A Phase II Study of Hyperfractionated Stereotactic Radiotherapy in the Treatment of Metastatic Pediatric Sarcomas of Bony Sites
Phase: NA
Conditions: Sarcoma, Metastatic Disease, Bony Sites
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

 
  
  
 
 
 
A Phase II Study of Hypofractionated 
Stereotactic Radiotherapy in the 
Treatment of Metastatic Pediatric 
Sarcomas of Bony Sites 
 
 
 
 
 
 
 
NCT01763970 
 
 
 
 
 
 
December 21, 2018 
 

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A Phase II Study of Hypofractionated Stereotactic Radiotherapy in the 
Treatment of Metastatic Pediatric Sarcomas of Bony Sites  
  
Principal Investigator:  
  
Matthew Ladra, MD                                                        
 
  
Johns Hopkins Hospital  
 
  
Department of Radiation Oncology   
 
  
401 N. Broadway, Suite 1440   
 
  
Baltimore, MD 21231  
 
  
Phone: 202-537-4788  
 
  
Fax: (410) 502-1419  
 
 
  
Email: mladra@jhmi.edu    
Coordinating Center:  
  
Johns Hopkins Hospital  
 
  
Sidney Kimmel Comprehensive Cancer Center  
 
  
401 N. Broadway   
 
 
  
Baltimore, MD 21231  
Co-Investigators:  
Nadia N. Laack, MD MS 
Mayo Clinic  
  
  
  
 
Department of Radiation Oncology  
  
 
200 First Street SW  
Matthew J. Krasin, MD  
 
Rochester, MN 55905  
St. Jude Children's Research Hospital  
 
Phone: (507) 284-4561   
Associate Member, Division of Radiation  
 
Fax: (507) 284-0079   
Oncology  
Email: laack.nadia@mayo.edu   262 Danny Thomas Place, Mail Stop 220   Memphis, 
Tennessee 38105-3678  
 
Iris C. Gibbs, MD  
Phone: (901) 595-3565   
 
Stanford University  
Fax: (901) 595-3113   
 
Department of Radiation Oncology  
Email: matthew.krasin@stjude.org  
 
875 Blake Wilbur Drive Clinic D  
  
Phone: (650) 723-6171  
Fax: (650) 725-8231  
 
Email: iris.gibbs@stanford.edu  
  

 
  
  
  
  
  
Table of Contents  
PROTOCOL SUMMARY ............................................................................................................. 5 
SCHEMA ........................................................................................................................................ 5 
1.   OBJECTIVES ........................................................................................................................... 6 
1.1  Primary Objectives ............................................................................................................... 6 
1.2  Secondary Objectives ........................................................................................................... 6 
2.  BACKGROUND ....................................................................................................................... 6 
2.1  Oligometastatic Disease ....................................................................................................... 7 
2.2  Stereotactic Body Radiotherapy (SBRT) ............................................................................. 7 
2.3  Rationale .............................................................................................................................. 7 
3.  PATIENT SELECTION ............................................................................................................ 8 
3.1 Inclusion Criteria .................................................................................................................. 8 
3.2 Exclusion Criteria ................................................................................................................. 8 
3.3  Inclusion of Women and Minorities .................................................................................... 9 
4.    REGISTRATION PROCEDURES ......................................................................................... 9 
4.1   General Guidelines .............................................................................................................. 9 
4.2  Registration Process ............................................................................................................. 9 
5.  TREATMENT PLAN .............................................................................................................. 10 
5.1   Pre-Treatment Procedures ................................................................................................. 10 
5.2   Simulation ......................................................................................................................... 10 
5.3  SBRT Treatment Delivery ................................................................................................. 12 
5.4  General Concomitant Medication and Supportive Care Guidelines .................................. 12 
5.5  Duration of Therapy ........................................................................................................... 13 
5.6  Post-SBRT Follow-up........................................................................................................ 13 
5.7  Duration of Follow-Up ...................................................................................................... 13 
5.8  Criteria for Removal from Study ....................................................................................... 13 
6.  DOSE MODIFICATIONS ....................................................................................................... 13 
7.  ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .................................. 14 
7.1  Adverse Events and Potential Risks .................................................................................. 14 
7.2  Definitions .......................................................................................................................... 15 
7.2.1  Adverse Event (AE) .................................................................................................... 15 
7.2.2  Serious Adverse Event (SAE) ..................................................................................... 15 
7.2.4  Attribution ................................................................................................................... 17 
7.3  Recording and Reporting of Adverse Events ..................................................................... 17 
7.3.1  Reporting Requirements ................................................................................................. 17 
8.  STUDY CALENDAR ............................................................................................................. 20 
9.  MEASUREMENT OF EFFECT .............................................................................................. 22 
9.1  Antitumor Effect – Solid Tumors ...................................................................................... 22 
10.  DATA REPORTING ............................................................................................................. 25 

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10.1   Data Collection and Submission ..................................................................................... 25 
11.   DATA SAFETY MONITORING ......................................................................................... 25 
11.1   Monitoring Plan .............................................................................................................. 25 
11.2 Stopping Rules .................................................................................................................. 26 
12.  REGULATORY CONSIDERATIONS ................................................................................. 27 
12. 1  Protocol Review and Amendments ................................................................................. 27 
12.2  Informed Consent ............................................................................................................. 27 
12.3  Ethics and Good Clinical Practice (GCP) ........................................................................ 27 
12.4  Study Documentation ....................................................................................................... 28 
12.5  Records Retention ............................................................................................................ 28 
12.6  Multi-center Guidelines ................................................................................................... 28 
13.  STATISTICAL CONSIDERATIONS ................................................................................... 29 
13.1   Study Design/Endpoints .................................................................................................. 29 
13.2  Sample Size/Accrual Rate ................................................................................................ 30 
13.3   Analysis of Secondary Endpoints ................................................................................... 30 
13.4 Reporting and Exclusions ................................................................................................. 31 
14.  REFERENCES ...................................................................................................................... 33 
APPENDIX A ............................................................................................................................... 35 
APPENDIX B ............................................................................................................................... 36 
APPENDIX C – BRIEF PAIN INVENTORY FORM ................................................................ 37 
APPENDIX D – DOSE CONSTRAINTS .................................................................................... 39 
APPENDIX E – PERFORMANCE STATUS CRITERIA – LANSKY PERFORMANCE 
SCALE ......................................................................................................................................... 41 
APPENDIX F - 10 POINT VISUAL ANALOG SCALE ............................................................ 42 
 
  
SUMMARY OF CHANGES  
  
Protocol  
Revision  
Date  
Protocol  
Revision  Description of Change  
8/26/2014  
1.0  
Transcription Error Reconciliation  
8/16/2016  
2.0  
Adding Sibley Memorial Hospital   
  
  
  
 
 

 
  
  
PROTOCOL SUMMARY  
  
Patient with pediatric sarcoma who have limited metastases are still potentially curable with 
aggressive local therapy. However, conventional moderate dose radiation is unlikely to provide 
durable local control. Given the recent technologic advances in radiation delivery, it is now 
possible to deliver tumoricidal doses, using stereotactic body radiotherapy (SBRT) over a short 
time course with highly focal techniques. Stereotactic radiation has proven efficacious in the 
intracranial setting and in multiple extracranial sites in adults. It has not yet been well studied in 
the pediatrics population where there is a particularly strong rationale due to the ablative doses 
that can be delivered to tumor while simultaneously reducing high dose to normal tissues. The 
proposed trial is a single arm phase II study to determine the efficacy of SBRT in pediatric 
sarcomas with surgically unresectable metastatic disease. Metastatic sites eligible for treatment 
in this study include bony sites of disease. SBRT will be delivered to each eligible site to a total 
dose of 4000 cGy delivered in 5 fractions of 800 cGy per fractions each day. Following 
completion of SBRT, patients will undergo treatment response assessment with the use of 
diagnostic imaging, clinical examination, and completion of the Brief Pain Inventory to assess 
quality of life. The primary objective of this study is to determine the efficacy of SBRT 
delivered to a dose of 4000 cGy in 5 fractions of 800 cGy each for patients greater than 3 years 
of age and < 40 years of age with metastatic disease of bone secondary to pediatric sarcoma. The 
secondary objectives of this study include describing the toxicity of SBRT with this regimen; 
assessing clinical response rate of each target lesion; assessing long-term clinical outcomes; and 
assessing quality of life following completion of treatment.  For patients with potentially curable 
oligometastatic disease, surgical resection in conjunction with systemic therapy remains the 
standard of care. Patients on this study will be able to receive chemotherapy 2 weeks after 
completion of SBRT. Issues that may limit participation include our inability to assess late 
effects that may not develop till at least 10 years after therapy. For this reason, we will limit the 
population in this study to patients who are surgically unresectable and would be otherwise 
incurable with current standard systemic therapies.    
SCHEMA  
  
  
Confirmation of eligibility/enrollment  
  
  
  
Diagnostic imaging obtained within 4 weeks of simulation  
  
  
  
CT simulation with a 4D CT scan to assess tumor motion for bony lesions that may be subject to 
respiratory motion  
  
  
  

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Tumor volume defined by radiation oncology  
  
  
  
Delivery of SBRT within 3 weeks of simulation  
  
  
  
  
Delivery of SBRT over a maximum treatment duration of 2 weeks  
  
  
  
Treatment response assessment  
  
  
1.   OBJECTIVES  
  
1.1 Primary Objectives  
  
To determine the lesion-specific local control at 6 months of SBRT delivered to a  dose of 
4000 cGy in 5 fractions of 800 cGy each for patients greater than 3 years of age and < 40 
years of age with metastatic disease of bone secondary to pediatric non-rhabdomyosarcoma 
soft tissue or bone sarcoma.  
  
