A UW Phase II Trial of Multi-catheter HDR Brachytherapy Following Lumpectomy for Early Stage Breast Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: University of Wisconsin, Madison

RO 04102  
 
A UW Phase II Trial of Multicatheter HDR Brachytherapy  
Following Lumpectomy for Early Stage Breast Cancer  
 
 
Principal Investigator:  Rakesh R. Patel, M.D.  
Department of Human Oncology 
University of Wisconsin Medical School 
Madison, Wisconsin  53792 
Phone: 608-263-8500 
Fax: 608-263-3526 
E-mail: patel@humonc.wisc.edu 
 
 
Co-Investigators:  
Radiation Oncology 
 
 
 
 
Rupak Das, Ph.D. 
Hiral K. Shah, M.D. 
 
 
 
 
 
Kimberly Brandt, RN 
 
Medical Oncology 
 
 
 
 
Sharon Meadows, M.D. 
 
 
 
 
 
 
 
James Stewart, M.D. 
Lynn Van Ummersen, M.D. 
 
Surgical Oncology 
 
 
 
 
Tara Breslin, M.D. 
 
 
 
 
 
 
 
Eberhard Mack, M.D. 
David Mahvi, M.D. 
 
Pathology 
 
 
 
 
 
Jo Harter, M.D. 
 
Radiology 
 
 
 
 
 
Beth Burnside, M.D. 
Jeong Mi Park, MD 
 
Statistics 
 
 
 
 
 
Rick Chappell, Ph.D. 
 
Research Coordinator s 
 
 
 
Diana Trask 
 
 
 
 
 
 
 
Wendy Walker 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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INDEX 
 
 
 
Schema 
 
Eligibility Check 
 1.0 
Introduction 
 2.0 
Objectives 
 3.0 
Patient Selection 
 4.0 
Registration Procedures 
 5.0 
Radiation Therapy/Brachytherapy Treatment Planning 
 6.0 
Systemic Therapy 
 7.0 
Pathology 
 8.0 
Patient Assessments 
 9.0 
Data Collection  
10.0 
Statistical Considerations 
 
References 
 
APPENDIX 
I 
Data and Safety Monitoring Plan 
II 
Consent 
III 
Data Collection Forms 
IV 
Modified RTOG Toxicity Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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RO 04102  
 
A UW Phase II Trial of Multicatheter HDR Brachytherapy  
Following Lumpectomy for Early Stage Breast Cancer  
 
 
SCHEMA 
 
 
 
HDR Breast brachytherapy 
to 32-34 Gy /8-10 fractions/ 
4-5 days 
 
Registration of 300 
eligible patients 
 
 
 
 
Systemic Therapy
 
Cytotoxic chemotherapy should not start until at least two-weeks post-brachytherapy to allow adequate 
time for healing. Chemotherapy prior to brachytherapy is not permitted. Hormonal therapy may be 
utilized in any clinically appropriate sequence but will be discontinued during the one-week 
brachytherapy treatment course. 
 
ELIGIBILITY:   
 
- 
Invasive ductal, medullary, papillary, colloid (mucinous), tubular histologies or Ductal carcinoma in 
situ (DCIS) 
- 
Tumor Stage: Tis, T1, T2 if lesion ≤ 3 cm  
- 
Nodal Stage: N0 (negative sentinel node mapping is acceptable) (subjects with DCIS are exempt 
from nodal staging) 
or N1(1-3 nodes positive and no extracapsular extension).  This represents a cohort of patients that 
would not ordinarily receive axillary irradiation. 
- 
Clearly visible target as defined by ultrasound, surgical clips, or mammography 
-  Unifocal breast cancer (single focus which can be encompassed by one lumpectomy) 
-  Negative surgical margins  
- 
Negative post-lumpectomy mammogram if cancer presented with malignancy-associated 
microcalcifications  
- 
No Paget’s disease of the nipple or extensive intraductal component (EIC by Harvard definition: 1) 
more than 25% of the tumor is DCIS and there is DCIS in adjacent breast tissue, or 2) an 
intraductal carcinoma with microinvasion). 
- 
No previous radiation or chemotherapy for current breast cancer 
- 
No collagen vascular disease (systemic lupus erythematosis, scleroderma, or dermatomyositis) 
-  No co-existing medical conditions with life expectancy < 2 years. 
- 
Age > 18 years old 
- 
No pregnant or lactating women. 
-    No psychiatric or addictive disorders which would preclude obtaining informed consent  
-    Signed study-specific consent form 
 
 
 
 
 
 
 
 
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ELIGIBILITY CHECK 
The following questions will be asked at registration: 
 
 
(Y) 
1. Does the patient have histologically confirmed invasive ductal, medullary, 
papillary, colloid (mucinous), tubular cancer of the breast, or DCIS 
 
(Y) 
2. Is the AJCC T classification Tis,T1-2, N0-1, M0?  
 
(Y) 
3. Is the tumor size ≤ 3 cm. 
_____(Y) 
4.  Are there ≤ 3 nodes positive without extracapsular extension?  
_____(Y) 
5. Does the patient have a well-defined target (ultrasound-defined seroma, surgical 
clips, or mammography)? 
_____(N) 
6. Has the patient undergone lumpectomy resulting in negative tumor margins? (if 
yes, skip to Q8) 
 
(Y) 
7. If no, is re-excision planned prior to introduction of radiation sources? (failure to 
meet all criteria subsequent to re-excision will result in ineligibility) 
 
(Y/N) 
8. Any evidence of pre-excision breast microcalcifications in the initial 
mammogram?  
 
 
 
 
(Y) If yes, was a postoperative mammogram done and found negative 
for residual suspicious microcalcifications? 
 
(N) 
9. Any evidence of multicentric breast tumor, or unresolved suspicious synchronous 
tumors/calcifications  
 
(N) 
10. Any evidence of Paget's disease of the nipple, tumor involving skin, internal 
mammary or supraclavicular lymph nodes or distant metastasis? 
 
