A Pilot Study of Hypofractionated Simultaneous Integrated Boost Radiotherapy in Stage 0, I and III Breast Cancer Patients
Phase: NA
Conditions: Cancer, Breast, Inflammation
Sponsor: Emory University

 
12/13/2016 
 
Title: A Pilot Study of Hypofractionated Simultaneous Integrated Boost Radiotherapy in Stage 
0-IIIBBreast Cancer Patients 
Version: 12/13/2016 
Investigators: 
PI- Mylin A. Torres, M.D. 
 
IRB00047240 
NCT03167359 
 
 
 

 
12/13/2016 
 
Title: A Pilot Study of Hypofractionated Simultaneous Integrated Boost Radiotherapy in Stage 0-
IIIBBreast Cancer Patients  
Version: 12/13/2016  
Investigators:  
PI- Mylin A. Torres, M.D. 
Co-investigators: Dr. Tian Liu, Dr. Andrew H. Miller 
 
Study Centers: The Emory Clinic Clifton Campus, Emory Midtown Hospital, Emory St. Joseph’s 
Hospital 
Background: 
For the majority of women with breast cancer (BrCA), radiation therapy (XRT) is critical for preventing 
local recurrence and improving breast preservation and survival.[1]  XRT to the whole breast is a 
necessary component of breast conserving therapy and is standard of care following partial 
mastectomy; XRT has been shown to decrease locoregional recurrence by 2/3 and improve absolute 
survival by a minimum of 5% over lumpectomy alone.[1]   
 
As the number of survivors has markedly increased, clinicians are now seeking to reduce treatment-
related toxicities and inconveniences of treatment, namely the traditional 6 weeks of daily 
radiotherapy.  Skin thickening, fibrosis, and edema are some of the most common acute and 
potentially long-term debilitating toxicities of BrCA XRT.[2, 3]  During XRT, approximately 50% of 
patients develop significant cutaneous toxicity including moist skin desquamation, erythema, and 
hyperpigmentation.[2, 3]   
 
Two recent studies have examined the role of hypofractionation (>2Gy per day with shorter overall 
treatment time) in the treatment of breast cancer.[4, 5]  A recently published Phase III Canadian study 
randomized early stage BrCA patients to 42.5 Gy in 16 fractions (fxns) (2.66 Gy per day) or 50 Gy in 
25 fxns (2 Gy per day) to the whole breast following lumpectomy and axillary lymph node dissection. 
[4] At 10 years, there was no difference in local control, survival, or cutaneous toxicity.[4]  The UK 
START B study also randomized patients to 40 Gy in 15 fxns (2.66 Gy per day) or 50 Gy in 25 
fractions (2 Gy per day) and found no difference in local control, survival, or cosmesis at 5 years.[5]  
Both studies successfully challenged the long held radiobiological belief that large daily fractions (>2 
Gy per day) portends severe late normal tissue toxicity and unacceptable breast cosmesis following 
XRT.  More recently, an updated analysis of the UK START trial was presented with 9.8 years of 
follow-up and there was still no difference in local control, survival or side effects between 
hypfractionated radiation and standard five weeks of XRT treatment.[6] 
 
However, both the Canadian and UK studies included patient populations at relatively low risk of 
XRT-induced toxicity.[4, 5]  Race, prior chemotherapy treatment, body habitus, and age have all been 
correlated with a patient’s radiotherapy tolerance.  More than 70% of participants in both 
hypofractionation studies were Caucasian and over the age of 50; fewer than 25% of patients 
received chemotherapy.[4, 5]  It is known that African American women with BrCA experience more 
severe XRT-induced side effects than Caucasians, possibly contributing in part to poorer treatment 
adherence and worse outcome.[7-9] During and after XRT, African-Americans have worse cutaneous 
toxicity (edema, fibrosis, and pigmentation) than Caucasians (45% versus 10%, respectively).   In 
addition, overall cosmesis, reflective of radiation-induced cutaneous toxicity, was good to excellent in 
90% of Caucasians versus only 55% of African Americans following breast conserving treatment with 
XRT.[8]  Negative perceptions of BrCA treatment including XRT may partially explain poor treatment 

