Conditions: Oligometastatic Disease
Keywords: Oligo mets Radiosurgery Stereotactic Body Radiotherapy (SBRT) (Stereotactic radiosurgery (SRS) plus stereotactic radiotherapy (SRT))
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
This study will evaluate the feasibility of radiosurgery for all metastatic sites in patients presenting with oligometastatic disease, defined here as 5 or fewer sites of metastatic disease involving 3 or fewer organ systems.

Detailed description:
Death from metastatic cancer is a common cause of death, accounting for 80-90% of cancer deaths. The classic thought process is that metastatic disease represents the continuum such that known metastatic disease is an inevitable harbinger for subsequent metastatic disease. However, it has been reported that a subset of patients with limited volume metastatic disease may have a better prognosis if given aggressive therapy. This group of patients has become known as "oligometastatic". These patients are potentially curable with stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) (collectively referred to as stereotactic body radiotherapy or SBRT) to the metastatic disease sites in combination with standard curative therapy to the primary site. Patients in this study receive SRS/SBRT to all sites of oligometastatic disease.

Arms:
arm 1: Sequence of therapy: SRS/SBRT will be used for all sites of metastatic disease in close approximation to initiation of treatment for the primary disease site (within 6 weeks). Ideally, SRS/SBRT would occur first followed by treatment to primary site. However, in some circumstances surgical resection of the primary site could precede SRS/SBRT, especially if surgical resection is required for pathological confirmation of disease.

Chemotherapy choice of agents is at the discretion of the treating medical oncologist; chemotherapy may be initiated after stereotactic radiosurgery treatment of the primary disease site has been completed.

Interventions: intervention 1: Stereotactic Radiosurgery (SRS) intervention 2: Chemotherapy
Intervention descriptions: intervention 1: Dose and fractionation will be dependent on the lesion location and lesion size, the exact fractionation and dose is at the discretion of the treating physician. A minimum of 48 hours must be used in between SRS treatments at each site. Patients may have SRS everyday or multiple SRS sessions in one day as long as the minimum time for each treatment site is met. intervention 2: Chemotherapy choice of agents is at the discretion of the treating medical oncologist.

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 28 
HCC 10-027 
 
HCC 10-027: Phase II study for Curative Intent Treatment for Patients with 
Oligometastatic Disease at Initial Presentation 
 
 
 
Protocol version:  
 
02/13/2023 
 
 
Principal Investigator: 
Steve Burton- Assistant Professor 
Department of Radiation Oncology 
UPMC Presbyterian Shadyside 
burtons@upmc.edu 
Ph (412) 623-6720 
Fax (412) 623-1475 
 
Statistician 
 
Hong Wang, PhD 
UPMC Cancer Pavilion POB2, Suite 4C 
5150 Centre Ave,  
Pittsburgh, PA 15232 
how8@pitt.edu  
Ph (412) 383-1588 
 
NCT Number:   
 
NCT01345539 
 
IND Number 
 
 
Exempt 


Page 2 of 28 
HCC 10-027 
 
 
 
 
  
Table of Contents 
Summary ................................................................................................................................................ 3 
1.0 
INTRODUCTION ........................................................................................................................ 4 
2.0 
OBJECTIVES ............................................................................................................................. 6 
3.0 
PATIENT SELECTION ............................................................................................................... 6 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT................................................................. 8 
5.0 
TREATMENT OVERVIEW ......................................................................................................... 9 
6.0 
RADIATION THERAPY .............................................................................................................. 9 
7.0 
DRUG THERAPY ..................................................................................................................... 11 
8.0 
SURGERY ................................................................................................................................ 11 
9.0 
OTHER THERAPY ................................................................................................................... 11 
10.0 
PATIENT ASSESSMENTS ...................................................................................................... 12 
11.0 
STATISTICAL CONSIDERATIONS ......................................................................................... 13 
12.0     DATA SAFETY AND RECORDING ......................................................................................... 14 
REFERENCES ..................................................................................................................................... 19 
APPENDIX I - Schedule of events ....................................................................................................... 22 
APPENDIX II - Performance status scoring ......................................................................................... 23 
APPENDIX III  - Guidelines for SRS/SBRT dosing and fractionation .................................................. 24 
APPENDIX IV - Sample of QOL form (FACT-G) ................................................................................. 27 
 
 
  


Page 3 of 28 
HCC 10-027 
 
 
Summary 
 
Title: Phase II Study for Curative Intent Treatment for Patients Presenting with 
Oligometastatic Disease at Initial Presentation 
 
Hypothesis: Patients with oligometastatic disease (defined here as 5 or fewer sites of metastatic 
disease involving 3 or fewer organ systems) are potentially curable with stereotactic radiosurgery 
(SRS) or stereotactic radiotherapy (SRT) (collectively referred to as stereotactic body radiotherapy or 
SBRT) to the metastatic disease sites in combination with standard curative therapy to the primary 
site.  
 
Primary objective: Delivery of SBRT to multiple sites in a safe and effective manner with acceptable 
toxicity 
 
Primary Endpoints:  
• 
Presence of multiple sites (between 2 and 5 sites)  
• 
Acceptable toxicity: Grade 3 or less 
 
Secondary Objectives/Endpoints: 
• 
Quality of life (as measured by the FACT quality of life surveys, see appendix IV)   
• 
Local control of metastatic sites (with measurable/quantitative assessment):  proportion of 
patients with Complete Response (CR), Partial Response (PR), or Stable Disease (SD)  
• 
Local control of primary site (with measurable/quantitative assessment): proportion of 
patients with local Complete Response (CR), Partial Response (PR), or Stable Disease (SD)  
• 
Overall survival (OS) 
• 
Two-year Overall Survival  
• 
Analysis of patterns of failure post-SRS/SBRT (subsequent sites of failure and time to 
failure): proportion of patients with Progressive Disease (PD)  
 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients with oligometastatic* disease 
At initial presentation# 
SRS/SBRT to sites of metastatic disease 
 
Treatment to primary disease as per UPMC Clinical 
Pathways or NCCN guidelines for an M0 patient 
(Treatment could involve surgery, chemotherapy, radiation or combination) 
Chemotherapy at discretion of medical oncologist 


Page 4 of 28 
HCC 10-027 
 
*  oligometastatic disease defined as 5 or fewer sites of metastatic disease involving 3 or 
fewer organs 
# Only patients with oligometastatic disease at presentation are eligible. Patients with 
recurrent disease are not eligible for this study.   
 
 
 
 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility)  
Patients with stage IV (M1) disease at initial presentation (newly diagnosed) who have 5 or fewer 
sites of metastatic disease involving 3 or fewer organ systems Patients have not had previous 
therapy for disease. 
 
