A Pilot Study of Stereotactic Body Radiotherapy (SBRT) in Oligometastatic Renal Cell Carcinoma
Phase: NA
Conditions: Metastatic Renal Cell Cancer, Recurrent Renal Cell Carcinoma, Stage IV Renal Cell Cancer
Sponsor: University of Chicago

TITLE:  A PILOT STUDY OF STEREOTACTIC BODY RADIOTHERAPY (SBRT) IN 
OLIGOMETASTATIC RENAL CELL CARCINOMA   
 
 
Principal Investigator: 
Stanley Liauw, M.D. 
 
 
Department of Radiation and Cellular Oncology 
 
 
University of Chicago Medical Center 
 
 
5758 S Maryland Avenue MC 9006 
 
 
Chicago, IL 60637 
 
 
Phone: (773) 702-6870 
 
 
Fax: (773) 834-7340 
 
 
sliauw@radonc.uchicago.edu 
 
 
Sub-Investigators: 
 
 
Radiation Oncology 
 
Steven Chmura, MD PHD 
 
Renuka Malik, MD  
 
Ralph Weichselbaum, MD 
 
 
 
Urology 
 
Scott Eggener, MD  
 
Arieh Shalhav, MD 
 
Norm Smith, MD 
 
 
 
Medical Oncology 
 
Chadi Nabhan, MD 
 
Walter Stadler, MD 
 
 
Russell Szmulewitz, MD 
 
 
David Vanderweele, MD 
 
 
 
Biostatistics 
 
Theodore Karrison, PhD 
 
 
Research and Nursing Support 
 
Fauzia Arif 
 
Denise Cloutier, RN 
 
Funding: 
Internally funded through the Department of Radiation and Cellular 
Oncology 
 
 
Sponsor: 
Stanley Liauw, M.D./University of Chicago 
 
 
Intervention: 
Stereotactic Body Radiotherapy to all sites of disease 
 
 
Protocol Version: 
2.0 
 
 
Protocol Version Date: 
08.05.19 
 
 

 
 
 
i
STUDY SUMMARY 
SCHEMA 
 
 
Required Sample Size:  25 patients would be required 
Study Center:  University of Chicago Medical Center, Chicago, IL 
 
Concept and Rationale:  Patients with metastatic renal cell carcinoma (RCC) have a poor prognosis 
with median survival between 6-15 months, as few patients have a lasting response to cytokine therapy or 
targeted agent therapy.  However, not all patients present with widely metastatic disease.  There may be a 
select group of patients with “oligometastatic” disease—a limited number of metastatic lesions that can be 
treated with curative intent using aggressive local and systemic therapy.  Randomized studies suggest a 
benefit of cytoreductive surgery in the setting of cytokine therapy, and retrospective series suggest an 
improvement in survival with metastasectomy.  These studies argue that aggressive local therapy to all 
known sites of disease can yield benefit in the properly selected patient.   
However, not all lesions are amenable to surgical resection, and surgery can be associated with 
significant morbidity.  Stereotactic Body Radiotherapy (SBRT) is a method of treatment which directs 
ablative doses of radiotherapy to the target lesion while limiting radiation to surrounding structures.  There 
is an increasing body of evidence supporting a role for SBRT in oligometastatic cancers throughout the 
body.  A prior Phase I trial at the University of Chicago suggested that a 3-fraction regimen is tolerable in 
oligometastatic cancer.  However, this study included a heterogeneous cohort of patients with multiple 
primary malignancy types; only 13% of the patients in the trial had RCC. Furthermore, variable radiation 
doses were prescribed to different sites, complicating the applicability of findings to the clinical setting.  
Conclusions are therefore more difficult to make regarding the tolerability of SBRT in RCC. 
We hypothesize that 5-fraction SBRT with a more uniform dose approach (by having a preferred 
SBRT dose that is similar for all sites of involvement) in the management of oligometastatic RCC is 
feasible, not associated with excess toxicity, and can be safely delivered prior to systemic therapy.  
Information gathered from this study will contribute towards the development of a larger, phase II Chicago 
consortium study. 
 
Primary Objective:  To establish that patients can be treated with 5-fraction SBRT to all sites of 
metastatic disease with a low (<16%) rate of severe (grade 4) toxicity. 

 
 
 
ii
 
Secondary Objectives: 
1. To determine the toxicity profile of SBRT. 
2. To determine the feasibility of delivering 5-fraction SBRT per protocol based on proposed normal 
tissue constraints in a variety of organ sites. (i.e., the ability to treat >80% of enrolled patients 
according to protocol guidelines). 
3. To describe treated lesion control (LeC), progression free survival (PFS), and patterns of failure. 
4. To determine the feasibility of accrual and adequacy of eligibility criteria by defining the proportion 
of eligible cases of metastatic RCC presented at the weekly multidisciplinary genitourinary 
conference at the University of Chicago Medical Center. 
5. To make a preliminary evaluation regarding potential biomarkers in patient serum which may be 
assessed in a follow-up study (e.g. genetic or immunologic biomarkers).  
 
Study Design:  This is a single-armed pilot study to estimate the rate of CTCAE v4.0 grade ≥4 RT-related 
toxicity of 5-fraction SBRT in patients with oligometastatic RCC.  Eligible patients must have histologically 
or cytologically diagnosed RCC with 1-5 sites of metastases, including up to 3 brain metastases.  Patients 
may present with metastatic disease, or have previously treated primary disease with metastatic 
recurrence.  All sites of metastasis must be ≤6 cm, and patients with recurrent/unresected primary tumors 
are eligible as long as said tumor is ≤10 cm and there is a plan to treat the primary tumor with a local 
therapy.  Patients may not have had any oncologic therapy within 1 month prior to enrollment, no prior 
history of bevacizumab, and any brain metastases must be address with surgery and/or radiotherapy prior 
to enrollment.  Patients will be treated with SBRT (preferred dose 50 Gy/5 fractions) to all radiographic 
sites of gross disease, including the primary if it can not be addressed with non-radiotherapeutic local 
therapy.  Patients can thereafter begin off-protocol systemic therapy per medical oncology discretion, but 
any therapy will occur no earlier than 2 weeks after completion of RT. 
 
The first 10 patients enrolled on the study will be considered the “initial cohort.”  If ≥3 of these patients 
have a CTCAE v4.0 grade ≥4 RT-related toxicity, enrollment will be discontinued and the trial stopped, 
otherwise 5 additional patients will be accrued.  Study investigators will determine whether treatment 
related toxicities are RT-related or non-RT-related.   
 
Statistical Methods:   
Definition of primary outcome/endpoint:  RT-related grade ≥4 toxicity will be determined on a case-by-case 
basis by the study group, taking into consideration the region treated with SBRT, timing of the toxicity, and 
the nature of the toxicity.  Toxicities will be graded as per CTCAE v4.0 criteria. 
 
Definition of secondary outcomes/endpoints:  LeC will be defined as absence of clinical or radiographic 
progression per RECIST criteria.    PFS will be defined as progression in the treated lesion, organ in which 
the treated lesion is present, distant failure, or death from any cause.   
 
Analytic plan for primary objective:  Rates of RT-related grade ≥4 toxicity will be recorded, time to RT-
related grade ≥4 toxicity will be recorded, and freedom from RT-related grade ≥4 toxicity will be 
determined using the Kaplan-Meier method.   
 
Analytic plan for secondary objectives:  LeC and PFS will be estimated at 1 year using the Kaplan-Meier 
method.   
 
Sample size justification:  A sample size of 25 patients will be needed to assess the safety and 
appropriateness of this method, identify the optimal candidates, and optimal SBRT fractionation/dose for 
different clinical scenarios. 

