Pilot Study of Proton Radiation Therapy for Invasive Breast Carcinoma Following Mastectomy
Phase: NA
Conditions: Invasive Breast Cancer
Sponsor: Massachusetts General Hospital



Pilot Study of Proton Radiation Therapy for Invasive Carcinoma of the Breast following Surgery, Shannon 
MacDonald, 1/11/18
Protocol Version Date:  January 11, 2018
Local Protocol #: 10-205
Title: Pilot Study of Proton Radiation Therapy for Invasive Carcinoma of the Breast 
following Surgery
Principal Investigator:
Shannon MacDonald, M.D.
Department of Radiation Oncology
Massachusetts General Hospital
Boston, MA 02114
Email : smacdonald@partners.org
Co-Investigators: Massachusetts General Hospital (MGH): 
Alphonse G Taghian, MD, Radiation Oncology
Rachel Jimenez, MD, Radiation Oncology
Hanne Kooy, PhD, Radiation Physics
Hsiao-Ming Lu PhD, Radiation Physics
Alex Trofimov. PhD, Radiation Physics
Karen Winkfield, MD, Radiation Oncology
Jennifer Bellon, MD, Radiation Oncology (DFCI/BWH)
Michelle Specht, MD, Surgical Oncology
Barbara L Smith, MD, PhD Surgical Oncology
Kevin Hughes, MD, Surgical Oncology
Michelle Gadd, MD, Surgical Oncology
Beverly Moy, MD, Medical Oncology
Irene Kuter, MD, Medical Oncology
Jerry Younger, MD, Medical Oncology
Jonathon Passeri, MD, Cardiology
William G. Austen, MD, Plastic Surgery
Jonathon Winograd, MD, Plastic Surgery
Dorothy Doran, NP, Radiation Oncology
Statistician: Beow Yeap, ScD

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SCHEMA:
Consent and Baseline 
Studies 
Study Treatment: Proton 
Radiation Therapy to chest 
wall, IMN,  +/- other regional  
lymph nodes
Registration
Follow up for 5 years to 
assess acute and late 
toxicities

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iii
TABLE OF CONTENTS
Page
SCHEMA
ii
1: OBJECTIVES 
1
1.1
Study Design
1
1.2
Primary Objectives
1
1.3
Secondary Objectives
1
2: BACKGROUND
2.1
Proton Radiation
2
2.2
Study Disease
5
2.3
Rationale
11
3: PARTICIPANT SELECTION
3.1
Eligibility Criteria
11
3.2
Exclusion Criteria
13
3.3
Inclusion of Women, Minorities and Other Underrepresented Populations
13
4: REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC and DF/PCC Institutions
13
4.2
Registration Process for DF/HCC and DF/PCC Institutions
14
5: TREATMENT PLAN
5.1
Pre-treatment Criteria
15
5.2
Radiation Administration
16
5.3
General Concomitant Medication and Supportive Care Guidelines
18
5.4
Duration of Therapy
19
5.5
Duration of Follow Up
19
5.6
Criteria for Removal from Study
19
6: EXPECTED TOXICITIES AND DOSING DELAY/DOSE MODIFICATIONS
6.1
Anticipated Toxicities
19
6.2
Toxicity Management
20
6.3
Dose Modifications/Delays
21
7: STUDY CALENDAR
22
8: MEASUREMENT OF EFFECT
8.1 Anti-tumor Effect – Solid Tumors
23
9: ADVERSE EVENT REPORTING REQUIREMENTS
9.1 General
23
9.2 Definitions
24
9.3 Recording Adverse Events
26

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  9.4   Reporting Adverse Events  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
26 
  9.5   Sponsor Notification by Investigator  
 
 
 
 
 
 
 
 
 
 
 
 
26 
  9.6   Institutional Review Board (IRB) Notification by Investigator  
 
 
 
 
27 
  9.7   Hospital Risk Management Notification by Investigator  
 
 
 
 
 
 
27 
 
10: DATA AND SAFETY MONITORING 
10.1   Data Reporting  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
27 
10.2   Safety Meetings  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28 
10.3   Monitoring  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28 
  
11: REGULATORY CONSIDERATION 
11.1   Protocol Review and Amendments  
 
 
 
 
 
 
 
 
 
 
 
 
 
29 
11.2   Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
30 
11.3   Ethics and Good Clinical Practice (GCP)  
 
 
 
 
 
 
 
 
 
 
 
30 
11.4   Study Documentation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
31 
11.5   Records Retention  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
31 
   
12: STATISTICAL CONSIDERATIONS  
 
 
 
 
 
 
 
 
 
 
 
 
 
31 
 
13: PUBLICATION PLAN  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
33 
 
14: REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
33 
 
15: APPENDICES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix A – Performance Status Criteria  
 
 
 
 
 
 
 
 
 
 
 
37 
 
 
Appendix B – Figure 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
40 
 
 

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1. OBJECTIVES 
 
1.1    Study Design 
 
This is a pilot trial to assess the feasibility of using proton radiation to treat breast cancer 
following surgery (mastectomy or breast-conserving).  The intent of this study is to 
exploit the properties of protons for delivery of radiation therapy to the chest wall and 
regional lymphatics, including internal mammary nodes, without need for removal or 
manipulation of breast reconstruction and/or to decrease cardiac exposure to radiation 
and to form the basis for future studies. This study is intended to determine the feasibility 
of both double scattered 3D conformal protons as well as intensity modulated proton 
therapy (IMPT). 
1.2 
Primary Objectives 
1.2.1 To determine the feasibility of using proton radiation for the treatment of invasive 
breast cancer following surgery (mastectomy or breast-conserving) based on the 
occurrence of grade 3 or higher radiation pneumonitis or any grade 4 toxicity within 3 
months after the completion of radiation treatment. The goal is to enable women with 
breast reconstruction to undergo radiation therapy without removal or manipulation of 
reconstruction in order to allow radiation delivery without excessive pulmonary and 
cardiac dose and to enable patients with unfavorable cardiac anatomy(as defined by ≥5% 
of the heart receives ≥ 20 Gy and/or LAD receives ≥ 20 Gy with conventional planning) 
to undergo chest wall irradiation with better cardiac sparing.   
1.3 
Secondary Objectives 
1.3.1 The endpoints in these objectives are descriptive and will form the basis for 
designing future studies.  The Common Terminology Criteria for Adverse Events 
(CTCAE) version 4 will be used for grading toxicities. 
x 
To evaluate the rate and severity of acute skin toxicity 
x 
To evaluate the rate and severity of radiation pneumonitis, a sub-acute toxicity 
x 
To evaluate the rate and severity of late skin toxicity 
x 
To evaluate cosmetic outcome and patient satisfaction with cosmetic outcome 

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x 
To evaluate acute and late toxicity of breast reconstruction following proton radiation 
x 
To evaluate the need for unplanned additional surgery for breast reconstruction  
x 
To evaluate early signs of cardiac effects from radiation therapy using Strain 
Echocardiogram 
1.3.2 To describe the 5 year progression free survival rate of patients with breast cancer 
treated with proton radiation.  
 
2. BACKGROUND 
2.1  
Proton Radiation 
 
Radiation therapy (RT) has been proven an essential component of therapy for breast 
cancer.  Unfortunately, radiation also carries substantial risks to surrounding healthy 
tissues and organs. Well documented side effects of radiation to the breast and/or chest 
wall include pulmonary and cardiac toxicity due to unavoidable delivery of radiation 
therapy to the heart and lungs.  Proton radiation is a form of particle radiation that can 
deliver radiation therapy to the chest wall and lymphatics with near complete avoidance 
of the heart and lung. Proton radiation therapy is currently available at only a handful of 
radiation treatment centers in the United States.  The Massachusetts General Hospital has 
the longest experience in the US and has been using protons for clinical treatments since 
1961.  Seven other proton centers have since opened in the United States, five within the 
past 5 years.  Mainly due to limited availability and increased costs, the clinical use of 
protons has been limited, for the most part, to tumors requiring high doses and/or in close 
proximity to critical structures (brain, spinal cord, etc) and for the treatment of pediatric 
malignancies.1-5  Over the past several years, the realization of the substantial benefit of 
this radiation modality has been recognized.  Despite substantial capital and operational 
costs, several proton facilities in both the private and academic sectors are in planning or 
construction phases. Furthermore, several companies are actively researching more 
efficient and less expensive machines capable of delivering proton radiation. Given the 
increased availability of this treatment, it is important to explore in academic centers the 
potential benefit for additional malignancies, such as breast cancer. While several centers 
have published comparative planning studies and hypothesize that protons will provide a 
decrease in acute and late toxicities for patients requiring radiation therapy for advanced 
breast cancer, no clinical studies have been performed or reported to date for this group 
of patients.  The Paul Scherer Institute in Switzerland plans to open a protocol for deliver 
of radiation for patients with advanced breast cancer early next year (personal 
communication, Carmen Ares, M.D.).  
 