 
REQUIRED SAMPLE SIZE: 44 PATIENTS (SEE SECTION 11.0) 
 
1.0 
INTRODUCTION 
Death from metastatic cancer is a common cause of death, accounting for 80-90% of cancer 
deaths (3). The classic thought process is that metastatic disease is incurable and thus treatment, if 
given, is often palliative. However, it has been reported that a subset of patients with limited volume 
metastatic disease are in fact curable if given aggressive therapy. This group of patients has become 
known as “oligometastatic”. The concept of oligometastatic disease was established by Hellman in 
the mid 90’s (11, 12). The concept states that there is an evolution or progression of malignant cells 
through acquired mutations or other mechanisms that allow the cancer to have a step-wise pattern of 
spread. Cancer cells must first acquire the ability to spread beyond the original disease site, then 
acquire the ability to establish metastatic lesions (often involving vascularization) and then acquire the 
ability for further spread. Furthermore, tumor cells may require specific conditions at each step in the 
process, and that different cancers have different host conditions required for successful metastases, 
this concept is known as the ‘seed and soil’ theory (13-14) which explains a step in the process from 
localized disease to widespread metastatic disease. The step in the process between localized 
disease and widespread metastatic disease is referred to as “oligometastatic disease”. Because 
oligometastatic disease has not yet acquired the ability for widespread tumor cell dissociation, the 
sites of tumor burden are limited. In theory, if the primary tumor and the sites of oligometastatic 
disease could be successfully treated, it would be possible to cure such patients.  
 
 
This theory has been, in retrospective reviews, shown to be potentially true for numerous 
cancer types. Patients with limited metastatic disease (oligometastatic disease) to the liver from colon 
cancer who received aggressive therapy to the liver lesions have had survival rates much better than 
would be predicted for stage IV disease. Five-year survival rates following liver resection for 
metastatic colon cancer range between 25% and 55% compared with 0% and 5% for non-operated 
patients (43). This has also been shown to be true for metastatic disease in bone (29), brain (30), 
pancreas (1) and lung (31).  
 
 
Similarly, treatment of the primary lesion in the setting of metastatic disease has been shown 
to improve survival in breast cancer (33-39), renal cell cancer (40), gastric cancer (41) and melanoma 
(42).University of Chicago (33) reported 22% long term survival in NSCLC patients presenting with 1-
2 metastatic sites treated with aggressive therapy. 
 
 
While surgical resection has been the first treatment option evaluated in oligometastatic 
patients, radiation is another viable treatment option. Stereotactic radiosurgery (SRS) and stereotactic 
radiotherapy (SRT) involve high radiation doses delivered in a very conformal manner. SRS and SRT 
(collectively known as stereotactic body radiotherapy or SBRT) involve limited radiation to 


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HCC 10-027 
 
surrounding normal tissue yet are capable of curative doses of radiation to the primary target. SBRT 
is well tolerated and can be performed in patients who are not fit for surgery, the mortality of SBRT is 
exceedingly low, and the number of treatments for SBRT ranges from 1 to 10 making it less 
burdensome for patients.  
 
 
SBRT has been evaluated for treatment of oligometastatic disease in multiple sites. Flickinger 
(15) reported good outcomes for patients with solitary CNS metastatic lesions treated with gamma 
knife radiosurgery. Similar good outcomes in this setting have been reported by others (44-46).  
 
Multiple reports are available on SBRT for lung tumors. In several series reporting both 
primary and metastatic lung tumors treated with SBRT (with 3-5 fractions), local control rates have 
been impressive, ranging from 70% to 90% (34,42,43). Furthermore, toxicity has been mild, most 
commonly limited to radiographic lung changes. A phase I dose-escalation trial was performed for 
patients with lung metastases from various primary sites. SBRT dose was successfully escalated to 
60 Gy in three fractions with minimal toxicity reported (21). A case series reported 50 patients with 
lung metastases who were treated at University of Rochester, most of whom (62%) received 5 
Gy/fraction for a total of 50 Gy. Up to five targets were treated per patient. With a mean follow-up of 
18.7 months local control of treated lesions was obtained in 42 of 49 evaluable patients (83%). Only 
2% had grade 3 toxicity (22). Investigators from Japan reported treating 1–2 pulmonary metastases in 
34 patients with various primary tumors using 12 Gy fractions to doses of 48 or 60 Gy, at 2 years, 
90% of patients were free of local failure. (18). Little toxicity has been reported when SBRT is used to 
treat peripheral lung tumors, with pneumonitis rates varying from 0% to 10% (19-20). 
 
The role of SBRT for liver lesions was evaluated in a pilot study of 31 patients with a variety 
of primary tumors, 17 liver metastases in 14 patients were treated with doses of 7.7–45 Gy in 1–4 
fractions. Of 13 lesions treated with greater than 20 Gy, only one lesion progressed with a mean 
follow-up of almost 10 months (23). A phase I multi-institutional trial sequentially escalated doses up 
to 60 Gy in three fractions. It was reported that the maximum tolerated dose (MTD) was not reached 
and a single patient out of 36 patients failed in-field at a median follow-up of 19 months (24). 
 
The outcomes of patients treated with SBRT for multiple organ metastases have also been 
reported. The University of Rochester reported an analysis on 121 patients with 1–5 metastases 
treated on two consecutive protocols. Patients on both protocols could have had previous therapy for 
their disease; only 27 patients had oligometastatic disease at initial presentation. The first protocol 
treated breast cancer patients with limited metastases, in which no brain lesions were treated. The 
second protocol included patients with cancer from any primary site and limited metastases including 
a brain primary. After treatment with ten fractions of 5 Gy over 2 weeks (10 fractions), metastatic 
lesions were controlled 77% of the time at 2 years (25). Milano (5) reported prospective data on 
breast cancer patients with oligometastatic disease (less than 5 sites) comparing patients treated with 
SBRT to those receiving only palliative therapy. Four-year survival was significantly improved in 
SBRT patients (59% versus 0%). University of Chicago (53) reported on a prospective trial in 29 
oligometastatic patients (one to five sites and a life expectancy > 3 months, 81% had prior systemic 
treatment) who had 56 metastatic lesions treated with SBRT (3 fractions ranging from a total dose of 
24 to 36 Gy). The authors found a control rate of 56% for treated sites and only 2 patients had grade 
3 or higher toxicity.   
  
 
From the data available, patients with oligometastatic disease appear to benefit in terms of 
disease control from SBRT. At this point, no one is able to adequately predict which patients have 
favorable oligometastatic disease and are good candidates for aggressive and potentially curative 
therapy and which patients are destined to have development of widespread metastatic disease. 
Some proposed factors for patients likely to proceed to widespread metastatic disease include size 
and grade of primary tumor, site of oligometastatic disease, and lymph node status. In order to best 
treat patients, it is important that careful studies be performed to collect clinical information on 
patients with oligometastatic disease to analyze patient subsets most likely to benefit from treatment.  
 