 
 
 
iii
TABLE OF CONTENTS 
 
 
Page 
SCHEMA ........................................................................................................................................................ i 
1. OBJECTIVES ......................................................................................................................................... 1 
 
1.1  
Primary Objectives .................................................................................................................. 1 
 
1.2  
Secondary Objectives ............................................................................................................. 1 
2. BACKGROUND ...................................................................................................................................... 1 
 
2.1  
Metastatic Renal Cell Carcinoma ........................................................................................... 1 
 
2.2  
Oligometastasis ....................................................................................................................... 1 
 
2.3  
Stereotactic Body Radiotherapy in Oligometastasis ........................................................... 2 
 
2.4  
Rationale for current study ..................................................................................................... 3 
 
 
2.4.1 
Rationale for Secondary Objectives ................................................................................ 4 
3. PATIENT SELECTION ........................................................................................................................... 4 
 
3.1  
Eligibility Criteria  .................................................................................................................... 4 
 
3.2  
Exclusion Criteria .................................................................................................................... 5 
 
3.3  
Inclusion of Women and Minorities ....................................................................................... 6 
4. REGISTRATION PROCEDURES .......................................................................................................... 6 
 
4.1  
Patient Recruitment ................................................................................................................. 6 
 
4.2  
Patient Renumeration ............................................................................................................. 6 
5. TREATMENT PLAN ............................................................................................................................... 6 
 
5.1  
Study Design ............................................................................................................................ 6 
 
5.2  
Definition of Grade ≥4 RT-related Toxicity ............................................................................ 6 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines .................................. 7 
 
5.4  
Duration of Therapy ................................................................................................................ 7 
 
5.5  
Duration of Follow Up ............................................................................................................. 7 
5.6 
Criteria for Removal from Study ............................................................................................ 7 
6. RADIATION THERAPY .......................................................................................................................... 7 
 
6.1       Simulation.................................................................................................................................. 7 
 
6.2       Premedications ......................................................................................................................... 8 
 
6.3       Target Volumes ......................................................................................................................... 8 
 
6.4       Treatment Planning .................................................................................................................. 8 
 
6.5       Dose Specifications .................................................................................................................. 8           
 
6.6       Critical Structures ..................................................................................................................... 9 
 
6.7       RT Treatment ........................................................................................................................... 13 
 
6.8 
Radiotherapy Adverse Events ............................................................................................... 13 
7. RISKS AND BENEFITS ....................................................................................................................... 13 
 
7.1       Radiotherapy Adverse Events ............................................................................................... 13 
8. Adverse Event Reporting ................................................................................................................... 15 
9. Data Safety Monitoring ....................................................................................................................... 16 
10. STUDY CALENDAR ............................................................................................................................. 16 
11. MEASUREMENT OF EFFECT ............................................................................................................. 17 
11.1 
Antitumor Effect and Endpoints .......................................................................................... 17 
11.2 
Dosimetric description of delivery of Radiotherapy .......................................................... 18 
12. STATISTICAL CONSIDERATIONS ..................................................................................................... 19 
12.1 
Study Design/Endpoints ....................................................................................................... 19 
12.2 
Sample Size/Accrual Rate..................................................................................................... 19 
12.3 
Stratification Factors ............................................................................................................ 19 
12.4 
Analysis of Primary Endpoint .............................................................................................. 19 
12.5 
Analysis of Secondary Endpoints ....................................................................................... 19 
13. CONFIDENTIALITY ............................................................................................................................. 20 
14. BLOOD BANKING FOR FUTURE RESEARCH  ................................................................................. 21 

 
 
 
iv
REFERENCES ............................................................................................................................................ 21 
 
INFORMED CONSENT .............................................................................................................................. 24 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria .......................................................................................................... 24 
 
 
 
 
 

 
1
1. OBJECTIVES 
 
1.1. 
Primary Objective 
 
To establish that patients can be treated with 5-fraction SBRT to all sites of metastatic 
disease with a low (<16%) rate of severe (grade 4) toxicity. 
 
1.2. 
Secondary Objectives 
 
1.2.1 To determine the toxicity profile of SBRT. 
 
1.2.2 
To determine the feasibility of delivering 5-fraction SBRT based on  proposed 
normal tissue constraints in a variety of organ sites. (i.e., the ability to treat >80% 
of enrolled patients according to protocol guidelines). 
 
 
1.2.3 To describe treated lesion control (LeC), progression free survival (PFS), and 
patterns of failure. 
 
1.2.4 To determine the feasibility of accrual and adequacy of eligibility criteria by 
defining the proportion of eligible cases of metastatic RCC presented at the 
weekly multidisciplinary genitourinary conference at the University of Chicago 
Medical Center. 
 
1.2.5 To make a preliminary evaluation regarding potential biomarkers in patient serum 
which may be endpoints in a follow-up study (e.g. genetic or immunologic 
biomarkers). 
 
 
2. BACKGROUND 
 
2.1 
Metastatic Renal Cell Carcinoma 
 
Between 20-33%  of patients with renal cell carcinoma (RCC) present with metastatic 
disease, and of patients with initially limited disease who undergo radical nephrectomy, 
approximately 25% will ultimately develop metastases [1, 2].  Most patients receive systemic 
therapy with cytokine therapy or molecularly targeted agents blocking the Vascular Endothelial 
Growth Factor (VEGF) pathway or mammalian target of rapamycin (MTOR).  Despite these 
interventions, the response rate to systemic therapy is low, with 5-20% responding to cytokine 
agents and approximately 30-50% to small molecule receptor tyrosine-kinase VEGF inhibitors 
such as sunitinib and pazopanib [3-8].  Responses are generally of short duration and the 
median overall survival is typically between 6-15 months [8].   
 
2.2 
Oligometastasis 
 
 
Not all patients with cancer present with widely metastatic disease, and there may be a 
select group of patients with a more indolent disease course.  A select cohort of patients 
develops a limited number of metastatic lesions, and can potentially be treated with curative 
intent using aggressive local and systemic therapy [9, 10]. Hellman and Weichselbaum 
described the existence of an intermediate state in the development of metastatic disease 
described as oligometastasis [11] – a state where a patient may have a malignancy limited to 
only a few sites and regions, suggesting an underlying biology not yet capable of widespread 
metastasis. 

 
2
 
 
The benefit of aggressive resection of metastatic tumors in patients with a limited number 
and sites of disease has been shown in various malignancies.  In patients with metastatic 
colorectal cancer to the liver, there appears to be a benefit in survival for patients with 
favorable clinical factors who undergo resection of a limited number of liver metastases, and 
this approach can produce 5 year overall survival rates between 25-60% [12-16].  Patients 
with limited pulmonary metastases may have a similar benefit [17].  Similarly, patients with 
pulmonary metastases from soft tissue sarcoma may have 5 year overall survival rates of 
approximately 25% when they undergo resection of lung metastases [18-22].   
 
For patients with metastatic RCC, there has been increasing use of cytoreductive 
nephrectomy prior to systemic therapy.  Two randomized studies comparing immediate 
Interferon-alpha to initial cytoreductive nephrectomy followed by Interferon-alpha showed a 
benefit in time to progression and median survival in patients who underwent maximal 
cytoreduction of the primary tumor followed by adjuvant interferon alpha therapy [23, 24].  For 
patients treated with molecularly targeted agents, a multicenter retrospective series of 314 
patients undergoing anti-VEGF therapy showed cytoreductive nephrectomy prior to systemic 
therapy improved overall survival (19.8 months vs. 9.4 months) [25].  An analysis of patients 
on a prospective open label, expanded access trial of sunitinib revealed that patients who had 
nephrectomy prior to sunitinib had a 9.8 month PFS, compared to 6 months for those who did 
not [26].  The Phase III CARMENA trial is currently assessing the role of cytoreductive 
nephrectomy prior to sunitinib therapy, and the SURTIME trial is assessing the appropriate 
timing of surgery in relationship to sunitinib therapy [27, 28]. 
 
In addition to resection of the primary tumor, many advocate removal of metastatic 
lesions in patients with a limited number of lesions of RCC.  A retrospective study of 278 
patients with metastatic RCC from Memorial Sloan-Kettering Cancer Center showed that 
patients who underwent surgical resection of metastatic lesions had an improved 5 year 
overall survival (44% vs. 11%) [29].  Additionally, the survival of patients after their second or 
third resection was not significantly lower.  Eggener et al. reviewed 129 patients with recurrent 
and metastatic renal cell carcinoma.  34% of patients underwent metastasectomy, which was 
associated with a survival benefit [30].  Alt et al. reviewed 125 patients who underwent 
metastasectomy compared to 762 patients who did not.  Complete metastasectomy was 
associated with improved cause-specific survival (median 4.8 vs. 1.3 years, p< 0.001).  The 
benefit was present for both synchronous or asynchronous multiple metastases [31].  These 
data suggest that in a select group of patients, local eradication of metastatic lesions and 
unresected primary tumors may have a benefit in the survival of patients with metastatic RCC. 
 