(N) 
11. Any evidence of collagen vascular disease or shortened life expectancy from 
coexisting medical conditions (< 2 yrs)? 
 
(N) 
12. Any prior radiotherapy, chemotherapy or non-hormonal therapy for the present 
breast cancer? 
 
(N)    
13. Is the patient pregnant or lactating? 
 
(Y) 
  14.  Is the patient ≥ 18 years old? 
 
 
 
 
 
 
 
 
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1.0 
BACKGROUND 
 
 
Breast Conservation Therapy (BCT) 
 
 
BCT is now widely accepted as a treatment option for most women with Stage I and II 
invasive breast cancer and most patients with ductal carcinoma in situ (DCIS).  Six 
prospective randomized trials have clearly demonstrated similar overall and distant 
disease-free survival for patients receiving breast-conserving therapy, compared with 
patients treated by conventional mastectomy.1-6 Despite superior cosmetic outcome, 
BCT is more complex and requires a protracted treatment regimen comprised of 6 
weeks of daily external beam radiation therapy to the whole breast.  This often proves 
prohibitive for the working woman, elderly patients, and those who live at a significant 
distance from a radiation treatment center.   In addition, with the more frequent use of 
adjuvant chemotherapy in both node-negative and node-positive patients, substantial 
delays can be incurred prior to the initiation of systemic chemotherapy if a 
conventional fractionated course of irradiation (XRT) is given first or in delivery of loco-
regional XRT if chemotherapy is delivered beforehand. Thus, despite the potential 
benefits, only 30-50% of patients who are candidates for breast conservation actually 
receive it.7
 
 
 
A Paradigm Shift from Whole Breast to Partial Breast Irradiation 
 
Most of the logistical problems associated with BCT relate to the protracted course of 
external beam XRT delivered to the whole breast.  Standard therapy after tumor 
excision generally includes five weeks of external beam XRT to the whole breast (45-
50 Gy) followed by an additional 10-15 Gy boost to the tumor bed.  The rationale for 
this approach is based upon two principles. First, higher doses of XRT are given to the 
'tumor bed' in an attempt to control residual small foci of cancer that may be left behind 
after excision alone. Second, whole breast XRT is used to eliminate possible areas of 
occult multicentric in situ or infiltrating cancer in remote areas of the breast. That such 
remote, multicentric areas of cancer exist has long been established.  However, the 
biological significance of these areas of occult cancer is unknown and the necessity to 
prophylactically treat the entire breast has recently been questioned.   
 
There are at least six prospective randomized trials that have been conducted 
comparing the outcome of patients treated with lumpectomy alone or followed by 
whole breast XRT.5,8-12   Across these studies, there is a similar 3-fold reduction in the 
ipsilateral breast failure rate with the addition of radiotherapy.  For instance, in the 
NSABP B-06 randomized prospective trial, which included patients with invasive 
cancers up to 4 cm in size with negative surgical margins, the breast recurrence rate of 
43% with lumpectomy alone is considerably higher than the 10% breast failure rate of 
the lumpectomy and whole breast irradiation arm.5  In these studies, the percentage of 
patients receiving whole breast irradiation who recur in a remote location of the breast 
potentially not covered by partial breast irradiation was low (< 3.5%).  Is this absence 
of the expected number of remote breast recurrences due to sterilization of other 
quadrants by the whole breast radiation therapy employed in these series or to the 
biological insignificance of occult cancer foci in remote quadrants of the breast?  If the 
former is true, then one would expect increased remote relapses in the conservative 
surgery alone patients. 
 
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To address this question, one must examine patients treated with surgery only and 
evaluate the number of remote recurrences.  In fact, the proportion of patients who 
recur in a portion of the breast that would not be covered by partial breast irradiation is 
the same as patients receiving whole breast irradiation.  This observation is validated 
by studies such as those conducted by Liljegren8 and Crile13 also demonstrated that 
85% and 84% of local recurrences were in the immediate vicinity of the lumpectomy 
site defined as the surgical scar and the skin directly over the surgical field translating 
to an absolute risk of remote recurrence of 3.0% and 1.7%, respectively.  From these 
data, one can infer that radiation therapy following lumpectomy has as its maximal 
effect on the reduction of breast cancer recurrence at or very near the lumpectomy site 
casting doubt on the belief that remote recurrences originate from multicentric disease 
at the time of the index lesion demonstrated on histopathology. If the above 
observations are valid, radiation therapy can be confidently directed to the tissue 
surrounding the excision cavity of the breast. 
 
 
Clinical Experience: 
 
There are currently several groups studying the efficacy of lumpectomy bed irradiation 
alone in the management of early stage breast cancer patients treated with BCT.  Both 
interstitial brachytherapy techniques as well as external beam irradiation protocols 
have been implemented. Preliminary results from these trials are very encouraging 
and the techniques have been shown to be safe, tolerable, and highly reproducible 
(Data outlined in table below).14
 
 
Although these studies require longer follow-up, they have demonstrated that with 
appropriate patient selection, excellent local control and cosmetic outcome can be 
achieved with breast brachytherapy with minimal toxicity.   
 