 
While disease outcome is certainly an important endpoint, quality of life (QOL) also is of 
significant importance, especially in patients with metastatic disease that have traditionally thought to 


Page 6 of 28 
HCC 10-027 
 
be incurable. It is important that, until aggressive treatment for oligometastatic disease becomes 
standard of care, careful attention is paid to the quality of life in treated patients. Multiple validated 
QOL surveys are available for a variety of cancer sites. Collection of such surveys will help to monitor 
the impact of treatment on QOL.  
 
 
To our knowledge, there have not been any prospective trials examining the role of 
aggressive therapy in the treatment of oligometastatic disease only at initial presentation. None of the 
previously described reports include only patients at initial presentation; the majority of patients in the 
prospective and retrospective oligometastatic studies have had previous therapy.  In order to better 
evaluate the role of curative therapy in patients presenting with oligometastatic disease we are 
proposing a prospective study of this patient cohort. Patients with oligometastatic disease (defined for 
this study as 5 or fewer sites of disease involving 3 or fewer organ systems) will receive SRS/SBRT 
to all sites of oligometastatic disease and standard curative therapy to the primary disease. The 
primary objective for this study will be feasibility with the potential for an eventual phase III study. In 
addition, clinical and translational information will be collected to better stratify patients with 
oligometastatic disease for future studies.  
  
 
2.0 
OBJECTIVES 
  
Primary objective: Delivery of SBRT to multiple sites in a safe and effective manner with acceptable 
toxicity 
 
Primary Endpoints:  
• 
Presence of multiple sites (between 2 and 5 sites)  
• 
Acceptable toxicity: Grade 3 or less 
 
Secondary Objectives/Endpoints: 
• 
Quality of life (as measured by the FACT quality of life surveys, see appendix IV)   
• 
Local control of metastatic sites (with measurable/quantitative assessment):  proportion of 
patients with Complete Response (CR), Partial Response (PR), or Stable Disease (SD)  
• 
Local control of primary site (with measurable/quantitative assessment): proportion of 
patients with local Complete Response (CR), Partial Response (PR), or Stable Disease (SD)  
• 
Overall survival (OS) 
• 
Two-year Overall Survival  
• 
Analysis of patterns of failure post-SRS/SBRT (subsequent sites of failure and time to 
failure): proportion of patients with Progressive Disease (PD)  
3.0 
PATIENT SELECTION 
 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED  
 
3.1 
Conditions for Patient Eligibility 
 
3.1.1 
Pathologically (histologically or cytologically) proven diagnosis of solid malignancy 
within 8 weeks of registration 
NOTE: FDG-PET/CT scans are required for full staging of metastatic disease.  If subject 
has had an FDG-PET/CT scan within the last 8 weeks, it will not need to be 
repeated. 
NOTE: Pathological confirmation is not required for all disease sites as long as the 
sites of metastatic disease are radiographically and clinically consistent with 
metastatic disease from a known (biopsy proven) primary.  
NOTE: the primary site does not have to be the site of pathological confirmation. For 
example, in a patient with a radiographic lung lesion with mediastinal 


Page 7 of 28 
HCC 10-027 
 
lymphadenopathy and a liver lesion, a liver biopsy which is constant with 
lung primary would preclude the necessity for further pathologic diagnosis.  
 
3.1.2 
Eligible disease sites include the following newly diagnosed disease types: 
1. Breast 
2. Prostate 
3. GI (including colorectal, anal, esophagus, pancreas, gastric with the exception 
of colon cancer with resectable liver-only lesions) 
4. Head and neck 
5. Skin (melanoma and squamous cell carcinoma) 
6. Lung (both small cell and non-small cell) 
7. Sarcoma (both soft tissue and bone) 
8. Gynecologic (endometrial, cervical, ovarian, vaginal, vulvar)  
3.1.3      Patients are stage IV (M1) with any combination of T and N with oligometastatic 
disease as defined by 5 or fewer total sites of metastatic disease involving 3 or 
fewer organ systems 
3.1.3.1 Examples of patients eligible for trial 
• 
T3N2M1 NSCLC with 1 CNS metastatic lesion, 2 liver lesions, and 1 
adrenal lesion.  
• 
T4N1M1 colorectal cancer with 1 liver lesion, 4 bone lesions  
• 
T3N0M1 gastric cancer with 1 supraclavicular lymph node, 2 liver 
lesions, and 2 CNS lesions 
3.1.4 
Metastatic disease sites must be treatable with SRS (at discretion of treating 
physician).  
3.1.5 
Primary disease site must be able to be treated with curative intent  
3.1.6 
Zubrod Performance Status 0-1 
3.1.7 
Age ≥ 18 
3.1.8 
CBC/differential obtained within 4 weeks prior to registration on study, with 
adequate bone marrow function defined as follows: 
3.1.8.1 
Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3;  
3.1.8.2 
Platelets ≥ 100,000 cells/mm3;  
3.1.8.3 
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other 
intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.); 
3.1.9 
Women of childbearing potential and male participants must practice adequate 
contraception 
3.1.10 
Patient must provide study specific informed consent prior to study entry. 
 
3.2 
Conditions for Patient Ineligibility 
3.2.1 
Ineligible disease sites include the following 
• 
Lymphoma 
• 
Leukemia 
• 
Multiple myeloma 
• 
Primary CNS 
• 
Peritoneal carcinomatosis  
• 
Colon cancer with resectable liver-only lesions  
 
3.2.2 Examples of patients ineligible for trial 
• 
T1N1M1 NSCLC with 1 CNS lesion, 1 bone lesion, 1 adrenal lesion and a cervical 
lymph node (4 sites of metastatic disease) 
• 
T2N1M1 Gastric cancer with 6 liver lesions (more than 5 sites of metastatic disease) 
  
3.2.3 Other  
• 
Lung cancer with pleural effusion (wet IIIB) are not eligible  
• 
Recurrent cancers are not eligible  
• 
Diffuse metastatic spread confined to one organ system is ineligible; examples of this 
include leptomeningeal spread in the CNS and peritoneal carcinomatosis.  


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HCC 10-027 
 
    
3.2.4 Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a 
different cancer is allowable but cannot have any other primary cancer diagnosed or 
treated within the last 3 years other than cutaneous skin cancers. Patient may have 
previous chemotherapy as treatment of this previous malignancy as long as the 
chemotherapy has completed more than 3 years ago. 
 
3.2.5 Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields 
 
3.2.6 
Severe, active co-morbidity, defined as follows: 
3.2.6.1 
Unstable angina and/or congestive heart failure requiring hospitalization 
within the last 6 months; 
3.2.6.2 
Transmural myocardial infarction within the last 6 months; 
3.2.6.3 
Acute bacterial or fungal infection requiring intravenous antibiotics at the 
time of registration; 
3.2.6.4 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation 
defects; note, however, that laboratory tests for liver function and 
coagulation parameters are not required for entry into this protocol. 
 