2.3 
Stereotactic Body Radiotherapy in Oligometastasis 
 
However, nephrectomy and metastasectomy are invasive procedures with risk for 
perioperative morbidity.  This is particularly the case for patients having comorbid conditions 
or requiring more extensive surgeries.  Also, not all patients are candidates for resection due 
to invasion of adjacent structures by tumors.  Radiotherapy is an alternative modality used for 
the treatment of radiographically visible tumors.  Although RCC has historically been thought 
to be resistant to conventionally fractionated radiotherapy (1.8-2 Gy per fraction) [32-34], 
multiple series suggest it may be sensitive to higher fraction sizes of radiotherapy (stereotactic 
radiotherapy) [35-38].   
 
Stereotactic Radiotherapy is the use of high doses of radiation per fraction to deliver 
ablative doses of radiation to lesions throughout various body sites.  Stereotactic radiotherapy 
administered in one fraction, commonly to intradural lesions, is usually described as 
stereotactic radiosurgery (SRS).  Stereotactic radiotherapy administered over 1-5 fractions to 
extracranial sites in > 5 Gy per fraction is known as stereotactic body radiotherapy (SBRT).   
 
There is considerable experience with SBRT in medically inoperable early stage lung 

 
3
cancers [39-42], and an increasing body of evidence suggesting a role of SBRT in 
oligometastatic cancers.  The ablative doses of SBRT in the oligometastasis setting have 
allowed for local control rates approaching 90% in such series [43-46]. 
 
Based on retrospective series suggesting a local control rate with SBRT of 87-98% [35, 
47-49], a prospective Phase II Swedish study assessed the role of SBRT in 30 patients with 
metastatic or inoperable primary tumor RCC [38].  Patients were treated with 20-50 Gy given 
in 2-5 fractions to involved sites.  With median follow-up of 52 months, 21% of patients had 
complete regression of tumor, 31% had a partial response, and 27% had stable radiographic 
size. The rate of local control for all treated lesions was 98%, and the overall survival for the 
entire cohort was 32 months.  This suggests SBRT can be effective to control RCC.  
Additionally, retrospective series also suggest limited toxicity with SBRT [37, 45, 47, 49-51].   
 
 
There are numerous SBRT fractionation regimens that have been evaluated [38, 39, 41, 
52-54].  However, the optimal dose and number of fractions of SBRT are unknown.  A prior 
phase I dose escalation trial was performed to evaluate SBRT for oligometastatic cancer at 
the University of Chicago.  This study used a modified Fibonacci dose escalation to identify 
the maximal safe organ-specific doses that could be delivered in a 3-fraction SBRT regimen 
[45].  However, the patient cohort in this study was heterogeneous, with only 8 of 61 patients 
(13%) having renal cell malignancies.  Additionally, different doses for each specific organ of 
involvement were used.  This approach is more complex and may be more difficult to 
implement in subsequent trials and in the community. In addition, 5-fraction SBRT may be 
better tolerated by critical structures, particularly for tumors near gastrointestinal critical 
structures.  For primary tumors, Wersall et al used 40 Gy in 5 fractions for tumors up to 10 cm 
in size [47].  Videtic et al evaluated the use of a SBRT regimen of 50 Gy in 5 fractions in 
medically inoperable non-small cell lung cancer and found a 3 year local control rate of 94.4% 
and acceptable toxicity [41].  In addition, 50 Gy in 5 fractions is the starting dose and 
fractionation of RTOG 0813, a Phase I/II dose escalation study of SBRT in non-small cell lung 
cancer currently open in multiple centers.  Typically, the dose and fractionation schemas used 
to treat metastatic lesions in the lung are similar to those used in primary lung cancer.  The 50 
Gy in 5 fractions schema also has the benefit of being tolerable in multiple organ sites other 
than the lungs [55].  Thus, 50 Gy in 5 fractions was selected as the preferred schema in our 
trial, with 40 Gy in 5 fractions used as an alternative dose when normal tissue constraints 
cannot be met using the preferred dose.   
 
Most series suggest a favorable risk profile of SBRT when keeping doses to normal 
tissues within established dose constraints.  However, there are a few case reports of patients 
treated with radiotherapy (both SBRT and conventionally fractionated radiotherapy)[56-60].  
The agent that appears to be most commonly associated with severe toxicity is bevacizumab; 
several larger series have demonstrated safety when combining tyrosine kinase inhibitors 
(e.g. Sunitinib, Pazopanib) with radiation therapy [61-64].  Therefore, this study will exclude 
men treated with bevacizumab prior to enrollment, but will allow patients treated with other 
tyrosine kinase inhibitors to be eligible for this trial. 
 
2.4 
Rationale for current study  
 
 
 
 
The above evidence suggests a role for aggressive local treatment of metastatic lesions 
in RCC.  We hypothesize that SBRT can be safely and effectively delivered in patients with 
oligometastatic RCC.  Results will inform the development of a larger, multicentric trial. 
 
 
This study will evaluate a 5-fraction regimen in patients who have a histology diagnosis of 
metastatic RCC with 5 or fewer sites of disease.  All organs of involvement will receive 5 
fractions with a preferred dose of 50 Gy in 5 fractions.  This pilot study will evaluate the ideal 
candidates for this approach, the likely accrual and accrual rate of a phase II study, and the 
optimal dosimetric and dose/fractionation considerations in pursuing this approach.  In 
addition, this study will allow for the collection of data to possibly refine eligibility and treatment 

 
4
delivery for future studies, and help determine sample size calculations for the next 
generation trials.  Subsequent testable hypotheses could include randomized comparisons of 
SBRT +/- concurrent molecularly targeted systemic therapy, observation +/- SBRT, or 
systemic therapy +/- SBRT. 
 
 
 
 
 
 
 
 
2.4.1 
Rationale for Secondary Objectives 
 
Patients with sites of metastatic disease commonly present with pain from these 
lesions.  Conventional radiotherapy can offer palliation for most patients, but the 
durability of pain control is variable.  In order to describe the clinical efficacy of this 
treatment approach, we will also evaluate objective response rate, treated lesion 
control, and the patterns of failure. 
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 
Patients must have histologically or cytologically confirmed metastatic or recurrent 
RCC (any histologic subtype).  
 
3.1.2 
Patients must have between 1 to 5 new or recurrent lesions suspicious for metastatic 
RCC on diagnostic imaging. 
 
 
 
 
 
3.1.2.1 Each extracranial lesion must be ≤ 6 cm and amenable to SBRT or surgical 
excision. 
 
 
 
3.1.2.2 Patients must have 3 or fewer brain metastases, of size ≤4 cm. 
 
 
 
 
 
 
 
 
 
3.1.2.2.1 
Brain metastases must be treated prior to enrollment in the 
study.  The modality of treatment of brain metastases can include 
surgical resection, whole brain radiotherapy, stereotactic 
radiosurgery, or any combination of the above. 
 
 
 
 
 
 
3.1.2.3 Patients who have an intact unresected primary tumor should be considered 
for radical nephrectomy and primary resection prior to enrollment in the study. 
 If the patient is not eligible for surgical resection, the primary tumor must be 
amenable to SBRT or RFA. Generally, this will be defined as a primary tumor 
<10 cm in size or a primary lesion which can be treated to a dose of ≥8 Gy x 
5 without excessive perceived risk of toxicity. 
 
3.1.3 
Patients must have had at least a CT of the chest, abdomen, and pelvis within 4 
weeks of registration in the trial.  CT or MRI of the brain is only required in the 
presence of neurologic symptoms. 
 
3.1.4 
Patients must have had no radiotherapy, immunotherapy, chemotherapy or therapy 
with targeted agents within the last 1 month. 
 
3.1.5 
Patients may not have had prior bevacizumab, based on case reports of tracheo-
esophageal fistula in patients treated with bevacizumab and radiotherapy [58, 59]. 
 
3.1.6 
Age >18 years.  Because of the risk of adverse events in patients <18 years of age, 
children are excluded from this study, but will be eligible for future pediatric SBRT 
trials. 
 

 
5
3.1.7 
ECOG performance status <2 (see Appendix A). 
 