University of Wisconsin Hospital Experience 
 
 
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From 11/2000 to 4/2004, 240 pts have been treated with high-dose rate accelerated 
partial breast irradiation at our institution (211 interstitial multiple catheters).  Selection 
criteria have included tumors < 3 cm pathologic size, 0-3 positive nodes with no 
extracapsular 
spread, 
negative 
margins 
and 
negative 
post-lumpectomy 
mammography.  Two techniques, prone template with digital mammographic-guidance 
and supine with ultrasound or fluoroscopic guidance were used for catheter placement.  
Target volume has remained constant as the surgical cavity with 2 cm margin but at 
least 5-mm deep to the skin surface and no deeper than the pectoral fascia.  In 
5/2002, CT-based 3-D treatment planning was implemented allowing more accurate 
target delineation, improved geometric coverage of the target volume, and dosimetric 
verification.  The volume of breast receiving 100% and 150% (Vol100%, Vol150%) of the 
prescribed dose have been determined from dose volume histograms for each patient.  
The dose homogeneity index, and percent target volume receiving 100% of the 
prescription dose was determined for quality assurance.  There has been excellent 
coverage of the target volume with fractionated HDR brachytherapy delivered in the 
supine position (32-34 Gy/8-10 bid fractions).  Interstitial breast brachytherapy has 
been successfully delivered with high quality assurance and was well-tolerated in all 
patients.  98% of pts had good to excellent cosmesis at 12 months with minimal acute 
toxicity on formal review of digital photographs.  All but one patient is without clinical or 
radiographic evidence of disease at a median follow-up of 19 months.  There has been 
minimal significant late toxicity.15
 
 
 
Study Rationale 
 
 
Can an acceptable outcome be achieved with radiation delivered only to the region of 
the tumor bed? If this were so, partial breast irradiation may lend itself to much shorter 
treatment times (one week) as the toxicities to adjacent normal structures (i.e., heart, 
lung, chest wall, skin, and contralateral breast) should be significantly reduced with this 
approach.  This significantly shortened treatment time could potentially reduce health 
care costs, improve the quality of life of many patients undergoing BCT, and just as 
importantly, extend the conservation option to more women by reducing the 
inconvenience of radiation therapy.  The implications of the presented clinical and 
pathologic data coupled with favorable early outcomes form the basis of the current 
study. 
 
 
Patient selection criteria in this protocol have been chosen to minimize the risk of 
multicentricity and a remote breast recurrence.  The key factors are the exclusion of 
patients with microscopic extension of tumor cells to the inked surgical margins, 
lobular histologies, tumors larger than 3 cm, and patients having an extensive 
intraductal component.  Patients with involvement of 4 or more axillary lymph nodes 
have a significant risk for regional nodal relapse, and most radiation oncologists 
choose to include them in external beam portals.  These patients would lose the 
logistical advantage of a shortened breast treatment regimen.  Even with these strict 
selection criteria, approximately 71,000 women per year in the United States would be 
candidates for this protocol.  
 
 
2.0 
OBJECTIVES 
 
 
This study will evaluate the local control rate of brachytherapy, cosmetic results, and 
complication rates when used as the sole method of radiation therapy for patients with 
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stage I and II (≤ 3 cm) carcinoma of the breast treated with lumpectomy, with 
histologically negative surgical margins. 
 
 
 
2.1   
Primary Objective 
To determine if for DCIS and stage I and II breast cancer (< 3 cm primary), 
brachytherapy will produce non-inferior local-regional control at 5 years 
compared to historical observed results with a conventional course of 
external beam radiotherapy (~94%)—(See 10.1.1) 
 
 
2.2 
   Secondary Objectives 
• 
To determine if brachytherapy will have non-inferior toxicity to external beam 
radiotherapy (5%) at 3 years.  Grade 3 or higher toxicity will be scored. 
• 
To evaluate cosmesis at each follow-up by utilizing a cosmesis score based 
on established Harvard criteria. 
• 
To assess patient satisfaction with breast brachytherapy by a questionnaire 
pre-brachytherapy, at completion, and post-brachytherapy.  
• 
To perform a dosimetric comparison with an external beam plan for each 
patient.  The following parameters will be evaluated: skin dose, target 
coverage, dose homogeneity index, and NTDmeans from dose volume 
histograms for each individual patient for heart, lung, and contralateral breast. 
• 
To 
assess 
the 
ability 
to 
interpret 
mammography 
after 
interstitial 
brachytherapy. 
• 
To evaluate Disease-free, Mastectomy-free, and Overall Survival. 
 
  
3.0 
PATIENT SELECTION CRITERIA 
 
3.1 
Eligibility Criteria 
 
• 
Diagnosis of invasive ductal, medullary, papillary, colloid (mucinous), tubular 
histologies or Ductal carcinoma in situ (DCIS) 
• 
Tumor stage: Tis, T1, T2 if lesion ≤ 3 cm  
• 
Nodal Stage: N0 (or a negative sentinel node mapping is acceptable) or  N1 
(1-3 nodes positive and no extracapsular extension).  This represents a 
cohort of patients that would not ordinarily receive axillary irradiation. 
(subjects with DCIS are exempt from nodal staging) 
• 
Clearly visible target as defined by ultrasound, surgical clips, or 
mammography 
• 
Unifocal breast cancer (single focus which can be encompassed by one 
lumpectomy) 
• 
Negative microscopically-assessed surgical margins  
• 
Negative 
post-lumpectomy 
mammogram 
if 
cancer 
presented 
with 
malignancy-associated microcalcifications 
• 
No Paget’s disease of the nipple or EIC by the  Harvard definition, i.e.  1) 
more than 25% of the tumor is DCIS and there is DCIS in adjacent breast 
tissue, or  2) an intraductal carcinoma with microinvasion. 
• 
No collagen vascular disease (systemic lupus erythematosis, scleroderma, or 
dermatomyositis) 
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• 
No previous radiation or chemotherapy for current breast cancer 
• 
No co-existing medical conditions with life expectancy < 2 years  
• 
 Age > 18 years old 
• 
No pregnant or lactating women. 
• 
No psychiatric or addictive disorders which would preclude obtaining 
informed consent or completing the full series of brachytherapy treatments on 
an outpatient basis.  
• 
Signed study-specific consent form 
 
4.0 
REGISTRATION PROCEDURE 
 
Patients must meet all eligibility requirements and sign an informed consent form 
prior to study enrollment.  All patients will be registered by the Radiation Oncology 
Research Coordinators at (608)263-8500 prior to treatment.  The Research 
Coordinators will verify eligibility, and completion of pretreatment evaluations. 
 