3.2.7 
Pregnancy or women of childbearing potential and men who are sexually active 
and not willing/able to use medically acceptable forms of contraception; this 
exclusion is necessary because the treatment involved in this study may be 
significantly teratogenic.  
 
3.2.8  
  Oligometastatic disease sites not eligible based on concern for toxicity:  
 * trachea involvement (direct invasion, tumors close to or abutting trachea are 
eligible) 
 * heart (direct invasion or involvement, pericardial lymph nodes can be 
treated) 
 
3.2.9       Patients unable to have an FDG-PET/CT scan, either through insurance coverage,  
patient decision or other reason are not eligible for this study.  
 
3.2.10 
Patients unable to have SRS/SBRT through insurance coverage or ability to pay for 
SRS/SBRT 
 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT 
NOTE: This section lists baseline evaluations needed before the initiation of protocol 
treatment that do not affect eligibility.  
 
4.1 The following are to be completed prior to treatment  
 
• 
Complete history and physical 
• 
Staging workup to determine oligometastatic disease, note that FDG-PET/CT scan is 
mandatory. Minimum metastatic workup is per NCCN guidelines for specific cancer 
type.  If subject has had an FDG-PET/CT scan within the last 8 weeks, it will not need 
to be repeated. 
• 
Measurements of metastatic disease sites (number of lesions and size of lesions, 
preferably volumetric data is available for better estimate of lesions).  
 
 
 
4.2 The following will be ascertained at Study Registration: 
• 
Name of institutional person registering this case 


Page 9 of 28 
HCC 10-027 
 
• 
Patient eligibility status 
• 
Date the study-specific Consent Form was signed (must be signed prior to study 
entry) 
• 
Patient’s Initials (First Middle Last)  
• 
Verifying Physician 
• 
Patient’s ID Number 
• 
Date of Birth 
• 
Race 
• 
Ethnic Category (Hispanic or Latino; Not Hispanic or Latino; Unknown) 
• 
Gender 
• 
Treatment Start Date 
 
 
5.0 
 TREATMENT OVERVIEW 
• 
Treatment of metastatic disease: all sites of metastatic disease will be treated with 
SRS or SBRT (see section 6.0) 
 
• 
Treatment of primary disease: primary disease will be treated using surgery, 
chemotherapy, radiation, or a combination of all three (see section 6.0, 7.0, 8.0). 
Treatment of the primary disease will be as per the UPMC pathway guidelines or 
NCCN guidelines individualized for the patient’s stage and disease site with the 
exception that the patient will be considered M0 instead of M1. (For example, 
T3N3M1 NSCLC would be considered T3N3M0 and treated with definitive 
chemoradiotherapy).   
 
• 
Sequence of therapy: SRS/SBRT will be used for all sites of metastatic disease in 
close approximation to initiation of treatment for the primary disease site (within 6 
weeks). Ideally, SRS/SBRT would occur first followed by treatment to primary site. 
However, in some circumstances surgical resection of the primary site could precede 
SRS/SBRT, especially if surgical resection is required for pathological confirmation of 
disease. After completion of SRS/SBRT to the oligometastatic sites and treatment to 
the primary site, systemic chemotherapy can be given at the discretion of the medical 
oncologists (see Section 7.0).  
 
 
6.0 
RADIATION THERAPY 
 
6.1 
Non-radiosurgery radiation 
External beam radiation (when indicated) would be initiated after completion of stereotactic 
radiosurgery. Details of radiation (IMRT or 3D, radiation energies, field sizes, doses, etc) is at 
the discretion of the treating radiation oncologist, encouragement will be given towards 
adherence to the UPMC Clinical Pathways specific to disease and patient characteristics. In 
some disease sites no radiation will be used after the completion of SRS/SBRT (for example, 
T2N0M1 lung cancer treated with SRS/SBRT to oligometastatic site then receiving surgical 
resection). Patients will be treated as if they are M0. 
 
6.2 
Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiation Therapy 
(SBRT) 
See Appendix IV for site-specific SRS/SBRT details. The following are general 
guidelines.  
 
6.2.1 SRS/SBRT Timing: All SRS/SBRT treatments will be completed within 3 weeks 
(preferably 2 weeks).  


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HCC 10-027 
 
 
6.2.2 Technical factors 
SRS/SBRT has been formally defined and described in a published guideline from the 
American College of Radiology and American Society for Therapeutic Radiology and Oncology 
(47). This protocol will respect those guidelines. The term stereotactic for the purposes of this 
protocol implies the targeting, planning, and directing of therapy using beams of radiation along 
any trajectory in 3-D space toward a target of known 3-D coordinates. The coordinate system is 
defined by reliable “fiducial” markers. This differs from conventional radiation therapy, in which 
therapy is directed toward less-than-reliable skin marks or bony landmarks that are indirectly 
referenced to the tumor (surrogates). This protocol will require treatments to be conducted with 
the use of a fixed 3-D coordinate system defined by fiducials. The coordinate system defined by 
the fiducials should be directly related to the radiation-producing device (e.g., couch and 
gantry) in a reproducible and secure fashion. Capability should exist to define the position of 
targets within the patient according to this same 3-D coordinate system. As such, the patient is 
set up for each treatment with the intention of directing the radiation toward an isocenter or 
target according to the known 3-D coordinates as determined in the process of treatment 
planning. The nature of the fiducials themselves may include radiopaque markers or rods 
placed at known locations in a frame or fixed structure adjacent to the patient as well as use of 
the tumor itself as a fiducial (e.g., acquiring tomographic views of the tumor simultaneously with 
the treatment). Metallic “seeds” placed within the tumor will be allowed to constitute a fiducial so 
long as the methods are validated and a plan is in place to identify seed migration (e.g., 
redundant seeds placed). To allow fiducial stabilization and resolution of swelling, planning 
studies will be imaged 5-10 days after fiducial placement. 
 
6.2.3 Patient Positioning 
Patients will be positioned in a stable position capable of allowing accurate reproducibility of the 
target position from treatment to treatment. Positions uncomfortable for the patient should be 
avoided so as to prevent uncontrolled movement during treatments. A variety of immobilization 
systems may be used, including stereotactic frames that surround the patient on three sides 
and large rigid pillows (conforming to patients’ external contours) with reference to the 
stereotactic coordinate system (see Section 6.1). Patient immobilization must be reliable 
enough to ensure that the gross tumor volume (GTV) does not deviate beyond the confines of 
the planning treatment volume (PTV) as defined in Section 6.2.4 with any significant probability 
(i.e., < 5%). 
 
6.2.4 Localization 
Isocenter or reference point port localization images (anterior/posterior and lateral) should be 
obtained at each treatment on the treatment unit or patients should undergo a tomographic 
imaging study immediately before treatment to ensure proper alignment of the geometric center 
(i.e., isocenter) of the simulated fields.  
 
