Definitive Re-irradiation With Proton Beam Radiotherapy for Patients With Recurrent Thoracic Cancers
Phase: NA
Conditions: Metastatic Malignant Neoplasm in the Lung, Recurrent Disease, Thoracic Neoplasm
Sponsor: University of Washington

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FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Current version: 5/21/2015 
 
Title of Protocol: 
Definitive Re-Irradiation with Proton Beam Radiotherapy for Patients with 
Recurrent Thoracic Cancers 
 
 
 
Investigators List: 
Jing Zeng, MD 
 
Principal Investigator 
Assistant Professor 
Department of Radiation Oncology 
206-598-4100 
Shilpen A. Patel, MD 
 
Associate Professor 
Department of Radiation Oncology 
206-598-4100 
Ramesh Rengan, MD, PhD 
 
Associate Professor 
Department of Radiation Oncology 
206-598-4100 
Research Staff: 
Barry Storer, PhD 
Statistician 
 
Joy Knopp 
Research Coordinator 
206-598-2396 
 
 
 
 
 
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1.0 INTRODUCTION 
 
Title 
Definitive Re-Irradiation with Proton Beam Radiotherapy for Patients 
with Recurrent Thoracic Cancers 
Short Title 
Proton Re-Irradiation in the Thorax 
Protocol Number 
 
Phase 
Pilot Study 
Methodology 
Single Arm Open-Label  
Study Duration 
3 years  
Study Center(s) 
University of Washington Medical Center/SCCA Procure Proton Center  
Objectives 
To utilize proton radiation to safely treat patients with tumors in the 
thorax, who have previously received radiation to the chest.  We will 
assess the efficacy and toxicity of treatment. 
Number of Subjects 
20 evaluable subjects 
Diagnosis and Main 
Inclusion Criteria 
Patients diagnosed with tumors in the thorax, who have previously 
received radiation to the chest, such that the current radiation treatment 
fields are likely to overlap with the prior radiation fields.   
Study Product, Dose, 
Route, Regimen 
Proton radiation to the thorax  
Duration of 
administration 
Radiation treatment regimens will be at the discretion of the treating 
radiation oncologist, BED2Gy at least 60 Gy 
Statistical 
Methodology 
We expect to see <25% grade 3 toxicity attributable to radiation, and 
≥80% local tumor control at 3-months post-treatment  
 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice (FDA Title 21 part 312 and International 
Conference on Harmonization guidelines), applicable government regulations and Institutional research 
policies and procedures.  
 
2.0 BACKGROUND 
 
2.1 
Study Disease 
Lung cancer is the most common cause of cancer related mortality in the US.  Radiation therapy 
is a main treatment modality for lung cancer: for resectable tumors, radiation can be given pre-
operatively or post-operatively to improve local tumor control and outcomes; for unresectable tumors, 
radiation can be given as definitive treatment for the cancer, either alone or in combination with 
chemotherapy.   
 
Local recurrence remains a significant cause of treatment failure in lung cancer.  For stage III 
lung cancer treated with definitive chemoradiation, local failure rates range from 30% to 50% [1, 2].  At 
the time of lung cancer recurrence, patients often present as a heterogeneous group, with a mixture of 
local as well as systemic disease, and varying time intervals to recurrence.  Outcomes are generally poor 
with recurrence, however, various treatments are often given to either prolong life or palliate symptoms.  
Depending on specific patient characteristics such as age, stage, histology, and performance status, 
aggressive treatments can sometimes be pursued with superior outcomes to supportive care alone.   
 
External beam radiation is often given to patients with recurrent lung cancer to provide local 
tumor control and palliate symptoms.  This can be challenging in patients who have previously received 
 
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radiation to the chest, usually as part of the initial cancer treatment.  Radiation oncologists are guided by 
normal tissue tolerances, which is the standard of care radiation dose that is felt to be safe for specific 
organs in the body.  Typically, for patients who have already received thoracic radiation, many organs in 
the area have already received a significant radiation dose.  Therefore, it is often assumed that thoracic 
radiation cannot be repeated.  Even when repeat radiation is given, it is typically for palliative doses, due 
to concerns about toxicity if higher radiation doses were attempted, as well as concerns over patient life 
expectancy [3].   
 