Protons are charged particles that enter tissue delivering a small and constant dose until 
near the end of the proton range where the majority of dose is delivered.6  Beyond this 

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distal portion of the proton beam no dose is delivered.  This enables complete sparing of 
uninvolved tissues and organs distal to the target volume.  This is in contrast to photons 
that must deliver dose both proximal and distal to region targeted as demonstrated in 
Figure 1.  Proton radiation is prescribed in Gray(RBE) as opposed to Gray, which is used 
for prescribing photon radiation.  This takes into account the slightly higher Relative 
Biological Effectiveness (RBE) of protons.  Thus, for a given prescribed dose the 
biological effect in tissues is the same for protons and photons and  benefits are due to 
physical properties of the proton beam.7,8 ,9 The benefit of delivering radiation with 
protons versus photons is derived from the physical properties of the proton particle 
itself.  Protons as are planned in this study will deliver the same dose to target structures.  
Advanced forms of photon radiation therapy do exist, but are suboptimal as the physical 
properties of photons necessitate delivery of dose beyond the target. Intensity modulated 
photon radiation therapy (IMRT) is the most advanced form of photon radiation currently 
available.  IMRT accomplishes excellent conformity to target volumes while decreasing 
high dose to specified avoidance structures.  This is accomplished by a sophisticated 
computer planning system and delivery of radiation through multiple small fields and 
beam angles.10  One of the major disadvantages of IMRT is the increase in low dose to a 
larger amount of normal tissue.  This greater volume of tissue receiving radiation is of 
particular concern for young patients with a high likelihood of surviving their malignancy 
and a higher risk of developing a radiation induced malignancy.  Low doses to a large 
volume of pulmonary tissue is also a concern.11-12   
 
 
 
At this time, the predominant mode of proton delivery is through passive beam scattering 
methods or “3D conformal” proton therapy. Scattering foils, range compensators, and 
apertures are designed to deliver a homogeneous dose distribution to the target with 
optimal dose conformity at the distal target region for each field.6 There is some degree 
of intensity modulation in these proton plans, but increased modulation is possible 
through pencil beam scanning techniques which became available only recently.  Plans 
that use scanning techniques are referred to as Intensity Modulated Proton Therapy 
(IMPT) plans.13-14   Similar to Intensity Modulated Radiation Therapy (IMRT), IMPT 
refers to plans that deliver a homogenous dose to the target with the superimposition of 
individually inhomogeneous fields.5 Although this increases the complexity of the plan, it 
allows for increased dose-shaping capabilities with optimal conformity not only at the 
distal region of the target but also to the proximal target edge.  IMPT may also facilitate 
the treatment of large areas without matching of fields (which introduces “cold” and 
“hot” areas at the match line of a plan) and allows for a decrease in the dose to skin if this 
is desired.  For PMRT, the skin and subcutaneous tissue is the target and the goal is to 
deliver full dose or near full dose.  “Bolus” or electron radiation is often used to increase 
dose to the skin.  For this protocol, treatment plans will be established to deliver a dose to 
the skin comparable to these treatment techniques.  Therefore, we do not anticipate 
greater skin toxicity compared to standard treatment plans, but patients will be monitored 
closely for this toxicity.  
 

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Despite advances in photon techniques, homogeneous coverage of targets and optimal 
sparing of cardiac and pulmonary structures can be a challenge, especially for the 
treatment of locally advanced breast cancer in the setting of breast reconstruction.   
Clinical data with protons is not available for treatment of whole breast, chest wall, or 
regional lymphatic irradiation, but studies evaluating the dosimetry for such cases  
studies have been reported.5, 15 Lomax et al, reported results of comparative treatment 
planning using standard photons, IMRT, and spot scanning proton therapy (IMPT) for 
radiation of the breast and regional nodes for a patient with left sided breast cancer.5  The 
IMPT plan provided improved target coverage and dose homogeneity, decreased dose to 
cardiac and pulmonary structures, and provided the lowest integral dose to surrounding 
tissues.   Johansson et al also examined the potential benefit of protons for left sided 
locally advanced breast cancer. 15   This study evaluated two conventional plans 
(tangents, and mixed photon/electron technique), IMRT, and 3D conformal proton 
treatment plans for eleven patients. The authors used normal tissue complication 
probabilities (NTCP) for evaluation of plans.16  Mean calculated NTCP values for cardiac 
mortality and pneumonitis were substantially lower for the proton plan compared to all 
other plans.  Although IMRT reduced the NTCP for the heart, it did not decrease NTCP 
for radiation pneumonitis in this study.  Both conventional and IMRT plans showed 
increased integral dose as compared to the proton plan.  In summary, the authors 
concluded that proton therapy has the potential to offer a major advantage in decreasing 
the risk of normal tissue complications in the treatment of left sided node positive breast 
cancer. At MGH, we have also analyzed plans for both 3D conformal protons and IMPT 
for the treatment of patients requiring post-mastectomy radiation therapy (PMRT) for left 
sided breast cancer. Proton plans were compared to treatment plans using partially wide 
tangent fields (PWTF) and a mixed photon electron (E/P) technique for eight patients.  
3D proton plans were superior to PWTF and E/P technique.  (Figure 2 & 3).  Given the 
increased number of proton facilities and heightened public awareness of this modality, it 
is of utmost importance that a clinical trial be performed to evaluate toxicity and clinical 
outcomes for patients treated with proton radiation (3D-CRT or IMPT) for patients 
requiring left PMRT. In summary, all studies indicate a decrease in the amount of heart 
and lung in the treatment field that receives ANY dose of radiation (high dose or low 
dose).  Decades of experience as well as physics research and clinical outcomes indicate 
that these dose distributions are accurate.  Therefore, clinically, this should result in a 
decrease in toxicity for patients treated with protons.  The ultimate question is whether or 
not the increased cost   of protons warrants the decreased risk of side effects. As the 
number of proton facilities increase, it is likely that the cost of treatment will decrease 
and that additional centers will explore and administer protons for locally advance breast 
cancer.  The intent of this study is to establish treatment plans for patients with 
technically challenging anatomy for adequate treatment planning with modalities that are 
currently more widely available (photons and electrons). We propose to deliver protons 
on a clinical trial to patients with implants requiring IMN radiation or for patients with 
unfavorable cardiac anatomy (as defined by > 5% of the heart receives ≥ 20 Gy and/or 
LAD receives ≥ 20 Gy with conventional planning) as the patients are the most 
challenging to adequately treat with standard photon and/or electron radiation therapy. 
These patients often require removal or manipulation of implant to allow for delivery of 

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radiation therapy to the chest wall and regional lymphatics without prohibitive amounts 
of heart and lung in the treatment field. In addition, we include patients with unfavorable 
cardiac anatomy.  These patients also present a challenge for current treatment 
techniques.  
 
2.2 
Study Disease; Breast Radiation Treatment & Toxicities 
Radiation therapy for locally advanced breast cancer has been well established to provide 
local control and, in some studies, has been shown to provide a survival benefit.17-20 
Conventional treatment delivers radiation to the breast/chest wall and draining 
lymphatics.  This increases the complexity of treatment planning.  Depending on patient 
anatomy, it is often technically difficult or impossible to provide homogeneous coverage 
of the target volume while producing acceptable doses to the heart and lung and it is often 
necessary to compromise coverage of target volumes in order to avoid toxicity.  This is 
particularly problematic for patients who have undergone breast reconstruction. The 
rationale for the use of proton radiation for the treatment of breast cancer is to provide 
adequate coverage of target volumes and to   decrease late toxicity by reducing the dose 
delivered to normal tissues and to allow for patients with breast reconstruction to proceed 
to radiation without the need for additional procedures to improve anatomy for radiation.   
Estimating the risk of late complications for this group of patients is difficult. The latency 
between radiation treatment and the appearance of long-term side effects is high and 
therefore lengthy follow-up is necessary to gather adequate data and draw meaningful 
conclusions.  Although many reports of late complications exist, these data are generally 
from studies utilizing dated techniques.  Modern radiation delivery may lower the 
occurrence of late side effects, but it is too early to perform adequate assessments.  We 
must assume a risk, even with current radiation treatment, and strive to decrease the 
amount of radiation delivered to areas and organs known to result in late toxicities for 
breast cancer patients in the past. In addition, new chemotherapeutic agents increase the 
risks of certain toxicities, thus making the avoidance of radiation dose to the heart and 
lung more critical. 
Earlier radiation trials reported an increase in morbidity and mortality due to cardiac 
disease, predominantly in patients treated for left sided breast cancer.15, 21-22 Some authors 
even suggest that increased mortality from ischemic heart disease was the reason for the 
absence of a survival benefit for patients treated in the earlier post-mastectomy radiation 
trials.23-24 More recent post-mastectomy studies utilizing modern techniques and 
fractionation schedules have demonstrated survival benefits and no increase in cardiac 
mortality to date. 25-26 After computed tomography (CT)-based radiation treatment 
planning was developed, the relationship between radiation dose, volume of heart 
irradiated, and cardiac outcomes could be more closely evaluated. It has generally been 
established that the risk of cardiovascular disease increases with increasing mean heart 
dose. Doses in excess of 30 to 40 Gy to small volumes of the heart are felt by some 
authors to increase a patient’s risk of cardiovascular disease and may lead to increased 

