
hoarseness/ 
cough not 
requiring 
antitussive/erythe
ma of mucosa 
Persistent 
hoarseness but 
able to 
vocalize/referred 
ear pain, sore 
throat, patchy 
fibrinous exudate 
or mild arytenoid 
edema not 
requiring 
antitussive 
Whispered speech, 
throat pain or 
referred ear pain 
requiring 
narcotic/confluent 
fibrinous exudate. 
Marked arytenoid 
edema. 
Marked 
dyspnea, stridor 
or hemoptysis 
with 
tracheostomy 
or intubation 
necessary 
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HIC 1110009173 
 
UPPER G.I. 
No change Anorexia with <= 
5% weight loss 
from pretreatment 
baseline/nausea 
not requiring 
antiemetics/abdo
minal discomfort 
not requiring 
parasympatholytic 
drugs or 
analgesics 
Anorexia with <= 
15% weight loss 
from pretreatment 
baseline/nausea 
&/or vomiting 
requiring 
antiemetics/abdom
inal pain requiring 
analgesics 
Anorexia with 
>=15% wt loss from 
pretreatment 
baseline or 
requiring N-G tube 
or parenteral 
support.  Nausea 
&/or vomiting 
requiring tube or 
parenteral 
support/abdominal 
pain, severe 
despite medication/ 
hematemesis or 
melena/abdominal 
distention (flat plate 
radiograph 
demonstrates 
distended bowel 
loops) 
Ileus, subacute 
or acute 
obstruction, 
perforation, GI 
bleeding 
requiring 
transfusion/abd
ominal pain 
requiring tube 
decompression 
or bowel 
diversion. 
RTOG Acute Radiation Morbidity Scoring Criteria  
[0] 
[1] 
[2] 
[3] 
[4] 
LOWER G.I. 
INCLUDING 
PELVIS 
No change Increased 
frequency or 
change in quality 
of bowel habits 
not requiring 
medication/rectal 
discomfort not 
requiring 
analgesics 
Diarrhea 
requiring 
parasympatholyti
c drugs (e.g., 
Lomotil)/mucous 
discharge not 
necessitating 
sanitary 
pads/rectal or 
abdominal pain 
requiring 
analgesics  
Diarrhea 
requiring 
parenteral 
support/sever
e mucous or 
blood 
discharge 
necessitating 
sanitary 
pads/abdomin
al distention 
(flat plate 
radiograph 
demonstrates 
distended 
bowel loops) 
Acute or subacute 
obstruction, fistula or 
perforation; GI 
bleeding requiring 
transfusion; abdominal 
pain or tenesmus 
requiring tube 
decompression or 
bowel diversion 
YCC Amd. # 14 
45 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
     Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
LUNG 
No change Mild symptoms of 
dry cough or 
dyspnea on 
exertion 
Persistent cough 
requiring 
narcotic, 
antitussive 
agents/dyspnea 
with minimal 
effort but not at 
rest 
Severe cough 
unresponsive 
to narcotic 
antitussive 
agent or 
dyspnea at 
rest/clinical or 
radiologic 
evidence of 
acute 
pneumonitis. 
Intermittent 
oxygen or 
steroids may 
be required 
Severe respiratory 
insufficiency/continuou
s oxygen or assisted 
ventilation 
GENITOURINA
RY 
No change Frequency of 
urination or 
nocturia twice 
pretreatment 
habit/dysuria, 
urgency not 
requiring 
medication 
Frequency of 
urination or 
nocturia which is 
less frequent 
than every hour.  
Dysuria, 
urgency, bladder 
spasm requiring 
local anesthetic 
(e.g. Pyridium) 
Frequency 
with urgency 
and nocturia 
hourly or 
more 
frequently/dys
uria, pelvis 
pain or 
bladder 
spasm 
requiring 
regular, 
frequent 
narcotic. 
Gross 
hematuria 
with/without 
clot passage 
Hematuria requiring 
transfusion/acute 
bladder obstruction not 
secondary to clot 
passage, ulceration or 
necrosis 
HEART 
No change 
over 
baseline 
Asymptomatic but 
objective 
evidence of EKG 
changes or 
pericardial 
abnormalities 
without evidence 
of other heart 
diseases 
Symptomatic 
with EKG 
changes and 
radiologic 
findings of 
congestive heart 
failure or 
pericardial 
disease/no 
specific 
treatment 
required 
Congestive 
heart failure, 
angina 
pectoris, 
pericardial 
disease 
responding to 
therapy 
Congestive heart 
failure, angina pectoris, 
pericardial disease, 
arrhythmias not 
responsive to non-
surgical measures 
YCC Amd. # 14 
46 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
     Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
CNS 
No change Fully functional 
status (i.e., able 
to work) with 
minor neurologic 
findings, no 
medication 
needed 
Neurologic 
findings present 
sufficient to 
require home 
care/nursing 
assistance may 
be 
required/medicat
ions including 
steroids/anti-
seizure agents 
may be required 
Neurologic 
findings 
requiring 
hospitalization 
for initial 
management 
Serious neurologic 
impairment which 
includes paralysis, 
coma or seizures > 3 
per week despite 
medication/hospitalizati
on required 
HEMATOLOGI
C WBC (X 
1000) 
=> 4.0 
3.0 -<4.0 
2.0-<3.0 
1.0-<2.0 
<1.0 
PLATELETS (X 
1000) 
>100 
75-<100 
50-<75 
25-<50 
<25 
or spontaneous  
bleeding 
NEUTROPHIL
S (X 1000) 
=>1.9 
1.5-<1.9 
1.0-<1.5 
0.5-<1.0 
<0.5 or sepsis 
HEMOGLOBIN 
(X 1000) 
>11 
11-9.5 
<9.5-7.5 
<7.5-5.0 
HEMATOCRIT 
(%) 
=>32 
28-32 
<28 
Packed cell 
transfusion 
required 
GUIDELINES:  The acute morbidity criteria are used to score/grade toxicity from radiation therapy.  
The criteria are relevant from day 1, the commencement of therapy, through day 90.  Thereafter, the 
EORTC/RTOG Criteria of Late Effects are to be utilized. 
The evaluator must attempt to discriminate between disease and treatment related signs and 
symptoms 
An accurate baseline evaluation prior to commencement of therapy is necessary. 
All toxicities Grade 3,4, or 5* must be verified by Dr. Suzanne Evans 
* ANY TOXICITY WHICH CAUSED DEATH IS GRADED 5. 
 
