A Phase I/II Study of Intraoperative Radiotherapy for Patients With Large Brain Metastases Treated With Neurosurgical Resection
Phase: NA
Conditions: Brain Metastases
Sponsor: University of Louisville

A PHASE I/II STUDY OF INTRAOPERATIVE RADIOTHERAPY FOR PATIENTS WITH LARGE BRAIN 
METASTASES TREATED WITH NEUROSURGICAL RESECTION  
Principal Investigator:  Shiao Woo, M.D.
Department of Radiation Oncology, James Graham Brown Cancer Center
University of Louisville School of Medicine
529 South Jackson St
Louisville, KY 40202
Phone: (502) 562-4360
Fax: (502) 562-2700
Coordinating Center: Clinical Trials Office
James Graham Brown Cancer Center
University of Louisville
529 South Jackson St
Louisville, KY 40202
Phone: 502.333.6934 Fax: 502.217.8273
Protocol Version: Version 4
Protocol Date: 07.07.2021

This protocol was designed and developed by the above authors. It is intended to be used only in conjunction 
with institution-specific IRB approval for study entry. No other use or reproduction is authorized by the 
above authors nor do the above authors assume any responsibility for unauthorized use of this protocol. 
Table of Contents
1.0 Schema
2.0 Objectives
2.1 Primary Objective
2.2 Secondary Objective (s)
3.0 Background and Study Rationale
4.0 Participant Selection
4.1 Inclusion Criteria
4.2 Exclusion Criteria
4.3 Inclusion of Minorities and Women
5.0 Registration Process
5.1 General Guidelines
5.2 Registration Process
6.0 Treatment Plan
6.1 Surgical Resection
6.1.1
Frozen Section
6.2 Intraoperative Radiotherapy (IORT)
6.2.1
Applicator Size Selection
6.2.2
Application of IORT
6.2.3
Radiation Safety
7.0 Study Visits and Procedures
7.1 Study Visits
7.2 General Concurrent Medications and Supportive Care
7.3 Duration of Follow-Up
7.4 Criteria for Removal
8.0 Expected Toxicities 
8.1 Early Dose Limiting Toxicities
8.2 Early-Delayed Dose Limiting Toxicities
9.0 Study Calendar
10.0
Measurement of Effect
10.1
 Lesion Response
11.0
 Additional Response Parameters (Quality of Life)
12.0
 Data Safety Monitoring Board
13.0
 Study Design/Statistical Analysis
13.1
 Sample Size
13.2
 Study Design
13.3
 End Point Definitions
13.3.1
 Primary Endpoint
13.3.2
 Secondary Endpoints
13.4
Statistical Analysis
13.5
Monitoring Rule for Phase II
13.6
Non-efficacious Treatment (futility)
14.0
Adverse Events

14.1
 Definition of an Adverse Event
14.2
 Definition of a Serious Adverse Event
14.3
 Required Action for Serious Adverse Event
15.0
 Administrative 
15.1
 Case Report Forms
15.2
 Source Documents
15.3
 Protocol Deviations
16.0
 References
17.0
 Appendices

1.0 Schema

2.0 Objectives
1.1 Primary Objectives
1.1.1
To establish a maximum tolerated dose (MTD) through a dose-escalation trial using 
intraoperative radiotherapy (IORT) following neurosurgical resection for large 
brain metastases. 
1.1.2
To determine median local progression-free survival, ie recurrence rate of treated 
brain metastasis
1.2 Secondary Objectives
1.2.1
Overall Survival
1.2.1.1 Differentiated between death secondary to systemic disease progression 
and neurologic death from intracerebral disease progression
1.2.2
Freedom from Further Treatment
1.2.2.1 Interval from IORT to further oncologic therapy (salvage radiosurgery, laser 
thermal therapy, etc)
1.2.3
Quality of Life (QOL)
1.2.3.1 FACT-Br
1.2.4
Global Progression Free Survival
1.2.4.1 Systemic Cancer Progression Free Survival
1.2.5
Intracranial Progression Free Survival
1.2.5.1 Time from IORT to development of new brain metastases
1.2.6
IORT Dose Limiting Toxicities
1.2.6.1 Craniotomy wound healing complications or infection requiring surgical 
intervention, intracranial hemorrhage, radionecrosis requiring intervention 
(surgical resection, laser intersitial therapy, prolonged (>7 days) steroid 
administration, avastin)