1.2 Secondary Objectives  
  
  
1.2.1  To describe the toxicity of SBRT delivered to a dose of 4000 cGy in 5 
fractions of    
  
800 cGy each for the population enrolled using grading with CTCAE 
v. 4.0  
  
 
  
1.2.2  To assess clinical response rate of each treated site by serial CT assessment   
 
  
(FDG- PET/CT is optional for assessment)  
  
  
  
  
1.2.3  To assess long-term clinical outcomes of this patient population after  
 
completion of SBRT by measuring relapse-free survival and overall survival   
  
1.2.4  
To assess quality of life following completion of SBRT using pre- and post-
SBRT completion of the Brief Pain Inventory form and 10 point Visual Analog scale 
which will be filled out by the patient  
  
  
2. BACKGROUND  
  

 
  
  
2.1 Oligometastatic Disease   
  
Cancer is the second leading cause of death in the United States, primarily due to an inability 
to control metastatic disease. The metastatic capacity of cancers behaves along a spectrum of 
disease progression, such that some tumors have spread widely before clinical detectability 
and others never metastasize. Contained within this spectrum, is an oligometastatic state 
where metastases are limited in number and location. The presence of an oligometastatic 
state was originally proposed by Hellman who suggested that these oligometastatic patients 
would benefit from effective local therapy in addition to systemic therapy (1). In agreement 
with this hypothesis, surgery and chemotherapy for isolated pulmonary metastases can result 
in long term disease-free periods (2). Additionally, some 25% of patients following resection 
and chemotherapy for colorectal cancer and isolated liver metastases can similarly have 
longterm disease free survival (3-5). Patients who may benefit most from curative therapy 
are most likely those patients with limited systemic disease when metastatic disease is 
generally confined to a lesion state of five metastatic sites or fewer.   
  
2.2 Stereotactic Body Radiotherapy (SBRT)  
The treatment of metastases depends on multiple factors including 1) the location of the 
primary tumor, 2) the presence or absence of other metastatic foci, 3) the size, number and 
location of metastases, 4) the effectiveness of various forms of therapy, and 5) the patient’s 
functional status.  Conventional moderate dose radiation for metastatic disease is given 
primarily for palliation. Recent advances in radiation delivery now make it possible to image 
and treat precisely within any anatomical region of the body. As a result, the capacity to 
deliver tumoricidal doses in a single or few (1-10) outpatient treatments is now possible. In 
addition, by minimizing the irradiation of surrounding healthy tissue, it should also be 
possible to decrease the rate of complications. Intracranial stereotactic radiation therapy has 
been shown to be a highly effective treatment for brain metastases in both the adult and 
pediatrics population (6,7). This suggests that selective small extracranial tumors may be 
effectively controlled by similar focal high-dose stereotactic body radiotherapy (SBRT). 
Local control in excess of 75% has been reported using extracranial SBRT for metastatic 
tumors of the spine, lung and liver, which is significantly higher than conventional moderate 
dose radiation (8-24). Toxicity has been minimal in these reports despite the use of very high 
biological equivalent doses (8-24).   
  
2.3 Rationale  
  
    The SBRT literature focuses on clinical outcomes in the adult population. However, SBRT   
 
has a particularly strong rationale for application in pediatrics given that high biologically  
effective doses have been shown to increase control in histologies, such as sarcoma, which    are 
common in the pediatrics population (11,25). With stereotactic radiation therapy        
      techniques, a reduction in normal tissue dose surrounding the target lesion of interest may  
also be accomplished resulting in lower toxicity. Given that pediatric patients with sarcomas,  
presenting with limited metastases  in lung and bone, are still considered to be a curable       

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population with aggressive local therapy, SBRT could have a significant impact on outcomes  
in oligometastatic patients who may be otherwise unresectable (25-28).   
  
  
3. PATIENT SELECTION  
  
3.1 Inclusion Criteria  
  
3.1.1  Patients must have histologically or cytologically confirmed 
nonrhabdomyosarcoma of soft tissue or bone at any site  
  
3.1.2  Patients must have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm with conventional techniques or as >10 mm with spiral 
CT scan within 4 weeks of treatment start.  See Section 9.1.3 for the 
evaluation of measurable disease.   
  
 
  
3.1.3 Greatest tumor dimension of all sites must be ≤ 5.0 cm or <250 cm3  
  
  
  
3.1.4 There is at least 1 metastatic site at one or more of the following sites: 
spine or non-spine bone and at maximum 5 sites can be treated on protocol   
  
  
  
3.1.5 Surgically unresectable site as determined by tumor board or surgeon  or 
patients who decline surgery.  
  
 
  
3.1.6 Patients must be greater than 3 years of age and ≤ 40 years of age.  
  
 
3.1.7  Life expectancy of at least 9 months  
  
 
3.1.8  Lansky performance status > 50 (See Appendix E)  
  
  
3.1.9  Ability to understand and the willingness to sign a written informed consent 
document and if a minor, have a guardian who meets the above criteria.   
  
 3.2 Exclusion Criteria  
  
3.2.1  Patients who have had chemotherapy or radiotherapy within 2 weeks prior to 
starting radiation treatment   
  
  
 
3.2.2  Patients who have had any prior radiotherapy to the treatment site(s).  
  

 
  
  
      3.2.4  A patient may not participate in a concurrent treatment protocol. All patients  
will be eligible to receive chemotherapy alone, systemic therapeutic agents, or 
conventional chemo-radiotherapy at the time of clinical or radiographic 
disease progression or at 2 weeks following completion of SBRT.  
  
  
3.2.5  Pregnant women are excluded from this study because radiation treatment has 
known potential for teratogenic or abortifacient effects.    
  
      3.2.6  Refusal to take a pregnancy test prior to treatment if the patient is a woman   
 
  
with child bearing potential.  
        
  
  
      3.2.7    Patients with a rhabdomyosarcoma will be excluded due to the 
radiosensitive    
  
  
  
nature of their disease.   
  
3.3 Inclusion of Women and Minorities  
  
Both men and women and members of all races and ethnic groups are eligible for this 
trial.    
  
  
 
4.    
REGISTRATION PROCEDURES  
  
 
4.1   
General Guidelines   
Institutions will register eligible participants with the Coordinating Center. Registration 
must occur prior to the initiation of therapy.  
  
A member of the study team will confirm eligibility criteria and complete the 
protocolspecific eligibility checklist.  
  
Participants should begin protocol treatment within 3 weeks from simulation. Issues that 
would cause treatment delays should be discussed with the Principal Investigator. If a 
patient does not receive protocol therapy following registration, the Study Coordinator 
should be notified as soon as possible.  
  
 
4.2  
Registration Process  
  
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an 
IRB approved consent form. All patients must be registered centrally at the Johns 
Hopkins Sidney Kimmel Comprehensive Cancer Center.  
   
To register a patient, the following documents should be completed and faxed or e-mailed 
to the Coordinating Center:  

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• 
Signed patient consent form  
• 
HIPAA authorization form  
• 
Completed and signed eligibility checklist  
• 
De-identified copies of source documentation verifying eligibility  
  
The Coordinating Center will review the documents to confirm eligibility. To complete 
the registration process, the Coordinating Center will:  
• 
assign a patient study number  
• 
register the patient on the study with the Sidney Kimmel Comprehensive Cancer 
Center’s Clinical Research Office  
• 
fax or e-mail the patient study number to the participating site  
  
  
 
5.  TREATMENT PLAN  
  
Treatment will be administered on an outpatient basis.  Expected toxicities and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 
6. No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the patient’s malignancy concurrently.  
  
