Mathematical Model-Adapted Radiation Fractionation Schedule for Patients With Recurrent Glioblastoma (MARS-Glio)
Phase: NA
Conditions: Recurrent Glioblastoma
Sponsor: Dana-Farber Cancer Institute

Mathematical Model-Adapted Radiation Fractionation Schedule 
for Patients with Recurrent Glioblastoma (MARS-Glio) 
NCT03557372 
Version date: May 21st, 2019 

 
 
 
 
 
 
 
 
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NCI Protocol #: 
N/A 
 
DF/HCC Protocol #: 18-105 
 
TITLE:  Mathematical Model-Adapted Radiation fractionation Schedule for patients with 
recurrent Glioblastoma (MARS-Glio) 
 
Coordinating Center: 
 
 
 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA 02115 
 
Principal Investigator (PI): 
 
Shyam Tanguturi, MD 
Dana-Farber /Brigham and Women’s Cancer Center 
75 Francis Street, ASB1-L2 Radiation Oncology  
Boston, MA 02115 
Tel: (617) 732-7560 
Fax: (617) 394-2668 
Email: STanguturi@partners.org  
 
Other Investigators: 
 
Franziska Michor, PhD 
Dana-Farber Cancer Institute 
CLS Building 
3 Blackfan Circle 
Boston, MA 02115 
Tell: (617) 632-5045 
Email: michor@jimmy.harvard.edu 
 
Jamie A. Dean, PhD 
Dana-Farber Cancer Institute 
CLS Building 
3 Blackfan Circle,  
Boston, MA 02115 
Email: jdean@jimmy.harvard.edu  
 
Statistician: 
Paul Catalano, ScD 
Department of Biostatistics & Computational Biology 
Dana-Farber Cancer Institute 
3 Blackfan Circle, CLS Building, Room 11015 
Boston, MA, 02115   
Phone: 617-632-2441 
Fax: 617-632-2444 
Email: catalano@hsph.harvard.edu 

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Study Coordinator: 
Teresa Cheng, MPH 
Brigham and Women’s Hospital 
Department of Radiation Oncology 
75 Francis Street 
Boston, MA 02115 
Phone: 617-582-8919 
 
 
Protocol Type = PI-initiated clinical trial/ Version # _____/ Version Date: May 21, 2019 
 

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INDEX 
 
SCHEMA .........................................................................................................................................5 
1. 
INTRODUCTION ...............................................................................................................6 
1.1 
Study Disease ...........................................................................................................6 
1.2 
Rationale ..................................................................................................................7 
2. 
OBJECTIVES ......................................................................................................................8 
2.1 
Study Design ............................................................................................................8 
2.2 
Primary Objective ....................................................................................................8 
2.3 
Secondary Objectives...............................................................................................8 
3. 
PARTICIPANT SELECTION .............................................................................................9 
3.1 
Eligibility Criteria ....................................................................................................9 
3.2 
Exclusion Criteria ....................................................................................................9 
3.3 
Inclusion of Women and Minorities ........................................................................9 
4. 
PRETREATMENT EVALUATIONS/MANAGEMENT ...................................................9 
5. 
REGISTRATION PROCEDURES ...................................................................................10 
5.1 
General Guidelines for DF/HCC Institutions ........................................................10 
5.2 
Registration Process for DF/HCC Institutions .......................................................10 
6. 
RADIATION THERAPY ..................................................................................................10 
6.1 
Dose Specifications:...............................................................................................10 
6.2 
Technical Factors ...................................................................................................19 
6.3 
EBRT Localization, Simulation, and Immobilization ...........................................19 
6.4 
Treatment Planning/Target Volumes .....................................................................19 
6.5 
Critical Structures ..................................................................................................20 
6.6 
Quality Assurance ..................................................................................................20 
6.7 
Radiation Adverse Events ......................................................................................21 
6.8 
Radiation Adverse Event Reporting ......................................................................21 
6.9 
Criteria for Discontinuation  of Protocol ...............................................................22 
7. 
DRUG THERAPY .............................................................................................................22 
8. 
SURGERY .........................................................................................................................22 
9. 
Adverse Events ..................................................................................................................23 
10. 
PARTICIPANT ASSESSMENTS .....................................................................................23 
11. 
DATA COLLECTION ......................................................................................................26 
11.1 
Summary of Data Submission ...............................................................................26 
11.2 
Summary of Dosimetry Data Submission for Protocol Treatment ...................... 26\ 