Recent technological advances in radiation therapy and imaging have led to more interest and 
more feasibility in the role of repeat radiation for a select group of recurrent cancer patients.  For 
patients with symptomatic locally recurrent tumors, or patients with good systemic disease control but 
persistent or progressive local disease, repeat radiation with moderately high radiation doses can provide 
lasting tumor control and symptom palliation.  Multiple clinical series have been published on thoracic 
re-irradiation, showing safety and efficacy [4-10]. However, the series are typically retrospective or 
prospective registry trials, with no prospective guidelines in terms of radiation dose limits for normal 
organs.  Radiation doses and fractionation varies widely.  Toxicity and efficacy information are often 
incomplete.  Table 1 summarizes some of the best published clinical data on repeat irradiation in the 
thorax.  As systemic treatments improve for lung cancer, local control will also become more critical for 
this patient population, and prospective guidelines to safely deliver repeat radiation must be developed.   
 
Table 1. Summary of Recurrent Thoracic Radiation 
Study 
Institution 
# of patients  
Radiation 
Technique 
Toxicity 
Local 
Control 
Kelly et al. 
IJROBP 
2010[8] 
MD Anderson 
36 
SBRT (10 
Gyx4 fractions 
or 10 Gyx5) 
33% grade 3. 
No grade 4 or 
5. 
92% at 2 
years 
Trakul et al. 
JTO 2012[9] 
Stanford 
17 
SBRT (dose 
fractionation 
varies) 
13% grade 3. 
No grade 4 or 
5. 
65.5% at 1 
year 
Seung et al. J 
Cancer 
Therapy 
2011[10] 
Oregon Clinic 
8 
SBRT (8-20 
Gy x3-5 
fractions) 
100% grade 2 
pneumonitis.  
No grade 3 or 
higher. 
86% at 1.5 
years 
 
In addition to recurrent lung cancers, other malignancies can also result in the need for repeat 
irradiation of the chest.  For example, recurrent thymomas that were previously treated with radiation 
therapy can still have a relatively long disease course.  In unresectable localized recurrences that show 
no evidence of dissemination, in patients with good performance status and life expectancy, it would be 
reasonable to consider repeat radiation.  Patients with one thoracic cancer can also develop a second 
primary malignancy in the chest (i.e. esophageal cancer that was treated with radiation years ago, now 
with lung cancer; or breast cancer treated previously, now with lung cancer).  Since radiation planning is 
guided by normal organ dose limits, this patient population would follow similar radiation guidelines as 
recurrent lung cancer patients, in terms of normal organ radiation constraints.   
 
  
2.2 
Rationale for Use of Proton Radiation  
Proton radiation has unique physical properties compared with photon-based radiation due to the 
Bragg peak[11].  For the more widely available photon-based radiation, the radiation beams enter the 
 
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patient’s body, deposits energy and causes tissue damage, and exists through the body on the other side.  
In comparison, proton radiation beams enter a patient’s body, deposits a relatively small amount of 
energy along the path, until the beam weakens to the point when it deposits all of its energy immediately 
before the proton particles come to rest.  This is called the Bragg peak.  This physical characteristic of 
proton therapy has the potential for less normal tissue exposure to radiation, and therefore less toxicity.  
Multiple publications have shown that proton radiation have superior normal tissue sparing compared 
with photon-based radiation [12-14].       
 