3.0 Background and Study Rationale 
Brain metastases (BMs) are the most common intracranial tumor in adult patients and affect between 
between 10-30% of all patients with systemic malignancies 1. It is estimated between 200,000 to 300,000 
patients per year 2 are affected by brain metastases and the incidence of brain metastases will likely rise with 
the advent of increasingly effective systemic therapy.  Therapeutic options for these patients commonly 
include definitive stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT) or surgical resection 
followed by adjuvant SRS or WBRT 3. Given the improved prognosis for at least select groups of patients with 
novel systemic treatment, optimizing brain metastasis control while minimizing side effects of intracranial 
radiotherapy (RT) is increasingly critical. 
Despite advances including more routine use of high precision SRS with submillimeter accuracy 4 and 
minimal dose to adjacent normal brain parenchyma, large brain tumors remain therapeutically challenging. 
Balancing the delivery of a sufficient dose of RT to achieve effective tumor control while minimizing 
treatment toxicity can be difficult to achieve for large tumors. When clinically appropriate, select brain 
metastases may be surgically resected with level I evidence demonstrating adjuvant SRS reduces local or 
tumor bed recurrence 5.  However, multiple prior investigations have suggested brain tumors with large 
preoperative diameter have worsened local control relative to smaller lesions even with postoperative SRS 6-
8.  Further, patients may develop postoperative complications including wound healing which may delay 
adjuvant SRS and thus may increase the risk for tumor repopulation.
The potential for delivering ablative doses of radiation to the tumor bed while simultaneously sparing normal 
brain parenchyma from significant doses of radiation and reducing the potential for tumor repopulation has 
led to interest in the use of intraoperative radiotherapy (IORT). IORT has achieved excellent rates of local 
control in multiple prior series 9-13 and may be optimal for patients with large brain metastases. In contrast to 
postoperative radiosurgery, IORT does not require an interval for postoperative healing and cavity shrinkage, 
limiting potential tumor repopulation and conceivably disease spread beyond the surgical cavity 14. Wernicke 
and colleagues recently published the results of a prospective protocol treating large (≥ 2.0cm) brain 
metastases undergoing surgical resection with IORT using a permanent Cesium-131 brachytherapy implant 9. 
Their results were quite impressive, with a local/regional freedom from progression at 1 year of 80% for the 
subgroup of patients with tumors >3.0cm with a median follow up of 11.9 months. Further, they did not 
report any cases of radiation necrosis. 
Delivering IORT for resected BMs using balloon based electronic brachytherapy with the Xoft Axxent device 
similarly facilitates single fraction treatment of the surgical cavity with a rapid dose falloff, exposing minimal 
normal brain parenchyma to doses of radiation 15. Further, balloon based brachytherapy dose not require 
ordering a prespecified mesh impregnated with a radioisotope such as Cesium-131, eliminates the need for 
cutting mesh (potentially altering radioisotope placement), and removes the potential for post-implant 
radioisotope seed migration. Xoft electronic brachytherapy uses a disposable electronic radiation source 
producing 50 kV x-rays instead of a radioisotope (Cesium-131 has an energy rate of 30.4 keV). The electronic 
brachytherapy source may be turned on or off at will, and uses a similar technology to the photon 
radiosurgery system used in the intrabeam device 16. The average treatment time ranges from 8 to 10 
minutes. 
An additional advantage of delivery electronic brachytherapy with kV energy is the minimal shielding 
requirement, with use approved for standard operating suites meeting the requirements for intraoperative 
fluoroscopy. The dose fall with Xoft is rapid, with the dose at 5mm and 10mm from the balloon applicator 
surface measuring 52.3% and 29.7% respectively for the small balloon applicator filled with 40cc of saline. 
Xoft IORT is commonly used when performing IORT for early stage breast carcinomas, with updated results 

from an international, multi-institutional protocol treating more than 1200 patients from 2012 to 2018 
presented at the 60th annual American Society for Radiation Oncology (ASTRO) meeting reporting excellent 
clinical outcomes (<1% in breast recurrence at 2 years) with minimal side effects. 
In this protocol, we propose a phase I/phase II dose escalation study of large (≥ 2.5cm) brain metastases 
undergoing surgical resection treated with IORT using balloon applicator based electronic brachytherapy 
using the Xoft Axxent device. The starting dose will be 18 Gy prescribed to the surface of the balloon 
applicator, given the increased relative biologic effectiveness (RBE) of kV radiation (RBE ~1.3) this dose is 
considered ablative for residual microscopic disease with limited dose delivered to adjacent normal brain 
parenchyma well below documented tolerance thresholds. As the local control rate at 1 year for brain 
metastases with a preoperative diameter ≥ 3cm receiving postoperative SRS in the phase III trial by Mahajan 
et al was 58% 5, we believe the ability of IORT using the Xoft applicator to safely deliver a higher dose of RT to 
the tumor cavity may result in improved lesion control. The maximum dose tested will be 24 Gy prescribed to 
the applicator surface. 
Dosimetric data investigating IORT plans using balloon applicator based electronic brachytherapy indicate 
IORT doses between 18 to 24 Gy produce plans with doses to organs at risk well below tolerance thresholds 
12.  IORT doses within these dose levels have been demonstrated to be associated with acceptable toxicity in a 
phase I/phase II study using IORT followed by additional external beam RT to treated primary brain cancer 
(Glioblastoma) with no dose limiting toxicities occurring in their specified 3 month post IORT interval (doses 
from 20 to 40 Gy) 17. 
4.0 Participant Selection
4.1 Inclusion Criteria
1. Participants must be ≥ 18 years of age.
2. Participants must have a Karnosfky performance status of ≥ 50%.
3. Participants must not have had prior intracranial radiation.
4. Participants must have a life expectancy greater than 3 months. 
5. Participants must have a preoperative MRI Brain T1-Gadolinum enhanced scan demonstrating a non-dural 
based lesion with greatest diameter ≥ 2.5 cm. 
6. Sufficient distance (≥ 2cm or at the discretion of the study principal investigator) of the intracranial lesion 
from optic structures (optic chiasm and bilateral optic nerves) and brainstem to meet established normal 
structure dose limits. 
7.  Subject or subject’s legal representative to provide signed/written informed consent to participate in the 
study protocol.  
8. Surface of balloon applicator must be ≥ 1cm from skin overlying closest portion of unresected calvarium.
9. Participants may remain on systemic therapy if they are receiving immunotherapy (anti-PD1, anti-PDL1, 
anti-CTLA-4), capecitabine, temozolomide, etoposide, vinorelbine, pemetrexed, lapatinib, traztuzumab, 
bevacizumab, mTor or ALK targeted agents with no break prior to initiating IORT. 