 
  
5.1  
 Pre-Treatment Procedures  
  
The following will be completed prior to radiation initiation:  
• 
Medical history and clinical examination  
• 
Pathologic confirmation of malignancy  
• 
CBC, chemistry panel   
• 
CT of treatment site (not required if MRI is obtained)  
• 
MRI of treatment site, optional depending on site (required for spinal  
lesions)  
• 
Positron Emission Tomography (FDG-PET) scan (optional)  
  
  
 
  
5.2   
Simulation  
  
Stereotactic radiation requires meticulous definition of the target, normal tissue 
structures, and visualization for localization during treatment delivery. Prior to 
treatment, a simulation CT scan will be performed for tumor localization using 
rigid immobilization appropriate for stereotactic treatment. A separate FDG-
PETCT or MRI is optional for diagnostic purposes  and can be used for treatment 
planning with fusion -- this study would be done  identically if the patient were 
having standard fractionated radiation. These studies can assist with delineation 
of the target and visualization for stereotactic treatment. While MRIs are optional 
for diagnostic evaluation and treatment planning of non-spine bony sites, they are 
required for patients who will be treated to the spine.   
  

 
  
  
Patients will be positioned in a reproducible treatment position with an 
appropriate immobilization device custom-made for each patient and specific to 
treatment site. A variety of immobilization systems can be used on study such as 
stereotactic frames which surround the patient on three sides or large rigid pillows 
that reference to a stereotactic coordinate system.   
  
CT simulation will be performed. The simulation study must include the target 
and all organs at risk for treatment planning. Simulation scan length should be 
510 cm superior and inferior to the target. All organs at risk within the scan length 
should be contoured for dose-volume histogram analysis. For stereotactic 
treatment, tomographic slice thickness of 1-3 mm through the target is 
recommended.   
  
Special consideration should be given to the analysis of internal organ motion if 
the target lesion is located in a site subject to motion such as the chest wall. 
Techniques to image moving targets such as active breath-hold techniques, 
accelerator gating with respiratory cycle, tumor tracking, 4D CT scan acquisition 
in conjunction with maximum intensity projection (MIP), will be considered 
acceptable maneuvers to account for organ motion. If the target cannot be 
visualized or localized on the planning imaging modality as a result of motion or 
metal artifact, stereotactic treatment should not be used.      
  
The treating radiation oncologist will identify the location of the tumor.  Gross 
tumor volume (GTV) delineation will be performed with a diagnostic radiologist 
on sequential axial computed tomography images. A radiosurgical treatment plan 
will be developed based on tumor geometry and location. Adjacent normal 
structures including but not limited to the heart, esophagus, aorta, spinal cord, 
kidneys, rectum, bowel, liver, and stomach within 5 cm of the GTV will be 
identified for the purpose of limiting incidental radiation to these structures 
(please see Appendix D for a list of normal tissue dose constraints to be used on 
protocol as well as constraints for high and low-dose spillage).  
We plan to deliver 800 cGy at each fraction for five fractions every day for a total   
  
  
        
dose of 4000 cGy, over a treatment duration at a maximum of 2 weeks. For 
bony    
  
  
  
sites aside from spine, the GTV will be expanded uniformly to 
the PTV by 2 mm    
  
  
  
and treated to 4000 cGy to cover at least 90% of 
the defined target volume. For      
  
  
patients with spinal metastases 
undergoing treatment    
  
  
  
on protocol, the vertebral body will be 
contoured as a separate clinical target      
       
volume (CTV) encompassing the GTV. 
The CTV vertebral body will be    
  
  
  
expanded by 2 mm to create a 
PTV. The GTV will be treated to 4000 cGy and the    
  
  
  
PTV treated to 
3000 cGy in 5 fractions..   
  
        
The main criteria for dose prescription will be the achievement of the spinal 
cord                      dose constraint (see table below):  

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Normal 
Tissue  
Volume  
Volume  
Max (cGy)  
Max Point Dose  
(cGy)  
Endpoint  
(≥Grade 3)  
Spinal 
Cord  
<0.25 cc  
<1.2 cc  
1550cGy   
1000cGy   
2000cGy (400cGy  
/fx)  
Myelitis  
  
The spinal cord will be contoured as the true cord with use of MRI for fusion.       
Spinal cord volume will be defined as 6 mm above and below the radiosurgery target 
volume. The spinal cord can move within the thecal sac.  The thecal sac will be 
contoured based on T2 MRI or bony limit of spinal canal and will serve as a PRV 
(planning organ at risk volume) for the spinal cord. Thecal sac volume will be defined 
as 6 mm above and below the radiosurgery target volume. The skin will be defined as 
the outer 0.5 cm of the body surface. The skin is essentially a rind of 0.5 cm 
enveloping the entire body in axial planes. The cranial and caudal surface of the 
superior and inferior limits of the planning CT should not be contoured as skin unless 
skin is actually present in these locations. Ribs within 5 cm of the PTV should be 
contoured by outlining bone and bone marrow. The intercostal spaces should not be 
included as part of the ribs.  The minimum, mean, and maximum dose to the PTV will 
be reported. Only < 1 cc or < 1-5% of unspecified tissue outside of the PTV can 
receive > 100-110% of the prescribed dose.   
  
 
  
5.3  
SBRT Treatment Delivery  
  
All patients should receive 5 fractions of 800 cGy over a five-day period (See Section 
6 for dose modification). Ideally all 5 fractions should be delivered Monday through 
Friday, however it may be delivered over two weeks.  
  
Within three weeks of the initial treatment planning imaging study, SBRT will be 
administered using image-guidance. This protocol allows conventional linear 
accelerators and specialized linear accelerators with image guidance (e.g. Novalis, 
Trilogy, Synergy, Artiste) capable of conformal dose delivery and IMRT. Specialized 
accelerators (e.g. Cyberknife or Tomotherapy) are also allowed.   
  
During treatment, real time cone beam CT images of the patient’s body site of interest 
will be obtained. Cone beam CT scan will be obtained immediately prior to treatment 
and will be repeated until the treatment shift, required to align the CT planning scan 
and the cone beam CT scan performed on the day of treatment, is within 2 mm.    
  
Anesthesia or sedation may be required in certain patients, such as very young 
patients, to prevent movement during simulation and daily treatments. Anesthesia will 
be delivered by a dedicated pediatric anesthesiologist.  
  
 
5.4  
General Concomitant Medication and Supportive Care Guidelines  
  

 
  
  
There are no known potential interactions between SBRT and concomitant 
medications.  
  
 
5.5  
Duration of Therapy  
  
In the absence of treatment delays due to adverse event(s), treatment may continue 
for 2 weeks or until one of the following criteria applies:  
  
  
• 
Disease progression,  
• 
Intercurrent illness that prevents further administration of treatment,  
• 
Unacceptable adverse event(s),  
• 
Patient or parent/guardian (for minors) decides to withdraw from the study, or  
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator.  
  
 
5.6   
Post-SBRT Follow-up  
  
Subsequent to SBRT, patients will be monitored as follows: 5.6.1 
 
4 Weeks Post-SBRT  
 
5.6.2  At 3, 6, 9, 12, 18, 24, 30, and 36 months Post-SBRT  
  
 
5.7   
Duration of Follow-Up  
  
It is anticipated the patients that remain on-study will be followed for 3 years.  
Patients will remain enrolled on this protocol until there is evidence that their disease 
has progressed either locally or distally, at which case they will be removed from the 
protocol and be followed for survival only.  Patients removed from study for 
unacceptable adverse events will be followed per protocol until resolution or 
stabilization of the adverse event and then followed for survival only.  
  
 
5.8  
Criteria for Removal from Study  
  
Patients 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 patient was removed must be 
documented in the Case Report Form.  
  
  
 
6.  DOSE MODIFICATIONS  
In young children less than 10 years of age where the study dose is not considered safe to 
deliver as a result of the radiation dose that will be delivered to surrounding normal tissues, a 
dose of 3500 cGy delivered in 700 cGy fractions in 5 fractions every day to the GTV, will be 
allowed as a prescription dose. A dose modification may be made at the discretion of the 
treating physician but the Principal Investigator must be informed and approve this change.  

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7.  ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
  
 
  
7.1  
Adverse Events and Potential Risks  
  
Because patients are receiving standard treatments, which are not part of this study, 
their treating physician will be counseling them on the risk of their treatments, 
including the risk of surgery, radiation therapy, and/or chemotherapy, whichever is 
appropriate for the type and the stage of their cancer. Clinically significant toxicities 
in the study will include Grade 3, 4, and 5 non hematologic toxicities. The procedures 
related to the study are phlebotomy, CT imaging, MRI imaging, and SBRT. 
Recording and reporting requirements are discussed in Section 7.3.  
  
Risks associated with blood draw:  
Phlebotomy can cause pain, bleeding, and rare needle site infection. CT imaging 
results in low dose radiation exposure, which has an extremely small risk of causing a 
secondary cancer.   
  