6.2.5 Treatment Planning/Target 
Gross target volume (GTV) will be the tumor lesion defined by CT scan, FDG-PET scan and 
clinical information. Planning treatment volume (PTV) will be GTV with margin appropriate for 
set-up error and movement. There will be no elective nodal coverage.  
 
6.2.6 Radiation doses and fractionation:  
Dose and fractionation will be dependent on the lesion location and lesion size, the exact 
fractionation and dose is at the discretion of the treating physician. However, encouragement is 
made to adhere to the guidelines outlined in Appendix III. A minimum of 48 hours must be used 
in between SRS/SBRT treatments at each site. Note that patients can have SRS/SBRT 
everyday or multiple SRS/SBRT sessions in one day as long as the minimum time for each 
treatment site is met. 
  
For example, if two lung lesions, adrenal, and liver sites were being treated, both lung sites 
could be treated Monday, Wednesday, and Friday, the liver on Tuesday, Thursday and the 
following Tuesday, and the adrenal on Monday, Wednesday, Friday of the second week.  


Page 11 of 28 
HCC 10-027 
 
 
 
 
    EXAMPLE: 
  
Mon 
Tues 
Weds 
Thurs 
Fri 
Wk 1 
Lung #1 
Lung #2 
Liver 
 
Lung #1 
Lung #2 
Liver 
 
Lung #1 
Lung #2 
Wk 2 
Adrenal 
Liver 
 
Adrenal 
 
Adrenal 
 
 
7.0 
DRUG THERAPY 
 
Chemotherapy  
 
7.1 Chemotherapy guidelines for primary disease  
 
Chemotherapy (when indicated) would be initiated after completion of stereotactic radiosurgery. 
Chemotherapy choice of agents is at the discretion of the treating medical oncologist, encouragement 
will be given towards adherence to the UPMC Clinical Pathways specific to disease and patient 
characteristics. In some disease sites no chemotherapy will be used.   
 
 
7.2 Chemotherapy guidelines after treatment for metastatic disease 
 
At the discretion of the medical oncologist, chemotherapy may be initiated after treatment of the 
primary disease site has been completed in accordance with UPMC Clinical Pathways or NCCN 
guidelines for treatment of M1 disease for the patient’s primary disease site.  
 
For example; T1N0M1 NSCLC with solitary adrenal lesion is treated with SBRT to the adrenal lesion 
followed by lobectomy (treatment option for T1N0M0 NSCLC). After surgical resection, medical 
oncologists could choose to place patient on systemic chemotherapy that would be indicated for 
patient with M1 NSCLC).  
 
8.0 
SURGERY 
 
8.1 Surgery guidelines 
 
Surgery (when indicated) would be initiated after completion of stereotactic radiosurgery. Type of 
surgical operation is at the discretion of the treating surgeon, encouragement will be given towards 
adherence to the UPMC pathways specific to disease and patient characteristics. In some disease 
sites no surgery will be used.   
 
9.0 
OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented 
on each site’s source documents as concomitant medication. [Include the following sections 
as appropriate] 
9.1.1 
Anticonvulsants 
9.1.2 
Antiemetics 
9.1.3 
Anticoagulants 
9.1.4 
Antidiarrheals 
9.1.5 
Analgesics 


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9.1.6 
Hematopoietic Growth Factors 
9.1.7 
Herbal products 
9.1.8 
Nutritional supplementation 
 
 
10.0 PATIENT ASSESSMENTS 
10.1 
Study Parameters: See Appendix I. 
 
 
 
10.2 
Evaluation during Study 
10.2.1 If clinically indicated, blood counts and other labs should be obtained during therapy. 
 
10.2.2 Toxicity will be evaluated during the study using Common Cancer Toxicity Criteria V 
4.0  
 
10.3 Evaluation after study 
10.3.1 Patients will be seen in follow-up with study physicians 6 weeks after completion of 
SRS/SBRT and then at 3 month intervals for 3 years and 6 months thereafter.  
 
10.3.2 QOL survey to be performed prior to therapy, after SRS/SBRT and at subsequent 
follow-up visits using the FACT-G survey. See Appendix IV.  
 
10.3.3 Toxicity will be evaluated after the study using Common Cancer Toxicity Criteria V 4.0 
 
10.3.4 Follow-up imaging should be performed at least every 3 months for the first two years 
from completion of therapy and every 6 months afterwards until five years from the 
completion of therapy. FDG-PET/CT scan for follow-up is recommended but not 
required.  
 
10.3.5 Measurement of Response for CT scans  
 
Response will be evaluated in this study using the international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 92(3): 
205-216, 2000] See http://ctep.info.nih.gov/guidelines/recist.html for further details. 
   
1. Measurable disease - the presence of at least one measurable lesion; if the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should 
be confirmed by cytology/histology.  
2. Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 
mm with spiral CT scan. 
3. Non-measurable lesions - all other lesions, including small lesions (longest 
diameter < 20 mm with conventional techniques or < 10 mm with spiral CT scan), 
i.e., bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, and 
also abdominal masses that are not confirmed and followed by imaging 
techniques 
 
Response Criteria: Evaluation of target lesions 
*Complete Response (CR): 
Disappearance of all target lesions 
*Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD 
*Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new 
lesions 


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*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 
10.3.6 Measurement of Response for FDG-PET scans  
Since it is extremely difficult to quantify the size of a lesion(s) by FDG-PET scan, the 
conventional RECIST criteria will not be used for the qualitative, non-SUV-based 
FDG-PET scan interpretation after chemoradiotherapy.  Instead, the qualitative visual 
criteria from MacManus et al will be utilized, as follows: 
 
 
Response Criteria: Evaluation of target lesions 
*Complete Response (CR): 
CR will be defined as no tumor FDG uptake in the tumor bed, 
or activity in the tumor bed similar to that in the adjacent 
normal tissue; 
 
*Partial Response (PR): 
appreciable reduction in intensity of tumor FDG uptake or 
tumor volume apparent to the nuclear medicine physician 
when pre-, during-, and post-treatment PET scans are 
displayed side by side;* 
*Progressive Disease (PD): 
appreciable increase in the intensity of tumor FDG uptake or 
volume of the tumor apparent to the nuclear medicine 
physician when pre-, during, and post-treatment PET scans 
are displayed side by side.* 
*Stable Disease (SD): 
no appreciable change in intensity of tumor FDG uptake or 
tumor volume between scans and no new sites of disease 
apparent to the nuclear medicine physician when pre-, during-, 
and post-treatment PET scans are displayed side by side;* 
* For these determinations, the pre-, during-, and post-treatment FDG-PET scans 
must be analyzed using the same display techniques to provide a consistent intensity 
of background soft-tissue activity. 
 
10.4 
Criteria for Discontinuation of Protocol Treatment 
• 
Progression of disease as measured by RECIST criteria outlined above, PET 
scan RECIST criteria will be used for patients with follow-up PET scans, CT scan 
RECIST criteria will be used for patients with follow CT scan only.  
 