 
12/13/2016 
 
adherence rates in the African American community.  Indeed, at our own institution, 26% of AAs with 
BrCA refused XRT in a recent study.[10]  In addition to race, several studies have also found that 
patients heavily pre-treated with chemotherapy experience at least twice as much XRT induced skin 
desquamation and edema.[11-13]  Moreover, women with larger breasts have higher rates of 
cutaneous toxicity due to the buildup of dose on the surface of the skin as the radiation beam tries to 
penetrate a large depth of tissue.  For this reason, the Canadian study limited their enrollment to 
those women with less than 25cm of separation of the breast (the largest distance between the entry 
and exit point of the XRT beam on the breast). [4]   Lastly, women less than age 50 have been found 
to have poorer cosmesis than older women following surgery and XRT.[7]  Given the patient 
population treated in both the Canadian and UK studies, it is unclear if a shortened XRT regimen may 
be applied to a “high risk” patient (e.g. young patients previously treated with chemotherapy).    
 
Furthermore, in the UK START study, post mastectomy patients were included as well as patients 
requiring regional nodal irradiation although only 15% of the enrolled patients were post-mastectomy 
patients  and only 15% of the entire cohort needed regional nodal irradiation.  Therefore, these 
patients at relatively higher risk for lymphedema/brachial plexopathy from XRT were under-
represented in the UK START study.  However, among the small number of patients treated with 
hypofractionated XRT to the regional lymph nodes (supraclavicular radiaton), there were no 
significant increases in lymphedema or brachial plexopathy compared to women treated with 
standard 5 weeks of XRT to the supraclavicular fossa.[6]     
  
Additionally, a now standard boost dose to the lumpectomy cavity or chest wall, proven to significantly 
improve local control by 10% or greater in women less than 50 years of age [14-16], was not required 
in either arm of the Canadian or UK study. [4, 5]    The boost dose has been shown to improve 
locoregional control in all patients by a minimum of 3% but appears to have the greatest impact in 
younger patients.[14-16]  This boost dose has extended conventional XRT treatment from 5 (50 Gy in 
25 fxns) to 6 weeks (60 Gy in 30 fxns) in the majority of patients treated within the United States.       
 
At our institution, we have one of the largest experiences with simultaneous integrated boost (SIB) 
technique in patients with BrCA; we deliver 45 Gy in 25 fxns to the whole breast while treating the 
cavity simultaneously to a higher dose of 59.92 Gy in 25 fxns. Our published experience shows that 
at 3 years, our 5-week regimen is generally well tolerated with <1% of patients developing Grade 3 
cutaneous toxicity and only 2.8% of patients recurring locally.[17]  Our results are particularly 
important given that 39% of these patients were AA,  33% were premenopausal, 30% had breast 
separation >25cm, and 45% received chemotherapy, all factors associated with heightened skin 
toxicity from XRT. [17]     
 
Seeking to shorten the treatment course further and improve convenience and treatment adherence, 
we propose to build upon our experience and the level I evidence advocating for hypofractionation in 
15 days of treatment. Our proposed study will utilize the SIB technique with the whole breast treated 
to 40 Gy in 15 fractions and the cavity boosted simultaneously to 48 Gy in 15 fractions.  Only one 
previous study has examined the feasibility of a similar fractionation with the whole breast treated to 
40.5 Gy in 15 fractions, while the cavity is treated to 48 Gy.(20) At 1 year median follow-up time, 67% 
of patients had developed reversible grade 1-2 skin dermatitis and only 1 of 91 patients had recurred 
locoregionally.(20) However, only 1/3 of patients received chemotherapy and less than a quarter had 
large breast size.  The majority of patients were over the age of 50 and 87% were Caucasian.(20)  No 
study has examined the feasibility of a 15-day hypofractionated SIB XRT regimen in women at high 
risk for cutaneous toxicity (e.g. women below the age of 50, African American, and/or treated with 
chemotherapy). The unique patient population served by Emory will enable a study of SIB XRT given 

 
12/13/2016 
 
over 15 treatments.  Quality of life measures (e.g. Multidimensional Fatigue inventory (MFI)[18], the 
Pittsburgh Sleep Quality Index (PSQI) [19], the perceived stress scale (PSS)[20], the Inventory of 
Depressive Symptomalogy-Self Reported (IDS-SR)[21], the Short-Form Health Survey (SF-36)(25) 
and the Godin Leisure Time Questionnaire (GLTEQ)(26)) which have been validated in multiple 
populations, will also be assessed in these patients to determine if 15 days of treatment is feasible.   
 