  
Risks associated with SBRT:  
It is difficult at this time to predict with confidence the complication rate from the 
proposed SBRT. However, it is reasonable to extrapolate from the current experience 
with SBRT to the spine, lung and pancreas in adults.    
  
Toxicities commonly associated with such treatment will depend on the location of 
the treated metastasis. These toxicities can include skin erythema and desquamation, 
pain, neuropathy, dysphagia, nausea, vomiting, anorexia, and weight loss.  Some of 
these symptoms can also be due to tumor progression. One significant toxicity is 
radiation pneumonitis, which can be manifested as fever, increased excertional 
dypsnea, pleuritic chest pain, and peritumoral infiltrate on chest imaging.  It generally 
occurs between 1 to 3 months of completion of radiotherapy.  The risk of grade 2-4 
radiation pneumonitis is aproximately 10-15% in patients treated with standard 
fractionated large field radiotherapy and higher in patients treated with combined 
chemoradiotherapy.  It is highly dependent on the volume of the lung treated to high 
dose and the mean lung dose.  At this point, the incidence of RT pneumonitis from 
stereotactic radiosurgery for small pulmonary tumors is unknown.  However, if the 
treated tumor volume is kept ≤ 65 cc, the risk should be < 10-15% with the proposed 
dose level. Also, given that this protocol focuses on SBRT to bone and spine, rather 
than lung, the risk of pneumonitis is expected to be low. Fracture is also a potential 
risk of radiotherapy to bone and spine, although doses in this study will be lower than 
the radiosurgery doses thought to put patients at high risk for fracture as reported in 
the literature (29).   
  
  
Growth delay or arrest is a potential late effect of radiotherapy to bone for children 
who have not completed puberty. For this reason, patients in this protocol are limited 

 
  
  
to those who have surgically unresectable disease or to those patients whose families 
refuse surgery. Given the data that demonstrates the improvement in clinical 
outcomes associated with aggressive local therapy in properly selected metastatic 
patients, the potential benefit of delivering a therapeutic dose of radiation likely 
outweighs the risks. The alternative treatment in this scenario is the delivery of 
subtherapeutic doses of radiation with palliative rather than curative intent.  
  
Clinical and radiographic assessments will be performed as indicated to identify all 
adverse effects, ascertain their etiology, and provide the most appropriate palliative 
measures.  Complications other than radiation pneumonitis, if any, will be graded 
according to the CTCAE version 4.0  
  
 
  
7.2  
Definitions  
  
 
  
7.2.1  Adverse Event (AE)  
  
An adverse event (AE) 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.  
  
 
  
7.2.2  Serious Adverse Event (SAE)  
  
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:   
• 
Results in death  
• 
Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form.  
• 
Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned).  

J1367 Protocol Version: December 21, 2018  
16  
• 
Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions.  
• 
Is a congenital anomaly or birth defect; or  
• 
Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
  
Events not considered to be serious adverse events are hospitalizations for:  
• 
routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures  
• 
elective or pre-planned treatment for a pre-existing condition that did not 
worsen  
• 
emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission  
• 
respite care  
  
  
 
7.2.3  Expectedness  
  
Adverse events can be 'Expected' or 'Unexpected.'   
  
 
  
7.2.3.1 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 7.1 for a listing of expected adverse events associated 
with the study agent(s).  
  
 
  
7.2.3.2 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.    
  

 
  
  
 
  
7.2.4  Attribution  
  
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows:  
  
• 
Definite – The AE is clearly related to the study treatment.  
• 
Probable – The AE is likely related to the study treatment.  
• 
Possible – The AE may be related to the study treatment.   
• 
Unlikely - The AE is doubtfully related to the study treatment.  
• 
Unrelated - The AE is clearly NOT related to the study treatment.  
  
 
7.3  
Recording and Reporting of Adverse Events  
  
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.   
  
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record. Low grade toxicities are to be 
expected given the disease profile. Any toxicity below CTCAE v4.0 grade 3 will not be 
reported on the Master AE Log or Case Report Forms. However, this information will 
be monitored and retained in patient charts.   
  
Hematologic toxicity will be assessed and monitored but not reported.  
  
Hospitalization events occur within this patient population. Hospitalizations that occur 
greater than 30 days from completion of SBRT and that are not attributable to research 
intervention will be recorded on the Master AE Log and reported at the time of 
continuing review and SMC monitoring.  
  
These parameters are drafted in accordance with CFR21, though provide realistic 
expectations based on the sickness of this patient population.  
  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at:  
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
  
  
 
  
  
7.3.1  Reporting Requirements  
  
 
7.3.1.1  
Adverse Events Reports  
  

J1367 Protocol Version: December 21, 2018  
18  
The Coordinating Center is the central location for the collection and 
maintenance of documentation of adverse events and is responsible for 
submitting adverse event reports to the Protocol Chair promptly.  The 
Coordinating Center will maintain documentation of all adverse event reports 
for each participating site.  Adverse event reports submitted to the 
Coordinating Center must be signed and dated by the participating site’s 
Principal Investigator.  The Coordinating Center will provide appropriate 
forms to be used by all participating sites for reporting adverse events.   
Information to be provided must include:  
• 
Subject ID number, and initials  
• 
Date of the event  
• 
Description of the event  
• 
Description of site's response to the event  
• 
Assessment of the subject's condition  
• 
Subject's status on the study (on study, off study, etc.)  
• 
Attribution of event to study treatment  
  
 
7.3.1.2  
Participating Sites  
  
Participating sites are responsible for reporting adverse events to their IRB 
according to its specific requirements and to the Coordinating Center as 
follows:  
  
Fatal Events whether anticipated or unanticipated, and whether or not related 
to the study must be reported to the Coordinating Center within 24 hours of 
the participating site Principal Investigator's learning of the event.  
  
Serious and Unanticipated Adverse Events as defined above must be 
reported to the Coordinating Center within 24 hours of the participating site 
Principal Investigator's learning of the event.   
  
Other Serious Adverse Events which may result in a change to the protocol, 
informed consent, or risk to subjects as specified in the protocol must be 
reported within three (3) working days of the participating site Principal 
Investigator's learning of the event.   
  
Adverse Events which result in no change to protocol, informed consent, or 
risk to subjects must be reported to the Coordinating Center on a monthly 
basis.   
  
Adverse event reports are to be faxed or e-mailed to the Coordinating Center 
Study Coordinator. Follow-up reports are faxed, mailed, or sent electronically 
to the Coordinating Center as necessary.  
  

 
  
  
The investigator must also report follow-up information about SAEs within 
the same time frames.  
  
If a non-serious AE becomes serious, this and other relevant follow-up 
information must also be provided within the same time frames described 
above.  
  
All SAEs must be collected whether or not they are considered causally 
related to the investigational product.  Investigators and other site personnel 
are responsible for reporting all casually related SAEs to their IRB and the 
Protocol Chair.  
  

 
 
J1367 Protocol Version: December 21, 2018  
 
8.  STUDY CALENDAR  
  
Note that the study calendar is based on the ideal subject. The schedule should be followed as closely as realistically possible, but may be 
modified due to problems such as scheduling delays, conflicts such as clinic closure or poor weather conditions, or other unforeseeable 
events.  
  
Pre-Study1  
SBRT3,9  
Follow-up (in time Post-RT)  
4 weeks  
(± 7 days)  
3 mo6  
6 mo6  
9 mo6  
12 mo6  
18 mo7  
24 mo7  
30 mo7  
36 mo7  
 
Informed Consent  
X  
  
  
  
  
  
  
  
  
  
  
Demographics  
X  
  
  
  
  
  
  
  
  
  
  
Medical History  
X  
  
  
  
  
  
  
  
  
  
  
Physical Exam  
X  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Height  
X  
  
  
  
  
  
  
  
  
  
  
Weight & Vitals  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Performance Status  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Biopsy-confirmed sarcoma  
X  
  
  
  
  
  
  
  
  
  
  
Treatment planning scan  
X  
  
  
  
  
  
  
  
  
  
  
CBC w/ diff, plts, CMP  
X4  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
CT of treatment site  
X8  
  
  
X  
X  
X  
X  
X  
X  
X  
X  
MRI  
X5  
  
  
X11  
X11  
X11  
X11  
X11  
X11  
X11  
X11  
FDG-PET (optional)  
X  
  
  
X11  
X11  
X11  
X11  
X11  
X11  
X11  
X11  
Tumor measurements  
X  
  
  
X  
X  
X  
X  
X  
X  
X  
X  
Pregnancy test2  
X  
  
  
  
  
  
  
  
  
  
  
Pain Assessments10  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Toxicity Assessment  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
1Pre-SBRT assessments  should be performed within 4 weeks of radiation treatment  
2Pregnancy test by urine or serum, for women who are not post-menopausal as defined in Appendix A  
Follow for survival 
 

 
 
3Patients will receive SBRT over a five-day period. Ideally all 5 fractions should be delivered Monday through Friday, however it may be delivered over two weeks  
4Within 1 week prior to radiotherapy  
5Optional depending on treatment site  
6 Follow-up should occur +/- 14 days  
7 Follow-up should occur +/- 30 days  
8CT scan must be performed within 4 weeks prior to the start of therapy, not required if MRI is obtained.    
9 Patients will be able to receive chemotherapy 2 weeks after the completion of SBRT.  
10 Brief Pain Inventory (Appendix C) and 10 point Visual Analog Scale (Appendix F); given the age population, the completion of these assessments may not be possible 
and therefore are optional for subjects under 18 years of age  
11Follow-up PET/CT and MRI are at the discretion of the treating physician and are optional  
  
19  

J1367 Protocol Version: December 21, 2018  
  
22  
 
9.  MEASUREMENT OF EFFECT  
 
9.1  
Antitumor Effect – Solid Tumors  
  
For the purposes of this study, patients should be re-evaluated for response 4 weeks 
after the initial treatment, every 3 months for the first year, and every 6 months for 
the second and third year.    
  
