A Phase I Trial Assessing the Safety and Feasibility of Prophylactic Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Immediate Reconstruction in Patients With In-Situ or Invasive Breast Cancer
Phase: NA
Conditions: Breast Cancer, Ductal Carcinoma
Sponsor: University of Miami



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TABLE OF CONTENTS
PROTOCOL SUMMARY...............................................................................................................1
HYPOTHESIS ...............................................................................................................................3
1.0
BACKGROUND.................................................................................................................3
2.0
OBJECTIVES ....................................................................................................................5
2.1 PRIMARY OBJECTIVES ..........................................................................................................................5
2.2.SECONDARY OBJECTIVES ...................................................................................................................5
3.0
PATIENT SELECTION ......................................................................................................5
3.1 INCLUSION CRITERIA ............................................................................................................................5
3.2 EXCLUSION CRITERIA...........................................................................................................................6
3.3 ENROLLMENT PROCEDURES ..............................................................................................................6
4.0
TREATMENT PLAN ..........................................................................................................7
5.0
CLINICAL AND LABORATORY EVALUATIONS ............................................................11
6.0
TOXICITIES AND COMPLICATIONS.............................................................................13
7.0
ADVERSE EVENT REPORTING ....................................................................................15
8.0
CRITERIA FOR DISCONTINUATION OF THERAPY .....................................................17
9.0
DATA REPORTING.........................................................................................................18
10.0
STATISTICAL CONSIDERATIONS.................................................................................18
11.0
INVESTIGATOR’S RESPONSIBILITIES.........................................................................22
12.0
REFERENCES ................................................................................................................26
APPENDIX I...............................................................................................................................................28
STUDY CALENDAR ................................................................................................................28
APPENDIX II ...............................................................................................................................29
NATIONAL CANCER INSTITUTE (NCI) COMMON TOXICITY CRITERIA (CTC)...................29
APPENDIX III ..............................................................................................................................30
DATA AND SAFETY MONITORING PLAN .............................................................................30
APPENDIX IV..............................................................................................................................31
DATA SUBMISSION SCHEDULE ...........................................................................................31
APPENDIX V I.............................................................................................................................32
Karnofsky AND ZUBROD Performance Scale.........................................................................32
APPENDIX VII.............................................................................................................................33
AJCC STAGING SYSTEM, BREAST, 6TH EDITION ................................................................33
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PROTOCOL SUMMARY
Overall rationale: Prophylactic NAC irradiation after nipple-areola sparing 
mastectomy and immediate reconstruction for patient with ductal carcinoma in-situ 
or invasive breast cancer will allow better cosmesis and patient’s satisfaction.
Study design: Phase I trial assessing the safety, feasibility and toxicity of prophylactic 
NAC irradiation after nipple-areola sparing mastectomy and immediate 
reconstruction in patients with ductal carcinoma in-situ or invasive breast cancer.
Primary objective: To determine the recommended phase I dose of post-operative 
prophylactic NAC irradiation.
Secondary objectives: To provide extensive descriptive data regarding NAC-sparing 
surgery with reconstruction, including both surgeon experience and patient 
evaluation of cosmetic results. Survival and recurrence will be assessed.
Study size: Between 12 and 18 patients will be enrolled in the dose-escalation/de- 
escalation part of this phase I study. An additional expansion cohort of 12 patients 
will be enrolled at the “potential” recommended phase II dose (RP2D) over an 
expected accrual period of 2 years.
Treatment plan (07-15-2011)
Week 1
NAC-sparing mastectomy with immediate reconstruction
Between weeks 5 to 8
Prophylactic NAC irradiation twice daily, minimum of 4 
hours apart, for 5 days, preferable in consecutive working 
days
2 weeks after irradiation
Chemotherapy, if indicated, at the discretion of the treating 
physician
Dose escalation/de-escalation design (section 4.2) (07-15-2011)
Dose levels†
Description
Dose Level I
= 20 Gy
10 fractions of 2.0 Gy
Dose Level II = 25 Gy (starting dose)
10 fractions of 2.5 Gy
Dose Level III = 30 Gy
10 fractions of 3 Gy
Dose Level IV = 35 Gy
10 fractions of 3.5 Gy
† Treatment will be delivered twice a day, minimum of 4 hours apart, for 5 days, preferable in 
consecutive working days.
The patients will be receiving postoperative NAC irradiation starting at Dose level II.
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DLT (dose-liming toxicity), as defined in section 4.2.6, will be evaluated during radiation 
treatment period plus an additional observation period of 30 days following completion 
of NAC radiation.
A modification of standard dose-escalation design, treating cohorts of 2 to 6 patients 
per dose level of NAC irradiation, will be used. The main features of the proposed 
escalation design is that (1) no more than 2 patients will experience DLT at a given 
radiation dose and (2) escalation to a higher dose occurs only after a cohort of 6 patients 
have been evaluated at a given radiation dose.
Dose escalation/de-escalation rules
Number of patients with DLT 
at a given dose level
Escalation Decision Rule
0 or 1 out of 6 patients
Enter 6 patients at the next higher dose level.
2 out of 2 to 6 patients
Dose escalation stops. However, if the dose tested is 
dose level II, the starting dose level, then de-escalation 
occurs. In this case, dose level I will be tested in 2 to 6 
patients.
The highest dose tested at which  1 out of 6 patients experiences DLT will be declared 
the MTD and it will be the recommended phase II dose.
Expansion cohort (section 4.2.7)
An additional expansion cohort of 12 patients will be enrolled at the “potential” 
recommended phase II dose (RP2D) over an expected accrual period of 2 years.
(See section 4.2 for further details.)
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HYPOTHESIS:

The use of NAC-sparing mastectomy followed by postoperative NAC (nipple- 
areola complex) external beam radiotherapy for selected patient with early stage 
invasive or in-situ breast cancers will be technically feasible and with acceptable 
complication rates.

The cosmetic results after NAC-sparing mastectomy followed by postoperative 
external beam radiotherapy to the NAC will be better comparable with Skin Sparing 
Mastectomy.

The local control rate in the NAC will be more than expected for a NAC sparing 
mastectomy without postoperative radiotherapy.

The patient’s satisfaction after NAC-sparing mastectomy followed by postoperative 
NAC external beam radiotherapy will be better than after Skin Sparing 
Mastectomy.
1.0
BACKGROUND
1.1 NAC-sparing Mastectomy:
Breast-conserving surgery is an option for the majority of patients with stage I/II 
invasive or noninvasive breast cancers. However, there are patients that require 
or elect to undergo mastectomy followed by a reconstruction. Skin-sparing 
mastectomy (SSM) has become a surgical option for an invasive or in-situ breast 
cancer requiring mastectomy or in high-risk patients undergoing prophylactic 
mastectomy. Several non-randomized series suggest that SSM does not add to 
the risk of local recurrence ¹ˉ³. The SSM removes the breast, nipple-areola 
complex (NAC), previous biopsy incisions and skin overlying superficial tumors. 
The preservation of the skin of the breast and inframmary fold with SSM, greatly 
improves the aesthic results of the immediate breast reconstruction. The 
preservation of the nipple-areola complex (NAC) would lead to the best cosmetic 
result; however, the oncologic safety of lesser surgery is not yet proven. The 
incidence of occult involvement of the NAC in patients with established breast 
cancer has been reported in several published studies. Laronga and colleagues 4 
reviewed a series of 286 mastectomy specimens at MD Anderson Cancer Center 
for the presence of occult NAC involvement. Occult tumor in the NAC was found 
in 5.6%. NSABP B-04 study (radical mastectomy versus total mastectomy ± 
radiation) noted the incidence of occult nipple involvement in 107 of 967 cases 
(11.1%) 5. Santini and colleagues 6 reported the largest series of NAC involvement. 