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cardiac events.27 Doses of 25 Gy have been shown to induce temporary perfusion defects 
and ≥ 5-6% of the heart receiving ≥ 25-27 Gy has been accepted by some to define 
“unfavorable cardiac anatomy” based on correlation of this heart volume to the 
Stockholm trial for patients with left sided tumors that showed a high rate of cardiac 
morbidity and mortality.15, 21-22, 28-29 There is emerging data that doses to specific parts of 
the heart, such as the coronary arteries, may be more important in predicting cardiac 
outcomes.30 Strain echocardiogram has recently shown promise as an accurate and 
relatively inexpensive study to determine myocardial abnormalities in the left ventricle 
for doses > 3 Gy immediately post radiation and at 2 months following radiation.31  
Control patients receiving right sided radiation did not show any changes on post 
radiation studies. Pericarditis is a very rare toxicity, occurring in <1% of patients, but 
may lead to hospitalization.32  In addition, the increased use of cardiotoxic chemotherapy 
over the past several years adds yet another confounding factor to determining the effect 
of radiation therapy on cardiac outcomes. Doxorubicin and Herceptin, particularly when 
used in combination, are known to increase the risk of cardiac disease.33-34 These agents 
were not included in the chemotherapeutic regimens used in the aforementioned trials. 
Currently, Doxorubicin and Herceptin are both included in standard chemotherapeutic 
regimens and are often administered in combination.35  It is not fully known how 
radiation therapy in the setting of these agents will affect cardiovascular outcomes. 
Maximal cardiac sparing achieved through proton therapy has the potential to decrease 
this risk by decreasing mean heart dose as well as volume receiving 40 Gy and 25 Gy 
(Figure2 &3).  
Symptomatic radiation pneumonitis is a sub-acute side effect of radiation for treatments 
involving lung tissue.36 When irradiating the chest wall and regional lymphatics, 20-30% 
ipsilateral lung may receive radiation to a dose of 20 Gy.  With implants in place, this 
dose may be even higher and this is one reason why it may be recommended that 
implants be removed or reconstruction be delayed.  In addition, recent literature for 
patients being treated for lung cancer report the importance of large volumes of lung 
receive low dose irradiation (5 Gy or 10 Gy).12  Although the meaning of this for patients 
with breast cancer is less clear, it is important to note the techniques using electron 
radiation and/or some IMRT techniques generally decrease the volume of lung receiving 
20 Gy, but increase the volume of lung receiving lower doses of radiation.  Protons are 
capable of reducing both high and low doses of radiation to the lung. (Figure 3). 
Radiation pneumonitis is reported in approximately 1-5% of patients treated for breast 
cancer without concurrent chemotherapy.33, 37-38 However, the risk of radiation 
pneumonitis has been shown to increase with treatment of the regional lymph nodes 
and/or concurrent chemotherapy and rates as high as 20% have been reported in patients 
treated with concurrent paclitaxel and radiation.39-41  Radiation pneumonitis generally 
resolves without treatment, but may require hospitalization or a course of steroids. The 
incidence of RP as reported by several recent series that utilized both modern 
chemotherapy and radiation therapy techniques are summarized below. The majority of 
these reports have used the Radiation Therapy Oncology Group (RTOG) acute lung 
morbidity scoring system to describe the severity of RP: 
 
 

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The following retrospective studies report on incidences of RP after adjuvant radiation 
for breast cancer. It is important to note that only two of the series included patients who 
required internal mammary lymph nodes.37, 39  Voduc reported a 2% incidence of grade 2-
3 RP using the RTOG scale in a group of 77 women with breast cancer treated at the 
British Columbia Cancer Agency (BCCA). No grade 4 or 5 events occurred. All patients 
had lymph node–positive disease with negative estrogen receptor expression and 
underwent surgery, adjuvant doxorubicin/cyclophosphamide for four cycles followed by 
four cycles of paclitaxel (AC,T) followed by radiation therapy. This study represents a 
patient population who were treated with the systemic regimen that most of these patients 
in the proposed study will receive. Yu and Buchholz reported the MD Anderson Cancer 
Center (MDACC) incidence of RP in a Phase III study comparing neoadjuvant four 
cycles of paclitaxel followed by four cycles of 5-fluorouracil, doxorubicin, 
cyclophosphamide (FAC) versus eight cycles of FAC.33 Of 524 patients treated in the 
study, 189 also received radiation therapy. RP was scored using the RTOG scale. 
Clinically evident pneumonitis was observed in 5% of the paclitaxel-FAC group and 
4.5% of the FAC-only group (difference not significant). Only two patients of 189 
required steroids, one other required narcotics, and none were hospitalized. Taghian et al. 
from the Massachusetts General Hospital (MGH) reported RP rates in 41 breast cancer 
patients treated with mastectomy and axillary lymph node dissection followed by four 
cycles of adjuvant doxorubicin/cyclophosphamide followed by four cycles of paclitaxel.39 
Radiation therapy to the chest wall and regional lymphatics was given concurrently with 
paclitaxel in 21 patients and sequentially in the remainder. In contrast to the BCCA and 
MDACC experiences, an incidence of 14.6% (6 of 41 patients) grade 2-3 RP using the 
RTOG scale was observed at the MGH regardless of the sequencing. Five of the events 
were grade 3 and no grade 4-5 events occurred. Lind et al reviewed Duke’s experience 
with RP in a cohort of breast cancer patients treated with breast-only radiation therapy 
versus comprehensive radiation therapy.37 In 319 patients who received radiation to the 
breast alone the RP rate was 0.9%. When comprehensive radiation therapy was 
employed, the RP incidence increased to 4.1% (12 of 294 patients). All 12 patients were 
RTOG 
ACUTE 
LUNG 
MORBIDITY 
SCORING 
CRITERIA 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
No Change 
Mild 
symptoms of 
dry cough or 
dyspnea on 
exertion 
Persistent cough 
requiring 
narcotic, 
antitussive 
agents/dyspnea 
with minimal 
exertion 
Severe cough, no 
response to narcotic 
antitussives or 
dyspnea at 
rest/clinical or 
radiological 
evidence of acute 
pneumonitis/ 
intermittent O2 or 
steroids may be 
required 
Respiratory 
insufficiency/ 
continuous 
oxygen or 
assisted 
ventilation 
Fatal 

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treated with oral corticosteroids. There were neither hospitalizations nor deaths from 
pneumonitis, which means that the incidence of 4.1% may be regarded as the incidence 
of RTOG grade 3 events. The Duke report predated the widespread use of taxane 
chemotherapy, but AC chemotherapy or cyclophosphamide, methotrexate, and 5- 
fluorouracil was given to 42% of the group, which resulted in a RP rate of 3.8%. Beal and 
McCormick reported a small series of 38 node-positive breast cancer patients treated with 
surgery, adjuvant (AC, T), followed by comprehensive radiation therapy at MSKCC.38 
No cases of RP were seen in this group after a median follow-up of 28 months. However, 
none of the patients in this study required irradiation of the internal mammary lymph 
nodes. 
 
 

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Summary of Retrospective Studies Reporting RP After Breast RT:  
Author 
Institution 
Publication 
Year 
n 
Overall 
RP 
Reported 
(RTOG 
Grade) 
Subset with 
RTOG 
Grade 3 
Taghian 
MGH 
2001 
41 
14.6% 
grade 2-3 
12% 
Lind 
Duke 
2002 
294 
4.1% 
grade 3 
4.1% 
Voduc 
British 
Columbia 
2004 
77 
2% grade 
2-3 
2% 
Yu 
MDAH 
2004 
189 
5% grade 
2-3 
1% 
Beal 
MSKCC 
2005 
38 
0% 
0% 
 
In order to assess the feasibility endpoint in the proposed study, we are most interested in 
capturing incidences of RP that requires corticosteroids or hospitalization (RTOG grade 
3-5). However, no series reported any fatalities or grade 4 events from RP after breast 
RT, so serious pneumonitis in this population appears to be limited to RTOG grade 3 
events. The weighted average for grade 3 RP in these series using the RTOG scale is 
around 3.3%. Again, not all of the reported series included patients who required internal 
mammary lymph node radiation. 
The National Cancer Institute (NCI) has advocated use of the CTCAE in clinical trials. 
Relevant sections from the CTCAE version 4 are available in Appendix 1. Therefore, in 
capturing treatment-related pulmonary toxicities secondary to our proposed treatment, we 
will use the CTCAE adverse events scale listed above. CTCAE toxicities >3 appear to 
correspond to the level of treatment-related pulmonary events that we are interested in 
using for the infeasibility end point and correspond most closely with grade 3-5 toxicities 
on the old RTOG scale. For the feasibility endpoint, we will score all cases of 
pneumonitis, but are most interested in those treatment-related pulmonary toxicity events 
that are greater than or equal to grade 3. Although we will score the level of toxicity over 
time for all patients, for purposes of determining infeasibility, we are only interested in 
the number of patients who experience grade 3-5 pulmonary toxicity. A given patient 
either has or does not have such an event, in which case she will be scored as a failure for 
this endpoint if present. 