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12. 
STATISTICAL CONSIDERATIONS...............................................................................26 
12.1 
Study Design/Endpoints.........................................................................................26 
12.2 
Sample Size and Power Justification .....................................................................27 
12.3 
Sample Size, Accrual Rate and Study Duration ....................................................27 
12.4 
Stratification Factors ..............................................................................................28 
12.5 
Interim Monitoring Plan ........................................................................................28 
12.6 
Analysis of Primary Endpoints ..............................................................................28 
12.7 
Analysis of Secondary Endpoints ..........................................................................28 
12.8 
Reporting and Exclusions ......................................................................................31 
13. 
REGULATORY CONSIDERATIONS .............................................................................32 
13.1 
Data Safety Monitoring..........................................................................................32 
14. 
PUBLICATION PLAN .....................................................................................................32 
REFERENCES ..............................................................................................................................34 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................37 
APPENDIX B 
M. D. Anderson Symptom Inventory – Brain Tumor survey ....................38 
 
 
 
 
 
 

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SCHEMA 
 
 

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1. INTRODUCTION 
 
1.1 
Study Disease 
 
Glioblastoma is the most common primary malignant brain tumor in adults, occurring at a rate of 
3.66 new cases per 100,000 people per year in the United States (1).  The role of adjuvant 
radiation therapy after surgical resection for glioblastoma was established in the 1970s and 1980s 
through several historic randomized trials comparing radiotherapy to observation (2–4), 
chemotherapy (3–5), or combination therapy (3–5).  These studies largely showed that post-
operative radiotherapy increased the median survival from 3.2-6.0 months to 8.0-12.8 months, 
establishing radiation therapy as a standard component to treatment for glioblastoma.   
 
Modern treatment for glioblastoma has built upon this backbone of post-operative radiotherapy 
to include concurrent and adjuvant temozolomide chemotherapy, following a landmark study in 
2005 showing the addition of chemotherapy to raise median survival from 12.1 months to 14.6 
months (6).  Despite optimal combined modality therapy with surgery, radiation, and 
chemotherapy, survival outcomes remain poor with most patients progressing within 10-15 
months and surviving only 14.6-16.2 months from their initial diagnosis (7).  The prognosis for 
patients upon first progression is similarly poor, with most patients only surviving approximately 
4 months from progression (8,9).   
 
Re-irradiation is a common treatment component for locally recurrent glioblastoma, often in 
combination with surgery and/or chemotherapy.  Based on a large institutional series of 147 
patients with recurrent high grade glioma treated with fractionated stereotactic re-irradiation 
resulting in a median survival of 11 months with excellent treatment tolerance, a standard 
regimen for re-irradiation is 35 Gy delivered in 10 fractions over two weeks (10).  Based on 
these data the RTOG is actively testing this regimen in a prospective randomized study with and 
without concurrent bevacizumab therapy for recurrent glioblastoma (11). 
 
The predominant pattern of initial and subsequent failure in glioblastoma is local, with 75-93% 
of first recurrences occurring within the high-dose volume of radiotherapy (12–18).  
Accordingly, several prior studies have investigated intensification of local therapy.  In the era 
before modern chemotherapy, such studies showed improved overall survival with 
conventionally fractionated radiation doses to 60 Gy over 45 Gy (19).  However, efforts to dose-
escalate further to 70 Gy (20) and 80 Gy (21) did not significantly improve survival or patterns 
of failure.  Similarly, randomized studies investigating intensification of local therapy with 
stereotactic boosting (22) and brachytherapy (23) showed no improvement in outcomes. 
 