1,291 consecutive mastectomy specimens with primary invasive breast cancer 
were reviewed, showing a 12% NAC involvement. Several published studies 
identified features of the primary breast cancer to increase risk of occult NAC 
involvement 4-8, including tumors < 2 cm from the areola, dimpling of the areola, 
tumors > 4 cm, multicentric tumors, location beneath the areola, presence of 
positive axillary nodes, presence of extensive intraductal component (EIC), etc.
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Gerber and colleagues 9 published the largest series of NAC preservation, 
comparing the results of 112 patients undergoing SSM with preservation of NAC 
to 134 patients that had standard mastectomy. All tumors were > 2 cm from the 
nipple. After intra-operative frozen sections of the NAC-ground, they were able to 
preserve NAC in 61 patients (54.5%). There was no statistical difference in the rate 
of local recurrence with a follow up of 59 months. The subcutaneous mastectomy 
(SCM), which saves both the nipple and areola, has also been studied to treat 
established breast cancers and for risk-reduction operations. The number of 
studies using SCM in established breast cancer is small and appeared to show no 
difference in survival comparing from standard mastectomy, but with a higher 
incidence of local recurrence 10-15.
1.2 NAC-sparing Mastectomy followed by Prophylatic NAC Irradiation.
Petit and colleagues 16 reported a prospective study using nipple-sparing 
mastectomy (NSM) in association with intra-operative radiotherapy with electrons 
(ELIOT) given to the NAC, in attempt to decrease risk of local recurrence and 
increase patient’s satisfaction and cosmetics. Frozen sections of the tissue under 
the areola were routinely sampled to exclude presence of tumor. A dose of 16 Gy 
was delivered intra-operative in the region of the NAC. Between March 2002 and 
September 2003, 106 NSM were performed in 102 patients, 63% with invasive 
carcinoma and 37% in situ carcinoma. In an average follow up of 13 months, only 
one local recurrence, located in the clavicular region, far from the NAC was 
observed. 15 patients (4.7%) lost their NAC due to total necrosis. Eleven patients 
(10.4%) developed moist desquamation, followed by spontaneous healing. A 
preliminary result of a psychological part of the study showed a very high 
satisfaction with the preservation of the nipple (97.6%).
1.3 Radiation Dose and Fractionation:
Several groups have recently published their data exploring the possibility of 
shortening the overall radiation treatment length after breast conserving surgery 
by increasing the fraction size, and decreasing treatment to the lumpectomy cavity 
with margins, where the majority of the recurrences occurred. 3D Conformal 
Radiation Therapy (3D-CRT) techniques have also been used in phase I/II trials. 
Formenti et al 17 published their experience treating 47 patients with early stage 
breast cancer after lumpectomy with 3D conformal partial breast irradiation. 
Patients received a total dose of 30 Gy at 6 Gy/fraction delivered in 5 fractions over 
ten days. At a median follow-up of 18 months, no patient developed a local 
recurrence, acute toxicity was modest (grade 1-2 erythema), with only grade 1 late 
toxicity. Baglan et al 18 also initiated a pilot study of 3D-CRT using doses of 34 Gy 
in 5 patients and 38.5 Gy in 4 patients, both delivered in 10 fractions, twice daily 
over 5 consecutive days. The acute toxicity was minimal. Radiobiological models 
suggest that this fractionation schedule of 38.5 Gy in 10 fractions using 3D-CRT 
external beam radiation should produce acceptable control rates in the breast and 
comparable late effects as with brachytherapy. These models estimate that the
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regimen of 38.5 Gy in 10 fractions should provide a biologically equivalent dose 
(BED) of 45 Gy in 1.8 Gy fractions assuming a α/β ratio of 10. The Radiation 
Therapy Oncology Group (RTOG) has launched a phase III trial (0413), comparing 
whole breast irradiation delivered over 6 ½ weeks versus partial breast irradiation 
in shortened treatment length of 5 days, using different techniques as MammoSite 
HDR brachytherapy (34 Gy, 3.4 Gy fraction, in 10 fractions, minimum of 6 hours 
apart), 3D-Conformal Radiotherapy (38.5 Gy in 10 fractions, twice daily, 6 hours 
apart) or Intertitial Brachytherapy with High or Low Dose Rate Brachytherapy.
The proposed study will evaluate the use of external beam radiotherapy using 
electrons, which is a superficial radiation, for treatment of the nipple-areola 
complex, postoperative. The dose escalation level IV of 35Gy in 3.5 Gy fractions, 
for a total of 10 fractions, twice daily, minimum of 4 to 6 hours apart, has a 
Biological Effective Dose (BED) equivalent of the standard fractionation of 45 Gy 
in 1.8 Gy fraction (BED for early effects will be 45 Gy, assuming α/β of 10; BED for 
late effects will be 72.5 Gy, assuming a α/β of 3).
2.0
OBJECTIVES
2.1
Primary objectives
To determine the recommended phase II dose of post-operative prophylactic NAC 
irradiation after nipple areola-sparing mastectomy and immediate reconstruction 
in patients with ductal carcinoma in-situ or invasive breast cancer.
2.2.
Secondary objectives
To provide extensive descriptive data regarding NAC-sparing surgery with 
reconstruction, including both surgeon experience and patient evaluation of 
cosmetic results. Survival and recurrence will be also assessed.
3.0
PATIENT SELECTION
3.1
Inclusion Criteria
3.1.1
Patients must have histologically confirmed in-situ or invasive breast 
carcinoma.
3.1.2
Tis, T1, T2 invasive or non-invasive carcinoma of the breast; lesion less 
than 4 cm.
3.1.3
Unifocal, multifocal or multicentric breast cancers that can be removed by 
nipple sparing mastectomy with negative surgical margins.
.
3.1.4
No extensive intraductal component or patient with distant metastases.
3.1.5
Patients must be > 18 years of age.
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3.1.6
No concomitant or history of nipple discharge or skin involvement.
3.1.7
No prior history of malignancy (less than 5 years prior to study entry), 
except non-melanomatous skin cancer.
3.1.8
No prior history of radiation to the chest.
3.1.9
No collagenous disease (systemic lupus erythematosis, scleroderma, 
dermatomyositis). No previous non-hormonal therapy including radiation 
or chemotherapy for current breast cancer.
3.1.10 No patients with Paget’s disease of the nipple.
3.1.11 No patients with co-existing medical conditions with life expectancy < 2 
years.
3.1.12 No pregnant or lactating women.
3.1.13 ECOG 0 - 2.
3.1.14 Signed study-specific informed consent form prior to the study entry.
3.2
Exclusion Criteria (08-06-2013)
3.2.1
Retroareolar breast cancer lesions within one cm. depth from the skin 
surface.
3.2.2
Concomitant or history of nipple discharge or skin involvement.
3.2.3
Patient with distant metastases.
3.2.4
Patient with extensive intraductal carcinoma.
3.2.5
Any previously irradiated ipsilateral breast cancer.
3.2.6
Patients with Paget’s disease of the nipple.
3.2.7
Patients with collagenous diseases, as systemic lupus erythematosis, 
scleroderma or dermatomyosis.
3.2.8
Other malignancy, except non-melanomatous skin cancer, less than 5 
years prior to participation in this study.
3.2.9
Patients who are pregnant or lactating due to potential exposure of the 
fetus to RT and unknown effects of RT to lactating females.