 
 
 
 
 
 
 
 
 
 
 
YCC Amd. # 14 
47 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
     Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
APPENDIX IV 
 
RTOG / EORTC Late Radiation Morbidity Scoring Scheme   
0 
1 
2 
3 
4 
5 
SKIN 
NONE 
Slight atrophy; 
Pigmentation 
change; Some 
hair loss 
Patch atrophy; 
Moderate 
telangectasia; 
Total hair loss 
Marked atrophy; 
Gross 
telangectasia 
Ulceration 
SUBCUTA-
NEOUS 
TISSUE 
NONE 
Slight induration 
(fibrosis) and loss 
of subcutaneous 
fat 
Moderate 
fibrosis but 
asymptomatic; 
Slight field 
contracture; 
<10% linear 
reduction 
Severe 
induration and 
loss of 
subcutaneous 
tissue; Field 
contracture>10
% linear 
measurement 
Necrosis 
D 
E 
A 
T 
H 
D 
I 
R 
E 
C 
T 
L 
Y 
R 
E 
L 
A 
T 
E 
D 
T 
O 
R 
A 
D 
MUCOUS 
MEMBRAN
E 
NONE Slight atrophy and 
dryness 
Moderate 
atrophy and 
telangectasia; 
Little mucous 
Marked atrophy 
with complete 
dryness Severe 
telangectasia 
Ulceration 
SALIVARY 
GLANDS 
NONE 
Slight dryness of 
mouth; Good 
response on 
stimulation 
Moderate 
dryness of 
mouth; Poor 
response on 
stimulation 
Complete 
dryness of 
mouth 
No response on 
stimulation 
Fibrosis 
SPINAL 
CORD 
NONE Mild L’Hermitte’s 
syndrome 
Severe 
L’Hermitte’s 
syndrome 
Objective 
neurological 
findings at or 
below cord level 
treated 
Mono, para 
quadriplegia 
BRAIN 
NONE Mild headache; 
Slight lethargy 
Moderate 
headache  
Great lethargy 
Severe 
headaches; 
Severe CNS 
dysfunction 
(partial loss of 
power or 
dyskinesia) 
Seizures or 
paralysis 
Coma 
YCC Amd. # 14 
48 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
     Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
EYE 
NONE 
Asymptomatic 
cataract 
Minor corneal 
ulceration or 
keratitis 
Symptomatic 
cataract 
Moderate 
corneal 
Ulceration; 
Minor 
retinopathy or 
glaucoma 
Severe keratitis;  
Severe 
retinopathy or 
detachment 
Severe 
glaucoma 
Panopthalmitis/Blin
dness 
I 
A 
T 
I 
O 
N 
L 
A 
T 
E 
E 
F 
F 
E 
C 
T 
S 
LARNYX 
NONE 
Hoarseness; 
Slight  
Arytenoid edema 
Moderate 
arytenoid 
edema; 
Chondritis 
Severe edema;  
Severe 
chondritis 
Necrosis 
LUNG 
NONE 
Asymptomatic or 
mild symptoms 
(dry cough) Slight 
radiographic 
appearances 
Moderate 
symptomatic 
fibrosis or 
pneumonitis 
(severe cough) 
Low grade 
fever; Patchy 
radiographic 
appearances 
Severe 
symptomatic 
fibrosis or 
pneumonitis  
Dense 
radiographic 
changes 
Severe respiratory 
insufficiency/ 
Continuous 
o2/Assisted 
ventilation 
HEART 
NONE 
Asymptomatic or 
mild symptoms; 
Transient T wave 
inversion & ST 
changes;  Sinus 
tachycardia>110 
(at rest) 
Moderate 
angina on effort 
Mild 
pericarditis;  
Normal heart 
size;  Persistent 
abnormal T 
wave and ST 
changes; Low 
ORS 
Severe angina;  
Pericardial 
effusion;  
Constrictive 
pericarditis;  
Moderate heart 
failure;  Cardiac 