 
11.0 STATISTICAL CONSIDERATIONS 
 
Primary objective: Delivery of SBRT to multiple sites in a safe and effective manner with acceptable 
toxicity 
 
Primary Endpoint(s):  
• 
Presence of multiple sites (between 2 and 5 sites)  
• 
Acceptable toxicity: Grade 3 or less 
 
Secondary objectives/Endpoints: 
• 
Quality of life (as measured by the FACT quality of life surveys, see appendix IV)   
• 
Local control of metastatic sites 
• 
Local control of primary site 
• 
Overall survival (OS), Two-year Overall Survival  
• 
Analysis of patterns of failure post-SRS/SBRT (subsequent sites of failure and time to failure) 
11.1 Objectives of the proposed study 


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HCC 10-027 
 
The primary objective of the proposed phase II study is to evaluate the feasibility of this curative 
intent treatment approach (SRS/SBRT to the metastatic disease sites in combination with standard 
curative therapy to the primary site) to patients presenting with oligometastatic disease.  
11.2 Sample size 
Phase II studies are usually small trials, recruiting participants up to about 20, although often a lot 
less.  However, we plan to analyze the data stratified by different primary cancer such as breast, 
prostate, and etc., since we are trying to detect which patient subsets are most likely to benefit from 
the proposed treatment. The sample size can be set at approximately 10 for each patient subset in 
order to have a reasonable estimate of overall survival, local control, and quality of life for each 
subset. We estimate that most of the patients will have breast, lung, and prostate primaries and that 
there will be smaller numbers with other primary types. Based on these assumptions, we estimate a 
sample size of 40 patients and expect a 10% drop-out rate and thus have set an estimated sample 
size of 44 patients. 
11.3 Data analysis 
Two-year survival rate will be calculated for all the patients and each patient subset respectively by 
using Kaplan-Meier survival analyses, with survival and event times defined from the day of 
enrollment until either an event or last follow-up. We can compare these two year survival rates with 
those from the patients using traditional therapy. Median overall survival will also be estimated. 
  
Univariate survival analysis will be performed to identify the statistically significant variables, using 
Log-Rank test or univariate Cox proportional hazard regression based on the data type of predictor 
variables. Significant (P <.05) variables on univariate analyses will then be tested with multivariate 
analyses by using Cox proportional hazard regression model (Milano MT, et al., 2007).   
 
Quality of life outcomes will be analyzed by using univariate and multivariate logistic regression 
successively and the quality of life will be coded as “improved” or “non-improved”.  
 
We will also report the entire patient characteristics at initial presentation of oligometastatic disease 
and characteristics of Long-term (>=2 years) survivors by using descriptive statistics.  
 
 12.0   DATA SAFETY AND RECORDING 
  
12.1 Data and Safety Monitoring Plan 
 
Investigators/Sub-investigators, regulatory, CRS management, clinical research 
coordinators, research coordinators, clinical research associates, data managers, and 
clinic staff meet regularly in disease center Data Safety Monitoring Boards (DSMB) to 
review and discuss study data to include, but not limited to, the following: 
• 
serious adverse events 
• 
subject safety issues 
• 
recruitment issues 
• 
accrual 
• 
protocol deviations 
• 
unanticipated problems 
• 
breaches of confidentiality 
 
Minutes from the disease center DSMB meetings are available to those who are unable to participate 
during the scheduled meeting time. 
 
All toxicities encountered during the study will be evaluated on an ongoing basis 


Page 15 of 28 
HCC 10-027 
 
according to the NCI Common Toxicity Criteria Version 4.0. All study treatment 
associated adverse events that are serious, at least possibly related and unexpected 
will be reported to the IRB.  Any modifications necessary to ensure subject safety and 
decisions to continue, or close the trial to accrual are also discussed during these 
meetings. If any literature becomes available which changes the risk/benefit ratio or 
suggests that conducting the trial is no longer ethical, the IRB will be notified in the 
form of an Unanticipated Problem submission and the study may be terminated.  
All study data reviewed and discussed during these meetings will be kept confidential. 
Any breach in subject confidentiality will be reported to the IRB in the form of an 
Unanticipated Problem submission. The summaries of these meetings are forwarded 
to the UPMC Hillman Cancer Center DSMC which also meets regularly following a 
designated format. 
For all research protocols, there will be a commitment to comply with the IRB’s 
policies for reporting unanticipated problems involving risk to subjects or others 
(including adverse events). DSMC progress reports, to include a summary of all 
serious adverse events and modifications, and approval will be submitted to the IRB at 
the time of renewal. 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis 
only, will be reviewed bi-annually. 
Both the UPMC Hillman Cancer Center DSMC as well as the individual disease center 
DSMB have the authority to suspend accrual or further investigate treatment on any 
trial based on information discussed at these meetings. 
All records related to this research study will be stored in a locked environment. Only 
the researchers affiliated with the research study and their staff will have access to the 
research records.  
 
12.2    Adverse Event Reporting 
12.2.1 Definitions 
The following definitions of terms apply to this section: 
 
Adverse event: Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction: An 
adverse event or suspected adverse reaction is considered "life-threatening" if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject 
at immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
Serious adverse event or serious suspected adverse reaction: An adverse event or suspected 
adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it results 
in any of the following outcomes: 
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
Congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 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. 


Page 16 of 28 
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Events not to be considered as AEs/SAEs:  
• 
Medical conditions present at the initial trial visit that do not worsen in severity or frequency 
during the treatment plan are defined as baseline medical conditions and NOT to be 
considered AEs/SAEs  
• 
Visits to the emergency room or other hospital department < 24 hours, that do not result in 
admission (unless considered an important medical or life-threatening event)  
• 
Elective surgery, planned prior to signing consent, and admissions for a planned 
medical/surgical procedure  
• 
Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)  
• 
Admission for administration of anticancer therapy in the absence of any other SAEs.  
 
Suspected adverse reaction: Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, "reasonable possibility" means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug. 
 
Adverse reaction means any adverse event caused by a drug.  Adverse reactions are a 
subset of all suspected adverse reactions where there is reason to conclude that the 
drug caused the event. 
 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse 
event or suspected adverse reaction is considered "unexpected" if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in 
the current application, as amended. For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the investigator 
brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the investigator brochure listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug, but 
are not specifically mentioned as occurring with the particular drug under 
investigation. 
12.2.2 Eliciting AE Information 
Research subjects will be routinely questioned about AEs at study visits. 
12.2.3 Recording Requirements 
All observed or volunteered adverse events (serious or non-serious) and abnormal 
test findings, regardless of study group or suspected causal relationship to the study 
drug(s) will be recorded in the subjects’ case histories. For all adverse events, 
sufficient information will be pursued and/or obtained so as to permit 1) an adequate 
determination of the outcome of the event (i.e., whether the event should be classified 
as a serious adverse event) and; 2) an assessment of the casual relationship between 
the adverse event and the study drug(s). 
 Adverse events will be followed until resolution while the patient remains on-study. 
Once the patient is removed from study, events thought to be related to the study 
medication will be followed until resolution or stabilization of the adverse event, or 
until the patient starts a new treatment regimen, or death, whichever comes first.  
Subjects will be followed for AEs/SAEs for 30 days after their last dose of study 
drug(s). 
AEs or abnormal test findings felt to be associated with the investigational drug or 


Page 17 of 28 
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study treatment(s) will be followed until the event (or its sequelae) or the abnormal test 
finding resolves or stabilizes at a level acceptable to the Sponsor-Investigator. 
 