Preliminary Data: 
Recent work from our group indicates that ultrasound tissue characterization (UTC) may objectively 
and reliably measure XRT-induced cutaneous toxicity in BrCA patients. UTC is a non-invasive 
technique developed by Tian Liu, PH.D.(co-Investigator), to delineate sub-resolution tissue features 
that are not visible by standard B-mode ultrasonography.[22, 23]   From the UTC analysis, we can 
obtain quantitative parameters (skin thickness, Pearson coefficient, and midband fit value) 
characterizing the dermal, hypodermal, and subcutaneous tissue. These spectral parameters are 
related to structural tissue properties including skin thickening, fibrosis, and edema. [22, 23] In 
published work, the clinical assessments of XRT-induced skin toxicity correlate strongly with UTC 
measurements and objectively validate this measurement of skin toxicity.[23]  However, inter-
observer subjective toxicity assessments have mild to moderate agreement.  UTC would provide a 
reproducible way of characterizing toxicity.  XRT-induced skin thickening increases with maximum 
thickness occurring at the completion of XRT. The thickening decreases significantly by 6 weeks post 
XRT in patients treated with a traditional 6 week course of XRT. We plan to use UTC to objectively 
quantify cutaneous toxicity during XRT in this study. Time points for analysis of cutaneous toxicity 
(baseline, fraction 15 of XRT and 2 - 5 weeks, 7 - 12 weeks, and 12 – 18 months post XRT) are 
based on these data.[23].  
 
Study Design:  
 
Eighty breast cancer patients with Stage 0-III BrCA treated with breast conserving surgery or 
mastectomy and clear margins will be recruited to the study.  Patients must have one or more of the 
following characteristics and be eligible for breast or chest wall with or without regional nodal 
radiotherapy:  
 
1.  Prior Chemotherapy for Breast Cancer 
2.  >25 cm of breast separation (the largest distance on an axial slice of the planning CT simulation 
scan between the entry and exit points of the radiation beam on the body)  
3.  Non-Caucasian Race 
4.  < 50 years of age 
5. Requiring regional nodal irradiation without evidence of N3 disease 
 
Because the above characteristics in isolation have been correlated with heightened levels of skin 
toxicity and/or were under-represented in previous trials of hypofractionated XRT, any patient fulfilling 
one of the above criteria, will be approached for enrollment in the study. 
 
Males will be excluded. 
 
   
To protect against possible side effects of radiation, women who are pregnant or nursing a child may 
not take part in this study.   

 
12/13/2016 
 
Patients who have not received chemotherapy may start  XRT up to 16 weeks after lumpectomy 
surgery.  Patients who receive adjuvant chemotherapy after lumpectomy may start XRT up to 7 
weeks after their last cycle of chemotherapy. 
Dosimetry Guidelines for Hypofractionation SIB protocol for Breast Cancer 
Please plan breast treatments according to ICRU Guidelines.(19)   
  
Treatment plans must be generated with heterogeneity corrections turned on. 
 
Eligible patients are those being treated after lumpectomy or mastectomy.   
 
  
Whole Breast or chest wall Treatment: 
The whole breast or chest wall will be treated with tangents (modulated with either wedges or field-n-
field technique) to a dose of 2.66 Gy per day x 15 fractions.   
 
The whole breast or chest wall should receive at least 95% of the prescribed dose.  The whole breast 
or chest wall should receive less than 115%.  No more than 8% of the whole breast should receive 
<95% of the prescribed dose. 
 
5mm bolus may be used on the chest wall in postmastectomy patients at the discretion of the treating 
physician.   
  
Central lung distance <2.5cm from chest wall to posterior edge of tangents 
Maximum heart distance <1.5cm from chest wall to posterior edge of  tangents 
  
 
Regional Nodal/ Supraclavicular Irradiation: 
For patients requiring regional nodal irradiation, the physician will determine which lymph nodes are 
at risk and these targeted lymph nodes will be contoured (e.g. level I, II, III, and/or supraclavicular 
nodes and/or internal mammary lymph nodes).   
 
The lymph nodes will be prescribed 2.66 Gy per day x 15 fractions and administered on the same day 
as the whole breast or chest wall treatment.  The targeted regional lymph nodes should receive at 
least 90% of the prescribed dose.  The targeted regional lymph nodes should receive less than 105% 
of the prescribed dose. If these dose constraints cannot be met, the treating physician has the option 
of decreasing the total dose to the targeted lymph nodes per day to 2.6 Gy per day x 15 fractions.     
 