enlargement;  
EKG 
abnormalities 
Tamponade/Severe 
heart failure/Severe 
constrictive 
pericarditis 
ESOPHAGU
S 
NONE 
Mild fibrosis; 
Slight difficulty in 
swallowing solids; 
No pain on 
swallowing 
Unable to take 
solid food 
normally;  
Swallowing 
semi-solid food; 
Dilatation may 
be indicated 
Severe fibrosis; 
Able to swallow 
only liquids;  
May have pain 
swallowing 
Dilation required 
Necrosis/Perforatio
n Fistula 
YCC Amd. # 14 
49 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
     Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
SMALL/LAR
GE 
INTESTINE 
NONE 
Mild diarrhea; 
Mild cramping; 
Bowel movement 
5 times daily  
Slight rectal 
discharge or 
bleeding 
Moderate 
diarrhea and 
colic;  Bowel 
movement >5 
times daily;  
Excessive 
rectal mucus or 
intermittent 
bleeding 
Obstruction or 
bleeding, 
requiring surgery 
Necrosis/Perforatio
n Fistula 
LIVER 
NONE 
Mild lassitude; 
Nausea, 
dyspepsia; 
Slightly abnormal 
liver function 
Moderate 
symptoms; 
Some abnormal 
liver function 
tests;  Serum 
albumin normal 
Disabling 
hepatic 
insufficiency; 
Liver function 
tests grossly 
abnormal; Low 
albumin; Edema 
or ascites 
Necrosis /Hepatic 
coma or 
encephalopathy 
KIDNEY 
NONE 
Transient 
albuminuria;  No 
hypertension; 
Mild impairment 
of renal function;  
Urea 25-35 mg%; 
Creatinine 1.5-2.0 
mg%; Creatinine 
clearance>75% 
Persistent 
moderate 
albuminuria 
(2+); Mild 
hypertension; 
No related 
anemia; 
Moderate 
impairment of 
real function 
Urea>36-
60mg% 
Creatinine 
clearance (50-
74%) 
Severe 
albuminaria; 
Severe 
hypertension 
Persistent 
anemia 
(<10g%); Severe 
renal failure; 
Urea >60 mg% 
Creatinine >4.0 
mg% Creatinine 
clearance<50% 
Malignant 
hypertension 
Uremic coma/Urea 
> 100% 
BLADDER 
NONE 
Slight epithelial 
atrophy Minor 
telangectasia 
(microscopic 
hematuria) 
Moderate 
frequency 
Generalized 
telangectasia 
Intermittent 
macroscopic 
hematuria 
Severe 
frequency & 
dysuria Severe 
generalized 
telangectasia 
(Often with 
petechiae); 
Frequent 
hematuria; 
Reduction in 
bladder capacity 
(<150cc) 
Necrosis/Contracte
d bladder (capacity 
<100cc) Severe 
hemorrhagic 
cystitis 
YCC Amd. # 14 
50 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
     Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
BONE 
NONE 
Asymptomatic; 
No growth 
retardation;  
Reduced bone 
density 
Moderate pain 
or tenderness;  
Growth 
retardation; 
Irregular bone 
sclerosis 
Severe pain or 
tenderness; 
Complete arrest 
of bone growth; 
Dense bone 
sclerosis 
Necrosis/Spontane
ous fracture 
JOINT 
NONE 
Mild joint 
stiffness; Slight 
limitation of 
movement 
Moderate 
stiffness 
Intermittent or 
moderate joint 
pain;  Moderate 
limitation of 
movement 
Severe joint 
stiffness; Pain 
with severe 
limitation of  
movement 
Necrosis/Complete 
fixation 
 