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There is limited data on second malignancy following the treatment of breast cancer, but 
available studies do indicate an increased risk.42  Radiation-induced sarcomas have been 
reported with  rates ranging between 0.2 to 0.48 percent at 10 to 15 years.43-44  Increased 
rates of lung cancer and squamous cell carcinoma of the  esophagus have also been 
reported.42, 45-48 Although the risk of a radiation induced malignancy is relatively small, 
considering the large number of patients treated and the gravity of a second malignancy, 
it cannot be ignored. Young patients are at particularly high risk of second malignancy. 
Breast reconstruction is considered an integral part of treatment for breast cancer and 
should be discussed and offered to women undergoing mastectomy.  For patients 
undergoing mastectomy, reconstruction offers benefits of improved psychosocial well 
being and body image 49. Many different types of reconstruction are available, but they 
can be categorized into 2 major groups; 1) prosthetic implants, including saline or 
silicone implants that can be placed in a one step procedure or with an expander placed at 
the time of mastectomy and permanent implant placed during a separate surgical 
procedure and 2) autologous implants using the patient’s own tissue. What type of 
reconstruction is chosen depends on several factors including patient anatomy, 
comorbidities, need for radiation, and patient preference. The decision to proceed with 
immediate or delayed reconstruction also depends on several factors, including radiation. 
Benefits to immediate reconstruction include the need for only one surgical procedure, 
psychological benefits, and cost. The potential disadvantages include the negative impact 
on radiation planning 50-52. Some radiation oncologists recommend that reconstruction 
always be delayed for patients receiving radiation therapy due to interference with 
radiation delivery with standard photon and electron techniques.50 In addition, many 
centers have seen an increase in the rate of contralateral prophylactic mastectomy and 
these cases create a particular challenge for radiation planning.53-54  The properties of 
protons will allow for radiation therapy for these patients without compromise of 
treatment plan or need for additional procedures to reduce the size of the implant or 
remove the implant (Figure 4 &5). Protons are delivered en face similar to electrons, but 
have the ability to treat to greater depths and with less scatter.  Electrons can be used to 
treat the chest wall superficially in cases without an implant in place, but they cannot 
treat to a sufficient depth to reach the chest wall beneath an implant.  Photons may be 
used, but it is often difficult to use optimal angles, particularly when bilateral implants 
are in place. Immediate breast reconstruction has advantages of providing greater 
psychosocial benefits compared with delayed reconstruction by allowing patients to 
awake from surgery with at least a partially reconstructed breast in place.  This has been 
shown to provide patients with improved body image and self esteem and less anxiety, 
depression, and impairment of sexual attractiveness.  Immediate reconstruction has also 
been shown to provide better esthetic results and often allows for more options for the 
type of reconstruction and is less costly than delayed reconstruction.   Some studies 
indicate that pedicled transverse rectus abdominis myocutaneous flap (TRAM) tolerate 
postmastectomy RT very well and delivery of radiation may be less technically 
challenging with TRAM reconstruction compared to prosthetic reconstruction. 50, 55-57. 
Prosthetic based implants are also feasible in the setting of postmastectomy RT. While 
some studies report feasibility and outcomes with permanent implant placement prior to 

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radiation, many advocate for placement of a tissue expander at the time of mastectomy 
and exchange of the expander for permanent implant following radiation to allow for 
manipulation of expander for radiation if needed.  Others advocate that exchange of the 
implant prior to radiation will result in a decreased rate of complications because of the 
avoidance of performing an operation in an already irradiation field (Ho, A, abstract 
ASTRO 2010).58  In any case, many women undergo immediate reconstruction due to 
preference or because the need for radiation is not known at the time of surgery.  Proton 
radiation will allow for these patients to avoid additional procedures necessary to deliver 
radiation and potentially improve quality of life and cosmetic outcome as a result. 
Because the dose delivery is more homogeneous with protons, there may also be a benefit 
in cosmesis due to decreased “hot spots”.  
2.3  
Rationale 
 
A major goal of breast oncologists as well as national and international breast oncology 
cooperative groups is to decrease late toxicities for patients with curable malignancies.  
Given the relatively high disease free and overall survival rates for breast cancer, 
improving functional outcomes by decreasing the long term complications of radiation 
therapy is a major goal. Many women now undergo reconstruction prior to radiation 
therapy.  Technical limitations of widely available radiation techniques often lead to the 
need for additional manipulation of the breast reconstruction or even removal of breast 
reconstruction or implant prior to radiation therapy.  This can impact quality of life, and 
self image for the patient, decrease the chance of a cosmetically acceptable result, and is 
more costly.  The physical properties of protons allow for delivery of radiation without 
compromise with breast reconstruction in place.   Cardiac exposure is still a major 
concern for patients with unfavorable cardiac anatomy.  Given anticipated long term 
survival for many of these patients and risks of cardiac disease from chemotherapeutic 
and targeted agents used for care, it is important to decrease exposure to radiation. 
Protons will decrease cardiac exposure to radiation. 
3.  PARTICIPANT SELECTION    
 
3.1  
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
3.1.1  Participants must have histologically confirmed invasive breast cancer confined to 
the breast and regional lymphatics (supraclavicular, axillary, internal mammary lymph 
nodes). 
3.1.2  Participants must have completed definitive breast surgery (mastectomy or breast-
conserving)+/- reconstructive surgery with referral for definitive chest wall 
radiation therapy.   Patients with breast reconstruction are eligible if it determined 

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by the referring or treating radiation oncologist that plan would be suboptimal 
without manipulation of breast implants.  For patients without reconstruction, they 
must meet eligibility by having unfavorable cardiac anatomy defined as ≥ 5% of 
the heart receives ≥ 20 Gy and/or LAD receives ≥ 20 Gy with conventional 
planning. Participants do not need to have measurable disease.  Most 
patients will not have measurable disease at the time of treatment.   
3.1.3 Age ≥ 18 at the time of diagnosis  
 
3.1.4 Life expectancy of greater than 12 months. 
3.1.5 ECOG performance status <2 (Karnofsky >60%, see Appendix A).  
3.1.6 Diagnostic Imaging Baseline mammography prior to surgery is required.  For 
patients with lymphatic involvement Computed Tomography (CT) scan of the 
chest, CT of the abdomen, and bone scan and/or Positron Emission Tomography 
(PET)/CT scan are required prior to delivery of chemotherapy. For most 
patients, this will be months prior to radiation. For patients with low burden 
nodal disease only mammography prior to surgery will be required. 
 
3.1.7  
Because radiation is known to be teratogenic, women of child-
bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study 
entry and for the duration of study participation. Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 
 
3.1.8    Ability of the patient or the patient’s legal guardian to understand and the        
 
 
 
    willingness to sign a written informed consent document.    
3.2       Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible 
for admission into the study. 
3.2.1  Patients will be ineligible if any prior therapeutic radiation therapy > 200 cGy 
has been delivered to the target volume.   

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3.2.2  Patients will be ineligible if surgery and chemotherapy was completed ≥ 20 
weeks from the planned start date of radiation therapy or if the patient is 
referred for radiation therapy after a relapse of prior ipsilateral breast cancer. 
Surgery can exceed 20 weeks if the patient undergoes chemotherapy 
following surgery. 
3.2.3 Individuals with a history of a different malignancy are ineligible except for the 
following circumstances. Individuals with a history of other malignancies are 
eligible if they have been disease-free for at least 5 years and are deemed by the 
investigator to be at low risk for recurrence of that malignancy. Individuals with 
the following cancers are eligible if diagnosed and treated within the past 5 years: 
cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.  
3.2.4 Pregnant females are excluded.  Female subjects of childbearing potential 
must indicate to their physician that there is not a possibility of being pregnant 
at the time of enrollment or have a negative pregnancy test prior to initiation 
of radiation therapy.  
3.2.5 Patients who received investigational chemotherapy prior to radiation therapy 
are excluded from this study. 
3.3    Inclusion of Women, Minorities and Other Underrepresented Populations 
We do not expect the inclusion and exclusion criteria to either over or under-represent 
minorities, or underrepresented populations.  This protocol does not exclude males, but 
will enroll primarily females as breast cancer occurs predominantly in women.   
 
 
4. REGISTRATION PROCEDURES 
 
4.1  
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must 
occur prior to the initiation of therapy. Any participant not registered to the protocol 
before treatment begins will be considered ineligible and registration will be denied.  
 