3.2.10 Positive surgical margins following nipple sparing mastectomy
3.3
Enrollment Procedures (07-03-2012)
To enter a patient, the investigator or study team will contact the CRS 
representative. All eligibility requirements must be reviewed prior to the 
patient entering the study. The following information must be provided to 
the CRS representative:
1) Completed and signed protocol-specific eligibility checklist;
2) All pages of the original signed informed consent forms (ICFs), 
including HIPAA Form B.
3) Relevant source documents such as: subject medical history 
and physical exam, admission or discharge notes, diagnostic
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reports, pathologic confirmation of diagnosis, and relevant 
subject-specific written communication.
3.3.1
Cancellation Guidelines
If a patient does not receive protocol therapy, the patient may 
withdraw. Contact the CRS representative, or e-mail the information 
including the reasons for withdrawal within 10 working days.
3.3.2
Emergency Registration
If an emergency registration takes place after business hours, the 
items listed in section 3.3 above must be submitted by the next 
business day.
4.0
TREATMENT PLAN
Week 1
NAC-sparing mastectomy with immediate 
reconstruction
Between weeks 5 to 8
Prophylactic NAC irradiation twice daily, minimum 
of 4 hours apart, for 5 days, preferable in 
consecutive working days;
2 weeks after 
irradiation
Chemotherapy, if indicated, at the discretion of 
the treating physician
4.1
Surgery
4.1.1
NAC-sparing mastectomy: Subcutaneous Mastectomy (SCM) to be 
performed, preserving the nipple and areola complex, after a frozen section 
of the tissue underneath the nipple-areola complex is sampled and found to 
be negative for tumor.
4.1.2
Axillary Dissection or Sentinel Node Biopsy (SNB) will be performed at 
surgeon’s discretion.
4.1.3
Reconstruction: Immediate reconstruction of the breast will be 
performed by the plastic surgeon’s discretion and patient’s desire.
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4.2
Radiation Therapy
4.2.1
Dose levels and schedule
Dose levels†
Description
Dose Level I
= 20 Gy
10 fractions of 2.0 Gy
Dose Level II = 25 Gy 
(starting dose)
10 fractions of 2.5 Gy
Dose Level III = 30 Gy
10 fractions of 3 Gy
Dose Level IV = 35 Gy
10 fractions of 3.5 Gy
† Treatment will be delivered twice a day, minimum of 4 hours apart, for 5 
days, preferable in consecutive working days.
4.2.2
Treatment Planning and Imaging: Treatment planning and delivery 
should be performed with the patient in supine position, on a breast board. A 
treatment planning CT scan will be required to define the clinical target volume 
(CTV) which will include the nipple-areola complex. At the time of CT Simulation, 
the NAC will be marked on the skin, to be seen on the CT images for planning. A 
second simple simulation might be performed to verify treatment parameters and 
treatment field on the patient, according to plan.
4.2.3
Beam Angles/Treatment Position: The patient will be treated in supine 
position, with electrons. The energy of the electrons assigned for treatment will be 
dependent on the plan to cover the area of NAC appropriately, as per radiation 
oncologist’s discretion.
4.2.4
External Beam Equipment: Megavoltage equipment is required with a 
range of electrons energy.
4.2.5
Dose escalation/de-escalation design
The following are the four possible dose levels to be tested in the study: 
Dose level I:
20 Gy total (2.0 Gy for 10 fractions)
Dose level II: 25 Gy total (2.5 Gy for 10 fractions) (Starting Dose)
Dose level III: 30 Gy total (3.0 Gy for 10 fractions) 
Dose level IV: 35 Gy total (3.5 Gy for 10 fractions)
The patients will be receiving postoperative NAC irradiation using electrons 
starting at Dose level II. Dose levels will be escalated by 0.5 Gy per fraction for 
an overall 5 Gy increase per level up to 3.5 Gy per fraction and a total dose of 35 
Gy. Evaluable patients will be defined as any eligible patient that begins NAC 
irradiation treatment.
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DLT (dose-liming toxicity), as defined in section 4.2.6, will be evaluated during 
radiation treatment period plus an additional observation period of 30 days 
following completion of NAC radiation.
We propose a modification of standard dose-escalation design, treating 
cohorts of 2 to 6 patients per dose level of NAC irradiation. The main features 
of the proposed escalation design is that (1) no more than 2 patients will 
experience DLT at a given radiation dose and (2) escalation to a higher dose 
occurs only after a cohort of 6 patients have been evaluated at a given radiation 
dose.
Dose escalation/de-escalation rules
Number of patients with DLT 
at a given dose level
Escalation Decision Rule
0 or 1 out of 6 patients
Enter 6 patients at the next higher dose level.
2 out of 2 to 6 patients
Dose escalation stops. However, if the dose tested 
is dose level II, the starting dose level, then de- 
escalation occurs. In this case, dose level I will be 
tested in 2 to 6 patients.
The highest dose tested at which  1 out of 6 patients experiences DLT will be 
declared the MTD and it will be the recommended phase II dose.
Thus, as stated in the dose escalation/de-escalation rules above, if 0 or 1 patient 
experiences DLT (as defined in section 4.2.6) among 6 patients, the dose level will 
be judged to be acceptable. If this occurs, then a new cohort of 2 to 6 patients will 
be accrued at the next higher dose level. If 2 patients experience DLT among 2 to 
6 patients at a given dose level, then the corresponding dose will be declared to 
be unacceptable. If the starting dose level (dose level II) proves to be 
unacceptable, then de-escalation occurs to dose level I and 2 to 6 patients will 
enrolled at dose level I.
The maximum tolerated dose (MTD), among the doses tested, will be determined 
as the highest NAC irradiation dose level at which 1 out of 6 patients 
experiences DLT. The MTD will be declared the “potential” recommended 
phase II dose (RP2D) of post-operative prophylactic NAC irradiation after NAC- 
sparing mastectomy with reconstruction in patients with ductal carcinoma in-situ 
or invasive breast cancer.
Simultaneous enrollment: Simultaneous enrollment will be permitted under the 
following circumstance:

If j (j4) patients have been treated at a given dose and there are no DLTs, 
patients (j+1) and (j+2) may be enrolled simultaneously at the same dose 
level.
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For instance, the first two patients could be enrolled simultaneously, that is, patient
2 could be enrolled within <30 days apart after patient 1 has completed the 
radiation treatment. As another example, If the first patient to receive a NAC 
radiation dose level does not experience DLT, within the DLT evaluation period of 
minimum 35 days, patients 2 and 3 may be enrolled simultaneously at the same 
dose level; that is, patient 3 can be enrolled before patient 2 has been fully 
evaluated for DLT within <30 days apart after patient 2 has completed the radiation 
treatment.
4.2.6
Definition of dose limiting toxicity (DLT)
Dose limiting toxicity (DLT) is defined as any of the following toxicities occurring 
during radiation treatment period plus an additional observation period of 30 
days following completion of NAC radiation:
a) Grade 4 skin rash
b) Grade 4 pain
c) NAC necrosis
d) Any toxicity requiring interruption of the NAC irradiation by > 2 weeks 
(14 calendar days), except if interruption is secondary to LINAC machine 
or unpredictable weather problems or unrelated medical conditions that 
would prevent the subject to come for treatment.
e) Any grade 4 or 5 treatment-related toxicity
4.2.7
Expansion cohort
An additional expansion cohort of 12 patients will be enrolled at the “potential”
recommended phase II dose (RP2D) to confirm its safety.
If safety is confirmed in the total 18 patients (6 from dose-finding part of study plus 
12 from the expansion cohort) treated at the “potential” (RP2D, the corresponding 
dose will be declared the RP2D.