Explanations for this paradoxical risk of local recurrence that is refractory to intensive local 
therapy have included intratumoral hypoxia, genomic and phenotypic heterogeneity, and 
limitations of current models of radioresistance.  Conventionally “fractionated” radiation 
schedules are based largely on the linear-quadratic model which is commonly used to estimate 
the probability of tumor control and normal tissue complications (24).  Despite good 
concordance with experimental results in other cancers (25,26), efforts to optimize radiation 
schedules based on the linear-quadratic model have not proven effective in the clinical setting for 
aggressive gliomas (27). 

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1.2 
Rationale 
 
These limitations have drawn interest in re-designing radiation schedules, accounting for 
mechanisms of treatment resistance.  Recent work by Leder, Michor and colleagues has created a 
novel mathematical model of a major mechanism of treatment resistance by accounting for 
intratumor heterogeneity. Specifically, they modeled the evolutionary dynamics of radioresistant, 
slowly proliferating stem-like cells and radiosensitive, rapidly proliferating differentiated cells.  
They used this model to determine an optimized radiation fractionation schedule. They 
parametrized the mathematical model and validated the predicted  optimal schedules using a 
genetically engineered mouse model of PDGF-driven proneural glioblastoma (28,29). The 
investigators refined their mathematical model and its underlying biological assumptions through 
an iterative process of mathematical modeling and experimental validation.   The mathematical 
model suggested that survival could be prolonged by enriching the tumor for slowly proliferating 
stem-like cells. The model predicted that the stem-like cell fraction could be substantially 
increased by timing the radiation administrations such that the radiation-induced 
dedifferentiation from differentiated to stem-like cells was maximized. When the initial predicted 
optimal schedule was tested in a mouse model of PDGF-driven glioblastoma, this model-adapted 
radiation schedule did, as predicted, significantly increase the stem-like cell fraction and 
significantly improved survival relative to conventionally fractionated radiation among treated 
mice (median survival 50 days vs. 33 days, HR = 0.30, p=0.001) (29).  A second optimal 
schedule, based on updating the model to account for time-dependent dedifferentiation from 
differentiated to stem-like cells, resulted in a further, non-significant, improvement in survival 
compared with the original optimal schedule (HR = 0.88, p = 0.18). The updated mathematical 
model fit the experimental data better than the original model. 
 
Further evidence from human data suggest that enriching the stem-like cell fraction may 
represent a suitable strategy to prolong survival in patients. In a study by Pallini and colleagues. 
the stem-like cell fraction was measured at the time of primary surgery and at recurrence, i.e. 
before and after chemo-radiation therapy, in glioblastoma patients (30). The stem-like cell 
enrichment was significantly associated with recurrence-free survival, survival following 
recurrence and overall survival. 
 
We have used the validated mathematical model to translate the optimal schedule used in the 
mouse experiments (based on delivering 10 Gy in 5 days) to humans, using the same toxicity 
constraints and overall treatment time as in the RTOG 1205 trial. The mathematical model 
predicts that tumor growth delay is increased by enriching the slowly proliferating, stem-like cell 
population.  The model predicts that this is achieved in two ways: by increasing the total 
radiation dose delivered and by increasing the fraction of differentiated cells that dedifferentiate 
to stem-like cells.  Ultrafractionation (three fractions per day) greatly increases the stem-like cell 
fraction leading to a slower tumor regrowth following the end of treatment.  However, by 
enriching for stem-like cells early during treatment the number of radioresistant cells increases 
and, hence, the effectiveness of the remaining fractions of radiation decreases. In addition to 
enriching the stem-like cell population, survival can be prolonged by minimizing the total 
number of cells.  The total cell number is minimized by increasing the total radiation dose.  
Through using the model to simulate different treatment strategies, it is apparent that it is 

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desirable to obtain a balance between minimizing the total cell number and maximizing the stem-
like cell fraction at the end of treatment.  This can be achieved, within toxicity and practicality 
constraints, using an initial phase of hypofractionation to deliver a relatively high dose in a short 
period to reduce the total cell number with a small number of fractions.  By following this with 
an ultrafractionation phase the slowly proliferating stem-like cell population is enriched at the 
end of treatment resulting in slower tumor regrowth and, hence, prolonged survival. The 
proposed treatment schedule consists of 3.96 Gy delivered once per day for the first seven 
treatment days followed by 1.0 Gy delivered three times per day with a 3.25-hour interval 
between fractions for the final three treatment days. 
 