A member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist.  
Following registration, participants may begin protocol treatment. Issues that would 
cause treatment delays should be discussed with the Principal Investigator. If a 
participant does not receive protocol therapy following registration, the participant’s 

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protocol status must be changed. Notify the QACT Registrar of participant status 
changes as soon as possible.
4.2
Registration Process for DF/HCC and DF/PCC Institutions
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 
5:00 PM Eastern Standard Time. If a participant must be registered during off-hours or 
holidays, call the QACT registration line at 
 and follow the instructions
for registering participants after hours.  
The registration procedures are as follows:
1.
Obtain written informed consent from the participant prior to the performance of 
any study related procedures or assessments.
2.
Complete the protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist. 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility 
for the treatment study. Registration to both treatment and ancillary studies will 
not be completed if eligibility requirements are not met for all studies. 
3.
Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT 
at 
Exception: DF/PCC Affiliate sites must fax the entire signed consent form 
including HIPAA Privacy Authorization and the eligibility checklist to the 
Network Affiliate Office. The Network Affiliate Office will register the 
participant with the QACT. 
4.
The QACT Registrar will (a) validate eligibility, (b) register the participant on 
the study, and (c) randomize the participant when applicable. 
5.
The QACT Registrar will send an email confirmation of the registration and/or 
randomization to the person initiating the registration immediately following 
the registration and/or randomization. 
5. TREATMENT PLAN
Treatment will be administered on an outpatient basis. Expected toxicities and potential 
risks of radiation are described in Section 6 (Expected Toxicities and Delays). 

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5.1 
Pre-treatment Criteria 
 
5.1.1 Diagnostic Imaging: Patients with lymph node involvement must have a 
metastatic work up that includes Computed Tomography(CT) scan of the 
chest, abdomen and pelvis and bone scan or Positron Emission Tomography 
(PET)/CT scan.  
 
 
5.1.2 Cardiology: Echocardiogram including Strain echocardiogram will be 
performed for all patients.  Echocardiogram data will be collected prior to 
radiation therapy (or within first week of treatment), within 4 weeks after 
completion of radiation therapy, and 2 months after radiation therapy.  
Echocardiography: Conventional two-dimensional (2D) and Doppler 
echocardiography will be obtained in standard views. Tissue Doppler imaging 
will be acquired using standard views. Imaging parameters will be optimized 
and the frame rate will be set greater than150 frames/sec for acquisition of 
tissue Doppler imaging. Echocardiographic loops of at least 3 beats will be 
recorded. Echocardiograms will be read in the conventional manner and 
reported in the subject’s medical record. TDI-derived parameters, such as 
myocardial velocities, strain, strain rate and torsion, will be analyzed offline 
using customized computer software (EchoPac, GE Healthcare, Milwaukee, 
WI). 
 
 
5.1.3 Pathological review of surgical specimen at the Massachusetts General 
Hospital or other DF/HCC institution. 
 
5.1.4 Complete History and Physical Examination 
 
 
5.1.5 CBC with differential. TSH at baseline. Biomarkers will be obtained with 
baseline routine labs and in follow with routine labs at 2 additional follow up 
visits (at 4 weeks after radiation therapy and 2 months after radiation therapy): 
Approximately 5 cc of blood will be taken for each measurement of BNP and 
NTproBNP, and 5 cc of blood for ultrasensitive troponin. Blood will be spun 
at 3000 rpms for 10 minutes, the plasma alloquotted into daughter tubes and 
stored at -80. BNP levels will be measured with a twosite dual-monoclonal 
immunochemiluminescent assay (ADVIA Centaur® BNP, Bayer Diagnostics, 
Tarrytown, NY) using the ADVIA Centaur immunoassay system. NT-proBNP 
levels will be measured with an electrochemiluminescence sandwich 
immunoassay (Elecsys® ProBNP, Roche Diagnostics Inc, Indianapolis, IN) 
using the Roche 2010 system. For non acutely dyspnic subjects aged <75 years 
of age, the upper limit of normal is considered 125 pg/ml (manufacturers 
recommendations). Troponin I will be measured using a new generation 

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technique that has shown increased sensitivity compared to routine 
measurements (Architect STAT troponin assay, Abbot Diagnostics). 
 
5.1.6 Photography: (optional) to objectively track cosmetic outcome. 
 
 
 
 
 
  
5.2 
Radiation Administration 
 
 
5.2.1 Treatment Volume Parameters 
  
 
The ICRU 50 recommended terminology will be used to define the radiation 
treatment parameters.  The definitions of clinical tumor volume (CTV) will vary 
according to the tumor location, stage of disease, response to pre-radiation 
therapy, and histology.  
The GTV corresponds to the gross tumor.  This study does not include tumors 
with gross disease.   
 
The CTV corresponds to the area that is likely to be microscopically involved 
with tumor.   
 
All patients must have target volumes (chest wall and regional lymphatics) 
contoured.  All contours should be performed according to Radiation Therapy 
Oncology Group (RTOG) guidelines. These guidelines are available online at 
http://www.rtog.org/atlases/breastCancer/main.html. In addition, the left ventricle 
and region of the left anterior descending artery will be contoured.  
 
 
An additional margin to account for penumbra is to be determined for specific 
beam parameters at the Francis H. Burr cyclotron.  The additional margin needed 
to account for penumbra depends on the depth of the tumor in the tissue being 
treated, size of the field, and field arrangement.  
 
5.2.2    Timing of the radiation therapy 

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Radiation therapy should be initiated no later than 20 weeks following chemotherapy 
and surgery.  Surgery can exceed 20 weeks if the patient undergoes chemotherapy 
following surgery. Radiation should not be started earlier than 3 weeks following 
Taxane based chemotherapy. 
5.2.3
Patient Simulation
Patient set-up and immobilization will be determined prior to obtaining the planning CT 
scan.  The type of immobilization will be determined by the treating physician, but 
treatment should be delivered in the supine position.
Patient set-up reproducibility is critical for both conventional radiotherapy and proton 
radiotherapy and the use of daily imaging with diagnostic quality imaging will be 
performed.  For photon therapy, it is most common to perform weekly portal images
that are not always of diagnostic quality.
Respiratory gating is allowed, but not required.  The decision to use this technique will 
be at the discretion of the treating radiation oncologist. Proton radiation should be less 
sensitive to breathing motion as it is delivered with en face fields rather than tangent 
fields.
To avoid treatment delays resulting from the machine being down, photon beam 
radiation can be administered.  The maximum dose delivered by photons will be 20% of 
the prescribed dose.  Treatment delays will be allowed if a serious adverse event occurs 
due to protocol therapy.  Treatment delays will also be allowed for patients who 
experience a serious adverse event not related to protocol therapy (e.g. concurrent 
chemotherapy requiring hospitalization for neutropenia). 
5.2.4
Dose Specification and Schedule
The dose prescribed to the chest wall should be 45-50.4 Gy(RBE) to the chest wall and 
45-50.4 Gy(RBE) to the regional lymphatics. Ninety-five percent of the target volume 
should receive 45-50.4 Gy(RBE) at the discretion of the physician. The chest wall 
incision may receive an additional 10 Gy with electron radiation at the discretion of the 
treating physician, but incision boost is not required. Questions regarding dose 
fractionation should be discussed by contacting 

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Treatments will be typically administered once per day, 5 days per week.  Doses will be 
prescribed to the appropriate isodose line encompassing the CTV such that the gradient 
within a volume is +7% to –5%.  Dose will be reported in Gy(RBE), Gray 
Radiobiological Equivalent (where 1 Gy(RBE)= proton dose Gy x RBE [radiobiological 
effective dose], RBE = 1.1).  A RBE of 1.1 has been selected for protons and is based 
on RBE determinations in animal and cell culture systems.8  
 
5.2.5      Proton Radiation Parameters and Quality Assurance 
The FHBPTC cyclotron produces a 230 MeV proton beam.  The energy can be 
degraded to an appropriate energy to treat the desired depth.  For treatment, intensity 
modulation of the proton beam may also be used for shaping of the beam and 
conformation to the target volume. Apertures and Lucite compensators may be used for 
shaping of protons and to conform to the distal aspect of the target volume.  
 
Pre-treatment port films should be compared with a digitally reconstructed radiography 
(DRR) from the treatment planning system.  Film or digital images will be taken prior 
to each treatment in accordance with the proton center’s standard practice for all 
patients.  These images are used to verify the position of the patient and the aperture.  
These digital images are permanently stored electronically for each patient. A physicist 
will perform dose verification for all treatment plans/fields.  
 
 5.3 
 General Concomitant Medication and Supportive Care Guidelines 
 Concomitant chemotherapy as dictated by protocol or the treating physician is allowed.  
 All appropriate non-investigational supportive care medications or treatments maybe    
used for optimal symptom management.   
 