 
  
  
9.1.1  Definitions  
  
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with SBRT.  
  
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, have completed all fractions of SBRT, and have had 
their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end 
of SBRT will also be considered evaluable.) Evaluable patients will also be those 
who received the protocol-specified dose.   
  
 
  
9.1.2  Disease Parameters  
  
Measurable disease.  Measurable lesions are defined as those that can be  
accurately measured in at least one dimension (longest diameter to be recorded) as 
>10 mm with diagnostic techniques (CT, FDG-PET/CT, or MRI). All tumor 
measurements must be recorded in millimeters (or decimal fractions of 
centimeters).   
  
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm with diagnostic techniques), are considered 
non-measurable disease. Leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal 
masses (not followed by CT or MRI), and cystic lesions are all non-measurable.  
  
Target lesions.  Target lesions in this study will be considered metastatic sites up 
to a maximum of 5 lesions per patient. They should be recorded and measured at 
baseline. Target lesions should be larger than 10 mm in the smallest 
crosssectional diameter on CT or MRI and/or any lesion that shows increase 
metabolic uptake on FDG-PET/CT scans.   
  
Non-target lesions.  N/A  
  
 
  
9.1.3  Methods for Evaluation of Measurable Disease  

J1367 Protocol Version: December 21, 2018  
  
 23  
  
  
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment.  
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment.  
  
Conventional CT, FDG-PET/CT, and MRI These techniques should be performed 
with cuts of 10 mm or less in slice thickness contiguously.  Spiral CT should be 
performed using a 5 mm contiguous reconstruction algorithm.  This applies to 
tumors of the chest, abdomen, and pelvis.  Head and neck tumors and those of 
extremities usually require specific protocols.  
  
 
  
9.1.4  Response Criteria  
  
9.1.4.1 Response Assessment of Bone Metastases  
  
Radiographic assessment of bone metastasis can be difficult as remodeling bone 
may lead to residual abnormalities on bone scan, CT scan, and MRI scan. This 
leads to inherent difficulties in using RECIST 1.1 criteria for response 
assessment. For the purposes of the current protocol, response at bone metastasis 
will be graded as follows:  
  
Complete response (CR) = A negative FDG-PET at the irradiated lesion in 
patients who have a positive FDG-PET at the time of SBRT at the target lesion. 
FDG-PET is optional on study. Therefore, CR will be recorded but not required to 
constitute a response.  
  
Progressive disease (PD) = Any of the following will constitute PD:  
  
• Development of a new soft tissue mass > 1 cm in maximum axial dimension at 
a previous site of bone metastasis without a soft tissue component or with a soft 
tissue component < 1 cm in maximum axial dimension on previous evaluations.  
  
• For bone metastasis with a soft tissue component > 1 cm in maximum axial 
dimension on previous evaluations, an increase in the longest axial diameter of 
the soft tissue component by > 20%.   
  
• A previous bone metastasis that was positive on FDG-PET, became negative 
with protocol therapy, and then becomes positive again should prompt concern 

J1367 Protocol Version: December 21, 2018  
  
 24  
  
for progression at that site. Confirmatory testing is required to document 
progression at a previous site of bone metastasis. Together with return of FDG-
PET uptake, MRI scan with documentation of an enhancing bone lesion will 
constitute adequate evidence to support progression at that site. Biopsy is 
strongly encouraged, but not required to confirm progression at a previous site 
of bone metastasis.   
  
• Biopsy evidence of viable sarcoma at a previously radiated bone metastasis.  
Stable disease (SD) = Patients not meeting either CR or PD criteria.  
  
 
  
9.1.4.2 Evaluation of Best Overall Response  
  
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started).  Best overall response will be based on the overall 
response of the target lesions.  
  
 
  
9.1.5  
Duration of Response  
  
Duration of overall response:  The duration of overall response is measured from 
the start of the treatment until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the treatment started.   
  
 
  
9.1.6  
Clinical Response Parameters  
  
Progression-free survival (PFS) is defined is the time from starting treatment to 
the time of first documented tumor progression or death due to any cause, 
whichever occurs first. Death is considered as an event here. For subjects whose 
disease does not progress or who do not die, PFS will be censored at the time of 
the last visit.  
Time to progression (TTP) is defined as the time from starting treatment to the 
time of first documented tumor progression. Subjects who do not progress will be 
censored at the time of the last contact. In addition, death from any cause will also 
be censored.    
Overall survival (OS) is defined as the time from starting treatment until death 
due to any cause. For subjects who do not die, time to death will be censored at 
the time of last contact.  
Local Control (LC) is defined as the time from starting treatment until local 
relapse is documented. The target lesion will be considered locally controlled if 
criteria for progression are not met, taking as reference the smallest measurements 
recorded since the treatment started.   

J1367 Protocol Version: December 21, 2018  
  
 25  
  
  
  
10. DATA REPORTING  
  
 
10.1   Data Collection and Submission  
  
Data and/or completed Case Report Forms (CRFs) must be transmitted by fax or 
email to the Coordinating Center. Case report forms will be provided to the 
participating sites by the Coordinating Center.  
  
  
  
  
The schedule for completion and submission of Case Report Forms to Johns Hopkins 
is as follows:  
  
Form  
Submission Timeline  
Eligibility Checklist  
Complete prior to registration  
On-Study Form  
Within 14 days of registration  
Baseline Assessment Form  
Within 14 days of registration  
Treatment Form  
Within 10 days of treatment completion  
Adverse Event Report Form  
Within 14 days of visit date  
Response Assessment Form  
Within 14 days of visit date  
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  
  
  
The composite volumetric radiation therapy treatment plan will be submitted in a 
DICOM format to the Radiation Oncology PI (as feasible) in a manner determined 
appropriate for each participating institution. This information will include:  
 DICOM RT dataset (structures, targets, dose, CT simulation study)  
Copy of the total dose records (treatment chart)  
  
11.  DATA SAFETY MONITORING  
  
 
  
11.1   Monitoring Plan  
  
This is a Level I  study under the SKCCC Data Safety Monitoring Plan.  Data Monitoring 
of this protocol will occur on a regular basis with the frequency dependent on the rate of 
subject accrual and the progress of the study.  The protocol will be monitored internally 

J1367 Protocol Version: December 21, 2018  
  
 26  
  
at SKCCC by Matthew Ladra, MD and externally by the SKCCC CRO in accordance 
with SKCCC guidelines.  Trial monitoring and reporting will be done through the Safety 
Monitoring Committee at SKCCC.  
  
Authorized representatives of the Coordinating Center may visit participating sites to 
perform audits or inspections, including source data verification.  The purpose of these 
audits or inspections is to systematically and independently examine all trial related 
activities and documents to determine whether these activities were conducted and data 
were recorded, analyzed, and accurately reported according to the protocol, Good 
Clinical Practice (GCP), and any applicable regulatory requirements.  
  
11.2 Stopping Rules  
  
The study will enroll 20 patients and toxicity will be monitored continuously throughout. 
Any Grade 5 toxicity that is possibly related to radiation will suspend accrual until the 
study chair reviews the case. The criteria for severe adverse events to be considered 
clinically significant toxicities are presented in Section 7.1. We established a safety 
monitoring rule that will recommend stopping the study if there appears to be high 
probability that the adverse event (AE) rate is convincingly above 30%. Specifically, if 
the posterior probability of the AE rate exceeding 30% is 65% or greater, we will 
consider stopping the study for safety consultation. The prior distribution for the risk of 
AE is beta (0.5, 3.5), representing our prior guess at the AE rate is 12.5% on average and 
there is 90% certainty that it is between 0.05% and 45%. The stopping rules and 
corresponding operating characteristics based on 5000 simulations are shown in the 
tables below.  
  