9.1 Participants receiving cisplatin, methotrexate, taxanes, tyrosine kinase inhibitors, or BRAF targeted 
agents must have a seven day washout period prior to receiving IORT. 
9.2 Participants receiving doxorubicin, T-DM1, or antibody-drug conjugates must have a fourteen day 
washout period prior to receiving IORT. 
9.3. Participants receiving all other concurrent systemic agents will undergo consideration for a washout 
period prior to receiving IORT at the discretion of the study  principal investigator. 
4.2 Exclusion Criteria
1.   Participants may not be pregnant or breast-feeding. 
2.  Patients must not have dural lesions or leptomeningeal disease.
3. Patients must not have psychiatric or social conditions limiting adherence to protocol guidelines. 
4. Patients must not have contraindications to anesthesia, surgery, or MR imaging with Gadolinium injection. 
5. Patients must not have a frozen section diagnosis of small cell carcinoma, lymphoma, germinoma or non-
malignant histology.
6. Patients with additional unresected brain metastases must have a limited number of lesions/or volume of 
intracranial disease amenable to stereotactic radiotherapy at the discretion of the study principal 
investigator.
7. Patients deemed to require postoperative whole brain radiotherapy should be excluded.
4.3 Inclusion of Women and Minorities 
1.  Women and men including members of all races and ethnicity groups are eligible for this protocol. 
5.0 Registration Procedures 
5.1 General Guidelines
All eligible patients will be entered centrally into the Clinical Trials Management System at the University of 
Louisville by the designated study coordinator. 
5.2 Registration Process
To register a patient, please ensure the completion of the following documents by the facility Research Nurse 
and fax or email the documents to the Study Coordinator:

Copy of required pathology and imaging tests

Signed patient consent form

Other appropriate forms (e.g., Eligibility Screening Worksheet, Registration Form)
To complete the registration process the Coordinator will:

Assign a unique patient protocol study number


Register the patient on the protocol

Create a study specific patient chart
The research nurse will ensure a copy of each patient’s informed consent form  is scanned in the patient’s 
official medical record at the treating facility. 
6.0 Treatment Plan
6.1 Surgical Resection
The resection procedure should be performed with image guidance (neuronavigation) with standard surgical 
technique. Resection techniques may include mono/bipolar cautery, suction or ultrasound aspiration. 
Maximal safe resection of tumor will be recommended.  Ventricular opening intraoperatively should be 
avoided if at all possible to limit the potential for the accumulation of CSF/fluid around the balloon applicator, 
potentially modulating the delivered dose of radiation. 
6.1.1 Frozen Section
Representative tissue samples must be sent intraoperatively for histopathologic examination/to establish the 
diagnosis of metastatic disease. Frozen section procedure will be performed in the standard fashion per 
facility protocol.
6.2 Intraoperative Radiation Therapy (IORT)
After the diagnosis of brain metastasis has been histopathologically established via confirmatory frozen 
section, preparations for IORT will be made. All potentially involved risk structures identified on preoperative 
imaging will be re-identified intraoperatively to ensure shifts after surgical resection resulting from changes 
in intracerebral pressure or CSF volume have not displaced the aforementioned structures with ultrasound or 
in-room CT/MRI. Constraints for the optic structures and brainstem with SRS detailed in the Quantitative 
Analyses of Normal Tissue Effects in the Clinic (QUANTEC) of 12Gy (optic structures) and 12.5 Gy (brainstem) 
are commonly used 18 .
However, given the increased relative biological effectiveness of kV-irradiation19 adapted dose contstraints of 
10 Gy will be used for both the optic structures and the brainstem. Based on established dosimetric data 15,19 
the dose delivered to tissue 1cm from the surface of the balloon applicator is between 6 to 7 Gy. Thus the 
aforementioned risk structures will receive well below threshold doses of RT using this criteria. 
6.2.1 Applicator Size Selection
Optimal balloon applicator size will be selected with accordance to tumor bed/cavity geometry and adjacent 
normal brain parenchyma by the team of surgeons and radiation oncologists.  A foley balloon catheter 
inserted into the tumor cavity and inflated with an appropriate volume of saline per cavity size may be 
utilized to help select optimal balloon applicator size. Applicator sizes range from 2.5cm to 3cm, 3 to 4cm and 
4 to 5cm. The balloon applicator will be inserted into the cavity, and after insertion adjacent risk structures 
will again be evaluated using in room imaging (ultrasound or CT). It should be ensured any fluids 
surrounding the surface of the balloon applicator are removed. 