5.0 
RADIATION THERAPY: 3-D Based Treatment Planning 
5.1 
Brachytherapy/Target Visualization 
Patients will undergo an interstitial implant, either utilizing a prone stereotactic 
method or a supine, ultrasound-guided or CT-guided technique, both under 
local anesthesia.  Multiple catheters must be placed either free-hand or with 
the template system.  Single balloon intracavitary catheter (MammoSite) is 
not permitted.   
5.2 
Target Volume Definition 
Radioactive implants following lumpectomy are intended to deliver a 
tumoricidal dose to the target volume.  The delineation of this target volume is 
essential for prescribing a dose and dose distribution capable of sterilizing 
occult tumor foci in the breast tissue surrounding the excision cavity.  The 
target can be defined either by surgical clips visualized on stereotactic digital 
mammography, ultrasound, or CT visualization of the post-surgical seroma 
with subsequent Omnipaque nonionic contrast injection.  The target volume 
will be defined as the volume encompassed by an irregularly-shaped surface 
1.5-2 cm outside the excision cavity in all dimensions unless limited by skin or 
chest wall.   
5.3 
Implant Geometry Design 
 
Peripheral coverage is obtained positioning at least one catheter on each 
side 1 cm or more beyond the target volume.  The other dimension of 
peripheral coverage is determined by the length of the active sources within 
each catheter. 
 
The catheters must be parallel to each other and as straight as possible. 
 
The rigid template will be used for the prone stereotactic method.  The 
advantage of templates is precise geometrical source distribution, but there 
may be a problem with coverage of a curved, irregularly-shaped target 
volume.  This can be overcome by the addition of free-hand catheters in 
areas of potential cold spots, thereby improving geometric volume coverage.  
This free-hand technique will be used with ultrasound or CT guidance for the 
supine method. 
5.4 
3-D CT Based Treatment Planning  
CT based planning will be used for dosimetric evaluation. Simulator-based 
planning is not permitted. 
5.5 
Dose Prescription  
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High dose-rate:  Patients will receive either a total dose of 34 Gy given BID at 
3.4 Gy per fraction (10 fractions), or 32 Gy given BID at 4.0 Gy per fraction (8 
fractions) to be delivered with a high dose-rate Ir-192 source as an outpatient.  
Each fraction will be separated by a minimum of 6 hours. 
 
 
5.6 
Dosimetric Characteristics 
• 
Dose optimization will be guided by dose homogeneity index (DHI) which is 
defined as DHI = (V100-V150)/V100, where V100 and V150 are the volumes 
covered by the 100% and 150% isodose lines, respectively.  The DHI must 
be between 0.7-1.0. 
• 
The dose must be prescribed to a depth of > 5 mm from the skin surface. 
• 
The following dosimetric parameters must be recorded on the dosimetry form: 
(1) target volume, (2) seroma volume, (3) percent target covered by chosen 
isodose line, (4) # of catheters, (5) volume of implant, and (6) V100 and V150, 
(7) DHI, and (8) NTDmeans of heart, lung, and contralateral breast from DVH 
analysis. 
5.7 
Photography Documenting Implant Geometry 
At least one digital image is required - a close-up encompassing the treated 
breast only in a position which optimally exhibits the implant geometry, taking 
care to exclude the patient's face.   
5.8 
Toxicity Reporting (Serious Adverse Effects):   
University of Wisconsin Hospital and Clinics has created a data and safety 
monitoring plan, and a data and safety monitoring board to closely monitor 
the proposed study (Appendix).  Modified RTOG toxicity scoring will be 
utilized (Appendix). 
 
6.0  
SYSTEMIC THERAPIES 
• 
No prior chemotherapy.  Subsequent systemic therapy will be at the 
discretion of the medical oncologist. 
• 
Chemotherapy regimens should be started no earlier than 2 weeks after the 
removal of the brachytherapy catheters. 
• 
Tamoxifen or other hormonal agents should not be given during 
brachytherapy. 
 
7.0 
PATHOLOGY 
• 
All outside pathology slides should be reviewed at UW. 
• 
Measurement of the resected breast specimen should be obtained in three 
dimensions and recorded if possible (gross or microscopic measurement is 
acceptable). 
• 
If of adequate size, tumor should be harvested for estrogen and progesterone 
receptor determination. Immunohistochemical staining is an alternative. 
• 
HER2/neu testing should be done in all patients if possible. 
• 
Multiple blocks of the primary tumor and of breast tissue from the inked 
margins should be taken, the latter to confirm negative margins.  Margins 
generally are positive if there is invasive or noninvasive tumor at the inked 
resection margin, close but negative if the tumor is within 2mm of the inked 
margin, and negative if the tumor is > 2mm from the inked margin.  Extent of 
negative margin should be recorded as (≤ 2mm; 2-10mm; ≥10mm) if 
possible. 
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• 
Pathology report must include DCIS or invasive, LVI, lymph node status, 
histological subtype, grade, and EIC if present. 
 
 
 
 
 
8.0 
PATIENT ASSESSMENTS 
8.1 
Study Parameters
Assessment 
Pre 
Rx 
During/After 
Brachytherapy 
Post RX 
4-6 weeks 
Post RX 
6 mos. 
Post RX 
1 year 
H & P (Initial Eval Form) 
X 
 
 
 
 
Chest x-ray 
X 
 
 
 
 
Lab studiesa
X 
 
 
 
 
H & P (Follow-up Form) 
 