 
 
YCC Amd. # 14 
51 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
APPENDIX V 
 
Rose MA, Olivotto I, Cady B, et al. Conservative surgery and radiation therapy for early 
breast cancer: Long-term cosmetic results. Arch Surg 1989;124:153–157. 
 
Harvard Cosmesis Scale 
Excellent 
the treated breast looked essentially the same as the opposite 
breast. 
Good 
minimal but identifiable effects of radiation on the treated breast. 
Fair 
significant effects of radiation on the breast were noted. 
Poor 
severe normal tissue sequelae. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
YCC Amd. # 14 
52 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
Appendix VI 
 
Patient reported Breast Cancer Treatment Outcome Scale (Stanton AL, Krishnan L, Collins CA. Form 
or function? Part 1. Subjective cosmetic and functional correlates of quality of life in women treated with breast-conserving surgical 
procedures and radiotherapy. Cancer. 2001;91:2273–2281.) 
 
We are interested in your evaluation of your physical appearance and functioning 
since your breast surgery and/or radiation. 
Please rate the following items on this four-point scale, according to your 
evaluation at this time: 1) no difference between treated and untreated breast and 
area, 2) slight difference between treated and untreated breast and area, 3) 
moderate difference between treated and untreated breast and area, and 4) large 
difference between treated and untreated breast and area. 
 
After rating all items, you are asked to place a check by any difference that was 
bothersome. 
 
1 
2 
3 
4 
Breast Size 
No difference 
Slight difference 
Moderate difference 
Large Difference 
Breast 
texture/hardening 
No difference 
Slight difference 
Moderate difference 
Large Difference 
Nipple appearance 
No difference 
Slight difference 
Moderate difference 
Large Difference 
Breast Pain 
No difference 
Slight difference 
Moderate difference 
Large Difference 
Breast Tenderness 
No difference 
Slight difference 
Moderate difference 
Large Difference 
Breast Shape 
No difference 
Slight difference 
Moderate difference 
Large Difference 
Breast Elevation (how 
high the breast is) 
No difference 
Slight difference 
Moderate difference 
Large Difference 
Scar Tissue 
No difference 
Slight difference 
Moderate difference 
Large Difference 
Fit of Bra 
No difference 
Slight difference 
Moderate difference 
Large Difference 
Breast Sensitivity 
No difference 
Slight difference 
Moderate difference 
Large Difference 
Fit of Clothing 
No difference 
Slight difference 
Moderate difference 
Large Difference 
 
 
 
YCC Amd. # 14 
53 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
Appendix VII 
 
CAVITY VISUALIZATION SCORE 
(Petersen RP, Truong PT, Kader HA, et al. Target volume delineation for partial breast 
radiotherapy planning: clinical characteristics associated with low interobserver 
concordance. Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):41-8.) 
 
0 = no visible seroma, 
1 = scar/shadow 
2 = seroma identifiable but with significant uncertainties 
3 = seroma identifiable with minor uncertainties 
4 = seroma easily identifiable, generally homogenous with slightly blurred margin 
5 = seroma easily identifiable, homogenous with sharp boundaries. 
 