4.3
Chemotherapy
4.3.1Chemotherapy, if indicated by oncologist, will be delivered at least 2 weeks 
from the last radiation treatment.
4.3.2 The type of chemotherapy will be at discretion of the oncologist physician.
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5.0
Clinical and Laboratory Evaluations
5.1 Preoperative assessment:
Preoperative assessment includes general medical status and organ function as 
well as tissue diagnosis and a work up for metastatic disease if applicable. The 
assessment will include standard history and physical examination, histology, 
laboratory and radiological tests as deemed appropriate by the operating surgeon.
5.2 Intraoperative parameters
Intraoperative events and findings will be reported as routinely done in the 
operative report. Pathologic examination of the frozen section of the tissue 
underneath the NAC will be performed at the time of surgical procedure and results 
will be recorded in the study records. If pathology is positive, the patient will be 
taken off the study as screen failure.
5.3 Perioperative parameters
The surgical team will monitor for complications in the usual manner and any 
complication will be treated accordingly. Duration of hospital stay, complications 
will be recorded.
5.4 Pathologic evaluation of specimens
Pathologic examination of the frozen section of the tissue underneath the NAC will 
be performed at the time of surgical procedure and results will be recorded in the 
study records. If pathology is positive, the patient will be taken off the study as 
screen failure. If pathology is negative, the surgeon will then perform a Skin 
Sparing Mastectomy, sparing the NAC. If the patient’s NAC tissue biopsy is 
negative by frozen, but positive after standard hematoxylin and eosin, the patient 
will be taken off the study and the discussion will be done with the patient about 
options of removal of the NAC or postoperative irradiation of NAC outside the 
protocol.
5.5 Photographs (07-15-2011)
5.5.1 Photographs shall be taken at the discretion of the P.I. and Sub-P.I.
5.6 Patient enrollment data
5.6.1 Complete history and physical examination
5.6.2 Mammographic reports
5.6.3
Pathology reports
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5.7 Patient treatment data
5.7.1 Operative reports from mastectomy and reconstruction.
5.7.2 Toxicity reports: skin reaction(s) to radiation therapy including erythema, 
desquamation, etc.; any acute or unusual severe side effects of surgical 
procedures or radiation treatment
5.7.3 Radiation treatment: prescribed and delivered doses
5.7.4 Copies of dosimetry calculations
5.7.5 At least one photograph of the treated breast prior to initiation of treatment
5.8 Patient follow-up
5.8.1 Vital status
5.8.2 Disease status, classified local, regional, or distant
5.8.3 Site(s) and date of first failure in each category above
5.8.4 Relationship of the recurrence to the irradiated volume
5.8.5 Cosmetic evaluation by patient and physicians
5.8.6 Effects of treatment
5.8.7 Follow-up physical examination
5.8.8 Photographs will be taken at the discretion of the P.I. and Sub-P.I.
5.8.9 AE and Concomitant Medication reporting from post-operative visit up to 30 
days post radiation treatment.
5.9 RESPONSE CRITERIA
5.9.1 The definition of local recurrence is histologic evidence of recurrent 
carcinoma, either invasive or non-invasive in the nipple-areola complex in the 
ipsilateral breast.
5.9.2 Clinical evidence of carcinoma by physical exam and/or mammograms/MRI 
will not be evidence of local recurrence until biopsy proof.
5.9.3 Overall survival time is defined from the date of surgery until the date of 
death due to any cause. In the absence of death, follow-up time will be censored 
by the date of last contact.
5.9.4 Disease-free survival time is defined from the date of surgery until the date 
of documented recurrence (local or distant) or breast cancer-related death, 
whichever occurs first. Patients who die without documentation of recurrence will 
be considered to have had disease recurrence at the time of death, unless there 
is documented evidence that no recurrence occurred before death. In other words, 
‘unknown cause of death’ will be considered an event for the disease-free survival 
analysis. In the absence of any event defining disease recurrence, follow-up time 
will be censored at the date of last documented recurrence-free status.
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5.10 DEFINITIONS OF LEVELS OF COSMETIC OUTCOME (07-15-2011)
5.10.1 Cosmesis will be graded by the patient and by the radiation oncologist or 
the surgeon prior to radiation (baseline), and 1, 3, 6 and 12 months after 
completion of radiation therapy as follows: Plus or minus 2 weeks.
Excellent: when compared to the untreated breast, there is minimal or no 
difference in the sizes, shape or texture of the treated breast. There may be mild 
thickening or scar tissue of the reconstructed breast or skin, but not enough to 
change the appearance.
Good: there is mild asymmetry in the size or shape of the treated reconstructed 
breast as compared to the normal breast. The thickening or scar tissue within the 
breast causes only mild change in the shape.
Fair: there is obvious difference in the size of shape of the reconstructed breast. 
This change involves ¼ or less of the breast.
Poor: marked change in the appearance of the treated breast involving more than
¼ of the breast tissue.
Clarification: (Evaluation of the treated nipple-areola complex)
Color: Natural Score 0 or 1
Shape: Round Score 0 or 1
Nipple: Central Score 0 or 1
Nipple: Everted Score 0 or 1Total Score Report; 
4 =excellent
3= good
2 = fair 
1=poor
6.0
TOXICITIES AND COMPLICATIONS
6.1 Surgery
6.1.1 General risks of Surgery
The general risks of surgery include anesthetic risk, bleeding, infection, pulmonary 
and cardiac complications and death. These general risks will be explained in 
detail to the patient and a separate standard surgical consent form will be 
completed prior to enrollment.
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6.1.2 Specific risks of NAC-sparing Mastectomy
The operative procedure is performed under general anesthesia and following 
standard breast cancer operation. The NAC sparing during mastectomy will add a 
frozen biopsy of the tissue underneath the NAC is expected to prolong the 
anesthesia for approximately ½ hour. A small risk of NAC necrosis postoperative 
exists due to possibility of decrease in vascularization.
6.2 General risks of Breast Reconstruction with Implants or Autologous 
Tissue.
The general risks of plastic surgery reconstruction include anesthetic risk, 
bleeding, infection, loss of the reconstructed breast with autologous tissue 
secondary to necrosis, capsulitis of the breast implant, cardiac and pulmonary 
complications and death.
6.2.1
Specific 
risks 
of 
NAC-sparing 
Mastectomy 
with 
Immediate 
Reconstruction 
with 
Implants 
or 
Autologous 
Tissue 
followed 
by 
prophylactic NAC Irradiation
Besides the general risks of mastectomy and plastic reconstructive surgery with 
implants or autologous tissue, postoperative prophylactic NAC Irradiation will give 
a small increased risk of NAC necrosis, which in some cases will resolve 
spontaneously or in some cases will require a second operation. The aesthetic 
result of NAC-sparing Mastectomy with Immediate Reconstruction with Implant or 
Autologous Tissue followed by Prophylatic NAC Irradiation might alter the cosmetic 
results secondary to skin fibrosis or discoloration.
6.3 General risks of Radiation
Fatigue is anticipated systemic reaction to radiation treatment. Skin erythema, 
hyperpigmentation and desquamation (dry or moist) may also occur, and they are 
usually temporary. Edema and tenderness are possible side effects of treatment. 
There is a rare possibility of development of secondary malignancy.
6.3.1
Specific risks of Prophylatic NAC Irradiation after NAC-sparing 
Mastectomy and Reconstruction.
The addition of Prophylatic NAC irradiation after NAC-sparing Mastectomy and 
Reconstruction include necrosis of NAC, with a need for additional surgical 
procedure for repair; delayed wound healing, poor cosmesis secondary to 
permanent hypopigmentation or hyperpigmentation of the skin of the NAC or skin 
fibrosis.