6.2.2 Application of IORT
The radiation oncologist will place the miniature x-ray source inside the balloon shaped catheter placed 
inside the tumor cavity. Medical personnel may remain in the operating theater behind a rolling shield. 
Radiotherapy will be initiated by the treating radiation oncologist for a defined time interval calculated by the 
machine planning software. 
After IORT has been delivered, the surgeon will remove the balloon applicator. Surgery will be continued in 
the regular fashion without additional requirements. 
6.2.3 Radiation Safety
Federal and state safety regulations regarding radiation protection and the delivery of radiotherapy will be 
strictly adhered to with protocol delivery of IORT. Structural alterations of the operating suite will not be 
required as long as the operating room is approved for C-arm fluoroscopy 20. 
7.0 Study Visits and Procedures
7.1.1 Visit 1: Screening/Enrollment

Appropriately counsel patient on risks, rationale and benefits of protocol therapy

Assess patient eligibility with regards to inclusion/exclusion criteria

Obtain written informed consent from patient

Obtain patient demographics and relevant medical history

Perform a physical examination including height and weight

Complete neurologic examination

Assess preoperative Karnofsy Performance Status (KPS)

Obtain vital signs including pulse, respirations, blood pressure and temperature

Basic laboratory workup including CBC with differential, CMP 

Fact Br at baseline

Pre-surgical MRI of the brain performed within 28 days of planned resection

Subject enrollment notification form must be submitted immediately upon study consent

Completed case report form must be submitted within 7-14 days after each visit
7.1.2 Visit 2: Short Interval Post-Operative Visit (within 4 weeks of IORT)

Interim medical history

Complete Neurologic and Physical Examination

KPS evaluation

FACT-BR completed by patient or representative

Review of early postoperative MRI (≤72 hours of resection) with removal of ≥98% of the T1  
Gadolinium enhancing lesion deemed a complete resection, and less 98% deemed a subtotal 
resection

Medication review

Completed Case Report Form must be submitted within 7-14 days after each visit

7.1.3 Visit 3: (3 months after IORT completion)

Interim medical history

Complete Neurologic and Physical Examination

KPS evaluation

FACT-BR completed by patient or representative.

MRI of the Brain (with and without Gadolinium contrast)

Adverse event reporting

Survival/Documentation of Local/Distant brain metastasis recurrence

Completed case report form must be submitted within 7-14 days after each visit
7.1.4 Visit 4  (6 months after IORT completion)

Interim medical history

Complete Neurologic and Physical Examination

KPS evaluation

FACT-BR completed by patient or representative.

MRI of the Brain (with and without Gadolinium contrast)

Adverse event reporting

Survival/Documentation of Local/Distant brain metastasis recurrence

Completed case report form must be submitted within 7-14 days after each visit
7.1.5 Visit 5  (9 months after IORT completion)

Interim medical history

Complete Neurologic and Physical Examination

KPS evaluation

FACT-BR completed by patient or representative.

MRI of the Brain (with and without Gadolinium contrast)

Adverse event reporting

Survival/Documentation of Local/Distant brain metastasis recurrence

Completed case report form must be submitted within 7-14 days after each visit
7.1.6 Visit 6  (12 months after IORT completion)

Interim medical history

Complete Neurologic and Physical Examination

KPS evaluation

FACT-BR completed by patient or representative.

MRI of the Brain (with and without Gadolinium contrast)

Adverse event reporting

Survival/Documentation of Local/Distant brain metastasis recurrence

Completed case report form must be submitted within 7-14 days after each visit

7.2 General Concomitant Medication and Supportive Care Guidelines
Anti-emetic, steroid or anti-epileptic medications may all be used at the discretion of the treating physician.
7.3 Duration of Follow up
Survival status will be collected every 3 months up to 1 year from IORT completion, then every 6 months until 
death. Local recurrence (nodular enhancement within the tumor bed), and distant intracranial progression 
(development of brain metastases outside of the resection cavity) will be monitored during the same 
intervals. Documentation for survival status should include both the date and cause of death. 
7.4 Criteria for Removal from the Study
Participants will be removed from the study when any of the criteria listed in section 8.2 applies. The specific 
reason for study withdrawal and the date of removal will be documented in the study-specific case report 
form. Alternative therapeutic/care options will be discussed with the participant.
In the event of a severe or life-threatening adverse event, the participating investigators must immediately 
alert the principal investigator. 
8.0 Expected Toxicities and Dose Modifications
Dose limiting toxicities will be assessed on the basis of clinical presentation with assessment of physical 
exam, KPS assessment, baseline medications, MRI Brain (preoperative imaging compared to subsequent 
scans including early postop), neurologic examination, and adverse event grading using the CTCAE v5.0.
8.1 Early (≤4 weeks of IORT) Dose Limiting Toxicities

Wound healing complications or wound infection requiring surgical intervention

Cerebral hemorrhage or ischemia attributable to IORT

Transient worsening of existing neurological deficits limiting ADLs (activities of daily living)

New or Recurrent Seizures Refractory to Antiepileptic Regimen 

Severe Headaches (CTCAE v 5.0 grade 3)
8.2 Early-Delayed DLTs (≤ 3 months after IORT)

Symptomatic radiation necrosis requiring surgical intervention, laser thermal therapy or 
bevacizumab

Transient worsening of existing neurological deficits limiting ADLs

New or Recurrent Seizures Refractory to Antiepileptic Regimen Seizures 

Severe Headaches (CTCAE v 5.0 grade 3)