The supraclavicular nodes may be treated with an anterior oblique photon field or opposed oblique 
photon fields. The internal mammary nodes may be treated with deep tangents or an en face electron 
field.    
 
 
 
Simultaneous Integrated Boost to the Cavity Treatment: 
  
The boost treatment will be given on the same days as the whole breast treatment.  

 
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The lumpectomy cavity + scar (in lumpectomy patients) or chest wall scar (mastectomy patients) will 
receive 0.54 Gy per day x 15 fractions.   
 
95% of the tumor bed volume should receive at least 95% of the prescribed dose.   
  
Effort should be made to reduce treatment volume receiving more than 115% of the boost dose to 
less than 1%.   
  
Electrons or photons may be used for the boost fields.  It is up to the clinician to decide and will often 
be decided based upon the depth of the cavity.   
 
If using photons (mini-tangents), for deep cavities, margin is 1.5cm on cavity + scar to field  
                               edge  
 
Suggested photon fields for the boost are to use the same gantry angles from the initial whole breast 
fields with the same couch kick as the whole breast tangents.  If the cavity is laterally located, kick the 
couch on the lateral tangent for a 3rd field 10 to 20 degrees.  Leave the medial tangent alone.  If the 
cavity is medially located, kick the couch 10 to 20 degrees from the initial couch kick on the medial 
tangent for the 3rd field.  Leave the lateral tangent alone.   
  
 
If using en face  electrons for shallow cavities or chest wall, margin is 2.0 cm on cavity + scar to 
block edge in all dimensions but posterior to  the cavity volume in the case of breast conserving 
surgery patients.   
 
 
 
***Please note that if using electrons to boost the cavity or chest wall, this must be done on a 
non-breathold scan even when using breathold for whole breast tangent treatment for left 
sided tumors.   
In addition to the port films, a cone beam CT scan will be done  1-2 times  per week for localization of 
the tumor bed cavity.  A cone beam CT scan is not necessary in post-mastectomy patients.  
 
Dose Constraints to Normal Tissues: 
 
Heart: 
Maximum heart distance <1.5cm on tangents or mean dose < 6 Gyor the heart volume receiving 13 
Gy must be less than or equal to 10%. (V13Gy<10%)  
 
 
Lung:  
Central lung distance <2.5cm on tangents orthe ipsilateral lung volume receiving 18 Gy must be less 
than or equal to 15%.  (V18Gy<15%), the contralateral lung volume receiving 2.5 Gy must be less than 
or equal to 15%. (V2.5Gy<15%), or Total Lung V20 <36% 
 
Contralateral breast dose: 

 
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The contralateral mean breast dose must be < or equal to 3 Gy but aim should be less than 1 Gy 
 
Data Collection:  
 
Cutaneous toxicity will be assessed at baseline, fraction 15 of XRT and 2 - 5 weeks, 7 - 12 weeks, 
and 12 – 18 months post XRT by objective ultrasound measurements (UTC).  Photographs of the 
treated breast or chest wall as well as the contralateral breast will also be taken. Documentation of 
the UTC and photographs will be kept in electronic format for reference.  For each visit after the 
baseline (after treatment has begun), cutaneous toxicity will be assessed by a clinician.  Participants 
will be seen by the investigator in follow up at the third and/or fourth visits and at the fifth visit and an 
investigator dictation will be performed.  
 
Patients who have had a mastectomy and plan for permanent breast reconstructive surgery after 
radiation will be assessed within one month of their permanent reconstructive surgery and 5 – 7 
months following their surgery using the same procedures as described above. It is highly variable as 
to when reconstruction will occur. If these time points do not fall within the time frame for the regular 
study visits, additional study visits will be added for these patients. 
 