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7.0
Adverse Event Reporting
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized for 
adverse event reporting. A copy of the CTCAE version 3.0 can be downloaded 
from the CTEP web site (http://ctep.cancer.gov/reporting/ctc.html).
7.1
Definitions:
7.1.1
Adverse events (AE’s) will use the descriptions and grading scales 
found in the NCI Common Toxicity Criteria in Appendix II.
Adverse events: Any unfavorable and unintended sign (including 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure, 
regardless of whether it is considered related to the treatment or 
procedures; also and “unanticipated problem” of any nature (e.g., 
psychological or social harm)
7.1.2
A serious adverse event (experience) or reaction is any untoward 
medical occurrence that at any dose: results in death, is life- 
threatening, requires inpatient hospitalization or prolongation of 
existing 
hospitalization, 
results 
in 
persistent 
or 
significant 
disability/incapacity, or is a congenital anomaly/birth defect.
The definition of serious adverse event (experience) also includes 
important medical events. Medical and scientific judgment should 
be exercised in deciding whether reporting is appropriate in other 
situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but 
may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. These 
should also usually be considered serious. Examples of such events 
are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.
7.1.3
Expected events are those that have been previously identified as 
resulting from administration of the treatment.
7.1.4
An adverse event is considered unexpected when either the type of 
event or the severity of the event is not listed in: the current NCI 
Agent-Specific Adverse Event List; the investigator's brochure or the 
information section of this protocol.
7.1.5
The definition of related is that there is a reasonable possibility that 
the drug caused the adverse experience.
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7.2
Purpose
Adverse event data collection and reporting, which are required as part of 
every clinical trial, are done to ensure the safety of patients enrolled in the 
studies as well as those who will enroll in future studies using similar 
agents. Note: Chemotherapy related adverse event reporting will not be 
performed for patients receiving standard of care chemotherapy in the 
follow-up period starting 2 weeks post radiation. Adverse events are 
reported in a routine manner at scheduled times during a trial (please 
follow directions for routine reporting provided in the Data Reporting 
Section). The following sections provide information about reporting.
7.2.1
Determination of Reporting Requirements
Reporting 
requirements 
may 
include 
the 
following 
considerations: 1) whether the patient has received an 
investigational or commercial agent; 2) the characteristics of 
the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior 
experience (expectedness) of the adverse event; 3) the 
Phase (1, 2, or 3) of the trial; and 4) whether or not 
hospitalization or prolongation of hospitalization was 
associated with the event.
7.2.2
Steps to determine if an adverse event is to be reported in an 
expedited manner:
Step 1:
Identify the type of event using the NCI Common Toxicity 
Criteria (CTC).
The CTC provides descriptive terminology and a grading 
scale for each adverse event listed. A copy of the CTC 
can be downloaded from the CTEP home page 
(http://ctep.cancer.gov). Additionally, if assistance is 
needed, the NCl has an Index to the CTC that provides 
help for classifying and locating terms. All appropriate 
treatment locations should have access to a copy of the 
CTC.
Step 2:
Grade the event using the NCI CTC.
Step 3:
Determine whether the adverse event is associated to the 
protocol therapy (investigational or commercial).
Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite.
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Step 4:
Determine the prior experience of the adverse event.
Step 5: Review 10.2 to determine if there are any protocol- 
specific requirements for reporting of specific adverse 
events that require special monitoring.
Step 6: Determine if the protocol treatment given prior to the 
adverse event included investigational agent(s), a 
commercial agent(s), or a combination of investigational 
and commercial agents.
7.3
Reporting Methods
7.3.1
All serious, unusual life-threatening or lethal adverse which may be study 
related will be reported within 24 hours by telephone to the Principal 
Investigator and must be followed by a written report which must be 
received by the Principal Investigator within 10 business days. The 
Principal Investigator shall also be responsible for promptly notifying the 
local Institutional Review Board of all such serious adverse events. For all 
fatal events (Grade 5) while on study or within 30 days of treatment, a 
written report will follow within 10 working days.
7.3.2
IRB Reporting
7.3.2.1 All unexpected adverse events, serious adverse events, events 
that are more severe than anticipated, events that are more frequent than 
anticipated, and deaths must be reported to the IRB within ten (10) 
working days of being made known to the Principal Investigator.
8.0
CRITERIA FOR DISCONTINUATION OF A PATIENT FROM THE STUDY
8.1.1. Disease progression
8.1.2. Unacceptable surgical adverse event that preclude administration of 
radiation treatment.
8.1.3. Patient decides to withdraw from the study
8.1.4. At any time, the patient or his/her physician may discontinue 
participation in the study if this is believed to be in the patient’s best 
interest.
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9.0
DATA REPORTING
Basic forms include

On-study information, including patient eligibility data and patient history

Flow-sheets, tumor/disease assessment forms or other forms for interim 
monitoring

Specialty forms for pathology, radiation or surgery

Off-study summary sheet, including a final assessment by the treating 
physician

Follow-up forms when requires.
The following can be used for the location if using SCCC forms.
Data must be submitted according to the protocol requirements for ALL patients 
registered. Patients for whom documentation is inadequate to determine eligibility 
will generally be deemed ineligible.
A list of forms to be submitted, as well as expectation dates, is found in Appendix 
IV.
10.0
STATISTICAL CONSIDERATIONS
10.1 Study Size
For the purpose of dose escalation of NAC-radiation treatment, evaluable 
patients will be defined as any eligible patient that begins NAC irradiation 
treatment. However to evaluate feasibility of the NAC-sparing mastectomy with 
reconstruction, any patient who undergo surgery will be considered evaluable.
Following the dose escalation/de-escalation procedure described in section 4.2, 
we anticipate that 12 to 18 evaluable patients will be enrolled in this phase I study 
during the dose-finding part. The number of evaluable patients that will be 
needed depends on the number of times the NAC-radiation dose is escalated or 
possibly de-escalated. If the escalation occurs from dose level II up to dose level 
IV, between14-18 evaluable patients will be required. If the dose is de-escalated 
after dose level II been evaluated in 6 patients, then 12 evaluable patients will be 
required, assuming 6 patients would be evaluated at dose level I. With 6 evaluable 
patients, the probability of not escalating when the true DLT rate is 35% is 68%. If 
the true DLT rate is 20%, the probability that the dose will be escalated is 66%.
A maximum of 6 patients per year is expected to be enrolled, since each patient 
must be evaluated for a minimum of 35 days and at most two patients will be 
enrolled simultaneously (within < 30 days after completion of the 5 days NAC 
radiation treatment). Thus, the expected accrual period is between 2-3 years.
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An additional expansion cohort of 12 patients will be enrolled at the “potential” 
recommended phase II dose (RP2D) over an expected accrual period of 2 years.
To gather data on recurrence and survival, all patients will be followed at their 
clinic visits as clinically indicated.
10.2 Planned Analysis
Patient demographics (age, race/ethnicity), laboratory parameters, disease 
characteristics (such as, tumor stage, grade), will be summarized using 
descriptive statistics: counts and percentages, range, median, mean, and standard 
deviation, as appropriate [23].
Toxicities resulting from radiation treatment will be tabulated by type, grade, 
duration, and attribution to treatment according to NCI CTCAE version 3.0, and by 
administered NAC radiation dose. A patient-level summary by worst grade toxicity 
will be included. Any grade 3, 4 or 5 or unexpected lower grade toxicities will be 
reported.
Intraoperative parameters and perioperative parameters (complications, 
events, and findings) will be described in the operative report as routinely done.
Surgery success rate, defined as the proportion of patients who had successful 
NAC sparing surgery with reconstruction divided by the total number of study 
patients, will be determined.