9.0 Study Calendar
Visits
Pre-Study
V1
V2
V3
V4
V5
V6
Scre
enin
g
Early Postop
≤ 4 weeks 
after IORT
3 months 
after 
IORT
6 months 
after 
IORT
9 months 
after 
IORT
12 months 
after IORT
MRI/Tumor 
Assessment
X (≤28 days 
before 
resection)
X (≤ 72 
hours after 
IORT)
X
X
X
X
Inclusion/Excl
usion
X
Informed 
Consent
X
Demographics
X
Medical 
History
X
Interim 
Medical 
History
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
Neurologic 
Exam
X
X
X
X
X
X
KPS
X
X
X
X
X
X
Vitals
X
X
X
X
X
X
FACT-BR
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
Adverse Event 
Reporting
X
X
X
X
X
Survival/Disea
se Progression
X
X
X
X
X
Case Report 
Forms
X
X
X
X
X
X
10.0 Measurement of Effect
All subjects will have standard magnetic resonance imaging (MRI) of the brain (with and without Gadolinium 
contrast) within 4 weeks (28 days) of surgical resection to assess preoperative tumor size and within 72 
hours of resection/IORT to assess for residual tumor. Subsequent MRI Brain scans will be ordered every 3 
months for the 1st year to determine tumor bed control/distant control (freedom from brain metastasis 
development outside resection cavity). After 1 year, MRI brain scans will be ordered every 6 months until 
death. All postoperative/IORT scans will be reviewed to assess for recurrent disease in the tumor bed, new 
brain metastases, infection or radiation necrosis. 

MRI is the standard imaging modality used in this protocol. All MRI scans will be recommended to include 
axial, coronal and sagittal sequences performed with and without gadolinium contrast enhancement. 
10.1 Response Criteria
10.1.1 Local Control
Recurrence in the tumor bed will be defined as the development of new nodular or contrast enhancement 
within 5mm of the resection cavity on T1-gadolinium contrasted MRI of the Brain.
10.1.2 Freedom From Further Therapy
Freedom from further therapy will be defined as the interval from IORT completion to additional treatment 
targeting the initial resection cavity including stereotactic radiosurgery, laser interstitial thermal therapy, or 
additional surgical resection. 
10.1.3 Distant Brain Control
 Distant brain failure will be defined as the development of brain metastases on T1-gadolinium contrasted 
MRI of the Brain elsewhere in the brain parenchyma (>5mm from the tumor cavity). 
10.1.4 Radiation Necrosis 
Radiation necrosis will be determined radiographically using contrast enhanced MRI of the Brain with 
consideration of additional MRI sequences including perfusion and diffusion imaging. Cases of questionable 
radiation necrosis versus local failure in the tumor bed will be discussed at our institutional multidisciplinary 
Central Nervous System tumor board with consideration of advanced MRI sequences including MR 
Spectroscopy in accordance with national Neuro-Oncology recommendations 21. 
10.1.5 Overall Survival
Overall survival will be defined as the interval from protocol enrollment to death from any cause. Surviving 
patients at time of analysis will be censored at time of last follow up.
10.1.6 Neurologic Death
Neurologic death will be defined as patients dying with progressive neurologic decline regardless of 
extracranial disease status. Patients deemed to die of intercurrent disease with severe neurologic function 
will also be considered to have had neurologic death. This definition is consistent with prior investigations 
22,23.
11.0 Additional Response Parameters
Quality of Life will be assessed for this protocol using the FACT-BR (brain) validated questionnaire 24. FACT-
BR measures general quality of life, reflecting symptoms or problems associated with brain malignancies 
across 5 scales. These scales detail information regarding physical well-being, social/family well-being, 
emotional well-being, functional well-being, and disease specific concerns. The questionnaire is written at 4th 

grade reading level and can be filled out in less than 10 minutes. No pre-certification is required for the self-
reported quality of life and can be completed by the patient or with assistance of the examiner. 
All pertinent and required permissions for use of the FACT-BR instrument have been obtained. 
12.0 Data Safety Monitoring Board
  Progress for this protocol will be monitored and reviewed by the Brown Cancer center Data Safety 
Monitoring Board (DSMB). Summaries of the protocol data will be provided by the Biostatistics Office after 
review by the Principal Investigator (PI). Data will include information regarding patient accrual, summary of 
demographic information, CTCAE grade 3 or 4 toxicities, and major adverse events including death or 
recurrent disease. 
13.0 Study Design/Statistical Analysis
13.1 Sample Size 
This study will be conducted in 2 phases. 
Phase I: 
We will use the classical 3+3 dose-escallation design during the phase I portion.  We anticipate requiring to 
enroll between 12-18 patients in phase I pending DLTs. We will allow at most 5 grade 3-4 DLTs in phase I in 
order to proceed to phase II. If any deaths attributable to protocol therapy are observed or ≥ 6 grade 3-4 
DLTs, we will halt the trial.
The Brown Cancer Center Data and Safety monitoring plan will be used for this phase I/II protocol. 
Continuous review of data including patient safety will be peformed by the study investigators. Quarterly 
summaries of severe adverse events (SAEs) will be submitted through the Clinical Trials Office to the DSMB. 
Phase II:  
Twelve month local control of large (≥ 3cm) resected brain metastases receiving single fraction postoperative 
radiosurgery was 58% in the recently published phase III trial by Mahajan and colleagues. A recently 
published phase II protocol of patients with large resected brain metastases treated with intraoperative RT 
using cesium brachytherapy meshes demonstrated a 12 month local control of 80%. We assume p0 = 0.60 (12 
month local control is at most 60% if protocol therapy is not effective) and p1= 0.80 (12 month local control is 
anticipated to be 80% or higher). Using Simon’s two-stage Minimax design with α = 0.05, β = 0.20 (power 
=80%), a maximum of 35 patients will need to be enrolled. Thirteen patients will need to be enrolled for 
initial stage, and an additional 21 will be enrolled in the second stage. Table S1 provides further detail 
regarding sample size justification. Please note patients from phase I at the MTD will be included in initial 
stage of phase II for protocol efficacy estimation. 
Table S1. Sample Size Justification with P0=0.60, P1= 0.80, α = 0.05, β = 0.20
Two-stage Design
MiniMax Design
First Stage Sample Size (n1)
13
Upper Limit for 1st Stage Rejection (r1)
8