5.4 
   Duration of Therapy 
Duration of therapy will be defined by protocol or dictated at the discretion of the 
treating physician. 
Duration of therapy will depend on individual response, evidence of disease 
progression and tolerance. In the absence of treatment delays due to adverse events, 
treatment may continue as planned until finish or until one of the following criteria 
applies: 
x Disease progression, 
x Intercurrent illness that prevents further administration of treatment, 

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x
Unacceptable adverse event(s),
x
Participant decides to withdraw from the study, or
x
General or specific changes in the participant's condition render the participant
unacceptable for further treatment in the opinion of the treating investigator.
5.5
Duration of Follow Up
Participants will be followed for at minimum 5 years after completion of study 
treatment or until death, whichever occurs first. Participants removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. 
5.6
Criteria for Removal from Study 
Participants will be removed from study when any of the criteria listed in 
Section 5.5 applies. The reason for study removal and the date the participant 
was removed must be documented in the study-specific case report form 
(CRF). Alternative care options will be discussed with the participant.
In the event of unusual or life-threatening complications, participating 
investigators must immediately notify the Principal Investigator (or 
Protocol Chair), 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS
The CTEP Active Version of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be utilized for AE reporting. The CTEP Active Version of the CTCAE is 
identified and located on the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm
<https://phsexchweb.partners.org/exchweb/bin/redir.asp?URL= 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm>. All appropriate 
treatment areas should have access to a copy of the CTEP Active Version of CTCAE.
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used.
All radiation related grade 2 and greater adverse events experienced by participants will be 
collected from the time of the start of radiation and throughout the study and until the final study 
visit. Participants continuing to experience toxicity at the off study visit may be contacted for 
additional assessments until the toxicity has resolved or is deemed irreversible. 
It is anticipated that toxicities will be decreased with proton radiation.

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6.1 Possible Toxicities 
 
 
Possible short-term side effects, during or shortly after radiation therapy. These are 
reversible. 
 
skin: redness, tanning, irritation (common); breakdown under breast or in armpit 
(variable) 
 
fatigue (variable) 
 
poor wound healing (variable) 
 
pneumonitis, with cough and fever (rare; occurs mostly in the first 3 months after 
radiation) 
 
radiation pericarditis (left breast only) (very rare) 
 
Unlikely long-term side effects, many months or years after radiation therapy. These may 
not be reversible. 
 
skin changes (rare) 
 
rib fracture (rare) 
 
arm or hand swelling, influenced by additional surgery and chemotherapy (variable) 
 
shoulder stiffness, influenced by additional surgery (rare) 
 
arm weakness and/or numbness (brachial plexopathy) (very rare) 
 
secondary cancer many years from now (very rare) 
 
cardiac disease 
 
 
6.2 Toxicity Management 
 
All appropriate non-investigational supportive care medications or treatments (e.g. 
topical ointments, pain medications, etc.) may be used for optimal symptom 
management. 
 
6.3 Dose Modifications/Delays 
 Doses of radiation used are considered standard, i.e., this is not a dose escalation study, 
and interruption of radiation is not anticipated.  Delays or interruptions of radiation 
therapy will be at the discretion of the treating physician, but the primary investigator 
should be notified in the number of days exceeds 3.  Dose modifications for side effects 
should not be made without informing the primary investigator.  
 Proton radiation for invasive breast carcinoma will be considered to be feasible following 
surgery (mastectomy or breast-conserving) if the rate of grade 3 or higher radiation 
pneumonitis within 3 months of treatment were no more than 5%, within the range 
associated with conventional techniques of adjuvant radiation. In addition to radiation 
pneumonitis, the feasibility of proton radiation will also be compromised by any grade 4 
effect occurring within 3 months of treatment, skin toxicity and pericarditis. If 2 or more 

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of the initial 12 patients were to experience grade 3 or higher radiation pneumonitis or 
any grade 4 toxicity within 3 months of finishing radiation, accrual will not continue 
further. The probability of stopping early is only 12% if the underlying rate of grade 3 or 
higher radiation pneumonitis or any grade 4 toxicity were truly 5%. Otherwise, the 
protocol will proceed to enroll a total of 26 patients and declare the feasibility of proton 
radiation if no more than 3 of them were to experience grade 3 or higher radiation 
pneumonitis or any grade 4 toxicity within 3 months after treatment. 
 
 
 

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7. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 6-weeks prior to start of protocol therapy. 
Scans must be done <12 weeks prior to the start of chemotherapy if delivered or radiation 
therapy if no chemotherapy is delivered. In the event that the participant's clinical condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours. 
 
Tests and Observations 
Pre-study 
During 
Radiation 
 
Follow Up (1) 
Informed Consent and registration 
X 
 
 
Pathology Review (DF/HCC) 
X 
 
 
Medical History 
X 
 
 
Physical Exam  
X 
 
X 
Echocardiogram (2) 
X  
 
X(2) 
Imaging  
X (3) 
 
As clinically 
indicated 
Toxicity/AE Assessment 
 
 
X weekly 
X 
Data Sheets 
 
 
X (4) 
Labs (5) 
X 
 
X 
Optional Photography 
X 
X 
X 
Notes: 
(1) Follow up schedule is at 4 weeks and 2 months, and 6 months after treatment , then at 12 months and annually to 
five years after treatment.  Labs are only collected at the first two follow up visits (4 weeks and 2 months). Visit 
window for follow up is +/- 3 weeks for the 4week and 8 week follow up visits, then +/- 6months for the 6month 
and annual visits.   
(2) Echocardiogram including Strain echocardiogram will be performed for all patients.  Echocardiogram data 
will be collected prior to radiation therapy (or within first week of treatment), at 4 weeks after completion of 
radiation therapy, and 2 months after radiation therapy. Conventional two-dimensional (2D) and Doppler 
echocardiography will be obtained in standard views. Tissue Doppler imaging will be acquired using standard 
views. Imaging parameters will be optimized and the frame rate will be set greater than150 frames/sec for 
acquisition of tissue Doppler imaging. Echocardiographic loops of at least 3 beats will be recorded. 
Echocardiograms will be read in the conventional manner and reported in the subject’s medical record. TDI-derived 
parameters, such as myocardial velocities, strain, strain rate and torsion, will be analyzed offline using customized 
computer software (EchoPac, GE Healthcare, Milwaukee, WI). 
 (3) Diagnostic imaging required pre-study:  
x 
Baseline mammography prior to surgery 
x 
For patients with lymphatic involvement Computed Tomography (CT) scan of the chest, CT of the 
abdomen, and bone scan and/or Positron Emission Tomography (PET)/CT scan are required. For patients 
with low burden nodal disease, these scans are not required. 
(4) The Patient Evaluation form and the Physician Data Therapy forms will be considered optional with the intent to 
complete at all follow up study timepoints and missed forms will not be considered as constituting protocol 
deviations or violations. 
(5) Standard clinical labs including CBC with differential; TSH at baseline; Biomarkers will be assessed only at 
the times of echocardiography. Approximately 5 cc of blood will be taken for each measurement of BNP and 
NTproBNP, and 5 cc of blood for ultrasensitive troponin. Blood will be spun at 3000 rpms for 10 minutes, the 
plasma will be alloguotted into daughter tubes and stored at -80. BNP levels will be measured with a twosite dual-
monoclonal immunochemiluminescent assay (ADVIA Centaur® BNP, Bayer Diagnostics, Tarrytown, NY) using 
the ADVIA Centaur immunoassay system. NT-proBNP levels will be measured with an electrochemiluminescence 

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sandwich immunoassay (Elecsys® ProBNP, Roche Diagnostics Inc, Indianapolis, IN) using the Roche 2010 system. 
For non acutely dyspnic subjects aged <75 years of age, the upper limit of normal is considered 125 pg/ml 
(manufacturers recommendations). Troponin I will be measured using a new generation technique that has shown 
increased sensitivity compared to routine measurements (Architect STAT troponin assay, Abbot Diagnostics).  Labs 
will be performed in conjunction with routine labs obtained pre- and post- treatment only at 3 time points, prior to 
radiation therapy, 4 weeks after radiation therapy, and 2 months after radiation therapy.  
 
8. MEASUREMENT OF EFFECT  
The patients on this study will not have measurable disease at the time of radiation therapy.  
These patients will be followed for disease recurrence.   
 
8.1  
Antitumor Effect– Solid Tumors 
8.1.1 Definitions 
Evaluable for toxicity. All participants who receive at least one dose of study 
treatment will be evaluable for toxicity from the time of their first treatment. 
Evaluable for response. Only those participants who have completed study 
treatment, and have had their disease re-evaluated will be considered evaluable 
for response. These participants will have their response classified according 
to the definitions stated below. (Note: Participants who exhibit objective 
disease progression or die prior to the end of study treatment will also be 
considered evaluable. 
8.1.2  Progression-Free Survival 
Tumor control is not the primary objective of this Pilot Study.  Participants will be 
followed for toxicities and Progression-Free Survival (PFS), which is defined as the 
duration of time from start of treatment to time of objective disease progression.  
Progressive disease will be defined as the appearance of one or more new 
lesions.  Disease progression will be assessed at follow up by clinical exam, and 
may be further assessed by imaging as determined by the treating investigator.  
 