Participants will also be asked to complete the Multidimensional Fatigue inventory (MFI)[18], the 
Pittsburgh Sleep Quality Index (PSQI) [19], the perceived stress scale (PSS)[20],  the Inventory of 
Depressive Symptomalogy-Self Reported (IDS-SR)[21], the PROMIS Fatigue Short form [28], the 
MOS-item Short-Form health survey (SF-36)(25) and the Godin Leisure-Time Exercise Questionnaire 
(GLTEQ)(26) to assess levels of fatigue, sleep, stress, and depression at the above time points.  
These surveys take approximately 15 minutes to complete. Patients who are simultaneously enrolled 
on the Fatigue in Breast Cancer Patients Undergoing Treatment (IRB00028295) may have survey 
visit assessments completed prior to baseline visit, as they are completing the same assessments for 
both studies. These surveys will be used for data purposes in lieu of having the patient complete the 
same paperwork twice.  At each visit, patients will be asked to rate their fatigue level and breast pain 
on a scale of 0-10, 0 being none and 10 being extreme. They will be asked to rate how happy they 
are with the look of their breast on a scale of 0-10, 0 being not happy and 10 very happy. They will be 
asked to rate how different their radiated breast is from their non-radiated breast,on a scale of 0 – 10, 
0 being no difference and 10 being completely different.  The patient’s self-report of fatigue at these 
visits will be used to assess the grade of their fatigue.  In addition, patients will complete the  LENT 
SOMA [27] scale patient questionnaire at all study timepoints to address pain within the breast.  The 
objective LENT SOMA questionnaire Part 3 will be completed by a study clinician or trained nurse at 
each visit after baseline.   
 
Blood will be drawn under fasting conditions at visits corresponding to cutaneous toxicity 
assessments.  The blood will be analyzed for inflammatory markers (tumor necrosis factor (TNF)-
alpha, soluble TNF receptor 2 (sTNFR2), interleukin (IL)-6, IL-1ra, and C - reactive protein (CRP) as 
well as genetic factors to determine if they are associated with development of cutaneous toxicity.   
 
Information regarding disease characteristics (including stage, tumor size, grade), patient 
demographics (including age, race, co-morbidities, social history, body mass index), systemic 
treatment (including hormone therapy, systemic therapy), surgical treatment, radiation treatment, and 
clinical outcomes (local control, distant metastasis, survival, and treatment complications) will be 
collected and recorded. 

 
12/13/2016 
 
 
 
Patients may also be asked to participate in a long term assessment between 1 and 10 years where 
they will complete the same study procedures as outlined above.  Patients will be compensated 
$50.00 for completing this visit. 
 
 
A follow up phone survey will be taken between 18 months and 10 years after treatment.  Using the 
same scales as in the study visits, the patients will be asked to rate their fatigue level, breast pain, 
how happy they are with the look of their breast and how different their radiated breast is from their 
non-radiated breast. They will also be asked if they are on any hormonal treatment for breast cancer 
and if so, the date they started.  We will obtain verbal consent for this survey from patients who 
completed this study before the follow up phone survey was originally approved on 9/24/2013.  
 
 
Assuming 10% of patients dropout, 53 patients requiring breast only radiation will be enrolled (2-3 
patients per month) to yield a total of 50 patients.  
 
An additional 33 patients requiring regional nodal irradiation and breast or chest wall radiation will be 
enrolled. Assuming 10% of patients dropout, 33 patients of these patients will be enrolled (2-3 
patients per month) to yield a total of 30 patients receiving regional nodal irradiation and breast or 
chest wall radiation. 
 
In patients undergoing regional nodal irradiation, arm measurements will be taken of the ipsilateral 
and contralateral upper extremity at baseline, 7 - 12 weeks, and 12 – 18 months post XRT by a 
licensed lymphedema therapist or study staff trained by a licensed lymphedema therapist.  These 
patients will also be assessed for brachial plexopathy using RTOG grading toxicity, LENT/SOMA 
grading toxicity, and a modified version of a validated questionnaire to assess symptoms of brachial 
plexopathy at baseline and 7 - 12 weeks, and 12 – 18 months post XRT.[24]  If a patient develops 
RTOG or LENT/SOMA Grade 3 toxicity, an objective measurement (MRI and/or nerve conduction 
studies) of brachial plexopathy will be employed.   
 