3.1.8 
Life expectancy of ≥3 months. 
 
3.1.9 
Patients must have normal organ and marrow function within 30 days of registration, 
as defined below: 
 
 absolute neutrophil count  
 
>500/mcL 
 hemoglobin 
 
 
 
 
 
≥ 8.0 g/dL 
 platelets  
 
 
 
 
 
>50,000/mcL 
 total bilirubin  
 
 
 
 
within normal institutional limits 
 AST(SGOT)/ALT(SGPT)  
 
<3X institutional upper limit of normal if liver  
  
 
 
 
 
 
 
 
metastases are present 
 
3.1.10 Women of childbearing potential must have a negative pregnancy test within 14 days 
of registration. 
 
3.1.11 Patients must have the ability to understand and the willingness to sign a written 
informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Patients who have had prior chemotherapy, immunotherapy, targeted therapy, or 
radiotherapy within 1 month of enrollment. 
 
3.2.2 
Patients who have had any prior bevacizumab, due to case reports suggesting a 
possible risk of severe toxicity in combination with radiotherapy [58, 59]. 
 
3.2.3 
Patients with radiographic or clinical findings of spinal cord compression or cauda 
equina syndrome with neurologic deficit thought to be due to malignancy. 
 
 3.2.4 
Patients may not be receiving any systemic anti-cancer agents or other investigational 
agents during radiation therapy. 
 
 
 
 
3.2.5 
Patients may not have received prior radiation therapy to a site of recurrence which 
would require overlap of appreciable radiation dose.  
 
3.2.6 
Known active invasive malignancy except for renal cell carcinoma and/or non-
melanoma skin cancer. 
 
3.2.7 
Severe, active co-morbidity, defined as follows: 
 
Unstable angina and/or congestive heart failure requiring hospitalization within the 
last 6 months prior to registration; 
 
Transmural myocardial infarction within the last 6 months prior to registration; 
 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration; 
 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy  within 30 days prior to 
registration; 
 
Severe hepatic disease, defined as a diagnosis of Child-Pugh Class B or C 
hepatic disease if the liver is involved with metastatic disease; 
 
HIV positive with CD4 count < 200 cells/microliter. Note that patients who are HIV 
positive are eligible, provided they are under treatment with highly active 
antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 
30 days prior to registration. Note also that HIV testing is not required for eligibility 
for this protocol; 

 
6
 
3.2.8 
Pregnancy or women of childbearing potential who are sexually active and not 
willing/able to use medically acceptable forms of contraception during protocol 
treatment or for at least 6 months following treatment; this exclusion is necessary 
because the treatment involved in this study may be significantly teratogenic. 
 
 
 
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
 
4. 
REGISTRATION PROCEDURES 
 
4.1  
Patient Recruitment 
 Patients will be identified and recruited through Radiation Oncology, Urology, and Medical 
Oncology clinic consultations and follow-up visits at the University of Chicago 
 
4.2  
Patient Renumeration 
Patients will receive no payment for participation in this trial. 
 
 
5.  
TREATMENT PLAN 
 
 
5.1 
Study Design 
This is a pilot study of the use of SBRT to all sites of disease for patients with oligometastatic 
RCC.  Patients may receive off-protocol systemic therapy per medical oncologist discretion no 
earlier than 4 weeks after starting SBRT. While there are no restrictions on systemic therapy 
following SBRT, caution is advised on the use of bevacizumab given prior case reports 
demonstrating the possibility of heightened toxicity when this agent is used in the setting of 
SBRT. Limited or symptomatic recurrences can also be treated with radiation therapy (either 
SBRT or conventional therapy) at the clinician’s discretion.  
 
Enrollment will proceed according to a sequential toxicity monitoring schema to test the null 
hypothesis of a π0=5% grade 4 toxicity rate against an upper acceptable boundary of a 
π1=20% grade 4 toxicity rate. Trial enrollment will be halted if there are two grade 4 events 
within the first 2 patients, if there are three events within the first 14 patients, or if there are 
four events within the first 25 patients. The treatment will be considered successful if there 
are less than four events in 25 evaluable patients (<16%).   
 
Treatment will be administered on an outpatient basis.  The details of planning and 
administration of radiotherapy are discussed in detail in section 6.  Reported adverse events 
and potential risks for SBRT are described in Section 8.  Appropriate dose modifications for 
SBRT 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. 
 
The pilot study will be considered successful if 25 patients are accrued, with less than 4 
having Grade 4+ toxicity events after SBRT.  
 
5.2  
Definition of Grade ≥4 RT-related Toxicity 
The evaluation period of acute toxicity will be defined by the period of 90 days following the 
first fraction of RT. Of note, late grade ≥4 toxicity occurring beyond 90 days and through the 
one year of planned post-treatment follow-up will still have the ability to modify the trial design 
and accrual per the discretion of the primary investigator. Grade ≥4 toxicity will be defined 

 
7
according to Common Toxicity Criteria version 4.0 (ctep.cancer.gov/reporting/ctc.html).  
Toxicities will be classified by a study committee as likely due to SBRT or non-radiotherapy-
related based on review of nature of toxicity and the areas being treated with radiotherapy. 
 
5.3  
General Concomitant Medication and Supportive Care Guidelines 
Patients may receive non-chemotherapeutic agents for premedication and supportive care as 
per the standard of care while on study.   
 
5.4  
Duration of Therapy 
In the absence of treatment delays due to adverse events, radiotherapy should be completed 
within 1 month of the first day of radiotherapy (Day 28 of protocol treatment).  Patients may 
receive systemic therapy off-protocol no earlier than 4 weeks after starting SBRT. 
 
5.5 
Duration of Follow Up 
Patients will be followed for 1 year after beginning radiotherapy.  Patients removed from study 
for unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event. 
 
5.6 
Criteria for Removal from Study 
Patients will be removed from study when one of the following criteria applies: 
 
 
Intercurrent illness that prevents administration of SBRT, 
 
Unacceptable adverse event(s), 
 
Death, 
 
Patient 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/treating 
physician. 
 
The reason for study removal and the date the patient was removed must be documented in 
the Case Report Form. 
 
 
 
 
6. RADIATION THERAPY 
 
 
6.1  
Simulation 
 
 
 
6.1.1 
SBRT 
 
 
 
 
 
6.1.1.1 Patient Positioning 
Patients must be simulated in a stable, supine position capable for reproducibility 
of positioning at the time of treatment, to allow for the patient to feel as 
comfortable as possible.  A prone position is not allowed. A variety of 
immobilization systems may be utilized with reference to the treatment delivery 
coordinate system. 
 
 
 
      6.1.1.2  Simulation 
CT simulation will be performed with proper patient positioning and 
immobilization.  CT will be the primary image platform for treatment planning. The 
use of intravenous contrast is recommended if it can help delineate the tumor or 
normal tissues (e.g. for liver metastases). Additionally, oral, rectal, or bladder 
contrast are recommended if these agents will improve tumor or target 
delineation. 
 
When available, 4D CT should be used for all sites where there is concern for 
movement due to normal respiration. 

 
8
 
 
 
6.2  
Premedications 
No premedications are required for any aspect of radiotherapy, however corticosteroid, 
anti-emetic, anti-anxiety, and narcotic/non-narcotic pain medications are allowed per 
physician discretion.   
 
 
 
6.3  
Target Volumes 
When available, imaging studies such as MRI and PET are may be fused with planning 
CT to aid contouring of the target volumes. 
 
 
 
 
6.3.1 
Target Definition 
 
 
 
 
 
 
 
6.3.1.1 The definition of volumes will be in accordance with the ICRU Report 62: 
Prescribing, Recording and Reporting Photon Beam Therapy. [65] 
 
 
 
 
 
6.3.1.2 A gross tumor volume (GTV) will be entered for each lesion, based on 
available imaging data.  
 
 
 
 
 
6.3.1.3 In the absence of respiratory gating, for any lesion that is subject to 
movement from respiration, an internal target volume (ITV) will be defined as 
the volume that accounts for intrafraction target motion. 
 
 
 
 
 
6.3.1.4 A clinical target volume (CTV) will be defined as the GTV or ITV (when 
available) plus a margin for microscopic extension. 
 
 
 
 
 
6.3.1.5 A planning target volume (PTV) will be determined which will correspond to 
CTV plus appropriate margin for tumor motion and set-up uncertainty.  
 