Maximum Sample Size (n)
35
Upper Limit for 2nd Stage Rejection (r)
25
Expected Sample Size if Response Probability = P0
21
Probability of Early Termination at P0
0.65
13.2 Study Design
This is a phase I/II study of patients with large (≥2.5cm in greatest preoperative diameter) resected brain 
metastases treated with intraoperative radiotherapy using the Xoft electronic brachytherapy system. 
Phase I will be a dose-escalation study performed in a classical 3+3 manner, with 3 patients entering at each 
dose level. Initially, 3 patients will be treated with IORT using the Xoft system to a dose of 18 Gy prescribed to 
the surface of the Xoft balloon applicator. The decision to escalate to the next dose level (21 Gy prescribed to 
balloon applicator surface) will be based on safety assessment after all 3 patients treated at the prior dose 
level (18 Gy) have reached 3 months (90 days) from completion of IORT. 
If no dose-limiting toxicities (as previously described) occur in the initial cohort of 3 patients after 90 days of 
follow up after IORT completion, the next three patients will be treated at the next dose level (21 Gy 
prescribed to applicator surface). If 1 of the 3 patients in the initial cohort of 3 patients experience a DLT, an 
additional cohort of 3 patients will be treated at the same dose level. If no DLTs occur in the additional cohort, 
dose escalation will proceed to the subsequent dose level. If ≥ 1 patient in the additional cohort experiences a 
DLT, the maximal tolerated dose (MTD) is considered exceeded and dose escalation will stop.
If ≥ 2 patients at a dose level experience a DLT, the MTD will be considered to have been exceeded and the 
MTD will be defined as the preceding dose level.  If only a total of 3 patients were tested at the potential MTD 
(preceding dose level), this potential MTD will be confirmed by recruiting an additional cohort of 3 patients to 
be tested at the potential MTD.  If ≤1 patients experience a DLT, the MTD will be confirmed.  If ≥ 2 patients 
experience a DLT, the preceding lower dose level will be considered as the potential MTD. 
If no DLT occurs, the highest dose level (24 Gy prescribed to applicator surface) will be considered the MTD. 
Phase II will then initiate. The first stage will require enrolling 13 patients (patients from phase I receiving 
MTD of IORT will be included for efficacy estimation). Phase II will terminate if 5 or more of these 13 patients 
experience local failure, and Phase II will proceed if 8 or more maintain 12mo local control.  After this 
determination, an additional 22 patients will be enrolled. 
13.3 End-Point Definitions
13.3.1 Primary Endpoint: The primary endpoint for phase I will be toxicity of therapy. Toxicity will be 
measured using the National Cancer Institute Common terminology criteria for adverse events (version 5.0). 
Rates of symptomatic brain radionecrosis (requiring medical interventions including surgical resection) are 
very low in recent reported series of patients with resected brain metastasis (<5%) 9,12.
13.3.2 Secondary Endpoints: Secondary endpoints of interest will include local control, freedom from 
further therapy, distant brain control all measured from time of enrollment to event. Quality of life will be 
assessed using the FACT-BR questionnaire at each of the aforementioned time points (study calendar). 