Indeed, ultrafractionation has been investigated in glioblastoma with promising results relative to 
historical controls and no reported grade 3-4 acute adverse events (31), emphasizing the promise 
and safety of this approach. 
 
We hypothesize that this novel, model-based radiation fractionation scheme will be safe and 
deliverable for patients with recurrent glioblastoma. This study will use the previously derived 
mathematical model to optimize a commonly used 2-week dose-fractionation scheme for re-
irradiation in glioblastoma (2), currently the standard re-irradiation regimen of the Radiation 
Therapy Oncology Group (11). 
 
 
2. OBJECTIVES 
 
2.1 
Study Design 
 
This is a non-randomized feasibility trial of a novel mathematical model-adapted radiation 
fractionation schedule, adapted from a standard 2-week treatment regimen for re-irradiation in 
glioblastoma (10). 
 
2.2 
Primary Objective 
 
To assess the feasibility of delivering a mathematical model-adapted radiation schedule over 2-
weeks for re-irradiation in recurrent glioblastoma. 
 
2.3 
Secondary Objectives 
 
To evaluate patient-reported outcomes and patient satisfaction among participants receiving re-
optimized radiation schedules.  
 
To prospectively evaluate acute treatment-related toxicity from this re-optimized re-irradiation 
regimen. 
 
To prospectively evaluate the following other endpoints among patients receiving this re-
optimized re-irradiation regimen:  
 
1.  All-cause mortality 

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2.  Incidence and time to local recurrence 
3.  Incidence and time to development of radiation necrosis 
4.  Incidence and time to salvage craniotomy 
5.  Incidence and time to systemic treatments after re-irradiation 
6.  Incidence and time to the development of seizures 
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
Participants must meet the following criteria to be eligible for the study: 
 
3.1.1 Participants must have recurrent glioblastoma (WHO Grade IV), as defined on brain 
imaging with CT or MRI, after prior receipt of definitive therapy including neurosurgical 
biopsy or resection and radiation therapy with or without systemic therapy.   
3.1.2 Participants must be deemed appropriate candidates for re-irradiation  
3.1.3 Histopathologic confirmation of disease as part of routine clinical care is required either 
at the time of initial diagnosis and/or at the time of recurrent disease.  There is no 
requirement for central pathologic review.   
3.1.4 Age > 18 years at the time of enrollment 
3.1.5 Karnofsky Performance Status (KPS) of at least 70 
 
3.2 
Exclusion Criteria 
 
3.2.1 Participants who have received more than one prior course of radiotherapy to the local 
site of progressive disease 
3.2.2 Participants who have received prior radiotherapy to the local site of progressive disease 
within < 3 months of the anticipated start of re-irradiation 
3.2.3 Participants with recurrent tumor extensively abutting or involving the optic structures or 
brainstem, as assessed by the treating radiation oncologist 
3.2.4 Participants without a definable tumor cavity on MRI or CT obtained at study enrollment  
3.2.5 Participants receiving concurrent cytotoxic chemotherapy (i.e. temozolomide, CCNU, 
vincristine, procarbazine) or concurrent immunotherapy (i.e. pembrolizumab, 
nivolumab); however, participants may receive sequential chemotherapy before or after 
radiation without limitation.  Participants may receive concurrent corticosteroid and/or 
anti-angiogenic therapy (i.e. bevacizumab) if clinically indicated.   
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
 
 
4. PRETREATMENT EVALUATIONS/MANAGEMENT 
 

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Patients presenting to Brigham and Women’s Hospital who meet the eligibility criteria above 
will be identified by a radiation oncologist, medical oncologist, or neurosurgeon and offered 
participation in the study. All patients must have undergone an MRI of the brain with T1 post-
contrast sequences (standard of care) or a CT scan (if MRI is not available due to non-compatible 
devices).  No other pretreatment evaluations are required. 
 