2.3 
Clinical Data to Date 
Proton radiation has been increasingly used for treating lung and other thoracic malignancies in the 
recent years, with multiple published patient series showing safety and efficacy [15-17].  Multiple 
clinical series have also been published on thoracic re-irradiation, showing safety and efficacy [4-7]. 
However, the series are typically retrospective or prospective registry trials, with no prospective 
guidelines in terms of radiation dose limits for normal organs.  Radiation doses and fractionation varies 
widely.  Toxicity and efficacy information are often incomplete.   
 
2.4 
Risks/Benefits 
The benefit for patients enrolled in this trial is to receive proton radiation treatment to the thorax for 
recurrent tumors, which adheres to strict radiation normal organ dose limits that has been developed 
after thorough literature review and multiple radiation oncology specialists.   
 
The potential harm for patients enrolled in this trial is the radiation toxicity related to re-irradiation.    
 
3.0 STUDY OBJECTIVES 
 
3.1 Primary Objective 
To assess the grade 3 toxicity associated with thoracic re-irradiation with proton therapy, with 
prospectively applied normal organ radiation dose limits.   
 
Hypothesis:  With the normal tissue dose limits listed in this protocol, repeat radiation to the chest can 
be delivered safely without grade 3 or greater toxicity exceeding 25%.   
 
3.2 Secondary Objective 
To assess the efficacy of thoracic re-irradiation with proton therapy.   
 
Hypothesis:  We will achieve >80% local tumor control at 3-months post-treatment inside the radiation 
field.    
 
4.0 STUDY DESIGN 
 
4.1 
General Design 
This is a pilot study to utilize proton radiation to safely treat patients with tumors in the thorax, 
who have previously received radiation to the chest.  We have set out specific radiation guidelines for 
normal tissue dose limits and tumor coverage.   
 
4.2 
Endpoints 
4.2.1 Primary Endpoint 
Grade 3 or greater toxicity attributable to radiation treatment. 
 
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4.2.2 Secondary Endpoint 
 Local control (Failure: tumor progression per RECIST criteria – at least a 20% increase in 
the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since 
the treatment started or the appearance of one or more new lesions inside the full dose 
radiation field.) 
 Overall survival (Failure: death due to any cause) 
 Grade 2 toxicity attributable to radiation treatment 
 
 
5.0 SUBJECT SELECTION 
 
5.1 
Inclusion Criteria  
5.1.1 Patients >18 years old.   
 
5.1.2 Women of child-bearing age must have a negative pregnancy test.  
 
5.1.3 Patients must have received prior radiation treatment to the chest.  Records of prior radiation 
treatment must be available.   
 
5.1.4 Patients must have received prior chest radiation at least 3 months prior to enrollment in this 
trial.  Radiation treatment to other body sites not overlapping with current radiation fields are 
allowed within the 3 months period (example, brain radiation is allowed).   
 
5.1.5 Patients must have a prior diagnosis of cancer inside the thoracic cavity.  Both primary thoracic 
malignancies (such as lung cancer) as well as metastatic lesions (such as metastatic breast cancer 
or colorectal cancer to the lungs) are allowed.  Patient must have pathologic confirmation of the 
recurrent thoracic tumor, or have an enlarging thoracic mass (as seen on two CT scans at least 6 
weeks apart, with either a >25% or >5 mm increase in longest dimension). 
 
5.1.6 Patients must have a life expectancy of > 6 months. 
 
5.1.7 Patients must have measurable disease to be treated with proton radiation (minimum tumor 
dimension at least 10 mm on CT imaging).  
 
5.1.8 Patients should have either non-metastatic cancer of the thorax, or metastatic cancer to the thorax 
and candidate for definitive radiation dose to the thoracic tumor (not palliative intent), tumor 
radiation dose to at least BED2Gy 60 Gy. 
 
5.1.9 Patients must be able to receive proton radiation treatment.   
 
5.1.10 All stages of cancer are eligible. 
 
5.1.11 There are no limits on prior therapy.  Patients are allowed to have prior chemotherapy and 
surgery.  Patients are allowed to have concurrent chemotherapy with radiation treatment.  
Patients are allowed to have chemotherapy or surgery after radiation treatment. 
 