 
 
 
 
6.3.1.6 Separate GTV, CTV, PTV, and if applicable, ITV contours, will be created for 
all sites of gross disease. 
 
 
 
6.4  
Treatment Planning 
6.4.1 
3D coplanar or non-coplanar beam arrangements will be custom designed for each 
case to deliver highly conformal prescription dose distributions. The treatment plan used 
for each patient will be based on an analysis of the volumetric dose, including dose 
volume histogram of the PTV and normal structures. 3D “forward” planning or “inverse” 
planning with beamlet intensity modulated treatment planning are allowed. 
 
 
 
6.4.2 
Respiratory gating is strongly recommended if there is significant movement of the GTV 
with respiration. 
 
 
 
6.4.3 
Treatment is to be delivered using a linear accelerator and photon energies ≥ 6 MV. 
6.4.4 
Corrections will be made to account for tissue heterogeneity. 
6.4.5 
Any dose > 110% must be within the PTV. 
 
 
 
6.5  
Dose Specifications 
Doses will be prescribed to the PTV. The PTV may be covered by a lower isodose line 
than usually used in conventional radiotherapy planning, ranging from 60-100%. Ideally, 
the prescription dose will cover >90% of the GTV (V100 GTV > 90%, and V95PTV > 
90%). Hot spots within the PTV are allowed, unless the PTV also overlaps an organ at 
risk. A lower coverage goal will be acceptable if necessary to meet normal tissue 
constraints, which will be assigned priority over tumor coverage. 
 
 
 
 
6.5.1 
SBRT 
At all dose levels in dose escalation, the preferred SBRT dose is 50 Gy in 5 fractions of 10 Gy to all sites 
of disease, including the primary tumor if it can not be treated with surgical resection or alternative local 
therapy.  However, normal tissue constraints are of priority in selecting the prescribed dose, and if the 
dose to normal tissues exceeds the normal tissue dose constraints, then dose can be de-escalated to a 
lower dose, such as 8 Gy x 5. One site in which de-escalation is routinely expected includes the treatment 
of vertebral body metastases, in which the preferred SBRT dose is 27-30 Gy in 3 fractions of 9-10 Gy.  
 

 
9
 
5.6 
Critical Structures 
 
 
 
6.6.1 
Critical structure dose constraints are per Table 1. These dose constraints are based 
on NRG BR002, a NRG Oncology cooperative group prospective Phase I clinical trial 
of SBRT for the treatment of multiple metastases in patients with oligometastatic 
cancer. 
 
 
 
 
 
 
 
 
 
Table 1:  Normal tissue critical structure dose constraints 
Serial Organ 
Volume 
Dose (Gy) 
Avoidance Endpoint 
Spinal Cord 
<0.03 cc 
28 
Myelitis 
 
<0.35 cc 
22 
Myelitis 
 
<1.2 cc 
15.6 
Myelitis [66] 
 
Ipsilateral Brachial Plexus 
< 0.03 cc 
32 
Brachial Plexopathy 
(RTOG 0813) 
<3 cc 
30 
Brachial Plexopathy 
(RTOG 0813) 
Cauda Equina 
<0.03 cc 
32 
Neuritis 
(AAPM TG-101) 
<5 cc 
30 
Neuritis 
(AAPM TG-101) 
Sacral Plexus 
<0.03 cc 
32 
Neuropathy 
(AAPM TG-101) 
<5 cc 
30 
Neuropathy 
(AAPM TG-101) 
Trachea and Ipsilateral 
Bronchus (Non-adjacent 
wall) 
<0.03cc 
40 
Stenosis/Fistula 
 
<5cc 
32 
Stenosis/Fistula 
(RTOG 0813) 
Esophagus*               
(Non-adjacent wall) 
<0.03cc 
35 
Stenosis/Fistula [66] 
 
<5 cc 
27.5 
Stenosis/Fistula 
(RTOG 0813) 
Heart/Pericardium 
<0.03 cc 
38 
Pericarditis [66] 
 
<15 cc 
32 
Pericarditis 
(RTOG 0813) 
Great vessels  
(Non-adjacent wall) 
<0.03 cc 
53 
Aneurysm [66] 
 
<10 cc 
47 
Aneurysm 
(RTOG 0813) 
Skin 
< 0.03cc 
38.5 
Ulceration 
 
< 10cc 
36.5 
Ulceration 
 
Stomach 
< 0.5cc 
35 
Ulceration/Fistula 
 
< 5cc 
26.5 
Ulceration/Fistula 
 
Duodenum* 
< 0.5 cc 
30 
Ulceration 
(RTOG 1112) 
< 5 cc 
18.3 
Ulceration [67] 
 

 
10
Jejunum/ileum* 
< 0.03 cc 
32 
Ulceration 
 
< 30cc 
20 
Enteritis/Obstruction  
Bowel* 
< 0.03 cc 
40 
Ulceration 
 
<20 cc 
28.5 
Colitis/Fistula  
Rectum* 
<0.03 cc 
55 
Ulceration 
 
<3.5 cc 
50 
Proctitis/Fistula  
<20 cc 
32.5 
Proctitis/Fistula  
Bladder 
< 0.03 
38 
Cystitis/Fistula 
 
<15 cc 
20 
Cystitis/Fistula 
 
Ureter 
<0.03 cc 
45 
Stenosis  
 
Penile Bulb 
<3 cc 
30 
Impotence [66] 
 
Femoral head 
<10 cc 
30 
Necrosis  
 
Bile Duct 
<0.03 cc 
41 
Stenosis  
 
Renal hilum/Vascular Trunk 
<15 cc 
23 
Malignant 
Hypertension 
 
Rib 
<0.03 cc 
57 
Pain or Fracture  
 
<5 cc 
45 
Pain or Fracture  
Parallel Organ 
Volume 
Dose (Gy) 
Avoidance Endpoint 
Lung (total) 
< 37% lung volume 
13.5 
Pneumonitis 
 
< 1500 cc 
12.5 
Basic Lung Function 
(RTOG 0813) 
< 1000 cc 
13.5 
Pneumonitis 
(RTOG 0813) 
Ipsilateral Kidney 
< 130 cc 
14.5 
Basic Renal Function 
 
Total Kidney 
< 200cc 
18 
Basic Renal Function 
 
Liver 
<700 cc 
21 
Liver Function [66] 
 
 
*Note: avoid circumferential irradiation. 
 
 
 
 
 
Dose volume histograms (DVHs) will be constructed to assess dose to PTV and normal tissue 
structures.  The pertinent critical structure dose constraints will be determined by the location 
of the treated lesion.  These must be met prior to plan approval, otherwise target coverage, or 
prescription dose, must be decreased to meet the constraints as above.   
 
6.6.2 
Critical Structure contouring 
In order to verify each of these limits, the organs must be contoured such that 
appropriate volume histograms can be generated. The specific critical structures to 
be contoured and assessed by DVH for each case will be determined by the treating 
radiation oncologist.  Instructions for the contouring of these organs are as follows: 
 
 

 
11
Spinal Cord 
The spinal cord will be contoured based on the bony limits of the spinal canal. The spinal 
cord should be contoured starting at least 5 cm above the superior extent of the PTV and 
continuing on every CT slice to at least 5 below the inferior extent of the PTV. 
 
Cauda Equina 
Starting at the conus (end of spinal cord, typically around L1 or L2) include the entire spinal 
canal into the sacrum to the filum. 
 
Sacral Plexus 
Include the nerve roots from L5 to S3 on each side from the neuroforamina to the coalescing 
of the nerves at the obturator internus muscle. 
 
Esophagus 
The esophagus will be contoured using mediastinal windowing on CT to correspond to the 
mucosal, submucosa, and all muscular layers out to the fatty adventitia. The esophagus 
should be contoured starting at least 5 cm above the superior extent of the PTV and 
continuing on every CT slice to at least 5 cm below the inferior extent of the PTV. 
 
Brachial Plexus 
The defined ipsilateral brachial plexus originates from the spinal nerves exiting the 
neuroforamina on the involved side from around C5 to T2. However, for the purposes of this 
protocol, only the major trunks of the brachial plexus will be contoured using the subclavian 
and axillary vessels as a surrogate for identifying the location of the brachial plexus. This 
neurovascular complex will be contoured starting proximally at the bifurcation of the 
brachiocephalic trunk into the jugular/subclavian veins (or carotid/subclavian arteries) and 
following along the route of the subclavian vein to the axillary vein ending after the 
neurovascular structures cross the second rib. If the PTV of all metastases is more than 5 cm 
away from the brachial plexus, this structure need not be contoured. 
 