 
5. REGISTRATION PROCEDURES 
 
5.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
5.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
 
6. RADIATION THERAPY 
 
6.1 
Dose Specifications:  
 

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6.1.1 Treatment Schedule: Treatment shall consist of  a regimen that is biologically equivalent 
(in terms of biologically effective dose with an alpha/beta ratio of 2) to 35 Gy delivered 
in 10 fractions over two weeks.  Using the regimen developed by Fogh et al (10) and used 
by RTOG 1205 (35 Gy in 10 fractions) as a standard (11), this protocol has re-optimized 
the radiation schedule.  Radiation therapy will be delivered in 2 phases over 2 weeks with 
fractions delivered on Monday through Friday only (with no treatments on Saturday or 
Sunday).  All patients will aim to have their first fraction on Monday of week 1. In phase 
1, participants will receive 7 daily fractions of 3.96 Gy per fraction. In phase 2, 
participants  will receive 9 fractions of 1.00 Gy per fraction, 3 fractions per day with 3.25 
hour interfraction intervals, over 3 days. This idealized treatment schedule is shown in 
Table 1 and in Figure 1a.  Target homogeneity limits and deviations are listed in Table 2. 
Should any part of the treatment schedule have an anticipated conflict for clinical or 
logistical reasons (i.e. scheduled department closure for holiday) in which case treatment 
will not be administered on a given day over the 2-week course, an alternative treatment 
schedule will be generated utilizing the prediction model for the missing fraction(s).  A 
separate sensitivity analysis was conducted and predicted for a similar benefit of the 
novel schedule over standard re-irradiation schedule, irrespective of which day of the 
week treatment is started, as shown in Figure 1b.    
 
Table 1. Idealized Model-Adapted Radiation Schedule* 
 
Week 1 Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Dose 
1 x 3.96 Gy 
1 x 3.96 Gy 
1 x 3.96 Gy 
1 x 3.96 Gy 
1 x 3.96 Gy 
Week 2 Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Dose 
1 x 3.96 Gy 
1 x 3.96 Gy 
3 x 1.00 Gy 
(3.25-hour 
interval) 
3 x 1.00 Gy 
(3.25-hour 
interval) 
3 x 1.00 Gy 
(3.25-hour 
interval) 
* Schedule subject to predetermined adaptation due to anticipated conflicts (i.e. holidays, department 
closures, etc.…) 
 
Figure 1a. Idealized Model-Adapted Radiation Schema 
 

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Figure 1b. Sensitivity Analysis for Tumor Response by Day of Treatment Initiation  
 
 
6.1.2 Tumor Dose Coverage Objectives: The tumor dose coverage objectives are equivalent, in 
terms of the percentages of the prescription dose, to those used in RTOG 1205 (11). The 
tumor Planning Target Volume (PTV) dose coverage objectives, for the total absorbed 
dose delivered in 10 fractions, employed in the RTOG 1205 trial are shown in Table 2. 
 

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Table 2. RTOG 1205 Tumor Dose Coverage Objectives (given as absorbed dose) 
 
 Dose Metric 
 Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Volume of PTV 
covered by the 
prescription dose 
35 Gy 
≥ 95% of the PTV 
should receive the 
prescription dose or 
higher 
≥ 90% of the PTV 
should receive the 
prescription dose or 
higher 
< 90% of the PTV 
should receive the 
prescription dose or 
higher 
Minimum dose to 
the PTV (0.03 cc) 
≥ 85% of the 
prescription dose 
(29.75 Gy) 
≥ 80% of the 
prescription dose 
(28.00 Gy); 
minimum doses < 
80% of the 
prescription dose 
are permissible if 
they occur at an area 
of overlap with an 
organ at risk (OAR) 
< 80% of the 
prescription dose 
(28.00 Gy); 
minimum doses < 
80% of the 
prescription dose 
are unacceptable if 
they do not occur at 
an area of overlap 
with an OAR 
Maximum dose to 
the 
PTV (0.03 cc) 
≤ 120% of the 
prescription dose 
(42.00 Gy) 
≤ 130% of the 
prescription dose 
(45.50 Gy) 
> 130% of the 
prescription dose 
(45.50 Gy) 
 