12.3 CAUSALITY 
The investigator must determine the relationship between the administration of 
radiation and study drug(s) and the occurrence of an AE/SAE as defined below: 
 
• 
Definitely Related – The AE is clearly related to radiation and/or study drug(s). There is a 
reasonable causal relationship between study treatment and the AE. The event responds to 
withdrawal of study treatment (dechallenge) and recurs with rechallenge when clinically feasible. 
• 
Probably Related – The AE is likely related to to radiation and/or study drug(s). There is a 
reasonable causal relationship between study treatment and the AE. The event responds to 
dechallenge. 
• 
Possibly Related – The AE may be related to radiation and/or study drug(s). There is a 
reasonable possibility that study treatment caused the adverse event. The investigator can 
provide a rationale or evidence to suggest a causal relationship between study treatment and the 
AE other than just a temporal relationship. 
• 
Unlikely Related– The AE is doubtfully related to radiation and/or study drug(s). There is only a 
temporal relationship to study treatment, but not a reasonable causal relationship between study 
treatment and the AE. 
• 
Unrelated – The AE is clearly NOT related to radiation and/or study drug(s). There is no temporal 
relationship to study treatment. There is a reasonable causal relationship to another drug product, 
concurrent disease, or circumstance. 
12.2.2.2 Abnormal Test Findings 
An abnormal test finding will be classified as an adverse event if one or more of the 
following criteria are met: 
• 
The test finding is accompanied by clinical symptoms. 
• 
The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug treatment or other therapy. 
Note: simply repeating a test finding, in the absence of any of the other listed criteria, 
does not constitute an AE. 
• 
The test finding leads to a change in study dosing or discontinuation of subject 
participation in the clinical study. 
• 
The test finding is considered an AE by the Sponsor-Investigator of the IND application. 
 
REPORTING OF SERIOUS ADVERSE EVENTS  
 
All events meeting the definition of a serious adverse event, which occur after the date of first dose of 
study treatment and within 30 days of the last dose of study treatment, should be reported according 
to the departmental SAE checklist and SAE form. The initial SAE form should be sent to the following 
within 24 business hours / 1 business day of the Principal Investigator becoming aware: 
1. Investigator: burtons@upmc.edu 
2. CRSSafetySubmissions@upmc.edu 
3. Local Institutional Review Board when reporting requirements are met. 
 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include as applicable the following information that is available at the time of report 
within the Sections B and C of the departmental SAE form: 
 
• 
CTCAE term(s) and grade(s)  
• 
current status of study drug 
• 
all interventions to address the AE (testing and result, treatment and response) 


Page 18 of 28 
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• 
hospitalization and/or discharge dates 
• 
event relationship to study drug 
 
Follow-up reports:   
 
Additional information may be added to a previously submitted report by adding to the original 
departmental SAE form and submitting it as follow-up or creating supplemental summary information 
and submitting it as follow-up with the original departmental SAE form. 
 
 
12.2.3 Reporting adverse events to the responsible IRB 
In accordance with applicable policies of the University of Pittsburgh Institutional 
Review Board (IRB), the Investigator will report, to the IRB, any observed or 
volunteered adverse event that is determined to be 1) associated with the 
investigational drug or study treatment(s); 2) serious; and 3) unexpected. Adverse 
event reports will be submitted to the IRB in accordance with the respective IRB 
procedures. 
Applicable adverse events will be reported to the IRB as soon as possible and, in no 
event, later than 10 calendar days following the investigator’s receipt of the respective 
information. Adverse events which are 1) associated with the investigational drug or 
study treatment(s); 2) fatal or life-threatening; and 3) unexpected will be reported to the 
IRB within 24 hours of the Sponsor-Investigator’s receipt of the respective information. 
Follow-up information to a reported adverse event will be submitted to the IRB as soon 
as the relevant information is available. If the results of the Investigator’s follow-up 
investigation show that an adverse event that was initially determined to not require 
reporting to the IRB does, in fact, meet the requirements for reporting; the Investigator 
will report the adverse event to the IRB as soon as possible, but in no event later than 
10 calendar days, after the determination was made. 
 
 
 


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Radiotherapy for Treatment of Adrenal Metastases. Int J Radiat  Oncol Biol Phys. 2009 Feb 26. 
Katz AW, Carey-Sampson M, Muhs AG, Milano MT, Schell MC, Okunieff P. Hypofractionated 
stereotactic body radiation therapy (SBRT) for limited hepatic metastases. Int J Radiat Oncol Biol 
Phys. 2007 Mar 1;67(3):793-8. 
Rusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg SJ, Chidel MA, Pugh 
TJ, Franklin W, Kane M, Gaspar LE, Schefter TE. Multi-institutional phase I/II trial of stereotactic body 
radiation therapy for liver metastases. J Clin Oncol. 2009 Apr 1;27(10):1572-8. 
Gerszten PC, Burton SA, Ozhasoglu C, Welch WC. Radiosurgery for spinal metastases: clinical 
experience in 500 cases from a single institution. Spine 2007;32:193–9. 
Yamada Y, Bilsky MH, Lovelock DM, et al. High-dose, single-fraction image-guided intensity-
modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys 2008;71:484–90. 
Salama JK, Chmura SJ, Mehta N, Yenice KM, Stadler WM, Vokes EE, Haraf DJ, Hellman S, 
Weichselbaum RR. An initial report of a radiation dose-escalation trial in patients with one to five sites 
of metastatic disease. Clin Cancer Res. 2008 Aug 15;14(16):5255-9. 
 


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APPENDIX I - Schedule of events 
 
 
 
 
 
Pre-Treatment 
During Treatment 
Follow-Up 
Histo/cyto eval 
X 
 
 
History/physical 
X 
 
X 
Imaging of sites 
of disease 
(FDG-PET/CT) 
X* 
 
X 
Performance 
status 
X 
X 
X 
CBC w/ diff & 
ANC 
X 
 
 
Serum 
pregnancy test 
(if applicable) 
X 
 
 
Informed 
consent 
X 
 
 
Tumor 
response eval 
 
 
X 
Adverse event 
eval 
 
X 
X 
QOL surveys 
X 
 
X 
 
*  If one was done within the past 8 weeks, then do not repeat. 