5.1.12 Patients are allowed to be on another study concurrent with this protocol.     
 
5.1.13 Ability to understand and the willingness to sign a written informed consent document. 
 
 
 
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5.2 
Exclusion Criteria 
5.2.1 Patients who have never received radiation to the chest. 
 
5.2.2 Patients who received radiation to the chest within the past 3 months (in a region that overlaps 
with current radiation fields).  
 
5.2.3 Patients with life expectancy < 6 months. 
 
5.2.4 Pregnant women. 
 
5.2.5 Patients unable to provide informed consent.  
 
5.2.6 Prisoners.  
 
5.3 
Recruitment 
Subjects will be recruited from investigator clinical practices and include men and women with recurrent 
thoracic cancer who will be receiving radiotherapy to at least BED2Gy 60 Gy.  Subjects will undergo an 
informed consent process in accordance with GCP. Informed consent will be obtained prior to the 
performance of any screening procedures. 
 
6.0 SUBJECT REGISTRATION 
  
Subjects will be registered by the FHCRC/UW Study Coordinator and entered into the Protocol Accrual 
Tracking System (PATS). Information regarding the PATS system is available at 
http://www.cancerconsortiumorg/rto/protocol_office/pats/. A complete, signed, study consent and 
HIPAA consent are required for registration. 
 
 
7.0 TREATMENT PLAN 
 
All patients will receive radiation treatment per standard of care, adhering to the normal organ radiation 
dose constraints outlined in this protocol.  The only additional procedure related to this protocol is 
informed consent at enrollment.   
 
The standard treatment outline for patients receiving radiation treatment, which also applies to patients 
on this protocol, begins with an initial consultation, including history and physical.  Patients’ prior 
radiation records will be obtained and reviewed.  If patients are eligible and consent to repeat irradiation, 
they are scheduled for a radiation simulation scan, to be used for radiation treatment planning.  
Physicians will delineate the target tumor volume as well as normal organs to be protected in the region.  
A radiation plan will be generated that meets the normal organ dose limits outlined in this protocol.  The 
plan undergoes quality assurance checks, and patients then start treatment.  During treatment, patients 
are seen at least once weekly by the physician to assess for toxicity.  After completion of radiation, 
patients are seen typically 3 months post-treatment with CT chest to assess for treatment response and 
toxicity.  Additional imaging or follow up visits may take place per routine medical standard of care.  
Research staff will review clinical record at 3 months post-treatment.  See Table 1 below for summary. 
 
 
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Table 2. Study Calendar. 
 
 
Screening 
Prior to Start of 
Radiation 
Treatment 
Weekly During 
Radiation 
Treatment 
3-Months*** 
Post-Radiation 
Treatment End 
Informed Consent 
X* 
 
 
 
Physical Exam 
X 
 
X  
X 
Medical History 
X 
 
X  
X 
Pulmonary Function 
Tests (PFTs) 
 
X 
 
X 
CT Chest 
X 
 
 
X 
Serum Pregnancy 
Test** 
X 
 
 
 
*  Denotes a Research Procedure, all others are standard of care 
** For women of child bearing potential only 
*** Exact time of follow up can vary depending on clinical judgment.  Patients are typically seen at 3 months 
after treatment, but this can vary between 2-6 months as judged appropriate by treating physician. 
 
7.1 
Radiation Treatment Parameters 
7.1.1 Localization, Simulation, and Immobilization 
 
Body cradle or similar immobilization device(s) must be utilized.  A treatment planning CT scan is 
mandatory. CT scan thickness should be 0.5 cm or smaller (preferably ≤0.3 cm) through the treatment 
volume. Intravenous contrast is recommended in patients who do not have a contraindication to it. MRI 
and/or PET scans with image fusion also may be helpful in treatment planning, particularly if these 
scans can be performed with the same immobilization device as was used for the planning CT scan.  4D 
CT scan with respiratory motion tracking is strongly preferred for lung tumors.  Any tumors moving 
more than 1 cm with respiration must be considered for motion management for radiation treatment, 
which can include but not limited to: abdominal compression, respiratory gating, and active breathing 
control.  These are all standard of care for lung radiation treatment.   
 