Cosmetic results will be assessed by both the physician(s) and the patients at 3, 
6 and 12 months, using a 4-category ordinal scale (excellent, good, fair, and poor). 
Data will be summarized in terms of number and % of patients in these 4 possible 
categories at those assessment times separately for assessment by physician and 
by patient. Statistical analysis methods for contingency tables will be used to 
compare changes over time for each evaluator (physician or patient), and also to 
compare agreement between physician and patient assessment at a given time. 
[24]
To gather data on recurrence and survival, all patients will be under follow-up for 
a minimum of 5 years, unless they withdraw consent or die within that time.
Given the small study size and the expected low incidence of recurrence, we do 
not expect any such recurrences within 5 years. However, if patients do recur, the 
number of recurrences will be reported, along with corresponding summary 
regarding time to recurrence, type of recurrence -- local (ipsilateral nipple-areola 
recurrence in-field, peripheral, or extra-field location) or distant, irradiated volume, 
and radiation dose. If the number of events allows, disease-free survival and 
overall survival will be estimated by the Kaplan-Meier method. [25]
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10.3
Interim Monitoring
10.3.1 Role of the Research Team and the DSMC
The Research Team will continuously monitor study accruals and adverse events 
from both surgery and radiation treatment. In particular, for the purpose of 
escalation and de-escalation (section 4.2) patients will be monitored closely during 
the 30 days after completion of NAC radiation treatment, and subsequently for any 
toxicity or adverse reaction to treatment. All toxicities, regardless their grade, will 
be recorded in the patient case report form using NCI/CTEP Common Terminology 
Criteria for Adverse Events (CTCAE) version 3.0.
The Sylvester Comprehensive Cancer Center’s Data and Safety Monitoring 
Committee (DSMC) will monitor this protocol according to the Cancer Center’s 
DSM Plan. In its oversight capacity, the DSMC bears responsibility for suspending 
or terminating this study.
DSMC oversight of the conduct of this trial includes ongoing review of accrual and 
adverse event data. The guidelines appearing in Sections 10.3.2, and 10.3.3 are 
offered for DSMC consideration in assessing accrual, adverse events. In addition, 
the DSMC will review reports from all audits, site visits, or study reviews pertaining 
to this clinical trial and take appropriate action.
10.3.2 Safety: Early stopping due to radiation-related toxicity
During the dose escalation/de-escalation for radiation dose-finding, there is no 
radiation-related toxicity that would suggest stopping the study early due to 
radiation-related toxicity beyond the dose escalation/de-escalation stopping rules 
described in section 4.2.5.
Expansion cohort:
An additional expansion cohort of 12 patients will be enrolled at the “potential” 
recommended phase II dose (RP2D).
If a radiation-related (possible, probable, or definite) death (grade 5 toxicity) 
occurs, enrollment will be suspended and continuation of the study will be 
reassessed by the DSMC.
Unacceptable radiation-related toxicity (possible, probable, or definite) is defined 
as grade 3, 4, or 5 adverse events, excluding grade 3 adverse events that resolve 
or down grade to grade 2 within 14 days.
Unacceptable radiation-related toxicity (possible, probable, or definite) is expected
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to occur in no more than 10% of patients. If there is evidence that the true rate of 
this toxicity exceeds 20%, then the study should be suspended or possibly 
terminated early. Specifically, we suggest as a guideline for early termination a 
posterior probability of 90% or higher that the true rate exceeds 20%. The table 
below shows specific instances where this guideline is met, suggesting early 
termination, and due to evidence of excessive toxicity.
Number (%) of patients experiencing 
unacceptable radiation-related toxicity#
Total patients 
evaluated
3
3 to 5
4
6 to 9
5
10 to 12
#:Radiation-related toxicity (possible, probable, or definite) is defined as grade 3 or higher 
adverse events, excluding grade 3 adverse events that resolve or down grade to grade 2 
within 14 days.
To illustrate the stopping guidelines, suppose that 5 evaluable patients in the 
expansion cohort have been assessed for radiation-related toxicity and 3 of them 
have experienced grade 4 unacceptable toxicity. (See row 1 of the above table.) 
Under this circumstance, the observed rate of unacceptable toxicity is 60%, 
resulting in a posterior probability of 92.7% (not shown) that the true underlying 
rate exceeds 20%, thereby suggesting early termination.
Posterior probabilities for the above table are calculated under a weak prior beta 
distribution with parameters 1 = 0.2 and 2 = 1.8, which corresponds to an 
expected unacceptable radiation-related toxicity rate of 20% based on very limited 
information, roughly equal to having studied 2 patients. This prior distribution 
implies also a priori chance of only 18% that true rate is 20% or greater.
10.3.3 Safety: Early stopping due to surgery-related toxicity
We propose the following guidelines for the DSMC in its review of accumulating 
data on surgery-related toxicity. These guidelines were developed using Bayesian 
methods, which can be applied at any stage of enrollment without pre-specification 
of the number of interim analyses to be performed, or the number of patients 
evaluable for toxicity or survival at the time such assessments are made (26,27). 
Under the Bayesian method, we assign a prior probability (level of belief at the 
start of the trial) to a range of possible values for the true rate. As data on treated 
patients become available, this probability distribution is revised and the resulting 
posterior probability becomes the basis for recommending either early termination 
or continuation of the study. In the sections that follow, we provide specific 
stopping guidelines based on posterior probabilities for interim monitoring of 
surgery-related toxicity over the course of this trial. Underlying assumptions for 
the prior distribution are also presented.
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If a surgery-related (possible, probable, or definite) death (grade 5 toxicity) occurs, 
enrollment will be suspended and continuation of the study will be reassessed by 
the DSMC.
Unacceptable surgery-related toxicity (possible, probable, or definite) includes 
grade 3-4 bleeding, infection, NAC necrosis, and any unexpected grade 3.
Unacceptable surgical-related toxicity (possible, probable, or definite) is expected 
to occur in no more than 10% of patients. If there is evidence that the true rate of 
this toxicity exceeds 20%, then the study should be suspended or possibly 
terminated early. Specifically, we suggest as a guideline for early termination a 
posterior probability of 90% or higher that the true rate exceeds 20%. The table 
below shows specific instances where this guideline is met, suggesting early 
termination, and due to evidence of excessive toxicity.
Number (%) of patients experiencing 
unacceptable surgery-related (possible, 
probable, or definite) toxicity
Total patients 
evaluated
3
3 to 5
4
6 to 9
5
10 to 12
6 (55 to 60%)
13 to 16
7
17
To illustrate the stopping guidelines, suppose that 5 evaluable patients have 
been assessed for surgical-related toxicity and 3 of them have experienced grade 
4 unacceptable toxicity. (See row 1 of the above table.) Under this circumstance, 
the observed rate of unacceptable toxicity is 60%, resulting in a posterior 
probability of 92.7% (not shown) that the true underlying rate exceeds 20%, 
thereby suggesting early termination.
Posterior probabilities for the above table are calculated under a weak prior beta 
distribution with parameters 1 = 0.2 and 2 = 1.8, which corresponds to an 
expected unacceptable surgery-related toxicity rate of 20% based on very limited 
information, roughly equal to having studied 2 patients. This prior distribution 
implies also a priori chance of only 18% that true rate is 20% or greater.
11.0
INVESTIGATOR’S RESPONSIBILITIES
11.1
INVESTIGATOR RESPONSIBILITY/PERFORMANCE
The investigator will ensure that this study is conducted in accordance 
with all regulations governing the protection of human subjects.