 
 
YCC Amd. # 14 
54 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
Example of Well-defined Seroma Cavity, 4 
 
 
 
 
 
 
 
 
 
 
 
YCC Amd. # 14 
55 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
Example of a poorly defined seroma cavity unsuitable for 3D CRT APBI, Score 1 
 
 
 
 
 
 
 
YCC Amd. # 14 
56 
Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
APPENDIX VIII 
 
CONTOURING GUIDELINES 
 
1.0 Normal Structure And Target Contouring 
 
The following structures will be contoured in all cases: the excision cavity throughout its 
respiratory motion (ITV), CTV, and planning target volume (PTV), the planning target for 
evaluation (PTV_EVAL), ipsilateral breast, contralateral breast, thyroid, ipsilateral and 
contralateral lung, and heart. Based on the 4D CT scan acquired during free breathing, 
the tumor bed will be segmented throughout its entire respiratory excursion to comprise 
the ITV.  This will be expanded by 15 mm to comprise the CTV, although CTV will not 
include the pectoralis muscles, the chest wall, or within 5mm of skin.  Questions about 
CTV are to be directed to Dr. Suzanne Evans.  The CTV must never be smaller than the 
ITV, and a Boolean operator may be necessary (Boolean CTV “OR” ITV).  The PTV will 
be a 2 mm expansion of the CTV.  Treatment planning will be performed on the average 
scan with heterogeneity corrections.  The chin, shoulders and contralateral breast 
should be included in the scan. The target structures and normal tissue structures must 
be outlined on all CT slices.  The average scan may be used for contouring structures 
other than the ITV. 
 
In patients who have a very posterior or anterior cavity where the CTV is trimmed 
down to the ITV off of skin or pectoral muscle, the PTV should be expanded such 
that the ptv is a minimum 5 mm away from the ITV. This is intended to make sure 
that ptv to itv distance is a minimum of 5 mm (normally 17 mm after 15 mm 
expansion for ptv, but can be less in very posterior or very anterior cavities. 
 
A.  Thyroid 
 
The thyroid is easily visible on a non-contrast CT due to its preferential absorption of 
Iodine, rendering it “brighter” or denser than the surrounding neck soft tissues. The left 
and right lobes of the thyroid are somewhat triangular in shape, and often do not 
converge anteriorly at mid-line. All “bright” thyroid tissue should be contoured. 
 
B.  Heart 
 
The heart should be contoured beginning just below the level in which the pulmonary 
trunk branches into the left and right pulmonary arteries (PA). Above the PA, none of 
the heart’s 4 chambers are present. All the mediastinal tissue below this level should be 
contoured, including the great vessels (ascending and descending aorta, inferior vena 
cava). The heart should be contoured on every contiguous slice thereafter to its inferior 
most extent near the diaphragm. If one can identify the esophagus, this structure should 
be excluded. Contouring along the pericardium itself, when visible, is appropriate, as the 
coronary arteries lie between the percarium and the myocardium  The left anterior 
descending artery may be contoured, although no specific dose constraints are applied 
to this structure. 
YCC Amd. # 14 
57 
Reflects Protocol Version 9 
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APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
 
C.  Whole Breast Reference Volume Contouring 
 
Delineation of breast tissue extent remains difficult and free-handed CT interpretation by 
each individual investigator will yield significant variability. For the purposes of this 
protocol, the whole breast volume will be referred to as the whole breast reference 
volume and defined as all tissue volume, excluding lung, within the boundaries of 
standard whole breast tangential fields.  The whole breast reference volume should also 
exclude any non-breast structure deep to the lung-rib interface such as heart, pre-
cardiac fat, and liver. 
 
An acceptable method of autocontouring with Eclipse is to convert the 50% isodose line 
from a standard tangential plan to a structure, then Boolean operator “breast” and 
“Body” (to include nipple which may be excluded).   Subsequently, the Boolean operator 
can be used to remove any “breast” volume extending inside lung. 
 