7.1.2 Volume Definitions 
 
Gross Tumor Volume (GTV): This is the region of interest that is known to contain gross cancer. This 
will include all gross tumor as based upon the planning CT scan. This also may include areas that appear 
“normal” by the planning CT scan but are known to harbor cancer based on the MRI, PET, physical 
examination, endoscopy, etc. 
Clinical Tumor Volume (CTV): The CTV is defined to be the GTV plus a margin as appropriate to 
account for microscopic tumor extension.  The exact CTV margin to be used is at the discretion of the 
treating physician, and can be as low as 0 mm if microscopic extension is not felt to be of concern in a 
particular patient situation.   
Internal Target Volume (ITV): If 4D CT scans are used to assess for breathing motion, the ITV will be 
used to encompass the CTV and all respiratory motion. 
Planning Tumor Volume (PTV): This includes the CTV (or ITV if appropriate) plus a margin to 
compensate for various uncertainties, such as systematic treatment setup variables, organ motion 
(especially with respiratory motion), and organ displacement. A minimum of 5 mm around the CTV is 
required in all directions, except where the CTV is immediately adjacent to a critical organ such as the 
spinal cord (in which case, the margin from CTV to PTV may be as small as 1 mm).  
 
 
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7.1.3 Treatment Planning Dose Constraints 
 
 A composite radiation plan that includes the prior thoracic radiation must be generated. 
 Minimum PTV dose should be 90% of the prescription dose and 95% of the PTV should receive 
the prescription dose, unless PTV overlaps with a critical normal organ.  In that case, the portion 
of PTV not overlapping with the critical organ should meet the constraint above.  Min PTV dose 
<80% will be a major violation, volume of PTV receiving prescription dose <90% will be a 
major violation.   
 Minimum prescription dose to PTV must be at least BED2Gy 60 Gy. 
 Spinal cord: max point dose 50 Gy (<0.03 cc) or BED equivalent (BED2Gy 83 Gy) from proton 
radiation plan.  Composite maximum spinal cord dose must not exceed BED2Gy 90 Gy.  For 
patients who received radiation > 3 years prior, the cord constraint can be increased with PI 
approval.   
 Normal lung: mean dose < 20 Gy and volume receiving 20 Gy (V20) < 35% for proton radiation 
plan.   
 Esophagus: mean dose <34 Gy and max dose < 66 Gy for proton plan.  Composite max point 
dose < BED2Gy 140 Gy. 
 Heart: mean dose < 40 Gy and max dose < 66 Gy for proton plan.  Composite max point dose < 
BED2Gy 140 Gy. 
 
7.1.4 Treatment delivery 
 
All patients will have daily imaging guidance for setup and positioning prior to proton radiation 
delivery.  This is typically done with port films. 
 
7.1.5 R.T. Quality Assurance Reviews  
 
All patients treated on this protocol will undergo standard review in the Department of Radiation 
Oncology.  At least two physicians will review the patient history, imaging findings, tumor contours, 
and radiation plan.   
 
7.1.6 Radiation Toxicity 
 
Toxicity will be graded based on CTCAE 4.0.  Grade two and above adverse events will be recorded.in 
a Redcap database.  The AE’s will be followed for three months post-treatment. 
 
7.2 
Criteria for Removal/Withdrawal from Treatment 
Patients will be withdrawn from treatment if their clinical conditions decline so they are no longer able 
to tolerate proton radiation, or are unlikely to clinically benefit from further therapy. 
 
Patients will still receive follow up care per standard of care even if they withdraw from the study.  If a 
subject withdraws consent to participate in the study or aspects of the study, attempts will be made to 
obtain permission to record at least survival data up to 6 months post-treatment.   
 