9. ADVERSE EVENT REPORTING REQUIREMENTS  
 
 
9.1       General  
 

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Adverse event collection and reporting is a routine part of every clinical trial. This study 
will use the descriptions and grading scales found in the CTEP Active Version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE 
reporting. The CTEP Active Version of the CTCAE is identified and located on the 
CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm
<https://phsexchweb.partners.org/exchweb/bin/redir.asp?URL=http://ctep.cancer.gov/pro
tocolDevelopment/electronic_applications/ctc.htm>. All appropriate treatment areas 
should have access to a copy of the CTEP Active Version of CTCAE.
Information on all adverse events, whether reported by the participant, directly observed, 
or detected by physical examination, laboratory test or other means, will be collected, 
recorded, followed and reported as described in the following sections. 
Adverse events experienced by participants will be collected and reported from initiation 
of study treatment, throughout the study, and within 30 days of the last dose of study 
treatment. Participants who experience an ongoing adverse event or related to  study 
procedures and/or study treatment beyond 30 days will continue to be contacted by a 
member of the study team until the event is resolved, stabilized, or determined to be 
irreversible by the participating investigator. 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. The investigator should notify the IRB 
and any other applicable regulatory agency of any unanticipated death or adverse event
occurring after a participant has discontinued or terminated study participation that may 
reasonably be related to the study. 
9.2
Definitions 
9.2.1
Adverse Event (AE)
An adverse event is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study. 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests. 
9.2.2 Serious adverse event (SAE)
A serious adverse event is an undesirable sign, symptom, or medical condition 
which:
x
is fatal or life-threatening;

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x requires or prolongs inpatient hospitalization; 
x results in persistent or significant disability/incapacity; 
x constitutes a congenital anomaly or birth defect; or 
x jeopardizes the participant and requires medical or surgical intervention to 
prevent one of the outcomes listed above.  
 
Events not considered to be serious adverse events are hospitalizations for: 
x routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
x elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
x emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
x respite care 
 
              9.2.3    Expectedness  
 
Adverse events can be 'Expected' or 'Unexpected.'  
 
9.2.3.1   Expected adverse event 
 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated 
with the study agent(s).   
 
 9.2.3.2  Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk.   
 
9.2.4 Attribution  
 
Attribution is the relationship between an adverse event or serious adverse 
event and the study treatment. Attribution will be assigned as follows: 
 
x Definite – The AE is clearly related to the study treatment. 

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x Probable – The AE is likely related to the study treatment. 
x Possible – The AE may be related to the study treatment.  
x Unlikely - The AE is doubtfully related to the study treatment. 
x Unrelated - The AE is clearly NOT related to the study treatment. 
 
 
9.3 
  Recording Adverse Events 
 
Adverse event information will be obtained at each contact with the participant. All 
adverse events will be recorded on the appropriate study-specific case report forms 
(CRFs).  
 
9.4 
 Reporting Adverse Events  
 
Each adverse event will be assessed to determine if it meets the criteria for serious 
adverse event. If a serious adverse event occurs, expedited reporting will follow local 
policies, and federal guidelines and regulations as appropriate.  
 
It is the responsibility of the participating investigator to notify the Principal 
Investigator (or Protocol Chair), IRB, and others of all serious adverse events as 
required in the protocol.  
 
The Principal Investigator (or Protocol Chair) will provide information with respect to 
adverse events and safe use of the study treatment (e.g., safety reports, Action Letters) 
to all participating investigators as soon as the information becomes available.  
 
 
9.5 
  Sponsor Notification by Investigator  
 
 
 
  9.5.1  
Serious Adverse Event Reporting Requirements 
 
All events meeting the criteria for Serious Adverse Event (see Section 11.2.2) 
that occur after the initial dose of study treatment, during treatment, or within 
30 days of the last dose of treatment must be reported as serious adverse 
events.  
 
The participating investigator must report each serious adverse event, 
regardless attribution, to the Principal Investigator (or Protocol Chair) within 
24 hours of learning of the occurrence. In the event that the participating 
investigator does not become aware of the serious adverse event immediately 
(e.g., participant sought treatment elsewhere), the participating investigator is 
to report the event within 24 hours after learning of it and document the time of 

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his or her first awareness of the adverse event. Report serious adverse events 
by telephone and facsimile to:
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the serious adverse event. Follow-up information 
should describe whether the event has resolved or continues, if and how the 
event was treated, and whether the participant will continue or discontinue 
study participation. 
9.5.2
Non-Serious Adverse Event Reporting Requirements
Non-serious adverse events will be reported to the Principal Investigator (or 
Protocol Chair) on the toxicity Case Report Forms.
9.6
Institutional Review Board (IRB) Notification by Investigator
The participating investigator will report all adverse events and serious adverse events 
to the Principal Investigator (or Protocol Chair) and to the IRB according to the local 
IRB’s policies and procedures in reporting adverse events. 
9.7
Hospital Risk Management Notification by Investigator
The participating investigator will report to the Principal Investigator (or Protocol Chair) 
and to local Risk Management any subject safety reports or sentinel events that require 
reporting according to institutional policy.
10. DATA AND SAFETY MONITORING
10.1
Data Reporting 
10.1.1 Method 
The QACT will collect, manage, and monitor data for this study. 
10.1.2 Data Submission 
The schedule for completion and submission of case report forms (paper or 
electronic) to the QACT is as follows:
Form
Submission Timeline

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Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of study 
treatment 
Toxicity/Adverse Event 
Report Form 
Weekly during study treatment; Within 10 
days of protocol-defined follow up 
Lab Form 
Within 14 days of protocol required labs 
Measurement/Response Form 
Within 14 days of registration; within 10 
days of  protocol-defined follow up 
Off Treatment/Off Study 
Form 
Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined 
follow up visit date or call 
 
  
10.2 
Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Principal Investigator and study team. 
 
The DSMC will meet as required to review toxicity and accrual data.  Information to be 
provided to the committee may include:  up-to-date participant accrual; current dose 
level information; DLT information; all grade 2 or higher unexpected adverse events 
that have been reported; summary of all deaths occurring within 30 days for Phase I or 
II protocols; for gene transfer protocols, summary of all deaths while being treated and 
during active follow-up; any response information; audit results, and a summary 
provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
10.3  Monitoring 
 

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All data will be monitored for timeliness of submission, completeness, and adherence to 
protocol requirements. Monitoring will begin at the time of participant registration and 
will continue during protocol performance and completion.  
 
11. REGULATORY CONSIDERATIONS 
 
11.1  Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The Principal Investigator (or Protocol Chair) will disseminate 
protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
 
 

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11.2
Informed Consent
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file. 
11.3
Ethics and Good Clinical Practice (GCP)
This study is to be conducted according to the following considerations, which 
represent good and sound research practice:
x
ICH Consolidated Good Clinical Practice: Guidelines (E6) 
www.fda.gov/cder/guidance/iche6.htm
x
US Code of Federal Regulations (CFR) governing clinical study conduct 
and ethical principles that have their origin in the Declaration of Helsinki

Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html

Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html

Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr54 02.html

Title 21 Part 56 – Institutional Review Boards
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html

Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr312 02.html
x
State laws
x
Institutional research policies and procedures 
www.dfhcc.harvard.edu/clinical-research-support/clinical-research-
operations-cro/policies-and-procedures

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It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
 
11.4  Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the study for each research 
participant. This information enables the study to be fully documented and the study data 
to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are not 
limited to hospital records, clinical charts, laboratory and pharmacy records, recorded 
data from automated instruments, microfiches, photographic negatives, microfilm or 
magnetic media, and/or x-rays.  
 