This is meant to be only an approximation of the actual breast tissue volume, and it is 
recognized some degree of adjacent soft tissue will be included. However, with this 
definition it is anticipated that this volume will be reproducible and consistent from case 
to case and that the process can be automated within the 3D planning system for time 
conservation.  
To facilitate, the patient should be positioned in standard whole breast external beam 
treatment position. It is recommended that external marker wires be placed to indicate 
the clinical expectations of the external beam tangential field borders as a guide. The 
CT should be obtained from the mandible to the base of the lungs with a slice thickness 
of ≤ 5 mm. 
 
Free-handed contouring of the breast 
Free handed contouring will not be performed. 
 
Automated contouring of the breast 
Each 3D planning system has available different contouring functions and the specific 
methods may vary from system to system. Institutions are encouraged to investigate the 
capabilities of their planning system in regards to these contouring functions.  
 
With the Eclipse planning system, standard tangent fields should be set up as in 
whole breast radiation therapy.  Beam weighting should be optimized as is 
typically done for tangential field planning and normalized so that the 100% 
isodose line satisfactorily covers the volume of interest as determined by the set 
field geometries.   A new Structure should be created titled “Breast Reference” 
and the “convert isodose line to structure” tool should be used to convert the 
50% isodose line to the breast reference structure.  This should then be 
booleaned with the “patient” or “external” structure to include the nipple.  The 
lung and heart should be subtracted, and the structure should be reviewed and 
edited to insure that no tissue deep to the ribs is included (i.e. pericardial fat, 
liver, bowel). 
YCC Amd. # 14 
58 
Reflects Protocol Version 9 
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APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

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Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
 
Within the  Pinnacle 3D planning system, auto-contouring the whole breast reference 
volume, as defined above, is easily accomplished and can be completed in several 
ways. Outlined below is an example of one of these methods:  The Pinnacle 3D 
planning system has within its contouring functions a Region of Interest (ROI) 
expansion/contraction tool, found under Options within the contouring window, which 
allows a selected contour to be altered/limited automatically by selected ROIs already 
entered in the patient's plan. At the start of each case, the skin and lung contours will be 
entered with automated functions and the virtual standard whole breast tangent fields 
designed. By way of the ROI expansion/contraction tool, the planning system will start 
with the skin contour and alter it by limiting this contour to within the boundaries of the 
tangential fields and lung/chest wall interface, thus creating a new contour that 
represents the whole breast volume as defined above. Since this ROI 
expansion/contraction tool only uses entered contours, ROI’s representing the borders 
of the tangential fields must first be entered. To represent the superior and inferior field 
borders, a simple box contour that encompasses the entire body on each CT slice 
superior and inferior to the tangential field borders, are entered under a new ROI (i.e., 
field borders). This can be accomplished by entering manually on each appropriate CT 
slice or expediting by utilizing the interpolation tools. Added to the newly created ROI, 
named here field borders, is a contour that is entered on every CT slice within the 
tangent fields that represents the posterior tangent border. This contour is placed along 
the posterior field border, extending the contour beyond the CT slice and viewing 
window.  This contour can be entered manually on each appropriate CT slice or, to save 
time, the interpolation tool can be used to automate. Once field boundary contouring is 
complete, each CT slice will have either a simple encompassing box contour (if superior 
or inferior to the tangent fields) or a posterior field boundary contour (if within the 
tangential field borders). At this time, the ROI expansion/contraction window is brought 
up. Designate the skin as the source ROI and designate the lung and field borders 
limiting ROI’s. Highlight “contract” as the function and designate the destination of the 
newly created ROI (simply create a new ROI which will then be listed in the destination 
list). Click on Proceed with Contraction to complete the process. 
 
D.   
Target Contouring 
 
Target definitions are listed here: 
• ITV: THIS WILL REPRESENT THE PHYSIOLOGIC MOVEMENT OF THE TUMOR. 
The ITV will be representative of the  tumor bed throughout its entire respiratory 
excursion.  
 
• CTV – 1.5 cm beyond excision cavity. Volume expansion limited to exclude 
pectoralis muscles, chest wall, and the first 5 mm beneath the skin .  This should 
not be smaller than the ITV. 
 
• PTV: this will be a 2mm expansion of the CTV to account for intrafractional motion.  
 