8.0 DATA AND SAFETY MONITORING PLAN 
 
Oversight for this study at the SCCA and UWMC will be provided by the Principal Investigator with 
delegation of appropriate responsibilities to sub-investigators and designated study personnel.  They will 
ensure all entry criteria are met prior to the initiation of the protocol and all study procedures and 
reporting of adverse events are performed according to the IRB-approved protocol.  
 
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8.1 
Early Stopping Rules 
In the event of a grade 5 event occurring within ≤ 30 days after the end of treatment , there will be a 
temporary cessation in patient enrollment for event review  If the event is defined as possibly, probably, 
or definitely related to treatment (per CTCAE, v.4.0), early stopping of this trial will occur permanently.   
All Grade 3 and 4 AE’s will be immediately monitored and reviewed by PI.   
 
8.2 
Interim Data Review 
Interim reports with statistical analyses will be prepared twice per year until the initial treatment results 
have been presented or published. In general, the interim reports will contain the following information: 
 Patient accrual rate with a projected completion date (while the study is still accruing) 
 Total patients accrued 
 Frequencies and severity of adverse events  
 Compliance rates of treatment delivery 
 
 
9.0 ASSESSMENT OF EFFICACY 
 
9.1 
Efficacy Parameters 
Tumor response will be assessed using the RECIST criteria.   
 
For tumors targeted by radiation:  
 Complete Response (CR): Disappearance of all target lesions 
 Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD 
 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started 
 Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment started or the appearance of one or 
more new lesions 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration”. Every effort will be made to document the objective progression even after 
discontinuation of treatment. 
 
 
9.2 
Method and Timing 
Tumors will be measured on axial CT chest images.  The radiation treatment planning scan will be used 
as baseline.  The 3-months post-treatment scan will be used for comparison.   
 
9.3 
Toxicity Profile 
Toxicity will be measured by the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0. 
 
 
 
 
 
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10.0 STATISTICAL CONSIDERATIONS 
 
The primary objective of this protocol is to provide a preliminary evaluation of the safety and efficacy of 
re-irradiation with proton beam radiotherapy in patients with recurrent thoracic cancer.  Ideally this 
therapy should have a grade 3 toxicity rate of < 25% and a local control rate of > 80%. 
 
Twenty patients will be enrolled.   If 7 or more of the 20 patients experience grade 3 toxicity, then we 
would be at least 80% confident that the true toxicity rate exceeds 25%; conversely, if 3 or fewer of the 
20 patients experience grade 3 toxicity, then we would be at least 80% confident that the true toxicity 
rate is less than 25%.   An intermediate result, 4-6 patients with grade 3 toxicity, would be regarded as 
inconclusive. 
 
With regard to efficacy, if the therapy results in 14 or fewer of the 20 patients with local tumor control, 
then we would be at least 80% confident that the true local control rate is less than 80%; conversely, if 
18 or more of the patients have local tumor control, then we would be at least 80% confident that the 
true local control rate exceeds 80%.  An intermediate result, 15-17 patients with local tumor control, 
would be regarded as inconclusive. 
 
An early stopping rule will be imposed for grade 5 adverse events, and the protocol will stop should any 
patients experience a grade 5 AE as described in Section 8.1.   If the true rate of grade 5 AE is 10%, then 
there is an 88% chance that this stopping rule will be triggered. 
 
 
11.0 DATA MANAGEMENT/CONFIDENTIALITY 
 
The investigator will ensure that data collected conform to all established guidelines. Each subject is 
assigned a unique patient number to assure subject confidentiality. Subjects will not be referred to by 
this number, by name, or by any other individual identifier in any publication or external presentation. 
The licensed medical records department, affiliated with the institution where the subject receives 
medical care, maintains all original inpatient and outpatient chart documents. 
 
Subject research files are stored in a secure place (or database). Access is restricted to authorized 
personnel. 
 
 
 
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