Heart 
The heart will be contoured along with the pericardial sac. The superior aspect (or base) for 
purposes of contouring will begin at the level of the inferior aspect of the aortic arch 
(aortopulmonary window) and extend inferiorly to the apex of the heart. 
 
Trachea and Proximal Bronchial Tree 
The trachea and proximal bronchial tree will be contoured as two separate structures using 
mediastinal windows on CT to correspond to the mucosal, submucosa and cartilage rings 
and airway channels associated with these structures. For this purpose, the trachea will be 
divided into two sections: the proximal trachea and the distal 2 cm of trachea. The proximal 
trachea will be contoured as one structure, and the distal 2 cm of trachea will be included in 
the structure identified as proximal bronchial tree. 
 
 
Proximal Trachea 
Contouring of the proximal trachea should begin at least 5 cm superior to the extent of the 
PTV for lung metastases or 5 cm superior to the carina (whichever is more superior) and 
continue inferiorly to the superior aspect of the proximal bronchial tree. 
 
 
Proximal Bronchial Tree 
The proximal bronchial tree will include the most inferior 2 cm of distal trachea and the 
proximal airways on both sides as indicated in Figure 6-1. The following airways will be 
included according to standard anatomic relationships: the distal 2 cm of trachea, the 
carina, the right and left mainstem bronchi, the right and left upper lobe bronchi, the 
intermedius bronchus, the right middle lobe bronchus, the lingular bronchus, and the right 
and left lower lobe bronchi. Contouring of the lobar bronchi will end immediately at the site 
of a segmental bifurcation. If there are parts of the proximal bronchial tree that are within 

 
12
GTV, they should be contoured separately, as “proximal bronchial tree GTV”, not as part 
of the “proximal bronchial tree”. 
 
Whole Lung 
Both the right and left lungs should be contoured as one structure. Contouring should 
be carried out using pulmonary windows. All inflated and collapsed lung should be contoured; 
however, gross tumor (GTV) and trachea/ipsilateral bronchus as defined above should not be 
included in this structure. 
 
Skin 
The skin will be defined as the outer 0.5 cm of the body surface. As such it is a rind of 
uniform thickness (0.5 cm) which envelopes the entire body in the 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 (e.g., the scalp on the top 
of the head). 
 
Great Vessels 
The great vessels (aorta and vena cava, not the pulmonary artery or vein) will be contoured 
using mediastinal windowing on CT to correspond to the vascular wall and all muscular layers 
out to the fatty adventitia. The great vessel should be contoured starting at least 10 cm above 
the superior extent of the PTV and continuing on every CT slice to at least 10 cm below the 
inferior extent of the PTV. For right sided tumors, the vena cava will be contoured, and for left 
sided tumors, the aorta will be contoured. 
 
Non-adjacent Wall of a Structure 
For the esophagus, trachea and proximal bronchial tree, and great vessels, the nonadjacent 
wall corresponds to the half circumference of the tubular structure not immediately touching 
the GTV or PTV, These contours would start and stop superiorly and inferiorly just as with the 
named structure. The half lumen of the structure should be included in this contour. 
 
Stomach 
The entire stomach and its contents should be contoured as a single structure as a 
continuation of the esophagus and ending at the first part of the duodenum. 
 
Duodenum 
The wall and contents of the 1st, 2nd, and 3rd parts of the duodenum will be contoured as 
one structure beginning where the stomach ends and finishing as the superior mesenteric 
artery crosses over the third part of the duodenum. 
 
Jejunum/Ileum 
As a conglomerate of bowel loops within the abdomen distinguished from stomach, 
duodenum, and colon/rectum. 
 
Bowel (Large/Small) 
From the ileocecal area to include the ascending, transverse, descending and sigmoid colon 
as one structure. 
 
Rectum 
The entire rectum with contents from the peritoneal reflection of the sigmoid to the anus.  
 
Bladder 
This organ will be contoured as bladder wall exclusive of urinary contents 
 
Kidney (renal cortex) 
Both the right and left kidney, excluding renal pelvis/collecting system, should be contoured in 
their entirety (the renal cortex) 

 
13
 
Liver 
The entire liver minus the GTV targets. 
 
Bile ducts 
May use the portal vein from its juncture with the splenic vein to its right and left birfurcation in 
the liver as a surrogate to identify the bile ducts. 
 
Femoral Heads 
The ball of the head and socket joint. 
 
Rib  
Ribs within 5 cm of the PTV should be contoured by outlining the bone and marrow. Typically, 
several portions of adjacent ribs will be contoured as one structure. Adjacent ribs, however, 
should not be contoured in a contiguous fashion (i.e., do not include the inter-costal space as 
part of the ribs). 
 
Other Structures  
The constraints tables above contain other structures. These are required if the structure is 
within 5 cm of the PTV. 
 
6.7 RT Treatment 
6.7.1 
Radiotherapy will begin on Day 1 of therapy. 
 
6.7.2 
SBRT fractions to each individual site may occur at most 3 times per week, but never 
on consecutive days. 
 
6.7.3 
SBRT fractions to the different sites of involvement may occur on the same day or on 
different days per patient and physician preference. 
 
6.7.4 
All radiotherapy must be completed by Day 28 of radiation, unless an adverse event 
occurs to delay treatment 
 
6.7.5 
Prior to each fraction of SBRT, patients will be brought to the treatment room and 
placed in the treatment position using custom immobilization.  Cone-beam CT prior to 
administration of fraction to confirm appropriate patient set-up is preferred if available 
and indicated, but alternatively patients may have pre-treatment KV portal imaging. 
 
 
 
6.8  
Radiotherapy Adverse Events 
Please refer to Section 8 for details regarding radiotherapy adverse events and adverse 
event reporting. 
 
 
7. RISKS AND BENEFITS 
 
 
 
7.1 RADIOTHERAPY ADVERSE EVENTS 
 
Adverse event (AE) monitoring and reporting will be performed.  Please refer to Section 5.2 for 
definition of Dose Limiting Toxicity. 
 
 
Radiotherapy reactions will be defined as acute or late as defined below: 
 
Acute Reactions:  Acute side effects are considered as occurring ≤ 90 days from the start of 
radiation therapy.  They will be documented using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 (ctep.cancer.gov/reporting/ctc.html).  

 
14
 
Late Reactions:  Late side effects are considered as occurring > 90 days from the start of 
radiation therapy through a 12 month total evaluation period.  They will also be documented using 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
(ctep.cancer.gov/reporting/ctc.html). 
 
Alopecia, skin hyperpigmentation, and erythema are likely in all treatment fields. It is likely that all 
patients treated on study will develop some level of fatigue.  Rarely, some patients may have a 
vasovagal response before, during, or after SBRT fractions. 
 
Other side effects of treatment will vary depending on the location of disease and volume of 
normal tissues in the radiation therapy portals. All attempts should be made to minimize side 
effects by limiting the normal tissue in the radiation therapy portals and adhering to the normal 
tissue dose constraints of this study. 
 
7.1.1 
Additional Adverse Events Associated with stereotactic radiation to the brain. 
Acute Reactions: Expected acute reactions include transient small amounts of bleeding and 
swelling (including in sites of frame placement for radiosurgery), transient head/neck 
pain/discomfort, transient nausea and vomiting, and headache.  Rare toxicities include infection of 
stereotactic frame pin sites, intracranial or extracranial hemorrhage, vasovagal response to frame 
placement.   
 
Late Reactions:  Edema of treated lesion is expected on imaging, but this is often asymptomatic.  
Unlikely toxicities include persistent nausea, vomiting or headache.  Rare toxicities include 
radionecrosis, lethargy, somnolence, damage to the eye with the possibility of blindness, 
cataracts, severe neuropsychological dysfunction, hearing loss, pituitary dysfunction, cranial 
neuropathy. 
 