 
X 
X 
  Xc 
Disease status 
X 
 
X 
X 
  Xc 
Toxicity Assessment 
 
X 
X 
X 
  Xc 
Mammograms 
Xd 
 
 
X 
  Xe 
Cosmesis, Pt (Form) 
X 
 
 
X 
  Xb 
Cosmesis, MD (Form) 
X 
 
 
X 
  Xb 
Photographs 
X 
X 
X 
X 
  Xc 
Questionnaire (QOL) 
X 
X 
X 
X 
  Xb 
a. CBC, platelets, PTT, PT, BUN. creatinine, lytes 
b. Yearly thereafter upto 5 years. 
c. Clinical examination and disease status assessment at 6 month intervals for the first 5 years and 
yearly intervals thereafter.  (Can be done via clinic visit notes from other physicians involved in 
patient’s care or via telephone follow-up). 
d 
pre and post lumpectomy (if applicable) 
e 
Every 6 months for 3 years and then yearly for 5 years (for treated breast) and yearly for opposite 
breast 
8.2 
Response Criteria - Treatment failure 
• 
The definition of a treatment failure is: histologic evidence of recurrent 
carcinoma, either invasive or non-invasive (except LCIS) in the ipsilateral 
breast at 5 years. 
• 
Ipsilateral breast recurrences will be considered local (infield) if they occur 
within the prescription isodose volume, peripheral if between the prescription 
isodose volume and a volume 2 cm outside of the prescription isodose 
volume.  Ipsilateral recurrences will be considered non-contiguous or 
extrafield if they are beyond the peripheral volume described above. 
• 
Ipsilateral axillary, infraclavicular, internal mammary, or supraclavicular 
recurrence or distant metastases will not be considered a treatment failure 
unless accompanied by ipsilateral breast recurrence. 
8.3 
Toxicity Criteria 
• 
Patient will be seen on a daily basis by treating physician while receiving 
radiation therapy. Toxicities resulting from brachytherapy will be collected and 
graded according to the Modified RTOG criteria (Appendix IV).  Any 
toxicities grade 3 or higher will be promptly reported to DSMB and IRB 
as specified in the appendix. 
8.4     Definitions of Levels of Cosmetic Outcome: 
• 
Patients will be grouped according to chemotherapy or hormonal therapy.  
Cosmesis will be graded by the patient and the radiation oncologist pre-RT, 6 
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and 12 months after completion of therapy and at yearly intervals thereafter.   
Cosmesis will also be evaluated from the photographs submitted to 
investigators at required intervals.  The following established cosmesis 
scoring system will be used: 
• 
Excellent - When compared to the untreated breast, there is minimal or no 
difference in the size, shape or texture of the treated breast.  There may be 
mild thickening or scar tissue within the breast or skin, but not enough to 
change the appearance. 
• 
Good - There is mild asymmetry in the size or shape of the treated breast 
as compared to the normal breast.  The thickening or scar tissue within the 
breast causes only a mild change in the shape. 
• 
Fair - There is obvious difference in the size and shape of the treated 
breast.  This change involves 1/4 or less of the breast.   
• 
Poor - There is marked change in the appearance of the treated breast 
involving more than 1/4 of the breast tissue. 
8.5 
Photographs 
• 
Routine photographs must be taken of the post-surgical breast prior to 
catheter placement.  At least one photograph of the breast with catheters in 
place, prior to loading the radioactive sources, is required.  Photographs 
should also be taken at prior to implantation, 4-6 weeks, 6 months, 12 months 
post-implant, and yearly thereafter.  Images will be evaluated for any visible 
complication, degradation, or improvement of cosmesis or local/regional 
treatment failure.  Digital images will be used.  Post surgical (pre-catheter) 
and all follow-up photographs should always follow the guidelines specified in 
the next section.  Photographs will be kept with the patient’s medical record.  
• 
The first photograph should be a closeup encompassing only the treated 
breast at a 45° oblique with arms elevated over the head.  The second 
photograph should 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 and framing or focusing on both the 
treated and untreated breast to allow optimal comparison of the breasts for 
symmetry.  .  
9.0 
DATA COLLECTION  
9.1 
Summary  
Prior to brachytherapy 
 
  
• 
Eligibility Checklist 
  
• 
Initial Evaluation Form (Appendix III) 
• 
Patient QOL form (Appendix III)  
• 
Cosmesis Forms (Appendix III) 
 
           At completion of brachytherapy 
• 
Patient QOL form (Appendix III) 
• 
Treatment Toxicity Form 
 
• 
Radiotherapy Treatment/Dosimetry Form (Appendix III)  
           At 4-6 wks, 6 mo., and 12 months after implant; q 6 months up to 5 years, then 
annually.  Also at progression/relapse and at death 
• 
Follow-up Form (Appendix III) -- Can be done via clinic visit notes from other 
physicians involved in patient’s care or via telephone follow-up 
           At 6 mo. and 12 months after the completion of therapy, then yearly up to 5 years 
• 
Cosmesis Forms 
 
• 
Patient (Appendix) 
 
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• 
Radiation Oncologist (Appendix III) 
• 
Patient QOL form (Appendix III) 
 
 
10.0 
STATISTICAL CONSIDERATIONS   
10.1 
Study Endpoints 
10.1.1 
Ipsilateral breast recurrences  
 
 
This is a one-arm equivalence trial comparing the local failure rate in 300 
patients receiving brachytherapy to the historical mean event rate of 6% (see 
Table below) among patients given external beam radiation.  The null 
hypothesis thus is that brachytherapy is worse than external beam radiation; 
the alternative hypothesis is that the two regimens are clinically equivalent, 
meaning that brachytherapy is not significantly worse than external beam.  
Symbolically  
 
H_0: Pr(Local Failure, brachy.) >  Pr(Local Failure, EB) + ∆ 
 
H_A: Pr(Local Failure, brachy.) <= Pr(Local Failure, EB) + ∆, 
 
where "Pr()" denotes the probability of its argument and ∆ is the margin of 
clinical equivalence.  That is, we consider two regimens whose event 
probabilities differ by less than ∆ to be equivalent.  For this study we take ∆ to 
be 5%. 
 