Suspend 
enrollment if  
3 AEs  4 AEs  5 AEs  6 AEs  7 AEs  8 AEs  
Out of N  
3-5  
6-8  
9-11  
12-14  15-17  18-20  
  
True risk of AE  
Probability declare 
treatment unsafe  
Average 
sample size  
0.20  
13.7%  
18.2  
0.25  
25.6%  
16.8  
0.30  
41.2%  
15.0  
0.35  
57.6%  
13.2  
0.40  
73.7%  
10.9  
0.45  
84.7%  
9.3  
0.50  
92.2%  
7.6  
  
  

J1367 Protocol Version: December 21, 2018  
  
 27  
  
12. REGULATORY CONSIDERATIONS  
  
 
12. 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 Coordinating Center will disseminate protocol amendment 
information to all participating institutions.   
All decisions of the IRB concerning the conduct of the study must be made in writing.  
  
 
12.2  
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 an 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 research file.  
  
 
12.3  
Ethics and Good Clinical Practice (GCP)  
This study is to be conducted according to the following considerations, which 
represent good and sound research practice:  
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf   
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki o Title 21 
Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html  
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html   
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html   
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  It is 
understood that deviations from the protocol should be avoided, except 
when necessary to eliminate an immediate hazard to a research 

J1367 Protocol Version: December 21, 2018  
  
 28  
  
participant. In such case, the deviation must be reported to the IRB 
according to the local reporting policy.   
  
 
12.4  
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.  
   
 
12.5  
Records Retention  
  
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.   
  
 
12.6  
Multi-center Guidelines  
  
  
  
 
  
  
12.6.1 Protocol Chair  
  
 
  
The Protocol Chair is responsible for performing the following tasks:  
• 
Coordinating, developing, submitting, and obtaining approval for the protocol 
as well as its subsequent amendments.  
• 
Assuring that all participating institutions are using the correct version of the 
protocol.  
• 
Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study.  
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAE)  
• 
Reviewing data from all sites.  
  
 
  
  
12.6.2 Coordinating Center  
  
The Coordinating Center is responsible for performing the following tasks:  
• 
Ensuring that IRB approval has been obtained at each participating site prior 
to the first patient registration at that site, and maintaining copies of IRB 
approvals from each site.  
• 
Managing central patient registration.  
• 
Collecting and compiling data from each site.  

J1367 Protocol Version: December 21, 2018  
  
 29  
  
• 
Establishing procedures for documentation, reporting, and submitting of AE’s 
and SAE’s to the Protocol Chair, and all applicable parties.  
• 
Facilitating audits by securing selected source documents and research records 
from participating sites for audit, or by auditing at participating sites.  
  
 
  
12.6.3 Participating Sites  
  
 
  
  
Participating sites are responsible for performing the following tasks:  
• 
Following the protocol as written, and the guidelines of Good Clinical 
Practice (GCP).  
• 
Submitting data to the Coordinating Center.  
• 
Registering all patients with the Coordinating Center by submitting patient 
registration form, and signed informed consent promptly.  
• 
Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the 
protocol.  
• 
Maintaining regulatory binders on site and providing copies of all required 
documents to the Coordinating Center.  
• 
Collecting and submitting data according to the schedule specified by the 
protocol.  
   
 
13.  
STATISTICAL CONSIDERATIONS   
  
 
13.1  
 Study Design/Endpoints  
  
13.1.1 Definition of primary outcome/endpoint  
  
The efficacy of SBRT delivered with a dose of 4000 cGy in 5 fractions on 800 cGy each 
to pediatric nonrhabdomyosarcoma soft tissue sarcoma or bone sarcoma patients who are 
greater than 3 years of age and < 40 years of age with metastatic disease will be 
determined by measuring local control at 6 months.  
  
13.1.2 Analysis plan for primary endpoint  
  
The primary endpoint of this study will be local control at 6 months of the patient treated  
with SBRT. Given the inherent difficulties in defining response in bony lesions after 
radiotherapy by RECIST 1.1 criteria, local control at the radiated site will be defined as 
the absence of progression of disease as defined in Section 9.1.4.1.  Thus, CR and SD 
will constitute local control. Local control assessment will start at one month following 
completion of protocol treatment and continuous assessment will be pursued during the 
follow-up period. The reference response probability for comparison will be 70%. This is 
based on the study by Kepka et al. (31)  
  

J1367 Protocol Version: December 21, 2018  
  
 30  
  
 
13.2  
Sample Size/Accrual Rate  
  
The primary endpoint of this trial is to estimate the local control of SBRT at 6 months.  
We anticipate that the local control rate will be roughly 90% as opposed to a 70% 
historical response with conventional moderate dose radiation. With 20 subjects 
participated, we will be able to estimate the local control rate to within 20% (i.e., 
maximum width of the 90% confidence interval reached is when the observed rate is 
50%). If we observe a 6-month local control rate of 90%, we will be 90% certain that the 
true rate is greater than 70%. The associated exact 90% confidence interval will be (0.72, 
0.98).     
  
Using a Simon optimal two-stage design with a type I error of 10% and a type II error of 
20%, the first stage would consist of 6 patients. A responder is considered to have local 
disease control at 6 months. If 4 or fewer patients respond, the study would terminate 
after the first stage.  Otherwise, accrual would continue to a total of 20 patients. If 17 or 
more patients respond at the end of the second stage, the regimen with SBRT is 
considered promising (i.e., local control at 6 months is greater than 70%).  This design 
has a 58% chance of early stopping when the true probability of response is 70% (the null 
hypothesis) and 11% chance of early stopping when the true probability of response is 
90%.  
  
The goal of enrollment is 20 patients. Based on the current institutional referral base, we 
expect that 12 patients will be eligible each year. Of these patients, we expect that two 
thirds will enroll on protocol. With this projection, we plan to complete accrual to the 
study in 3 years.    
  
The proportion of patients with local control at six months will be reported with an exact 
binomial 90% confidence interval.  
  
 
13.3   
Analysis of Secondary Endpoints  
  
13.3.1 Definition of secondary outcomes/endpoints:  
• 
To describe the toxicity of SBRT delivered to a dose of 4000 cGy in 5 fractions of  
800 cGy each for the population enrolled using grading with CTCAE v. 4.0  
• 
The clinical response rate of each lesion will be assessed by serial CT assessment 
(FDG-PET/CT is optional for assessment) and defined by criteria as defined 
above. The absence of progression will constitute a response. Therefore, 
lesionspecific CR or SD will be measured as a response.   
• 
To assess long-term clinical outcomes of this patient population after completion 
of SBRT by measuring relapse-free survival and overall survival. Relapse-free 
survival will be measured from time of enrollment to date of disease progression 
or death. Patients who are lost to follow-up will be censored for determination of 

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progression-free survival on the date of their last evaluation. Overall survival is 
defined as time from enrollment to death due to any cause.   
• 
To assess quality of life following completion of SBRT using pre- and post-SBRT 
completion of the Brief Pain Inventory form and 10 point Visual Analog Scale 
which will be filled out by the patient at the treatment response intervals outlined 
above.    
  
13.3.2 Analysis plan for secondary endpoints:  
• 
Toxicities will be graded and tabulated at the time of each follow-up assessment.  
The proportion of toxicities by type and grade will be reported with exact 95% 
confidence intervals.  
• 
Each metastatic lesion will be considered a target lesion and independently 
evaluated for response. The proportion of these lesions that have a stable or better 
response and the intra-cluster correlation will be estimated with an intercept only 
generalized estimating equation (GEE) regression.  This will be estimated directly 
with SAS Genmod by specifying binomial variation, the identity link function, 
and an exchangeable correlation structure.   
• 
Hazard rate estimates and 95% confidence intervals as well as Kaplan-Meier 
(KM) estimates will be used to summarize survival (OS), progression free 
survival (PFS), time to progression (TTP) and locoregional control (LRC) 
functions over time.  The median OS, PFS, TTP and LRC will be reported.  Cox 
proportional hazards models will be used to evaluate the impact of key covariates 
on these endpoints as the sample size permits.    
• 
Quality of life will be assessed using the Brief Pain Inventory form and 10 point 
Visual Analog Scale.  An overall score will be calculated pre-treatment and at the 
time of the 2nd radiologic reassessment. The change in score will be evaluated 
with a Wilcoxon signed-rank test.      
  
13.4 Reporting and Exclusions  
  
13.4.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment with SBRT.  
  