• PTV_EVAL – the PTV excluding pectoralis muscles, chest wall and the first 5 mm 
YCC Amd. # 14 
59 
Reflects Protocol Version 9 
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APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
beneath the skin. 
YCC Amd. # 14 
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Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
Appendix IX 
 
QUALITY ASSURANCE OF DOSE DISTRIBUTION 
 
Each treatment plan shall be judged as: 
 
• Acceptable: 
 
− Dose volume histogram analysis of the target volume confirms 90% of the prescribed 
dose covers ≥ 90% of the PTV_EVAL. 
− Critical normal tissue DVHs within 5% specified value  
− Maximum dose does not exceed 120% of prescribed dose. 
- Dose delivered twice a day for a total of 10 treatments over a period of 5 to 10 days. 
 
• Unacceptable: 
 
− Dose volume histogram analysis of the target volume will confirm < 90% of the 
prescribed dose covers < 90% of the PTV_EVAL. 
− Critical normal structure DVH exceeds 5% of the specified value  
− Maximum dose exceeds 120% of prescribed dose. 
− Dose delivered over a period of time extending greater than 10 days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
APPENDIX X 
 
DOSIMETRY WORKSHEET: 
 
Indices of an approved treatment plan 
 
Patient Name 
Case 
# 
Target 
Organ/Tar
get 
Volume 
(cc) 
Dosimetry Index Value  
Unit Ideal 
Value** 
Seroma/Excision 
Cavity=ITV 
CTV 
PTV 
PTV-Eval 
V90 
(34.65 Gy) 
% 
>90% 
Whole  Breast 
Reference 
Volume (V50 and 
V100 are only 
required 
constraints to be 
met, all other are 
reporting only) 
V5 
(1.92 Gy) 
% 
<75% 
suggested 
V10 
(3.85 Gy) 
% 
<70% 
suggested 
V25 
( 9.625Gy) 
% 
<55% 
suggested 
V50 
(19.25 Gy) 
% 
< 45% 
IDEAL, 
<60% OK* 
V75 
(28.875 Gy) 
% 
<30% 
suggested 
V100 
(38.5 Gy) 
% 
< 23.5% 
IDEAL, 
<35% OK* 
Contralateral 
Breast 
Dmax 
cGy <115 cGy 
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Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018

APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018
Suzanne Evans, M.D., M.P.H. 
 
HIC 1110009173 
 
Ipsilateral Lung 
V30  
(11.55 Gy) 
% 
<15% 
Contralateral 
Lung 
V30  
(11.55 Gy) 
% 
<15% 
Heart (right sided) 
V5  
(1.92 Gy) 
% 
<5% 
Heart (left sided) 
V5  
(1.92 Gy) 
% 
<40% 
Thyroid 
Dmax 
cGy <115cGy 
* plans which exceed the V50 >60% or V100>35% will be reviewed by Dr. Suzanne 
Evans prior to approval. The definition and the method of collecting the above dosimetry 
quantities from an approved treatment plan for each patient are described as follows.  
 
• Whole  breast reference volume: Ideally, < 45% of the whole breast reference volume 
should receive ≥ 50% of the prescribed dose and < 23.5% of the whole breast reference 
volume should receive the prescribed dose.  As was done in NSABP B39, < 60% of the 
whole breast reference volume receiving ≥ 50% of the prescribed dose and < 35% of 
the whole breast reference volume receiving the prescribed dose is acceptable, 
although not ideal. 
• Contralateral breast: The contralateral breast reference volume, contoured using the 
same methods described for the ipsilateral breast reference volume, should receive 
<1.15 Gy (3% of prescribed dose) to any point. 
• Ipsilateral lung: < 15% of the lung can receive 11.55 Gy (30% of the prescribed dose.) 
• Contralateral lung: < 15% of the lung can receive 1.92 Gy  (5% of the prescribed 
dose). 
• Heart (right-sided lesions): < 5% of the heart should receive 1.92 Gy  (5% of the 
prescribed dose). 
• Heart (left-sided lesions): The volume of the heart receiving 1.92 Gy  (5% of the 
prescribed dose) (V5) should be less than the 40%. 
• Thyroid: maximum point dose of 1.15Gy (3% of the prescribed dose). 
 
 
 
 
 
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Reflects Protocol Version 9 
Version Date: September 5, 2014 
APPROVED BY THE YALE UNIVERSITY IRB 11/10/2017 VALID THROUGH 11/29/2018