The analysis will be conducted by calculating an exact 95% confidence 
interval for the probability of local failure in the brachytherapy group and 
noting whether it includes 11% (obtained as Pr(Local Failure, EB) + ∆ = 6% + 
5%).  If it does then we will not reject the null hypothesis and equivalence 
cannot be concluded.  If the confidence interval for the probability of local 
failure given brachytherapy falls entirely below 11% then we conclude that 
brachytherapy is clinically equivalent (or possibly superior) to external beam 
radiation as a treatment for these patients.  If, among 300 patients, there are 
23 local failures (7.7%) then the exact 95% confidence interval for the true 
failure rate will be (5.2%, 11.2%).  If there are 22 failures (7.3%) then the 
confidence interval will be (5.0%, 10.8%).  Therefore we will reject the null 
hypothesis and conclude equivalence if we observe 22 or fewer local failures. 
 
Power here is the probability that we will reject the null hypothesis and 
conclude equivalence given that it truly holds.  If the two regimens rates are 
identical, such that Pr(Local Failure, brachy.) = Pr(Local Failure, EB) = 6%, 
then the power with 300 patients is 86%.  If the brachytherapy rate is inferior 
to external beam by 2%, so that Pr(Local Failure, brachy.) = 8% and Pr(Local 
Failure, EB) = 6% (which is still within our definition of clinical equivalence) 
then power drops to 39%.  However if the brachytherapy rate is superior to 
external beam by 2% so that Pr(Local Failure, brachy.) = 4% and Pr(Local 
Failure, EB) = 6% then the power is 99.8%.  Therefore if the local failure is 
6% or less in the brachytherapy group then this study is well-powered to 
conclude equivalence within a margin of 5%.  
 
 
 
 
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Page 14 of 30 
 
 
 
Study
# Patients
5-year LF Rate (%) 
Weighted LF rate
French 
 
 
 
88
4.5
396
NSABP B-06 
 
 
 
628
5
3140
NCI 
 
 
 
121
2
242
Danish 
 
 
 
430
5
2150
EORTC 
 
 
 
456
11
5016
Milan 
 
 
 
352
3
1056
Total/Mean 
2075 
5.08 
5.78% 
 
 
10.1.2 
Toxicity Assessment 
 
Patient will be seen on a daily basis by treating physician while receiving 
radiation therapy and during each follow-up visit. Toxicities resulting from 
brachytherapy will be collected and graded according to the Modified RTOG 
Toxicity Criteria (appendix).  Any toxicities grade 3 or higher will be promptly 
reported to DSMB and IRB. 
10.1.3 
Cosmesis 
 
Cosmetic results will be assessed by both the physician and the patient pre-
brachytherapy, at six and twelve months, then annually.  Photographs are to 
be taken at these time points according to the specifications in Section 8.5.   
10.1.4    Quality of Life Assessment 
 
Patient satisfaction with breast brachytherapy will be assessed by a 
questionnaire at defined intervals: pre-brachytherapy, at completion, 4-6 
weeks post-brachytherapy, 6 months post-brachytherapy and annually 
thereafter. (attached forms) 
10.1.5    Dosimetric analysis 
 
Dosimetric analysis will be performed and compared to an external beam 
plan for each patient.  The NTDmeans from dose volume histogram analysis 
for each individual patient for skin, heart, lung, and contralateral breast will be 
determined. 
10.1.6 
Mammography Interpretation 
 
The ability to interpret mammography after interstitial brachytherapy will be 
prospectively evaluated by the radiologist. 
10.1.7 
Disease-Free Survival and Mastectomy-Free Survival 
 
All disease recurrences and surgical interventions will be recorded.  In 
disease-free survival (DFS), any tumor recurrence or death will be considered 
a failure. In mastectomy-free survival (MFS), the failures will be mastectomy 
and death.  Ipsilateral breast recurrence rate (subdivided by in-field, 
peripheral and extra-field locations) ipsilateral nodal recurrence rate and 
distant metastasis rate will be calculated. 
10.1.9 
Overall Survival (OS) 
 
Death from any cause will be considered a failure. 
10.2 
Study Design 
 
The sample size will be approximately 300 patients. The toxicity rate will be 
summarized along with exact 95% confidence intervals.  DFS, MFS and OS 
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results will be summarized using Kaplan-Meier curves with the usual 
Greenwood estimates of standard errors.  Summary statistics will be given for 
cosmesis, quality of life, dosimetric, and mammography interpretation 
measures.  All analyses will be conducted on an intent-to-treat basis; that is, 
all registered patients will be included in the analyses.     
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REFERENCES 
 
1. Veronesi U, Banei A, Del Vecchio M, et al: Comparison of Halsted mastectomy with 
quadrantectomy, axillary dissection, and radiotherapy in early breast cancer: Long-term 
results. Eur J Cancer Clin Oncol. 9:1085-1089, 1986. 
2. Blichert-Toft M, Brincker M, Andersen JA, et al: A Danish randomized trial comparing 
breast-preserving therapy with mastectomy in mammary carcinoma. Acta Oncol. 27:671-
677, 1988. 
3. Van Dongen JA, Bartelink H, Fentiman IS, et al: Randomized clinical trial to assess the 
value of breast conserving therapy in stage I and II breast cancer. EORTC 10801 trial. 
JNCI Monogr. 11:l5-18, 1992. 
4. Sarrazin D, Le MG, Arriagada R, et al: Ten-year results of a randomized trial comparing a 
conservative treatment to mastectomy in early breast cancer. Radiother Oncol. 14:177-
184, 1989. 
5. Fisher B, Redmond C, Poisson R, et al: Eight-year results of a randomized clinical trial 
comparing total mastectomy and lumpectomy with or without radiation in the treatment of 
breast cancer. N Eng J Med. 320:822-828, 1989. 
6. Lichter AS, Lippman ME, Danforth DN, et al: Mastectomy versus breast-conserving therapy 
in the treatment of stage I and II carcinoma of the breast: A randomized trial at the 
National Cancer Institute. J Clin Oncol. 1996. 
7. Farrow DC, Hunt WC, Samet, JM. Geographic variation in the treatment of localized breast 
cancer. N Engl J Med. 326:1097-1101, 1992. 
8. Lilijegren G, Holmberg L, Adami H0, et al. Sector resection with or without postoperative 
radiotherapy for Stage I breast cancer. Five year results. J Natl Cancer Inst. 86:717-722, 
1994. 
9. Clark RM, McCulloch PB, Levine MN, et al. A randomized clinical trial to assess the 
effectiveness of breast irradiation following lumpectomy and axillary dissection for node 
negative breast cancer. J Natl Cancer Inst. 84:683-689, 1992. 
10. Veronesi U, Luini A, Del Vecchio M, et al. Radiotherapy after breast preserving surgery in 
women with localized cancer of the breast. N Engl J Med. 328:1557-1591, 1993. 
11. Forrest AP, Stewart HJ, Everington D, et al. Randomized controlled trial of conservation 
therapy for breast cancer: 6-year analysis of the Scottish trial. Lancet. 348:708-713, 
1996. 
12. Schnitt S, Hayman J, Gelman R, et al. A prospective study of conservative surgery alone 
in the treatment of selected patients with stage I breast cancer. Cancer. 77:1094-1100, 
1996. 
13. Crile G Jr, Esselstyn CB Jr.  Factors influencing local recurrence of cancer after partial 
mastectomy.  Cleveland Clin J Med 1990;57:143-146. 
14. Arthur, D et al.  Accelerated partial breast irradiation: an updated report 
 