13.4.2 Evaluation of response.  All patients included in the study must be assessed 
for response to treatment, even if there are major protocol treatment 
deviations.  Each patient will be assigned one of the following categories:  1) 
complete response, 2) stable disease, 3) progressive disease, 4) early death 
from malignant disease (defined as death prior to first evaluation after 
completion of SBRT), 5) early death from toxicity, 6) early death because of 
other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of 
any type of data in a clinical database.]  
  

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All of the patients who were enrolled on the trial should be included in the 
main analysis of local control.    
  
All conclusions should be based on all enrolled subjects. Sub-analyses may 
then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to 
other reasons, early discontinuation of treatment, major protocol violations, 
etc.).  However, these sub-analyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding 
patients from the analysis should be clearly reported.  The reason for 
performing subset analyses would be to generate hypotheses for future 
prospective clinical trials.  
  
  
  
  
  
  
  
  
  
 

J1367 Protocol Version: December 21, 2018  
  
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14.  
REFERENCES  
  
1. 
Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995; 13: 8-10.  
2. 
Bacci G, Rocca M, Salone M, et al. High grade osteosarcoma of the extremities with lung 
metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous 
resection of primary and metastatic lesions. J Surg Oncol 2008; 98:415-20.  
3. 
Steele G Jr, Bleday R, Mayer RJ, et al. A prospective evaluation of hepatic resection for 
colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group 
Protocol 6584. J Clin Oncol 1991; 9:1105-12.  
4. 
Fong Y, Cohen AM, Fortner JG et al. Liver resection for colorectal metastases. J Clin 
Oncol 1997; 15: 938-46.  
5. 
Simmonds PC, Primrose JN, Colquitt JL, et al. Surgical resection of hepatic metastases 
from colorectal cancer: A systematic review of published studies. Br J Cancer 2006; 94: 
982-99.  
6. 
Keshavarzi S, Meltzer H, Ben-Haim S, et al. Initial clinical experience with frameless 
optically guided stereotactic radiosurgery/radiotherapy in pediatric patients. Childs Nerv 
Syst. 2009 Jul;25(7):837-44.   
7. 
Lo S, Fakiris A, Adbulrahman R, et al. Role of stereotactic radiosurgery and fractionated 
stereotactic radiotherapy in pediatric brain tumors. Expert Review of Neurotherapeutics 
2008; 8:121-132.  
8. 
Okunieff P, Petersen AL, Philip A, et al. Stereotactic Body Radiation Therapy (SBRT) 
for lung metastases. Acta Oncol 2006; 45:808-17.  
9. 
Schefter TE, Kavanaugh BD, Timmerman RD, et al.: A phase I trial of stereotactic body 
radiation therapy (SBRT) for liver metastases. Int J Radiat Oncol Biol Phys 2005; 
62:1371-78.  
10. 
Kavanaugh BD, McGarry RC, Timmerman RD. Extracranial radiosurgery (stereotactic 
body radiation therapy) for oligometastases. Semin Radiat Oncol 2006; 16:77-84.  
11. 
Levine AM, Coleman C, Horasek S. Stereotactic radiosurgery for the treatment of 
primary sarcomas and sarcoma metastases of the spine. Neurosurgery. 2009 Feb;64(2 
Suppl):A54-9.  
12. 
Lutz ST, Chow EL, Hartsell WF, et al. A review of hypofractionated palliative 
radiotherapy. Cancer 2007 Apr:109:1462-70.  
13. 
Milano MT, Katz AW, Schell MC, et al. Descriptive analysis of oligometastatic lesions 
treated with curative-intent stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 
2008; 72: 1516-22.  
14. 
MacDermed DM, Weichselbaum RR, and Salama JK. A rationale for the targeted 
treatment of oligometastases with radiotherapy. J Surg Oncol. 2008; 98:202-06.   
15. 
Ben-Josef E and Lawrence TS. Using a bigger hammer: the role of stereotactic body 
radiotherapy in the management of oligometastases. J Clin Oncol. 2009 Apr; 1537-38.  
16. 
Niibe Y and Hayakawa K. Oligometastases and Oligo-recurrence: The new era of cancer 
therapy. JJCO 2010; 107-11.  

J1367 Protocol Version: December 21, 2018  
  
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17. 
Niibe Y Kuranami M, Matsunaga K, et al. Value of high-dose radiation therapy for 
isolated osseous metastasis in breast cancer in terms of oligo-recurrence. Anticancer Res. 
2008; 3929-31.  
18. 
Lo SS, Fakiris AJ, Teh BS, et al. Stereotactic body radiation therapy for oligometastases. 
Expert Rev Anticancer Ther. 2009; 621-35.  
19. 
Hamilton AJ, Lulu BA, Fosmire H, et al. Preliminary clinical experience with linear 
accelerator-based spinal stereotactic radiosurgery. Neurosurgery 1995 36(2): 311-19.  
20. 
Gerszten PC, Burton SA, Ozhasoglu C, et al. Radiosurgery for spinal metastases: clinical 
experience in 500 cases from a single institution. Spine 2007 32(2): 193-99.  
21. 
Gibbs IC, Kamnerdsupaphon P, Ryu MR, et al. Image-guided robotic radiosurgery for 
spinal metastases. Radiother Oncol 2007; 82(2): 185-90.  
22. 
Chang EL, Shiu AS, Mendel E, et al. Phase I/II study of stereotactic body radiotherapy 
for spinal metastasis and its pattern of failure. J Neurosurg Spine 2007; 7(2): 151-60.  
23. 
Milano MT, Katz AW, Muhs AG, et al. A prospective pilot study of curative-intent 
stereotactic body radiation therapy in patients with 5 or fewer oligometastatic lesions. 
Cancer 2008; 112(3): 650-58.   
24. 
Ryu S, Fang Y, Rock J, et al. Image-guided and intensity-modulated radiosurgery for 
patients with spinal metastasis. Cancer 2003; 97(8):2013-18.  
25. 
Hauesler J, Ranft A, Boelling T, et al. The value of local treatment in patients with 
primary, disseminated, multifocal Ewing sarcoma (PDMES) Cancer 2010: 443-50.  
26. 
Ladenstein R, Potschger U, LeDeley MC, et al. Primary disseminated multifocal Ewing 
sarcoma: results of the Euro-Ewing 99 trial. JCO 2010: 3284-91.  
27. 
Balamuth NJ, Womer RB. Ewing’s Sarcoma. Lancet Oncol. 2010: 184-92.  
28. 
Paulussen M, Ahrens S, Burdach S, et al. Primary metastatic (stage IV) Ewing tumor:  
survival analysis of 171 patients from EICESS studies. European Intergroup Cooperative 
Ewing Sarcoma Studies. Ann Oncol 1998; 9: 275-81.  
29. 
Laufer I, Rose P, Lis E, et al. An analysis of risk factors for vertebral body fracture 
following high-dose single fraction image-guided intensity modulated radiotherapy (IG- 
IMRT) of spinal metastases. Int J Radiat Oncol Biol Phys 2008; 72(1 Suppl) S52.  
30. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228–247.  
31. 
Kepka L, Delaney T, Suit HD, et al. Int J Radiat Oncol Biol Phys 2005; 63: 852-59.   
32. 
Benedict SH, Yenice KM, Followill D, et al. Stereotactic Body Radiation Therapy: The                 
Report of AAPM Task Group 101.  
  
  
  
  
  
  
  

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Appendix A  
  
Definition of Menopausal Status:  
  
  
Menopausal status will be defined according to the following criteria:  
  
Post-menopausal:  
  
• Woman 60 years of age or older  
• Woman aged 45-59 years with spontaneous cessation of menses for at least 12 
months prior to registration  
• Woman aged 45-59 years with cessation of menses for less than 12 months prior to 
registration AND an FSH level in the postmenopausal range (or >34.4 IU/L if 
institutional range is not available)  
• Woman aged 45-59 years on hormone replacement therapy who have discontinued 
hormone replacement therapy at diagnosis of breast carcinoma and have an FSH 
level in the postmenopausal range according to institutional/laboratory standards (or 
34.4  
IU/L if the institutional range is not available)  
• Prior bilateral oophorectomy  
• Woman younger than 60 years of age who have had a prior hysterectomy (without 
bilateral oophorectomy) AND who have an FSH level in the postmenopausal range 
(or >34.4 IU/L if institutional range is not available)  
  
Pre- or peri-menopausal:  Not meeting definition for postmenopausal as outlined above.  
  
  
  
  
  
  
  
  
  
  

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APPENDIX B  
  
 
Dose Fractionation Schedule  
 
 
   
  
Dose Level  
   
Dose/Fraction (cGy)  
300  
180  
800  
   
Fractions  
10  
28-30  
5  
   
Total  
Dose  
(cGy)  
3000  
50405400 
4000  
Biologic  
Equivalent  
Dose*  
(BED4) 
cGy   
   
5250  
7308-7830  
12000  
Standard Dose for 
Palliation  
  
Standard Dose for 
Definitive RT  
Study Dose  
  
 Biologically Equivalent Dose (BED) Calculation  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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APPENDIX C  Brief Pain Inventory Form  
  

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APPENDIX D  DOSE CONSTRAINTS  
  
Dose Constraints for Five Fractions – Based upon the AAPM Report TG 10132 reduced by 10% 
based on the assumption that patients on protocol have received prior systemic chemotherapy.  
   