11.5  Records Retention 
 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies.  
12. STATISTICAL CONSIDERATIONS  
We propose to enroll a total of 96 patients in three cohorts following the study design indicated 
in 12.1 to evaluate independently the feasibility of intensity modulated proton therapy (IMPT) 
and 3D conformal protons following mastectomy or breast-conserving surgery. The separate 
cohorts will ensure adequate patient numbers for achieving reasonable precision in the 
assessment of acute, sub-acute and late toxicities associated with each proton technique in the 
specific population. The accrual goal includes 20% inflation to account for patients unevaluable 
or lost to follow-up so that adequate precision is maintained for longer-term endpoints. The 
target accrual has been adjusted based on the observed data among mastectomy patients with at 
least 6 months follow-up, including the completeness of strain echocardiogram testing. 
12.1    Study Design/Endpoints  
This is a pilot study substituting proton radiation for photon radiation, seeking to show the 
feasibility of proton radiation and to assess the rate of acute, sub-acute and late toxicities during 
and after proton radiation to the left chest wall and regional lymphatics. It is anticipated that 
patients undergoing proton radiation will not have increased toxicity compared to patients who 
have historically undergone photon radiation. 
Proton radiation will be considered to be feasible as adjuvant treatment for invasive breast 
carcinoma in each cohort following surgery if the rate of grade 3 or higher radiation pneumonitis 
within 3 months of treatment were no more than 5%, within the range associated with 
conventional techniques of adjuvant radiation. In addition to radiation pneumonitis, the 
feasibility of proton radiation will also be compromised by any grade 4 effect occurring within 3 
months of treatment, as well as skin toxicity and pericarditis. If 2 or more of the initial 12 

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patients were to experience grade 3 or higher radiation pneumonitis or any grade 4 toxicity 
within 3 months of finishing radiation, accrual to a cohort will not continue further. The 
probability of stopping early is only 12% if the underlying rate of grade 3 or higher radiation 
pneumonitis or any grade 4 toxicity were truly 5%. Otherwise, the cohort will proceed to enroll a 
total of 26 patients and declare the feasibility of proton radiation if no more than 2 of them were 
to experience grade 3 or higher radiation pneumonitis or any grade 4 toxicity within 3 months 
after treatment. The two-stage design provides 81% power to accept that proton radiation is 
associated with a 5% rate of grade 3 or higher radiation pneumonitis or any grade 4 toxicity in a 
treated cohort. However, the probability is only 20% for declaring the feasibility of proton 
radiation if the underlying rate grade 3 or higher radiation pneumonitis or any grade 4 toxicity 
were truly 15%. 
12.1.1    Sample Size/Accrual Rate  
We estimate an annual enrollment of 16-20 patients based on the existing referral patterns and 
proton slot availability over 3 years of active accrual. Since protocol enrollment began in August 
2011, the accrual rate has been about 15 patients per year, thus increasing the accrual goal from 
58 to 64 post-mastectomy patients is  projected to take another 4-5 months. Based on existing 
referral patterns of patients following breast-conserving surgery, we estimate the intact breast 
cohort will require 5-6 months to enroll the cohort goal of 32 patients. All patients will be 
followed for an additional 5 years to allow for the assessment of late toxicities and progression-
free survival. 
 
12.1.2 Stratification Factors 
 
Protocol accrual will be stratified by proton technique (3D conformal and IMPT) and by surgery 
procedure (mastectomy and breast-conserving). Post-mastectomy patients will be enrolled in 
sequential cohorts, while patients with intact breast will only be treated with IMPT. In general, 
primary and secondary endpoints will be analyzed separately for each proton cohort.  
 
12.2 Analysis of Secondary Endpoints 
 
Secondary endpoints of this study will be analyzed as follows: 
 
12.2.1 Exact binomial methods will be used to construct 95% confidence intervals for estimating 
the rates of acute, sub-acute and late toxicities during and after proton radiation to the left 
chest wall and regional draining lymphatics. The precision provided by a sample size of 
26 patients is associated with a maximum half-width of 20%, but the 95% confidence 
intervals will be narrower in practice, as the observed toxicity rates are expected to be 
generally low. The same methods will also be used to analyze the post-radiation 
outcomes of breast reconstruction, including the rates of implant complication, 
contracture, infection, unplanned cosmetic surgeries. 
12.2.2 Progression-free survival is defined as the duration from the start of radiation to the date 
of objective disease progression or death due to any cause, whichever is earlier. 
Progression-free survival will be estimated using Kaplan-Meier methodology. The 5-year 

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progression-free survival rate will be reported and a 95% confidence interval for this rate 
will be calculated using Greenwood’s formula. Patients who do not experience a 
progression and are still alive will be censored at their date of last contact.   
12.2.3 Data from the strain echocardiogram will be analyzed for each parameter, including 
myocardial velocity, strain, strain rate and torsion. ANOVA methods will be used to 
analyze the pre- and two post-radiation measurements, using linear contrasts to test the 
significance of cardiac function changes over time. Fixed effects may be incorporated to 
explore subgroup differences defined by patient and treatment factors, for example, dose 
level. 
 
 
12.3 Reporting and Exclusions 
 
12.5.1 
Evaluation of toxicity. All participants will be evaluable for toxicity from the time 
of their first treatment. 
 
12.5.2 
Evaluation of response. Although patients will not have measurable disease at the 
time of treatment and therefore response is not an endpoint of this study, all patients 
will be followed for disease recurrence.  
 
 
13. PUBLICATION PLAN 
 
The results should be made public within 24 months of the end of data collection. If a report is 
planned to be published in a peer-reviewed journal, then that initial release may be an abstract that 
meets the requirements of the International Committee of Medical Journal Editors. A full report 
of the outcomes should be made public no later than three (3) years after the end of data collection.  
 
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37 
 
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15. APPENDICES 
 
Appendix A. Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
20 
Very sick, hospitalization 
indicated. Death not imminent. 

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care. Totally confined to bed or 
chair. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 
 
 

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Toxicity CTCAE version 4.0 from http://ctep.cancer.gov 
  
Condition 
Short 
Name 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Fatigue 
(lethargy, malaise, 
asthenia) 
Fatigue 
Mild fatigue over 
baseline 
Moderate or causing 
difficulty performing 
some ADL 
Severe fatigue interfering 
with ADL 
Disabling 
-- 
Radiation dermatitis 
Radiation 
dermatitis 
faint erythema or 
dry desquamation 
moderate to brisk 
erythema or a patchy 
moist desquamation, 
mostly confined to 
skin folds and creases; 
moderate edema 
Moist desquamation other 
than skin folds and 
creases; bleeding induced 
by minor trauma or 
abrasion 
skin necrosis or 
ulceration of 
full thickness 
dermis; 
spontaneous 
bleeding from 
involved site 
Death 
Dysphagia 
Dysphagia 
Symptomatic, able 
to eat regular diet 
Symptomatic and 
altered 
eating/swallowing (e.g. 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 
hrs 
Symptomatic and severely 
altered eating/swallowing 
(e.g., inadequate oral 
caloric or fluid intake); IV 
fluids, tube feedings, or 
TPN indicated ≥24 hrs 
Life-threatening 
consequences 
(e.g., 
obstruction, 
perforation) 
Death 
Fibrosis-deep connective 
tissue 
Fibrosis-deep 
connective 
tissue 
Increased density, 
“spongy” feel 
Increased density with 
firmness or tethering 
Increased density with 
fixation of tissue; 
operative intervention 
indicated; interfering with 
ADL 
Life-
threatening; 
disabling; loss of 
limb; 
interfering with 
vital 
organ 
function 
 
Death 
Pneumonitis/Pulmonary 
Infiltrates 
Pneumonitis 
Asymptomatic, 
radiographic 
findings only 
Symptomatic, not 
interfering with 
ADL 
Symptomatic, 
interfering with ADL; 
O2 indicated 
Life-
threatening; 
ventilatory 
support 
indicated 
Death 
Dyspnea (Shortness of 
Breath) 
Dyspnea 
Dyspnea on 
exertion, but 
can walk 1 flight 
of stairs without 
stopping 
Dyspnea on 
exertion but unable 
to walk 1 flight of 
stairs or 1 city 
block (0.1 km) 
without stopping 
Dyspnea with ADL 
Dyspnea at 
rest; 
intubation/ 
ventilator 
indicated 
 
Death 
Hypoxia 
Hypoxia 
-- 
Decreased O2 
saturation with 
exercise (e.g. pulse 
oximeter <88%); 
intermittent 
supplemental 
oxygen 
Decreased O2 
saturation at rest, 
continuous oxygen 
indicated 
Life-
threatening; 
intubation or 
ventilation 
indicated 
Death 
Cough 
Cough 
Symptomatic, 
non-narcotic 
medication only 
indicated 
Symptomatic and 
narcotic medication 
indicated 
Symptomatic and 
significantly interfering 
with sleep or ADL 
-- 
-- 
FEV1 
FEV1 
90-75% of 
predicted value 
<75-50% of 
predicted value 
<50-25% of predicted 
value 
<25% of 
predicted 
value 
Death 

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Pulmonary Fibrosis 
(radiographic changes) 
Pulmonary 
fibrosis 
Minimal 
radiographic 
findings (or 
patchy or bi-
basilar changes) 
with estimated 
radiographic 
proportion of 
total lung 
volume that is 
fibrotic of < 
25% 
Patchy or bi-basilar 
changes with 
estimated 
radiographic 
proportion of total 
lung volume that is 
fibrotic of 25 - 
<50% 
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic 
proportion of total lung 
volume that is fibrotic 
of 50 - <75% 
Estimated 
radiographic 
proportion of 
total lung 
volume that is 
fibrotic is 
≥75%; 
honeycombing 
Death 
 
Remark: Fibrosis is usually a “late effect seen >3 months after radiation or combined modality therapy 
(including surgery). It is thought to represent scar/fibrotic tissue. It may be difficult to distinguish from 
pneumonitis that is generally seen within 3 months of radiation or combined modality therapy.