7.1.2 
Additional Adverse Events Associated with Head and Neck radiotherapy. 
Acute Reactions:  Depending on the structure irradiated in the region, possible but expected 
toxicities include pharyngitis, esophagitis, laryngitis, mucositis, xerostomia, xerophthalmia, voice 
hoarseness, otic changes, dysgeusia, dysphagia, odynophagia.  Other possible but less likely 
acute reactions include sinusitis, pruritis of external auditory canal, pharyngotympanic dysfunction, 
mucosal hemorrhage, and weight loss.  
 
Late Reactions: Unlikely toxicities include xerostomia, dental caries, dysgeusia, 
tracheoesophageal fistula, vascular rupture, hypothyroidism.  Cataracts are possible but 
uncommon. Other possible but rare late effects include damage to the eye with the possibility of 
blindness, accelerated atherosclerosis, severe neuropsychological dysfunction, damage to spinal 
cord, brachial plexopathy, symptomatic esophageal stricture. 
 
7.1.3 
Additional Adverse Events Associated with Lung/Mediastinal Radiation 
Acute Reactions: Cough and esophagitis (if the esophagus is included in the radiation therapy 
portal) are likely. Severe esophagitis (requiring IV hydration, therapy interruption, or severe 
cough), shortness of breath, and hemoptysis are possible but less likely. 
 
Late Reactions: Asymptomatic fibrotic changes in the lung seen on chest imaging are likely.  
Severe pneumonitis or fibrosis of lung resulting in severe respiratory compromise, symptomatic 
esophageal stricture, radiation pericarditis, and myocardial injury, spinal cord injury, and 
brachioplexopathy are possible but unlikely side effects of radiation.   
 
7.1.4 
Additional Adverse Events Associated with Abdominal/Pelvic Radiation 
Acute Reactions: Anorexia, diarrhea, nausea, and vomiting are likely but dependent on the 
volume of stomach and bowel in the treatment fields. Urinary urgency and dysuria are likely if the 
bladder is in the radiation therapy fields. Severe nausea, vomiting, and/or diarrhea that requires 
therapy interruption or IV fluid replacement, abnormal liver function or renal function tests, and low 

 
15
blood counts are less likely but possible.  Pain with defecation and mild to severe rectal bleeding 
are possible. 
 
Late Reactions: hepatitis, nephritis, bowel obstruction or perforation, radiation cystitis, or proctitis 
are possible but unlikely.  Erectile dysfunction is also unlikely.  Damage to spinal cord is possible 
but unlikely.   
 
7.1.5 
Additional Adverse Events Associated with Radiation to the Soft Tissues or Bones in the 
Extremities 
Acute Reactions: Minor skin reactions are likely; moist desquamation is possible but unlikely. 
 
Late Reactions: Swelling of the treated region and poor wound healing are possible but unlikely. 
Pathologic fracture of the bone, severe debilitating swelling, weakness, and radiation-induced 
neoplasm are possible but unlikely.  Fibrosis of extremity and joints with resulting pain and/or 
decreased extremity function is possible but unlikely. 
 
7.1.6 
Additional Adverse Events Associated with Radiation to the Spine 
The possible acute and late toxicities of radiation to the spine will include those that affect 
radiation to the region of the body in which the spine is being treated (i.e. head and neck, chest, 
abdomen, pelvis).  Additionally, rarely, patients could develop damage to the spinal cord or cauda 
equina resulting in severe neurologic dysfunction/paralysis. 
 
7.1.7 
Treatment of Adverse Events: 
All attempts should be made to limit the symptoms and the overall impact of acute and late effects 
of radiation.  Side effects of treatment may be treated per standard of care supportive agents.   
 
 
 
8.  
Adverse Event Reporting 
 
 
University of Chicago Reporting Guidelines 
8.1 If the adverse event requires reporting, the Research Nurse or MD reports the adverse reaction to 
the Cancer Clinical Trials Office (CCTO) at 773-702-5149 by the end of the business day when 
he/she becomes aware of the event.  Events occurring after business hours will be reported to the 
CCTO by 12 pm (noon) the next business day. 
 
8.2 The following information is required when calling in the event: 
 
Caller’s Name and Telephone Number 
 
Patient Initials 
 
Patient Medical Record Number 
 
IRB Protocol Number 
 
PI of Study 
 
Attending Physician 
 
Date of Event 
 
Description of Event (including grade of the event and attribution of the event and if the 
event required hospitalization) 
 
8.3 E-mail is sent to the research nurse, attending physician and PI of the study informing them that   
adverse reaction notification has been received. 
 
 
8.4 The University of Chicago’s IRB Serious Adverse Event Form must be sent to the CCTO within 5 
calendar days of event occurrence.  The UC IRB Serious Adverse Event form is available on-
line at: http://ors.bsd.uchicago.edu/HS/newirbforms. This form must be typed. Once the forms are 
completed, the original is forwarded to the study PI to review and sign. The signed report is 
delivered to the QA Coordinator. A weekly report of delinquent or pending documents will be 
forwarded to the applicable person who reported the event. All delinquent reporting (greater than 

 
16
10 days from event occurrence) must include documentation of reason for delinquency and may 
require implementation of an action plan.   
 
8.5 Once the appropriate AE documents have been received, the CCTO forwards these to the IRB. A 
copy will be forwarded to the appropriate Research Nurse. 
 
 
9. 
Data Safety and Monitoring 
 
Data Safety and Monitoring will occur at the weekly University of Chicago GU oncology phase I/II 
conference meetings, which are lead by senior level medical oncologists.  At each meeting, all 
active studies will be reviewed for safety and progress toward completion. Toxicities and adverse 
events will be reviewed at each meeting and a Data Safety and Monitoring form will be completed 
for each protocol and signed by either the Principal Investigator, the Chairman of the Department 
or by his designate if the Chairman is not available. 
 
 
10. 
STUDY CALENDAR 
 
Baseline CBC, serum chemistry, and pregnancy test (if indicated) are to be conducted within 30 
days prior to study registration.  Scans and x-rays must be done <6 weeks prior to study 
registration.   
 
 
 
 
Pre-
Study 
Wk 1 
Wk 2 
Wk 3-
4 
1 Mo 
Post-
RT^ 
2 Mo 
Post-
RT^ 
3 mo 
Post-
RT^ 
6 mo 
Post-
RT^ 
9 mo 
Post-RT^ 
1 yr 
Post-
RT^ 
Radiotherapy 
R 
R 
(R) 
 
 
Informed Consent 
X 
 
 
Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concurrent meds 
X 
x 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinic Visit  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pain Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC/platelets 
X 
X* 
X* 
 
X* 
 
 
 
Serum chemistrya 
X 
X* 
X*  
X*  
X* 
 
X* 
X* 
X* 
X* 
Plasma# 
X 
 
 
 
 
 
X 
X 
 
X 
Radiographic 
imagingb 
X 
 
 
 
 
 
X 
X 
X 
X 
B-HCGc 
X 
 
 
^: Date of post-treatment visit will correspond to the start date (first day) of SBRT 
R:  Radiotherapy: 10 Gy x 5 fractions, or maximum safe dose to all extracranial sites, and size based SRS 
a:  Albumin, alkaline phosphatase, total bilirubin, bicarbonate,  calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
b:  CT of the head, chest, abdomen, and pelvis, and any other pertinent imaging based on clinical situation  are required within 
28 days of each visit. 
c:  Serum pregnancy test (women of childbearing potential) 
*:  CBC and serum chemistry may be obtained per physician discretion following initial assessment. However, it is required to 
check AST and ALT if SBRT is delivered to liver, at each week of RT, at 1 month post-RT, and at each q3 month follow-up 
interval (3, 6, 9, 12 months post-RT). 
#: For patients who provide consent 

 
17
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effects and Endpoints  
Although response is not the primary endpoint of this trial, patients with measurable disease 
will be assessed by standard criteria.  For the purposes of this study, patients should be re-
evaluated at follow-up visits within one month of completion of radiotherapy, and then 
subsequently every 3 months for one year.  CT of the chest, abdomen, and pelvis, and any 
other pertinent imaging (e.g. CT or MRI head for brain metastases) are required within 28 
days of each follow-up visit. 
 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [68].  
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST criteria. 
 
11.1.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with radiotherapy. 
 
Evaluable for objective response.  Patients who have had their disease re-evaluated 
following completion of radiotherapy will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated below.   
 
11.1.2 Disease Parameters 
Target lesions.  All lesions which are visible on imaging prior to SBRT and are targets for 
radiotherapy will be considered target lesions and should be recorded and measured at 
baseline.   
 