 
 
Objectives: 
Primary objective:  To assess the safety and feasibility of delivering 15 fractions of SIB radiotherapy 
to the breast in patients at risk for developing cutaneous toxicity.   
Primary Outcome Measure: 
1.  Cutaneous Toxicity Rate 
Cutaneous toxicity rate will be assessed by the National Cancer Institute Common Toxicity 
Criteria (NCI-CTC) v 3. grading scale. 
1. Rate of 20% or greater increase in arm lymphedema (compared to baseline arm measurements)  will be 
assessed Among breast cancer patients receiving regional nodal irradiation  
2. Rate of Grade 3 brachial plexopathy will be  assessed among breast cancer patients receiving regional 
nodal irradiation by RTOG and LENT/SOMA scales 

 
12/13/2016 
 
 
 
Secondary Outcome Measures: 
1. Rate of cutaneous toxicity, as measured by changes in cutaneous measurements , acquired vis 
ultrasound tissue characterizations (UTC)  
2. Local control will also be assessed through routine physical examination, annual screening 
mammograms, ultrasound, and biopsy to confirm local recurrence. 
3. Blood will be analyzed for biomarkers and inflammatory markers including(tumor necrosis factor 
(TNF)-alpha, soluble TNF receptor 2 (sTNFR2), interleukin (IL)-6, IL-1ra, and C - reactive protein 
(CRP) as well as genetic factors to determine if they are associated with development of 
cutaneous toxicity.   
 
4. Change in Multidimensional Fatigue Inventory (MFI) Score  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to 
measure fatigue. Scores range from 20 to 100.The higher the score, the more fatigued. 
5. Change in Pittsburgh Sleep Quality Index (PSQI) Score  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
The PSQI is a self-rated questionnaire which assesses sleep quality and disturbances over a 
1-month time interval. Scores range from 0 to 21. A score of less than or equal to 5 is 
associated with good sleep quality. A score greater than 5 is associated with poor sleep 
quality. 
6. Change in Perceived Stress Scale (PSS) Score  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
The PSS is a self-reported instrument used to measure the perception of stress. Scores range 
from 0 to 40. Score of 20 or higher are considered high stress. 
7. Change in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue 
Short Form Score  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
The PROMIS Fatigue questionnaire is a self-report tool used to evaluate frequency, duration, 
and intensity of fatigue over the past seven days. Scores range from 7 to 35. The higher the 
score, the more fatigue. 
8. Change in an Inventory of Depressive Symptomatology-Self Reported (IDS-SR) score  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
The IDS-SR is a self-reported measure in which participants rate the frequency of depression 
symptoms within the past seven days. Scores range from 0 to 84, with higher score reflecting 
greater severity of depressive symptoms. 
9. Change in Short Form-36 (SF-36) Health Survey Score  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
The SF-36 is a self-reported survey of health status. Scores range from 0 to 100. Lower scores 
indicate disability. The higher the score, the less disability. 

 
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10. Change in Godin Leisure-Time Exercise Questionnaire (GLTEQ) Score  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
The GLTEQ is a self-reported questionnaire used to measure usual leisure-time exercise 
habits during a typical seven day period. A score of 24 or more indicates active and substantial 
exercise benefits. A score of 23 units or less indicates insufficiently active and less substantial 
exercise benefits. 
11. Change in Lent Soma Scale Patient Questionnaire Score  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
The Lent Soma questionnaire is a self-reported measure of pain. Scores range from 0 to 9. 
The higher the score, the more pain reported. 
12. Change in Fatigue Level  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
Participants will be asked to rate their fatigue level on a study specific scale from 0 to 10 where 
0 represents no fatigue, and 10 represents the most extreme fatigue. 
13. Change in Breast Pain Level  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
Participants will be asked to rate their breast pain level on a study specific scale from 0 to 10 
where 0 represents no pain, and 10 represents the most extreme pain. 
14. Change in Breast Appearance Satisfaction Score  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
Participants will be asked to rate the look of their breast on a study specific scale from 0 to 10 
where 0 represents not happy, and 10 represents very happy. 
15. Difference in Radiated Breast Appearance Score  
[Time Frame: Baseline, End of Follow Up (Up to 18 months)] [Safety Issue: No]  
Participants will be asked to rate how different the look of their radiated breast is compared to 
their non-radiated breast on a study specific scale from 0 to 10 where 0 represents no 
difference, and 10 represents completely different. 
 