The investigator will ensure that all work and services described in or
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associated with this protocol will be conducted in accordance with the 
investigational plan, applicable regulations, and the highest standards of 
medical and clinical research practice.
11.2
CONFIDENTIALITY
The investigator must ensure that each subject’s anonymity will be 
maintained and each subject’s identity will be protected from 
unauthorized parties. A number will be assigned to each subject upon 
study entry and the number and the subject’s initials will be used to 
identify the subject for the duration of the study. The investigator will 
maintain all documents related to this study in strict confidence.
11.3
INFORMED CONSENT AND PERMISSION TO USE PROTECTED 
HEALTH INFORMATION
It is the responsibility of the investigator to obtain written informed consent 
from each subject participating in this study after adequate explanation, 
in lay language, of the methods, objectives, anticipated benefits, and 
potential hazards of the study. The investigator must also explain that the 
subject is completely free to refuse to enter the study or to discontinue 
participation at any time (for any reason) and receive alternative 
conventional therapy as indicated. Prior to study participation, each 
subject will sign an IRB approved informed consent form and receive a 
copy of same (and information leaflet, if appropriate). For subjects not 
qualified or able to give legal consent, consent must be obtained from a 
parent, legal guardian, or custodian.
The investigator or designee must explain to the subject before 
enrollment into the study that for evaluation of study results, the subject’s 
protected health information obtained during the study may be shared 
with the study sponsor, regulatory agencies, and the IRB. It is the 
investigator’s (or designee’s) responsibility to obtain permission to use 
protected health information per HIPAA from each subject, or if 
appropriate, the subjects’ parent or legal guardian.
11.4
SOURCE DOCUMENTATION AND INVESTIGATOR FILES
The investigator must maintain adequate and accurate records to fully 
document the conduct of the study and to ensure that study data can be 
subsequently verified. These documents should be classified into two 
separate categories: (1) investigator study file and (2) subject clinical 
source documents that corroborate data collected on the CRF’s. Subject 
clinical source documents would include hospital/clinic patient records; 
physician's and nurse's notes; appointment book; original laboratory, 
ECG, EEG, radiology, pathology, and special assessment reports;
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pharmacy dispensing records; subject diaries; signed informed consent 
forms; and consultant letters. When the CRF or any form is used as the 
source document, this must be clearly stated in the investigator study file.
Minimally, the following be documented in source documents:
►
Medical history/physical condition and diagnosis of the subject 
before involvement in the study sufficient to verify protocol entry 
criteria
►
Study number, assigned subject number, and verification that written 
informed consent was obtained (each recorded in dated and signed 
notes on the day of entry into the study)
►
Progress notes for each subject visit
►
Documentation of treatment
►
Laboratory test results
►
Adverse events (action taken and resolution)
►
Condition and response of subject upon completion of or early 
termination from the study
11.5
RECORDING AND PROCESSING OF DATA
If using hard copies of CRF’s, study center personnel will complete 
individual CRF’s in black ink. All corrections to entered data will be made 
by drawing a single line through the information to be corrected without 
obscuring it. All corrections will be initialed, dated and explained, if 
necessary. Do not use “white-out” or obscuring correction tape. A 
CRF is required for every patient who received any amount of study 
treatment. The investigator will ensure that the CRF’s are accurate, 
complete, legible and timely. Separate source records are required to 
support all CRF entries.
11.6
NON-PROTOCOL RESEARCH
No investigative procedures other than those described in this protocol 
will be undertaken on the enrolled subjects without the agreement of the 
IRB.
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11.7
Ethics
The investigator agrees to conduct the study in compliance with the 
protocol, current good clinical practices, and all applicable (local, FDA, 
ICH) regulatory guidelines and standard of ethics.
11.8
Essential documents for the conduct of a clinical trial
Essential documents are those documents with individually and 
collectively permit evaluation of the conduct of a trial and the quality of the 
data produced. These documents serve to demonstrate the compliance 
of the investigator with the standards of Good Clinical Practice and with 
all applicable regulatory requirements.
The following documents should be on file: 
CV’s and license of all investigators
IRB documentation/correspondance 
Documentation of IRB certification
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12.0
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23.Armitage P, Berry G, Matthews, JNS. Statistical Methods in Medical Research, 
4th Ed. Oxford: Blackwell Scientific, 2002.
24.Agresti A. Categorical Data Analysis. 2nd Edition, New Jersey: John Wiley & 
Sons, INC, 2002.
25.Collett D. Modeling Survival Data in Medical Research, 2nd Ed. New York: CRC 
Press, 2003.
26.Spiegelhalter DJ, Freedman LS, Parmar MK, Bayesian approaches to 
randomized trials (with discussion). J Royal stat soc Ser A 1994; 157: 357-416
27.Fayers, PM, Ashby D., Parmer MKB, Tutorial in biostatistics: Bayesian data 
monitoring in clinical trials. Stat Med 1997; 16: 1413-30
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APPENDIX I (02-21-2013)
STUDY PARAMETER TABLE (See Section 5.0 for details)
SURGERY
PRIOR
to RT
DURING 
RT
FOLLOW-UP AFTER 
TREATMENT
Long-term 
Follow-up
Assessment
Pre-Op
Intra-
Op
Post-Op
PRIOR to
RT
From END of RT
From End of
RT
Week
Week
1
3 Mo
6 Mo
12 Mo
Thereafter,
Week 1-4
1-7
5-8
Mo
± 1
± 2
wks
± 2
wks
± 2 wks
Every 6 Mo
(+ 1 Mo) and
wk.
in years 2-5
at the
discretion of
the
Investigator
Informed Consent
X
Biopsy
X
Surgical Frozen
Section Path
X
Pathology
X
X
History/Physical
X
X
X
X
X
X
X
X
X
ECOG 0-2
X
X
X
X
X
X
X
Mammogram
X
Pregnancy test
X
Labs per MD
discretion
X
Radiological tests
per MD discretion
X
X
Operative Report
X
Photographs *
X
X
X
X
X
NAC sparing
mastectomy
X
RT Treatment Plan
X
Cosmesis
X
X
X
X
X
AE Evaluation
X
X
X
X
* Photographs will be taken at the discretion of the PI and Sub-PI
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APPENDIX II:
NATIONAL CANCER INSTITUTE (NCI) COMMON TOXICITY CRITERIA (CTC)
The NCI CTC can be viewed on-line at the following NCI web site: 
http://ctep.cancer.gov/reporting/ctc.html
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APPENDIX III:
DATA AND SAFETY MONITORING PLAN
The Sylvester Comprehensive Cancer Center (SCCC) Data and Safety Monitoring 
Committee (DSMC) will monitor this clinical trial according to the Cancer Center’s DSM 
Plan. In its oversight capacity, the DSMC bears responsibility for suspending or 
terminating this study.
DSMC oversight of the conduct of this trial includes ongoing review of accrual and 
adverse event data, and periodic review of response to treatment or other study endpoint. 
The guidelines appearing in Section 10.3.1 to 10.3.3 are offered for DSMC consideration 
in assessing surgery-related toxicities. In addition, the DSMC will review reports from all 
audits, site visits, or study reviews pertaining to this clinical trial and take appropriate 
action.
The SCCC DSM Plan to which this study is subject can be obtained by call the CRS office 
at (305) 243-4903.
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Appendix IV:
DATA SUBMISSION SCHEDULE
FORM
TO BE COMPLETED
BASELINE
Eligibility Checklist
SCCC Protocol Enrollment Form
Consent Forms Signed/dated
Prior to registration
On-study Form
Within 30 days of registration
DURING PROTOCOL THERAPY
Due every week for phase I studies, every cycle for 
phase II-IV studies
AFTER PROTOCOL THERAPY
Off Treatment Form
Within 14 days of discontinuation/completion of
protocol therapy
FOLLOW-UP SCHEDULE (for studies with long term follow-up)
Follow-up Form
1 month, 3 month, 6 month, 1 year, then every 6 
months (+/- 1 month) and in years 2-5, at the 
discretion of the Investigator.