13.4 Statistical Analysis
Patients receiving protocol treatment will be included in the presented analyses. Patients who received 
protocol treatment who are later discovered to have not fully met the protocol eligibility criteria will be 
presented. Patients who do not complete required observations will be listed, detailed and evaluated 
separately as necessary. All reasons for study withdrawal and date of withdrawal will be presented. 
Descriptive statistics using the chi-square, Kruskal-Wallis and Fisher exact tests will be to characterize 
baseline patient demographic, treatment and tumor related factors for the study cohort. Kaplan-Meier 
methods and the log-rank test will be used to estimate survival outcomes including overall survival, local 
control and distant control. Multivariable Cox regression will be used to evaluate prognostic factors 
associated with survival. 
Descriptive statistics will also be used to characterize toxicity incidence rates in the study cohort. 
Multivariable logistic regression will be performed to identify factors associated with grade 3 or 4 adverse 
toxicity.
The relationship between quality of life using the FACT-BR instrument and demographic, tumor and 
treatment related factors will be explored using a mixed linear regression model 25. Each of quality of life 
scales examined in the FACT-BR instrument will be examined using a set of mixed linear regression analyses 
using the 6 study time points (calendar) as within-patient factors, and assuming an autogressive correlation 
structure of the first order. This model will ensure repeated measures in the same patient are not evaluated 
as independent observations, and ensures patients with some missing data are not excluded entirely from the 
analysis but contribute results at the study time points where values are available. This will ensure patients 
who died before protocol completion are included for quality of life analysis until death. 
All analyses will be performed using the R project for statistical computing software, version 3.3.126
13.5. Monitoring Rule for Phase I/II
Monitoring of the accumulated outcomes data will be designed to ensure the continuing safety of the 
currently enrolled participants and participants not yet enrolled. To ensure the above, this protocol may be 
stopped prior to accrual to reduce the number of participants exposed to a suboptimal treatment. 
13.6 Non-efficacious Treatment (Futility): 
In the first stage if phase II, 13 patients will be enrolled. If 8 or fewer patients fail to demonstrate local control 
of the treated tumor bed at 12 months, we will not enroll any further patients. If 9 or more patients 
demonstrated local control at 12 months, we plan to enroll a further 22 patients. In order for the protocol 
therapy to be declared effective, at least 26 patients must have local control of the tumor bed at 12 months. If 
the 12 month local control is 60%, we have a 65% chance of stopping the protocol early, and at the most, 21 
patients will have received potentially ineffective therapy. 
Statistical References:
1. Dean CB, Nielsen JD: Generalized linear mixed models: a review and some extensions. Lifetime Data Anal 
13:497-512, 2007

14.0 Adverse Events 
14.1 Definition of an Adverse Event
Adverse Events (AEs) are defined as worsening of an existing medical condition in a protocol participant 
administered an investigational (medicinal) product or new development of an untoward medical 
occurrence. A causal relationship between the adverse event and the investigational product is not necessary. 
Any unfavorable/unintended sign (abnormal laboratory value), symptom or disease associated with the 
investigational product, whether considered related to the product or not can be considered an AE. 
Adverse events should be spontaneously reported, or elicited during an open-ended line of questioning, 
evaluation or examination of the protocol participant. Direct questioning regarding the specific occurrence of 
one or more AEs should be avoided to minimize reporting bias. 
Adverse events will be recorded continuously from signing of informed consent. 
Adverse events will be graded using the National Cancer Institute Criteria for Adverse Events (CTCAE) 
Version 4.0. (Appendix 17.3)
14.2 Definition of a Serious Adverse Event 
An adverse event, whether considered to be associated with the treatment protocol or not, will be classified 
as a Serious Adverse Event (SAE) in accordance US Food and Drug Administration regulations (FDA) when it 
meets any of the following criteria:

Result in Death

Is life threatening (patient is at immediate risk of death)

Requires inpatient hospital admission or prolongs existing hospital admission (please note: planned 
hospital admission or outpatient surgery due to an existing condition will not be regarded as a SAE in 
this study)

Results in persistent or significant disability/incapacity; 

Is a congenital anomaly/birth defect; 

Or other important medical events that based on appropriate medical judgment are believed to 
jeopardize the patient and/or require medical or surgical intervention to prevent one of the other 
outcomes defining an SAE
Any SAE ongoing when the patient ends study participation, regardless of relationship to protocol treatment, 
will be followed with appropriate therapeutic management and documented in the study records until the 
SAE resolves or is stabilized. 
14.3 Required Action for Serious Adverse Events
All SAEs related or unrelated to protocol treatment must be reported to the Coordinating Center, the James 
Graham Brown Cancer Center (JGBCC) within 24 hours of knowledge of the event. All SAEs occurring after 
consent will be reported via the Clinical Trial Serious Adverse Event Form. 
Supporting medical documentation for SAEs must be submitted as soon as available to supplement missing 
information (this may include but is not limited to hospital admission records, discharge summaries, autopsy 
reports, etc.). 

Follow up SAE reports must be submitted as soon as the relevant information is available to supplement any 
missing information. 
Final reports must be submitted upon resolution or stabilization of the SAE.
Investigators are responsible for reporting all serious and/or unexpected adverse events to the reviewing 
IRB/EC per local regulations. The original report must be maintained at the investigative location and filed in 
the regulatory file. A copy of the completed report must be submitted to the JGBCC.
15.0 Administrative
15.1 Case Report Forms
The principal investigator (PI) will be supplied with Case Report Forms (CRFs) associated with the study 
protocol. CRFs should be completed by the PI or delegated personnel. Information entered onto the CRFs 
must be verified by source documents. Completed CRFs and supporting source documentation must be 
submitted to the JGBCC within 7 to 14 days after completion of each study visit. 
15.2 Source Documents
Information documented on CRFs should be verifiable using source documents. Records considered source 
documents include but are not limited to hospital records, clinical charts, radiologic data, lab and pathology 
reports. 
15.3 Protocol Deviations
The PI is responsible for documenting and reporting all protocol deviations to the coordinating center, as 
soon as possible (but no more than 5 business days from knowledge), and for complying with IRB procedures 
for reporting deviations. 
16.0 References
1.
Cagney DN, Martin AM, Catalano PJ, et al: Incidence and prognosis of patients with brain 
metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol 19:1511-1521, 2017
2.
Ostrom QT, Gittleman H, Xu J, et al: CBTRUS Statistical Report: Primary Brain and Other 
Central Nervous System Tumors Diagnosed in the United States in 2009-2013. Neuro Oncol 18:v1-v75, 2016
3.
Soffietti R, Abacioglu U, Baumert B, et al: Diagnosis and treatment of brain metastases from 
solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro Oncol 19:162-174, 
2017
4.
Adler JR, Jr., Chang SD: Cyberknife image-guided radiosurgery. Neurosurgery 64:A1, 2009
5.
Mahajan A, Ahmed S, McAleer MF, et al: Post-operative stereotactic radiosurgery versus 
observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. 
Lancet Oncol 18:1040-1048, 2017
6.
Jagannathan J, Yen CP, Ray DK, et al: Gamma Knife radiosurgery to the surgical cavity 
following resection of brain metastases. J Neurosurg 111:431-8, 2009
7.
Brennan C, Yang TJ, Hilden P, et al: A phase 2 trial of stereotactic radiosurgery boost after 
surgical resection for brain metastases. Int J Radiat Oncol Biol Phys 88:130-6, 2014
8.
Jensen CA, Chan MD, McCoy TP, et al: Cavity-directed radiosurgery as adjuvant therapy after 
resection of a brain metastasis. J Neurosurg 114:1585-91, 2011