  
  
  
  
  
  
  
  
Serial Tissue  
Volume  
Volume Max (Gy)  
Max Point Dose (Gy)  
Endpoint (≥Grade 3)  
Optic Pathway  
<0.2 cc  
18 Gy (3.6 Gy/fx)  
22.5 Gy (4.5 Gy/fx)  
neuritis  
Cochlea  
  
  
24.7 Gy (4.95 Gy/fx)  
hearing loss  
Brainstem  
<1 cc  
23.4 Gy (4.68 Gy/fx)  
31 Gy (6.2 Gy/fx)  
cranial neuropathy  
Spinal Cord  
<0.25 cc  
<1.2 cc  
20.2 Gy (4.05 Gy/fx)  
12.1 Gy (2.43 Gy/fx)  
27 Gy (5.4 Gy/fx)  
myelitis  
Thecal Sac  
<2.5 cc  
<5 cc  
20.2 Gy (4.05 Gy/fx)  
15 Gy (3 Gy/fx)  
30 Gy (6 Gy/fx)  
myelitis  
Cauda Equina  
<5 cc  
27 Gy (5.4 Gy/fx)  
28.8 Gy (5.76 Gy/fx)  
neuritis  
Sacral Plexus  
<3 cc  
27 Gy (5.4 Gy/fx)  
28.8 Gy (5.76 Gy/fx)  
neuropathy  
Rib  
<1 cc  
31.5 Gy (6.3 Gy/fx)  
38.7 Gy (7.74 Gy/fx)  
Pain or fracture  
Esophagus*  
<5 cc  
24.7 Gy (4.95 Gy/fx)  
31.5 Gy (6.3 Gy/fx)  
stenosis/fistula  
Ipsilateral Brachial Plexus  
<3 cc  
27 Gy (5.4 Gy/fx)  
28.8 Gy (5.76 Gy/fx)  
neuropathy  
Heart/Pericardium  
<15 cc  
28.8 Gy (5.76 Gy/fx)  
34.2 Gy (6.84 Gy/fx)  
pericarditis  
Great vessels  
<10 cc  
42.3 Gy (8.46 Gy/fx)  
47.7 Gy (9.54 Gy/fx)  
aneurysm  
Trachea and Ipsilateral Bronchus*  
<4 cc  
16.2 Gy (3.24 Gy/fx)  
34.2 Gy (6.84 Gy/fx)  
stenosis/fistula  
Skin  
<10 cc  
27 Gy (5.4 Gy/fx)  
28.8 Gy (5.76 Gy/fx)  
ulceration  
Stomach  
<10 cc  
25.2 Gy (5.04 Gy/fx)  
28.8 Gy (5.76 Gy/fx)  
ulceration/fistula  
Duodenum*  
<5 cc  
16.2 Gy (3.24 Gy/fx)  
28.8 Gy (5.76 Gy/fx)  
ulceration  
Jejunum/Ileum*  
<5 cc  
17.5 Gy (3.51 Gy/fx)  
31.5 Gy (6.3 Gy/fx)  
enteritis/obstruction  
Colon*  
<20cc  
22.5 Gy (4.5 Gy/fx)  
34.2 Gy (6.84 Gy/fx)  
colitis/fistula  
Rectum*  
<20cc  
22.5 Gy (4.5 Gy/fx)  
34.2 Gy (6.84 Gy/fx)  
proctitis/fistula  
Bladder wall  
<15 cc  
16.4 Gy (3.28 Gy/fx)  
34.2 Gy (6.84 Gy/fx)  
cystitis/fistula  
Penile Bulb  
<3 cc  
27 Gy (5.4 Gy/fx)  
 45 Gy (9 Gy/fx)  
impotence  
Femoral Heads (Right & Left)  
<10 cc  
27 Gy (5.4 Gy/fx)  
  
necrosis  
Renal hilum/vascular trunk  
<2/3 
volume  
 20.7 Gy (4.14 Gy/fx)  
  
malignant hypertension  
Parallel Tissue  
Volume   
Critical Volume Dose   
  
Endpoint (≥Grade 3)  
Lung (Right & Left)  
1500 cc  
11.2 Gy (2.25 Gy/fx)  
  
Basic Lung Function  
Lung (Right & Left)  
1000 cc  
12.1 Gy (2.4 Gy/fx)  
  
Pneumonitis  
Liver  
700 cc  
18.9 Gy (3.78 Gy/fx)  
  
Basic Liver Function  
Renal cortex (Right & Left)  
200 cc  
15.7 Gy (3.15 Gy/fx)  
  
Basic renal function  
*Avoid circumferential irradiation  
  
Guidelines for Spillage   

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High Dose Spillage:  
1. Any dose > 105% of the prescription dose should occur primarily within the PTV itself and not 
within the normal tissues outside the PTV. Therefore, the cumulative volume of all tissue outside 
the PTV receiving a dose > 105% of prescription dose should not be more than 15% of the PTV 
volume.  
2. Conformality of PTV coverage will be judged such that the ratio of the volume of the prescription 
isodose meeting criteria 1 through 4 to the volume of the PTV is ideally < 1.2 (see table below). 
These criteria will not be required to be met in treating very small tumors (< 2.5 cm axial GTV 
dimension or < 1.5 cm craniocaudal GTV dimension) in which the required minimum field size of 
3.5 cm results in the inability to meet a conformality ratio of 1.2.  
  
Low Dose Spillage  
  
1. The falloff gradient beyond the PTV extending into normal tissue structures must be rapid in all 
directions and meet the following criteria:  
a. The maximum total dose over all fractions in Gray (Gy) to any point 2 cm or greater away from 
the PTV in any direction must be no greater than D2cm where D2cm is given by the table below.  
2. The ratio of the volume of 50% of the prescription dose isodose to the volume of the PTV must be  
no greater than R50% where R50% is given. See Table below.  
3. Respect all critical organ dose-volume limits listed above  
  
  
Table 1: Conformality of Prescribed Dose for Calculations Based on Deposition of Photon Beam 
Energy in Heterogeneous Tissue  
  
  
PTV  
Volume  
(cc)  
Ratio of  
Prescription  
Isodose Volume 
to the PTV  
volume  
  
Ratio of 50%  
Prescription  
Isodose Volume 
to the PTV  
Volume, R50%  
Maximum dose  
(in% of dose 
prescribed) @ 2 
cm from PTV in  
Any Direction,  
D2cm (Gy)  
Percent of Lung  
Receiving 20 Gy  
Total or More, V20  
(%)  
  
  
  
  
  
1.8  
<1.2  
<1.5  
<5.9  
<7.5  
<50.0  
<57.0  
<10  
<15  
3.8  
<1.2  
<1.5  
<5.5  
<6.5  
<50.0  
<57.0  
<10  
<15  
7.4  
<1.2  
<1.5  
<5.1  
<6.0  
<50.0  
<58.0  
<10  
<15  
13.2  
<1.2  
<1.5  
<4.7  
<5.8  
<50.0  
<58.0  
<10  
<15  
22.0  
<1.2  
<1.5  
<4.5  
<5.5  
<54.0  
<63.0  
<10  
<15  
34.0  
<1.2  
<1.5  
<4.3  
<5.3  
<58.0  
<68.0  
<10  
<15  
50.0  
<1.2  
<1.5  
<4.0  
<5.0  
<62.0  
<77.0  
<10  
<15  
70.0  
<1.2  
<1.5  
<3.5  
<4.8  
<66.0  
<86.0  
<10  
<15  
95.0  
<1.2  
<1.5  
<3.3  
<4.4  
<70.0  
<89.0  
<10  
<15  
126.0  
<1.2  
<1.5  
<3.1  
<4.0  
<73.0  
>91.0  
<10  
<15  

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 41  
  
163.0  
<1.2  
<1.5  
<2.9  
<3.7  
<77.0  
>94.0  
<10  
<15  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
APPENDIX E  Performance Status Criteria – Lansky Performance Scale  
  
ECOG Performance Status Scale  
  
  
Karnofsky Performance Scale  
Grade  
Descriptions  
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.  

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4  
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.  
20  
Very sick, hospitalization indicated. 
Death not imminent.  
10  
Moribund, 
fatal 
processes 
progressing rapidly.  
5  
Dead.  
0  
Dead.  
  
APPENDIX F - 10 point Visual Analog Scale