Progression/Relapse
Within
4
weeks
of
knowledge
of
progression/relapse
Notice of Death Form
Within 4 weeks of knowledge of death
Subsequent Malignancy
Within
4
weeks
of
knowledge
of
another 
malignancy
NOTE: FORMS WILL BE CONSIDERED PAST DUE 14 DAYS AFTER THE DUE DATE.
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APPENDIX VI
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
ZUBROD PERFORMANCE SCALE
0
Fully active, able to carry on all pre-disease activities without restriction 
(Karnofsky 90-100).
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature. For example, light housework, office work 
(Karnofsky 70-80).
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours (Karnofsky 50-60).
3
Capable of only limited self-care, confined to bed or chair 50% or more of waking 
hours (Karnofsky 30-40).
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair (Karnofsky 10-20).
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APPENDIX VII
AJCC STAGING SYSTEM BREAST, 6th Edition 
DEFINITION OF TNM
Primary Tumor (T)
Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic classification. 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 measurements, are used, the subsets 
of T1 can be used. Tumors should be measured to the nearest 0.1 cm increment.
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
Tis (DCIS)
Ductal carcinoma in situ
Tis (LCIS)
Lobular carcinoma in situ
Tis (Paget’s)
Paget’s disease of the nipple with no tumor
Note: Paget’s disease associated with a tumor is classified according to the size of the tumor.
T1
Tumor 2 cm or less in greatest dimension
T1mic
Microinvasion 0.1 cm or less in greatest dimension
T1a
Tumor more than 0.1 but not more than 0.5 cm in greatest dimension 
T1b
Tumor more than 0.5 cm but not more than 1 cm in greatest dimension 
T1c
Tumor 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 size with direct extension to (a) chest wall or (b) skin, only as described 
below.
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
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APPENDIX VII (CONT’D)
Regional Lymph Nodes (N) 
Clinical
NX
Regional lymph nodes cannot be assessed (e.g., previously removed) 
N0
No regional lymph node metastasis
N1
Metastasis to movable ipsilateral axillary lymph node(s)
N2
Metastasis in ipsilateral axillary lymph nodes fixed or matted, or in clinically apparent* 
ipsilateral internal
mammary nodes in the absence of clinically evident axillary lymph node metastasis 
N2a
Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other
structures
N2b
Metastasis only in clinically apparent* ipsilateral internal mammary nodes and in the
absence of clinically evident axillary lymph node metastasis
N3
Metastasis in ipsilateral infraclavicular lymph node(s) with or without axillary lymph node 
involvement, or in clinically apparent* ipsilateral internal mammary lymph node(s) and in 
the presence of clinically evident axillary lymph node metastasis; or metastasis in 
ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary 
lymph node involvement
N3a
Metastasis in ipsilateral infraclavicular lymph node(s)
N3b
Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) 
N3c
Metastasis in ipsilateral supraclavicular lymph node(s)
* Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical 
examination or grossly visible pathologically.
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APPENDIX VII (cont’d)
AJCC STAGING SYSTEM
BREAST, 6th Edition
Pathologic (pN) a
pNX
Regional lymph nodes cannot be assessed (e.g., previously removed, or not removed for 
pathologic study)
pN0
No regional lymph node metastasis histologically, no additional examination for isolated 
tumor cells (ITC)
Note: Isolated tumor cells (ITC) are defined as single tumor cells or small cell clusters
not greater than 0.2 mm, usually detected only by immunohistochemical (IHC) or molecular 
methods but which may be verified on H&E stains. ITCs do not usually show evidenced of 
malignant activity e.g., proliferation or stromal reaction.
pNO(i-)
No regional lymph node metastasis histologically, negative IHC
pNO(i+)
No regional lymph node metastasis histologically, positive IHC, no IHC cluster greater than 
0.2mm
pNO(mol-)
No regional lymph node metastasis histologically, negative molecular findings (RT-PCR)b 
pNO(mol+)
No regional lymph node metastasis histologically, positive molecular findings (RT-PCR)b
a Classification is based on axillary lymph node dissection with or without sentinel lymph node dissection. 
Classification based solely on sentinel lymph node dissection without subsequent axillary lymph node 
dissection is designated (sn) for “sentinel node,” e.g., pNO(i+) (sn).
B RT-PCR:reverse transcriptase/polymerase chain reaction.
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APPENDIX VII (cont’d)
AJCC STAGING SYSTEM
BREAST, 6th Edition
pN1
Metastasis in 1 to 3 axillary lymph nodes, and/or in internal mammary nodes with 
microscopic disease detected by sentinel lymph node dissection but not clinically 
apparent**
pN1mi
Micrometastasis (greater than 0.2 mm, none greater than 2.0 mm) 
pN1a
Metastasis in 1 to 3 axillary lymph nodes
pN1b
Metastasis in internal mammary nodes with microscopic disease detected by sentinel 
lymph node dissection but not clinically apparent**
pN1c
Metastasis in 1 to 3 axillary lymph nodes and in internal mammary lymph nodes with 
microscopic disease detected by sentinel lymph node dissection but not clinically 
apparent.** (If associated with greater than 3 positive axillary lymph nodes, the internal 
mammary nodes are classified as pN3b to reflect increased tumor burden).
pN2
Metastasis in 4 to 9 axillary lymph nodes, or in clinically apparent* internal mammary lymph 
nodes in the absence of axillary lymph node metastasis
pN2a
Metastasis in 4 to 9 axillary lymph nodes (at least one tumor deposit greater than 2.0 mm) 
pN2b
Metastasis in clinically apparent* internal mammary lymph nodes in the absence of axillary
lymph node metastasis
pN3
Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in 
clinically apparent* ipsilateral internal mammary lymph nodes in the presence of 1 or more 
positive axillary lymph nodes; or in more than 3 axillary lymph nodes with clinically negative 
microscopic metastasis in internal mammary lymph nodes; or in ipsilateral supraclavicular 
lymph nodes
pN3a
Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit greater than 2.0 
mm), or metastasis to the infraclavicular lymph nodes
pN3b
Metastasis in clinically apparent* ipsilateral internal mammary lymph nodes in the presence 
of 1 or more positive axillary lymph nodes; or in more than 3 axillary lymph nodes and in 
internal mammary lymph nodes with microscopic disease detected by sentinel lymph node 
dissection but not clinically apparent**
pN3c
Metastasis in ipsilateral supraclavicular lymph nodes
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APPENDIX VII (cont’d)
AJCC STAGING SYSTEM
BREAST, 6th Edition
*Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical 
examination.
**Not clinically apparent is defined as not detected by imaging studies (excluding lymphoscintigraphy) or 
by clinical examination.
Distant Metastasis (M)
MX Distant metastasis cannot be assessed 
M0 No distant metastasis
M1 Distant metastasis
STAGE GROUPING
Stage 0 Tis N0 M0 
Stage I T1* N0 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 M0 
T4 N1 M0
T4 N2 M0
Stage IIIC Any T N3 M0 
Stage IV Any T Any N M1
* Note: T1 includes T1mic
Note: Stage designation may be changed if post-surgical imaging studies reveal the presence of distant 
metastases, provided that the studies are carried out within 4 months of diagnosis in the absence of disease 
progression and provided that the patient has not received neoadjuvant therapy.
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