9.
Wernicke AG, Hirschfeld CB, Smith AW, et al: Clinical Outcomes of Large Brain Metastases 
Treated With Neurosurgical Resection and Intraoperative Cesium-131 Brachytherapy: Results of a 
Prospective Trial. Int J Radiat Oncol Biol Phys 98:1059-1068, 2017
10.
Weil RJ, Mavinkurve GG, Chao ST, et al: Intraoperative radiotherapy to treat newly diagnosed 
solitary brain metastasis: initial experience and long-term outcomes. J Neurosurg 122:825-32, 2015
11.
Pantazis G, Trippel M, Birg W, et al: Stereotactic interstitial radiosurgery with the Photon 
Radiosurgery System (PRS) for metastatic brain tumors: a prospective single-center clinical trial. Int J Radiat 
Oncol Biol Phys 75:1392-400, 2009
12.
Vargo JA, Sparks KM, Singh R, et al: Feasibility of dose escalation using intraoperative 
radiotherapy following resection of large brain metastases compared to post-operative stereotactic 
radiosurgery. J Neurooncol 140:413-420, 2018
13.
Curry WT, Jr., Cosgrove GR, Hochberg FH, et al: Stereotactic interstitial radiosurgery for 
cerebral metastases. J Neurosurg 103:630-5, 2005
14.
Herskind C, Wenz F, Giordano FA: Immunotherapy Combined with Large Fractions of 
Radiotherapy: Stereotactic Radiosurgery for Brain Metastases-Implications for Intraoperative Radiotherapy 
after Resection. Front Oncol 7:147, 2017
15.
Dickler A: Xoft Axxent electronic brachytherapy: a new device for delivering brachytherapy 
to the breast. Nat Clin Pract Oncol 6:138-42, 2009
16.
Sethi A, Emami B, Small W, Jr., et al: Intraoperative Radiotherapy With INTRABEAM: 
Technical and Dosimetric Considerations. Front Oncol 8:74, 2018
17.
Giordano FA, Brehmer S, Murle B, et al: Intraoperative Radiotherapy in Newly Diagnosed 
Glioblastoma (INTRAGO): An Open-Label, Dose-Escalation Phase I/II Trial. Neurosurgery 84:41-49, 2019
18.
Marks LB, Yorke ED, Jackson A, et al: Use of normal tissue complication probability models in 
the clinic. Int J Radiat Oncol Biol Phys 76:S10-9, 2010
19.
Herskind C, Wenz F: Radiobiological comparison of hypofractionated accelerated partial-
breast irradiation (APBI) and single-dose intraoperative radiotherapy (IORT) with 50-kV X-rays. Strahlenther 
Onkol 186:444-51, 2010
20.
Schneider F, Clausen S, Jahnke A, et al: Radiation protection for an intraoperative X-ray 
source compared to C-arm fluoroscopy. Z Med Phys 24:243-51, 2014
21.
Lin NU, Lee EQ, Aoyama H, et al: Response assessment criteria for brain metastases: 
proposal from the RANO group. Lancet Oncol 16:e270-8, 2015
22.
Patchell RA, Tibbs PA, Regine WF, et al: Postoperative radiotherapy in the treatment of single 
metastases to the brain: a randomized trial. Jama 280:1485-9, 1998
23.
McTyre ER, Johnson AG, Ruiz J, et al: Predictors of neurologic and nonneurologic death in 
patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain 
radiation therapy. Neuro Oncol 19:558-566, 2017
24.
Weitzner MA, Meyers CA, Gelke CK, et al: The Functional Assessment of Cancer Therapy 
(FACT) scale. Development of a brain subscale and revalidation of the general version (FACT-G) in patients 
with primary brain tumors. Cancer 75:1151-61, 1995
25.
Dean CB, Nielsen JD: Generalized linear mixed models: a review and some extensions. 
Lifetime Data Anal 13:497-512, 2007
26.
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Austria, R Foundation for Statistical Computing, 2016

17.0 Appendices
17.1 Performance Scoring Criteria

17.2 Toxicity Criteria (CTCAE v5.0)
For naming and grading of adverse events, please use the NCI CTCAE v5.0 which may be referenced using the 
following hyperlink: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.p
df

17.3 FACT-BR (Version 4)