Monitoring Plan for Severe Adverse Events:  
We hypothesize that a maximum of 20% of patients might experience severe acute skin side effects 
defined as NCI-CTC Grade 3.  This corresponds to symptoms interfering with activities of daily life.  A 
Data Safety and Monitoring Board (DSMB) will monitor patient outcomes and suspend the protocol in 
the event that more than 16 of 80 patients demonstrate severe acute skin toxicity.  During the study, 
the patients will be monitored continuously throughout the study such that if at any time during the 
study the upper limit of the number of patients developing Grade 3 toxicity exceed what is listed in the 
table below, the trial will be discontinued.  With a 10% dropout rate, a total sample size of 83 patients 
was calculated to effectively test our hypothesis.  For patients not requiring regional nodal irradiation, 
we will only collect adverse events related to skin toxicity, lung toxicity and heart toxicity. We will not 
report grade 1-2 radiation dermatitis as adverse events because most patients will at least have gr 1 
dermatitis.   We will keep a record of toxicity at each visit by collecting the Lent Soma evaluation of 

 
12/13/2016 
 
the clinician at each visit after treatment starts.  Patient reported fatigue rate will not be collected on 
the adverse event report, but will also be recorded at each visit 
 
Total Patients 
Upper limit of 
number of 
patients with 
toxicity for the trial 
to continue 
Proportion of 
patients with 
toxicity if exceed 
the upper limit 
Lower limit of 95% 
CI 
Upper Limit of 
95% CI 
3 
<3 
100% 
29% 
100% 
4 
<4 
100% 
40% 
100% 
5 
<4 
80% 
28% 
99% 
6 
<4 
67% 
22% 
96% 
7 
<5 
71% 
29% 
96% 
8 
<5 
63% 
24% 
91% 
9 
<5 
56% 
21% 
86% 
10 
<6 
60% 
26% 
88% 
11 
<6 
55% 
23% 
93% 
12 
<6 
50% 
21% 
79% 
13-50 
<7 
>20% 
NA 
 
Patients Requiring Regional Nodal Irradiation 
Among patients requiring regional nodal irradiation, we hypothesize that <3.0% of patients will 
develop severe brachial plexopathy following radiation to the regional nodes defined as 
LENT/SOMA or RTOG Grade 3 or higher (Continuous paresthesias with incomplete motor 
paresis; pain medication is generally required or objective neurologic findings with paresthesia 
or paresis)  As this toxicity occurs after radiation treatment is complete, patients will be formally 
assessed for brachial plexopathy at baseline and  at 7-12 weeks and 12-18 months post 
radiation for comparison with baseline assessments.  However, patients will be asked to 
contact Dr. Torres if symptoms of brachial plexopathy develop in between or after study visits.  
We also hypothesize that less than 15% of patients receiving regional nodal irradiation will 
develop 20% or greater increase in arm lymphedema (compared to baseline measurements) 
assessed at 7-12 weeks and 12-18 months post radiation.   Of note, lymphedema that 
develops in the context of weight gain (>/=15% increase in weight) or trauma to the arm will 
not be attributed to the radiation treatment itself and will not be considered an event to due to 
the treatment.  If this side effect is secondary to radiation rather than surgery, it generally 
occurs after radiation is complete.  Lymphedema that takes place during the 3 weeks of 
radiation or before radiation begins will be attributed to surgery.  During the study, the patients 

 
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will be monitored throughout the study such that if at any time during the study the upper limit 
of the number of patients receiving regional nodal irradiation developing Grade 3 brachial 
plexopathy or 20% or greater increase in arm lymphedema exceed the number just described 
or more than 20% develop grade 3 skin toxicity within the breast or chest wall, the trial will be 
discontinued to the patients requiring regional nodal irradiation but may remain open to 
patients who do not require regional nodal irradiation. For patients requiring regional nodal 
irradiation, we will only collect adverse events related to brachial plexopathy, lymphedema, 
skin toxicity, lung toxicity, heart toxicity.  We will not report grade 1-2 radiation dermatitis as 
adverse events because most patients will at least have gr 1 dermatitis.   We will keep a record 
of toxicity at each visit by collecting the Lent Soma evaluation of the clinician at each visit after 
treatment starts.  Patient reported fatigue rate will not be collected on the adverse event report, 
but will also be recorded at each visit. 
 