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APPENDIX II - Performance status scoring 
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without 
restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry work of a light or sedentary nature.  For example, light 
housework, office work  
 
2 
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 
Capable of only limited self-care, confined to bed or chair 50% or 
more of waking hours  
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to 
bed  
 
5 
Death  
 
 
 
KARNOFSKY PERFORMANCE SCALE 
 
100 
Normal; no complaints; no evidence of disease 
 
90 
Able to carry on normal activity; minor signs or symptoms of 
disease 
 
80 
Normal activity with effort; some sign or symptoms of disease 
 
70 
Cares for self; unable to carry on normal activity or do active work 
 
60 
Requires occasional assistance, but is able to care for most personal 
needs 
 
50 
Requires considerable assistance and frequent medical care 
 
40 
Disabled; requires special care and assistance 
 
30 
Severely disabled; hospitalization is indicated, although death not 
imminent 
 
20 
Very sick; hospitalization necessary; active support treatment is 
necessary 
 
10 
Moribund; fatal processes progressing rapidly 
 
0 
Dead 
 
 


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APPENDIX III  - Guidelines for SRS/SBRT dosing and fractionation 
 
 
Guidelines for SRS (see also section 6.2) 
 
CNS 
Treatment will be performed with single fraction SRS/SBRT. Patient will be positioned in supine 
position with appropriate fixation device, frameless SRS/SBRT can be performed if set-up uncertainty 
is minimal. SRS/SBRT doses are dependent on lesion size as follows:   
 
 
Lesion Diameter 
(cm) 
SRS/SBRT dose 
(Gy) 
< 2 
24/ 1 fx 
2-3 
18/ 1 fx 
> 3 
15 / 1 fx 
> 4 
30 / 3 fx 
 
For larger lesions, fractionated SRS/SBRT may be used (3 fractions of 10 Gray per fraction) instead 
of a single fraction of 15 Gy.  
 
LUNG 
SBRT to lung lesions will consist of 3-5 treatments depending on location of tumor. Patient will be 
positioned in supine position with gated treatments or tumor tracking with fiducial markers. For central 
tumors (defined as within 2 cm of carina, right and left main bronchi, right and left upper lobe bronchi, 
intermedius bronchus, right middle lobe bronchus, lingular bronchus, and left lower lobe bronchus) 
SRS dose will be 48 Gy in 4 fractions. For non-central lesions, SBRT dose will be 60 Gy in 3 
fractions.  
 
Dose constraints for 48 Gy in 4 fractions: 
Organ 
Volume 
Volume Max 
Max Point Dose 
Spinal Cord  
 
<0.25 cc 
22.5 Gy (4.5 
Gy/fx) 
 
30 Gy (6 Gy/fx) 
Skin 
<10 cc 
30 Gy (6 Gy/fx) 
32 Gy (6.4 Gy/fx) 
Lung (both right and 
left lung volumes) 
1500 cc 
12.5 Gy (2.5 
Gy/fx) 
 
Skin 
< 10 cc 
33.2 Gy (8.3 Gy/fx) 
36 Gy (9 Gy/fx) 
Chest wall 
Any point 
32 Gy (8 Gy/fx) 
40 Gy (10 Gy/fx) 
 
Dose constraints for 60 Gy in 3 fractions:  
Organ 
Volume 
Max Point Dose 
Spinal Cord  
 
Any point 
18 Gy (6 Gy per 
fx) 
Esophagus 
Any point 
27 Gy (9 Gy per 
fx) 
Heart/Pericardium 
Any point 
30 Gy (10 Gy per 
fx) 
Bronchus 
 
Any point 
30 Gy (10 Gy per 
fx) 
Skin 
Any point 
24 Gy (8 Gy per 
fx) 
Chest wall 
Any point 
24 Gy (8 Gy per fx) 


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HCC 10-027 
 
 
 
ADDRENAL 
SBRT dose will be 50 Gy in 5 fractions. Patient will be positioned in supine position with gated 
treatments or tumor tracking with fiducial markers.  
 
Dose constraints  
 
  
Normal Tissue Constraints 
 
Organ 
Maximum Dose in 5 Fractions 
Contralateral Kidney 
(2/3 volume) 
5 Gy 
35% of Total (left & 
right) Kidney Volume 
25 Gy 
Spinal Cord 
20 Gy 
Stomach 
35 Gy 
 
BONE 
Dose and fractionation dependent on size and location. For lesions in vertebral bodies near the spinal 
cord, single fraction with doses 18-25 Gy. If fractionation is necessary (as deemed by the treating 
physician, 24 Gy in 3 fractions may be used (8 Gy/fraction). Bone metastatic lesions will not have 
received previous radiotherapy (see 3.0 for eligibility criteria) 
 
 
LIVER 
Liver lesions less than 6 cm in diameter will be treated to 60 Gy in 3 fractions or 60 Gy in 4 fractions 
at the discretion of treating physicians. Preference should be giving for 60 Gy in 4 fractions, but the 
shorter course radiotherapy be used to allow for all SBRT treatments to occur within the 3 week time 
frame. . Patient will be positioned in supine position with gated treatments and/or near real-time tumor 
tracking with fiducial markers. 
 
Dose constraints for liver lesions:  
typical estimate of normal liver size is 2000 cm3.  At least one-third of the liver should be spared from 
receiving a dose likely to cause notable hepatic dysfunction, meaning that 700 cm3 should receive a 
total SBRT dose of less than 15 Gy over 3 fractions and 25 Gy over 5 fractions.   
Two-thirds of the right kidney cannot receive a dose of more than 15 Gy in 3 fractions or 25 Gy in 5 
fractions.  
The percent of total kidney volume receiving a dose of 15 Gy in 3 fractions or 25 Gy in 5 fractions 
must be less than 35% of the total kidney volume  
The maximum dose to any point within the spinal cord can not exceed 18 Gy total in 3 fractions or 20 
Gy total in 5 fractions.  
The maximum point dose to the stomach can not exceed 30 Gy in 3 fractions or 35 Gy in 5 fractions.   
 
  
Normal Tissue Constraints 
  
Organ 
Maximum Dose in 3 
Fractions 
Maximum Dose in 4 
Fractions 
Liver (700 cm3) 
15 Gy 
25 Gy 
Right Kidney (2/3 
volume) 
15 Gy 
25 Gy 
35% of Total (left & 
right) Kidney Volume 
15 Gy 
25 Gy 
Spinal Cord 
18 Gy 
20 Gy 
Stomach 
30 Gy 
35 Gy 
 
 


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HCC 10-027 
 
 
 
LYMPH NODES 
Lymph nodes that are considered M1 for primary tumor site will be treated based on size and 
location. SBRT can range from single fraction 18-24 Gy or 3 fractions to 60 Gy, or 5 fractions to 50 
Gy. 
 


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Appendix IV - Sample of QOL form (FACT-G) 
 
  


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