For MARS-Glio phase 1 the prescription absorbed dose is 3.96 Gy per fraction, giving a 
cumulative (over 7 fractions) absorbed dose for phase 1 of 3.96 x 7 = 27.72 Gy. The 
tumor dose coverage objectives for phase 1 are shown in Table 3. 
 
Table 3. MARS-Glio phase 1 tumor dose coverage objectives (given as absorbed 
dose) 
 
 Dose Metric 
 Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Volume of PTV 
covered by the 
prescription dose 
27.72 Gy 
≥ 95% of the PTV 
should receive the 
prescription dose or 
higher 
≥ 90% of the PTV 
should receive the 
prescription dose or 
higher 
< 90% of the PTV 
should receive the 
prescription dose or 
higher 
Minimum dose to 
the PTV (0.03 cc) 
≥ 85% of the 
prescription dose 
(23.56 Gy) 
≥ 80% of the 
prescription dose 
(22.18 Gy); 
minimum doses < 
80% of the 
prescription dose 
are permissible if 
they occur at an area 
of overlap with an 
organ at risk (OAR) 
< 80% of the 
prescription dose 
(22.18 Gy); 
minimum doses < 
80% of the 
prescription dose 
are unacceptable if 
they do not occur at 
an area of overlap 
with an OAR 
Maximum dose to 
≤ 120% of the 
≤ 130% of the 
> 130% of the 

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the 
PTV (0.03 cc) 
prescription dose 
(33.26 Gy) 
prescription dose 
(36.04 Gy) 
prescription dose 
(36.04 Gy) 
 
For MARS-Glio phase 2 the prescription absorbed dose is 1.00 Gy per fraction, giving a 
cumulative (over 9 fractions) absorbed dose for phase 2 of 1.00 x 9 = 9.00 Gy. The tumor 
dose coverage objectives for phase 2 are shown in Table 4. 
 
Table 4. MARS-Glio phase 2 tumor dose coverage objectives (given as absorbed 
dose) 
 
 Dose Metric 
 Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Volume of PTV 
covered by the 
prescription dose 
9.00 Gy 
≥ 95% of the PTV 
should receive the 
prescription dose or 
higher 
≥ 90% of the PTV 
should receive the 
prescription dose or 
higher 
< 90% of the PTV 
should receive the 
prescription dose or 
higher 
Minimum dose to 
the PTV (0.03 cc) 
≥ 85% of the 
prescription dose 
(7.65 Gy) 
≥ 80% of the 
prescription dose 
(7.20 Gy); minimum 
doses < 80% of the 
prescription dose 
are permissible if 
they occur at an area 
of overlap with an 
organ at risk (OAR) 
< 80% of the 
prescription dose 
(7.20 Gy); minimum 
doses < 80% of the 
prescription dose 
are unacceptable if 
they do not occur at 
an area of overlap 
with an OAR 
Maximum dose to 
the 
PTV (0.03 cc) 
≤ 120% of the 
prescription dose 
(10.80 Gy) 
≤ 130% of the 
prescription dose 
(11.70 Gy) 
> 130% of the 
prescription dose 
(11.70 Gy) 
 
 
For MARS-Glio phases 1 and 2 combined the prescription absorbed dose is 3.96 x 7 + 
1.00 x 9 = 36.72 Gy. The tumor dose coverage objectives for phases 1 and 2 combined 
are shown in Table 5. 
 