Non-target lesions.  Any metastatic lesions that arise in follow-up imaging after completion 
of radiotherapy which were not target lesions for the initial radiotherapy. These sites of 
relapse are not required to receive treatment with SBRT, but may be treated at the 
discretion of the treating clinician. The treatment may be palliative or locally aggressive, 
and is not subject to the guidelines of the radiation treatment parameters described in 
section 6.  
 
11.1.3 Methods for Evaluation of Disease 
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 study 
enrollment and treatment and never more than 4 weeks before study enrollment. 
 
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. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Conventional CT and MRI:  These techniques should be performed with cuts of 5 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. 
 
11.1.4 Response Criteria 

 
18
 
11.1.4.1 Evaluation of Target Lesions will occur to determine lesion control at each CT scan 
evaluation. Local control will be defined as the lack of progressive disease based on the 
criteria below: 
 
Complete Response (CR):  
Disappearance of target lesion 
 
Partial Response (PR):  
At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesion, taking as 
reference the baseline sum LD 
 
Progressive Disease (PD):  
At least a 20% increase in the sum of the LD of 
target lesion, taking as reference the smallest 
sum LD recorded since the treatment 
 
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 
 
11.1.4.2 Evaluation of Non-Target Lesions 
By definition, the appearance of new non-target lesions following completion of 
radiotherapy will be considered overall progressive disease.  
 
If for any reason the response of non-target lesions to systemic therapy is 
needed, the same criteria as those for target lesions will be used for Complete 
Response, Partial Response, Progressive disease, and Stable disease for each 
individual non-target lesion during follow-up evaluations. 
11.1.5 Endpoint Definitions 
 
 
 
 
 
Duration of treated lesion control 
Duration of time from start of treatment to the time of local progression at each treated lesion. 
 Local progression is defined as any progressive disease as judged by RECIST criteria of 
treated lesions 
 
 
 
 
Organ-specific control 
Duration of time from start of treatment to the time of development of a new lesion on imaging 
within an organ in which a lesion was treated with SBRT. 
 
 
 
 
Progression-free survival 
Duration of time from start of treatment to time of progression.  Progression is defined as any 
new sites of disease on imaging or any progressive disease by RECIST criteria at initially 
treated sites of disease (within 80% isodose line).  
 
 
 
 
 
 
 
11.2 Dosimetric description of delivery of Radiotherapy 
Radiation plans, target volumes, and DVHs will be reviewed to assess for acceptable doses 
based on site and normal tissue toxicity dose constraints.  Descriptive statistics will be 
calculated for each dose cohort to characterize these dosimetric parameters. The relationship 
between grade of toxicity and dose parameters will also be described.  
 
12. STATISTICAL CONSIDERATIONS 
 
 
12.1 Study Design/Endpoints 

 
19
This is a pilot study of the use of 5-fraction SBRT for oligometastatic RCC.  Patients enrolled 
in the study will be treated with SBRT to all sites of disease. Enrollment will proceed according 
to a sequential toxicity monitoring schema [69] to test the null hypothesis of a π0=5% grade 4 
toxicity rate against an upper acceptable boundary of a π1=20% grade 4 toxicity rate. Trial 
enrollment will be halted if there are two grade 4 events within the first 2 patients, if there are 
three events within the first 14 patients, or if there are four events within the first 25 patients. 
The treatment will be considered successful if there are less than four events in 25  patients, 
i.e., <16% observed toxicities. This design has approximately 80% power (78.8%) to declare 
the treatment too toxic if the true grade 4 toxicity rate is π1=20%.   
 
Patients will be followed for a total of one year after completion of the trial per protocol.  
Patients may be treated with off-protocol systemic therapy no earlier than 2 weeks after 
completion of RT.  The primary endpoint is the rate of grade 4 RT-related toxicity with this 
treatment approach.  Secondary endpoints include determining the toxicity profile of 5-fraction 
SBRT, determining the feasibility of 5-fraction SBRT based on normal tissue dosimetric 
constraints based on the organ site of involvement, describing the LeC, PFS, and patterns of 
failure of this approach, as well as to explore the feasibility of accrual and the adequacy of the 
eligibility criteria of this approach. 
 
 
 
12.2 Sample Size/Accrual Rate 
 
 
 
 
The maximum sample size will be 25 evaluable patients according to the schema above. 
This sample size is needed in order to signify feasibility of this disease approach and accrual 
to a larger, later phase trial. 
 
 
12.3 Stratification Factors 
 
 
 
 
Patients will be stratified by the number of lesions and presence/absence of brain 
metastasis; index lesions will be stratified by the size and location.   
 
 
12.4 Analysis of the Primary Endpoint  
 
 
 
 
The primary endpoint is the rate of grade ≥4 RT-related toxicity with this treatment 
approach.  RT-related toxicity will be recorded as specified in the study calendar (section 10). 
 All toxicity will be determined to be RT-related or non-RT-related by the study committee.   
 
 
12.5 Analysis of Secondary Endpoints 
 
 
 
 
The secondary endpoints of this study include determining the toxicity profile, LeC, and 
patterns of failure of this approach, as well as the feasibility of a 5-fraction SBRT regimen 
based on normal tissue dose constraint and treatment goals, and the feasibility of accrual to 
an oligometastasis trial in RCC and adequacy of the eligibility criteria.   
 
 
 
 
A database will be created that is HIPAA compliant to store the information to perform 
analyses.  A unique study number will be assigned to each patient that will be used for all 
analyses. Variables will be defined as described in section 11.  The results of analyses will be 
described but no formal statistical analysis will be performed. 
 
 
 
 
Grade ≥4 RT-related toxicities will be recorded in database and are described as in section 
5.2.  The ultimate allocation of a toxicity as RT-related or non-RT-related will be decided by 
the study committee.  Toxicities of interest that occur within the 3-12 month time frame after 
RT start will be documented and analyzed using descriptive statistics.  
 
 
 
 
The durations of treated lesion control, organ-specific control, distant metastasis free survival, 
progression-free, overall and cause specific survival as defined in section 11.1.5 will be 
calculated for each patient.  Descriptive statistics will be used to estimate these secondary 
endpoints using the Kaplan-Meier method (secondary aims 1.2.1, 1.2.3). 
 
 
 
 
The radiotherapy doses for each treated site will be recorded.  The doses to the 

 
20
corresponding normal tissues will also be recorded.  The maximum dose to each site while 
staying within dose constraints will be described.  The dose to each lesion will also be 
compared to the local control of the corresponding lesion and described. 
 
13.  CONFIDENTIALITY 
 
 
13.1 
Patient Confidentiality Issues 
 
Study records that identify patients will be kept confidential. Study records will contain 
patients’ name, address, and medical history number and will be available to the study 
doctor, research nurse, and data coordinator.  Data collected in this study will be 
maintained on a password protected computer that only the primary investigator, co-
investigators, research nurse, and data coordinator will be able to access.  Study records 
will be secured in locked offices in the Department of Radiation and Cellular Oncology.  
Neither patient’s name nor other personally identifying information will be used in any 
publication resulting from the research study. 
 
14. BLOOD BANKING FOR FUTURE RESEARCH 
 
 
14.1 
Collection of blood  
 
Biomarkers that have prognostic or predictive value are of great interest in the setting of 
managing patients with oligometastatic disease. Currently, the selection of patients for 
locally aggressive treatment to metastatic disease is based on clinical factors, such as 
tumor characteristics, interval to metastatic progression, burden of metastatic disease, 
and patient age or health. Circulating cell-free DNA is one such potential biomarker that 
can help identify the best patients for this therapy, given that patients with renal cell 
carcinoma have a higher content of cell-free DNA compared to normal controls [70]. 
 
Blood samples for future research will be collected for patients who provide consent. 
Blood (5 mL) will be drawn at 4 points during the study. This blood draw will be performed 
at the same time as phlebotomy for routine care purposes at baseline (pre-treatment), 3, 
6 and 12 months post -RT. The blood will be labeled with the date of collection, the 
patient’s initials, and protocol number.  

 
21
 
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24
 
 
APPENDIX A 
 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction.
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). 
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. 
3 
In bed >50% of the time.  
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to 
bed or chair. 
5 
Dead.