 
Stopping rule for monitoring 3 types of toxicities in patients Receiving Regional Nodal Irradiation. 
(If any one of the 3 stopping rules is met, the trial stops for excessive toxicity.) 
Total Patients 
Upper limit of 
number of patients 
with Grade 3 brachial 
plexopathy (<3%) 
Upper limit of 
number of patients 
with 20% or greater 
increase in arm 
lymphedema 
(<15%) 
Upper limit of number of 
patients with grade 3 skin 
toxicity within the breast 
or chest wall (<20%) 
3 
<2 
<3 
<3 
4 
<2 
<3 
<4 
5 
<2 
<4 
<4 
6 
 
 <2 
<4 
<4 
7 
<2 
<4 
<5 
8 
<2 
<4 
<5 
9 
<2 
<5 
<5 
10 
<2 
<5 
<6 
11 
<2 
<5 
<6 
12 
<2 
<5 
<6 
13-30 
<2 
<5 
<7 
 
 

 
12/13/2016 
 
 
Correlative Studies:  Blood will be analyzed for inflammatory markers (TNF-alpha, soluble sTNFR2, 
IL-6, IL-1ra, and CRP) to determine if they are associated with development of cutaneous toxicity.  By 
acquiring the objective UTC measurements at 5 time points, the development and resolution of 
cutaneous toxicity as it relates to time may be further understood.   
A description of the Feasibility: 
There is no drug in the proposed study.  Our department has 7 linear accelerators all capable of 
delivering hypofractionated external beam radiotherapy.  We also have extensive experience treating 
patients with simultaneous integrated boost radiotherapy.  As determined by 2000 census, the 
majority of minorities in our community are African American, and African Americans make up 61.4% 
of the population of metropolitan Atlanta.  A study including this population would be feasible.  At the 
three Emory radiation centers, there are approximately 350 patients seen annually with 200 patients 
having early stage breast cancer.  With approximately 80 African American breast cancer with Stage 
0-II patients treated annually at Emory Clifton Campus, Emory Midtown, and Grady Memorial 
Hospital.  In a recent study, over 60% of our patients had breast separation >25cm. [17]  This trial 
should be able to accrue 33 high risk patients (2 to 3 patients per month, and assuming a 10% 
dropout rate) needed to assess the feasibility of this novel hypofractionated simultaneous integrated 
boost (SIB) regimen.  
Dr. Tian Liu (co-PI) is an NIH funded physicist with expertise in ultrasound tissue characterization 
(UTC) of radiation induced cutaneous toxicity.  Dr. Liu’s Ultrasonic Imaging Laboratory is fully 
equipped with three clinical ultrasound machines including a state-of-the art Sonix RP scanner with 
raw radiofrequency echo signals and advanced research interface.  The laboratory is located on the 
tunnel level within the Department of Radiation Oncology.  It comprises 500 sq. ft. and is equipped 
with ultrasound data acquisition system and calibration targets.  UTC measurements will be easily 
performed in patients using Dr. Liu’s equipment and software.  Measurements of breast tissue take 
about 10 minutes to complete. 
The MFI, PSS, PSQI, IDS-SR, SF-36 and GLTEQ, and LENT SOMA are surveys which have been 
validated in various populations and take 15 minutes to complete in total.   
Blood for inflammatory markers is routinely processed within the laboratory of my research mentor, 
Dr. Andrew Miller, Professor of Psychiatry and an international expert on inflammatory induced 
behavioral changes.  He has agreed to help process the blood from this study.   
       Potential risks:  
 
                             The risk to patients is minimal. Blood draws will be performed at a maximum of 
eight different time points during the course of their treatment and follow-up.   
You may feel slight discomfort from the blood draws at the site of the needle 
stick.  Slight swelling and bruising are fairly common but usually go away soon.  
Rarely, people may have a vasovagal syncope. 
Vasovagal syncope (vay-zoh-VAY-gul SING-kuh-pee) occurs when you faint 
because your body overreacts to certain triggers, such as the sight of blood or 
extreme emotional distress. It may also be called neurocardiogenic syncope. 

 
12/13/2016 
 
The vasovagal syncope trigger causes your heart rate and blood pressure to 
drop suddenly. That leads to reduced blood flow to your brain, causing you to 
briefly lose consciousness. 
Vasovagal syncope is usually harmless and requires no treatment. But it's 
possible you may injure yourself during a vasovagal syncope episode. Your 
doctor may recommend tests to rule out more serious causes of fainting, such as 
heart disorders. 
 
 
All patients will be assigned a study number, and this number will be used in 
place of patient’s names or identification numbers so there should be minimal 
risk of loss of patient confidentiality.  The master sheet containing the patient 
number and study ID will be kept in a password protected database.   
      Compensation: 
Women who complete the long term assessment will be compensated $50.00 for that study 
visit.  
 
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