from the American Brachytherapy Society Brachytherapy 2:124-130; 2003 
15. Patel, RR; Shah, HK; Das, RK; Forouzannia A; Odau, H; Kuske, RR:  Interstitial High 
Dose Rate Accelerated Partial Breast Irradiation Alone in Breast Conservation Therapy:  
The University of Wisconsin Experience.  Proceedings of the 89th  Scientific Assembly 
and Annual Meeting of the Radiologic Society of North America 2003; 147: #012-RO 
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Appendix I 
 
Data Safety and Monitoring Plan 
   
Oversight And Monitoring Plan 
The UWCCC Clinical Trials Monitoring Committee (CTMC) is responsible for monitoring 
data quality and patient safety for all UWCCC clinical studies.  A summary of CTMC 
activities follows: 
Review of all clinical trials conducted at the UWCCC for progress and safety 
Review of all adverse events requiring expedited reporting as defined in the protocol 
Review of reports generated by the UWCCC data quality control review process  
Submit recommendations for corrective action to the Clinical Affairs Committee (CAC)  
Notify the Study Chair of the CTMC recommendation to the CAC 
Notify external sites participating in multiple-institutional clinical trials coordinated by the 
UWCCC of adverse events requiring expedited reporting and subsequent committee 
recommendations for study modifications. 
 
Monitoring And Reporting Guidelines 
Phase I/II and Phase II Trials 
Data related to these trials are discussed at regularly scheduled Disease Oriented 
Working Group meetings where the result of each patient’s treatment is discussed and the 
discussion is documented in the minutes. The discussion will include for each treatment 
arm/dose level, the number of patients, significant toxicities as described in the protocol, 
dose adjustments, and responses observed.  Twice yearly, summaries will be submitted to 
the Clinical Trials Monitoring Committee for review. 
 
REVIEW AND OVERSIGHT REQUIREMENTS 
Adverse Event – Reported By Phone Within 24 Hours 
Adverse events requiring expedited reporting by phone within 24 hours (as described in the 
protocol) will also be reported by phone to the Clinical Trials Monitoring Committee administrator 
within one working day.  Confirmation that all appropriate parties were notified will be done at this 
time.  Hardcopies or electronic versions of NCI ADEERS form (#3500) and/or any other 
documentation available at that time will also be reviewed by the Committee Chair who will 
determine if immediate action is required. Within ten working days all subsequent SAE 
documentation that is available will be submitted with a completed UWCCC SAE Evaluation 
Checklist to the Committee Chair who will determine if further action is required.  All information 
will be tracked in the UWCCC database. 
If the AE occurs on a multiple-institutional clinical trial coordinated by the UWCCC, the 
Safety Coordinator will insure that all participating sites are notified of the event and resulting 
action within one working day of the determination. 
Adverse Event  – Reported within 10 Days 
Adverse events requiring expedited AE reports in writing within 10 working days (as 
described in the protocol) will be sent to the UWCCC Safety Coordinator. Hardcopies or electronic 
versions of NCI ADEERS form (#3500) or other required forms will be submitted along with a copy 
of the SAE Evaluation Checklist.  The Committee Chair will review these forms and determine if 
further action is required.  This information will be tracked in the UWCCC database. 
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If the AE occurs on a multiple-institutional clinical trial coordinated by the UWCCC, the 
Safety Coordinator will insure that all participating sites are notified of the event and resulting 
action within one working day of the determination. 
Study Progress – Quarterly Review 
Study progress assessment to determine whether accrual projections are being met and to 
determine if the trial should be continued based upon the likelihood of timely completion are 
reviewed at quarterly Clinical Trials Monitoring Committee meetings.  Cumulative reports of 
adverse events requiring expedited reporting and any new adverse event requiring expedited 
reporting are also reviewed at the committee’s quarterly meetings. 
An overall assessment of accrual, toxicities as described in the protocol, and responses will 
enable the committee members to assess whether significant benefits or risks are occurring that 
would warrant study closure. This information is provided by Disease Group meeting minutes, 
internal audit and/or response review reports.  The committee may request external DSMB reports 
or further information from the Disease Groups, or Study Chair. 
 
The Clinical Trials Monitoring Committee recommendations for modifications to the trial are 
forwarded to the Clinical Affairs Committee. The Study Chair is notified of this recommendation in 
order that he/she may alert all investigators, at the UWCCC and at external sites involved in the 
trial, about the potential action.  At this time the Study Chair may submit to the Clinical Affairs 
Committee additional information that could affect the Committee’s decision.  The Clinical Affairs 
Committee will notify the Study Chair if they concur with the Clinical Trials Monitoring Committee 
recommendations, including suspension or closure.  The Study Chair will notify all investigators 
involved with the study at UWCCC and external sites, the IRB, the sponsor and the funding agency 
and provide written documentation of these notifications to the Clinical Affairs Committee. 
The UWCCC Clinical Research Committee (CRC), composed of Cancer Center senior 
leaders oversees these activities. 
Review of Adverse Event Rates 
Once a month, adverse event rates will be monitored utilizing the UWCCC Clinical Trials 
database.  If any study has had two or more of the same AE reported in a month or more 
than six of the same AE in six months, the CTMC Chair will review the summary of SAEs, 
discuss events with Study Chair, and conduct a more detailed review with the Study Chair 
or the external DSMB if warranted.  The Committee Chair will determine if further action is 
required. 
If this occurs on a multiple-institutional clinical trial coordinated by the UWCCC, the Safety 
Coordinator will insure that all participating sites are notified of the resulting action. 
 
 
EXPEDITED REPORTING OF ADVERSE EVENTS 
Depending on the nature, severity, and attribution of the event an ADR report will be 
phoned in, submitted in writing, or both according to Tables A-D below. Telephoned 
Adverse Events must also be reported by phone to the UWCCC Clinical Trials Monitoring 
Committee within one working day of the event.   All adverse events must also be reported 
to the UW IRB, and any sponsor/funding agency not already included in the list. 
 
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Telephone reports to: 
Rakesh Patel, M.D. 
(608)263-8500 Phone 
(608)263-3526 fax 
UWCCC Clinical Trials Monitoring Committee Administrator  608-263-0169 
within one working day of the event  
Written reports to: 
Rakesh Patel, M.D. 
(608)263-8500 Phone 
(608)263-3526  fax 
UWCCC Clinical Trials Monitoring Committee Administrator –  
FAX 608-263-8613 or deliver to K4/642 
UW IRB – Copy of final written report to Sponsor. 
 
 
 
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Summary of Reporting Requirements for Adverse Events on Trials 
Involving Commercial Agents with No IND Is Voluntary (Med Watch Form) 
EXPEDITED REPORTING FOR PHASE 2 AND PHASE 3 STUDIES 
Unexpected Event 
Expected Event 
GRADES 2 - 3 
Attribution of 
Possible, 
Probable, or 
Definite 
GRADES 4 and 5 
Regardless of 
Attribution 
GRADES 1 - 3 
GRADES 4 and 5, 
Regardless of 
Attribution 
Expedited report 
within 15 working 
days to FDA. 
 
(Grade 1 - Adverse 
Event Expedited 
Reporting NOT 
required.) 
Report by phone to 
FDA within 24 hrs. 
Expedited report to 
follow within 15 
working days. 
 
This includes all 
deaths within 30 
days of the last 
dose of treatment 
with an 
investigational 
agent regardless of 
attribution. 
 
Any late death 
attributed to the 
agent (possible, 
probable, or 
definite) should be 
reported within 15 
working days. 
 
Adverse Event 
Expedited Reporting 
NOT required. 
Report by phone to 
FDA within 24 hrs. 
Expedited report to 
follow within 15 
working days. 
 
This includes all 
deaths within 30 
days of the last 
dose of treatment 
with an 
investigational 
agent regardless of 
attribution. 
 
Any late death 
attributed to the 
agent (possible, 
probable, or 
definite) should be 
reported within 15 
working days. 
 
Grade 4 
Myelosuppression 
or other Grade 4 
events that do not 
require expedited 
reporting will be 
specified in the 
protocol. 
 
Note:  Use Med Watch Form 
 
For Hospitalization Only – Any medical event equivalent to the CTC Grade 3,4,5 which 
precipitated hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of requirements for phase of study, expected or unexpected and attribution. 
 
Expedited reporting may not be appropriate for specific expected adverse events for certain 
later phase 2 and phase 3 protocols.  In those situations the adverse events that will not have 
expedited reporting must be specified in the text of the approved protocol.  An expected 
Grade 3 event that is using the generic reporting criteria, for instance. In a trial of 
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investigational agents where grade 3 diarrhea requiring hospitalization is expected, only 
diarrhea requiring ICU care (Grade 4) might be designated for expedited reporting.  
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 Appendix III:  Initial Evaluation Form (Page 1) 
 
 
 
 
 
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Appendix III:  Initial Evaluation Form (Page 2) 
 
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Appendix III:  Follow-up Form 
 
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Appendix III:  Patient Cosmesis Form 
 
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Appendix III:  Physician Cosmesis Form 
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Appendix III:  Spitzer Quality of Life Index (SQLI) 
 
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Appendix III:  Spitzer Quality of Life Index (SQLI) 
 
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Appendix IV:  Toxicity Scale 
 
RTOG Acute Toxicity Scoring 
TISSUE 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
SKIN 
No 
change 
over 
baseline 
Follicular, faint 
or dull 
erythema/ 
epilation/dry 
desquamation/ 
decreased 
sweating 
Tender or 
bright 
erythema, 
patchy moist 
desquamation/ 
moderate 
edema 
Confluent, 
moist 
desquamatiom 
other than 
skin folds, 
pitting edema 
Ulceration, 
hemorrhage, 
necrosis 
 
 
RTOG Late Toxicity Scoring 
ORGAN TISSUE 
Grade  
0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
SKIN 
None 
Slight atrophy
Pigmentation 
change 
Some hair 
loss 
Patch 
atrophy; 
Moderate 
telangiectasia; 
Total hair loss
Marked atrophy; Gross 
telangiectasia 
Ulceration
SUBCUTANEOUS 
TISSUE 
None 
Slight 
induration 
(fibrosia) 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 
 
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Appendix III: Radiotherapy Treatment/Dosimetry Form 
 
 
  
 
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