Table 5. MARS-Glio phases 1 and 2 combined tumor dose coverage objectives 
(given as absorbed dose) 
 
 Dose Metric 
 Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Volume of PTV 
covered by the 
prescription dose 
36.72 Gy 
≥ 95% of the PTV 
should receive the 
prescription dose or 
higher 
≥ 90% of the PTV 
should receive the 
prescription dose or 
higher 
< 90% of the PTV 
should receive the 
prescription dose or 
higher 
Minimum dose to 
the PTV (0.03 cc) 
≥ 85% of the 
prescription dose 
(31.21 Gy) 
≥ 80% of the 
prescription dose 
(29.38 Gy); 
< 80% of the 
prescription dose 
(29.38 Gy); 

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minimum doses < 
80% of the 
prescription dose 
are permissible if 
they occur at an area 
of overlap with an 
organ at risk (OAR) 
minimum doses < 
80% of the 
prescription dose 
are unacceptable if 
they do not occur at 
an area of overlap 
with an OAR 
Maximum dose to 
the 
PTV (0.03 cc) 
≤ 120% of the 
prescription dose 
(44.06 Gy) 
≤ 130% of the 
prescription dose 
(47.74 Gy) 
> 130% of the 
prescription dose 
(47.74 Gy) 

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6.1.3 Normal Tissue Constraints: Participants shall receive prescription doses to the PTV (with 
the above constraints). All attempts should be made to deliver the PTV dose with the 
above heterogeneity constraints with adherence to critical structure dose constraints.  The 
normal tissue dose constraints are designed to be equivalent in terms of biologically 
effective dose (BED), to those used in the RTOG 1205 trial. The BED is defined as: 
 
 
 
where n is the number of fractions and d is the dose per fraction. For central nervous 
system toxicity an alpha/beta ration of 2 was used. The MARS-Glio dose constraints for 
the two phases combined in BED with an alpha/beta ratio of 2 are thus given by 
 
 
 
where 
 is the RTOG 1205 absorbed dose. For the individual phases the dose 
constraints, in absorbed doses, are given by 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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The dose constraints for the RTOG 1205 trial, in absorbed dose, are displayed in Table 6. 
 
Table 6. RTOG 1205 Normal Tissue Dose Constraints (given as absorbed dose) 
 
 Dose Metric 
 Per Protocol 
Variation Acceptable 
Deviation 
Unacceptable 
Scenario (1): Previous radiation to the local area including critical organs at risk 
Maximum Dose to 
PRV for Optic 
Nerves and Chiasm 
(D0.03 cc) 
Less than or 
equal to 20.00 
Gy 
Greater than 20.00 Gy 
but less than or equal to 
25.00 Gy 
Greater than 25.00 
Gy 
Maximum Dose to 
Brainstem (0.03 cc) 
Less than or 
equal to 24.00 
Gy 
Greater than 24.00 Gy 
but less than or equal to 
30.00 Gy 
Greater than 30.00 
Gy 
Scenario (2): No previous radiation to the local area or critical organs at risk 
Maximum Dose to 
PRV for Optic 
Nerves and Chiasm 
(0.03 cc) 
Less than or 
equal to 35.00 
Gy (the 
prescription 
dose) 
Greater than 35.00 Gy 
but less than or equal to 
36.75 Gy (105 % of the 
prescription dose) 
Greater than 36.75 
Gy (105% of the 
prescription dose) 
Maximum Dose to 
Brainstem (0.03 cc) 
Less than or 
equal to 35.00 
Gy (the 
prescription 
dose) 
Greater than 35.00 Gy 
but less than or equal to 
36.75 Gy (105 % of the 
prescription dose) 
Greater than 36.75 
Gy (105 % of the 
prescription dose) 
 
Table 7 shows the dose constraints for the combined phases in BED with an alpha/beta 
ratio of 2 for the optic nerves, optic chiasm and brainstem (BED2). 
 
Table 7. MARS-Glio phases 1 and 2 combined normal tissue dose constraints (given 
as BED with an alpha/beta ratio of 2) 
 
 Dose Metric 
 Per Protocol 
Variation Acceptable 
Deviation 
Unacceptable 
Scenario (1): Previous radiation to the local area including critical organs at risk 
Maximum Dose to 
PRV for Optic 
Nerves and Chiasm 
(D0.03 cc) 
Less than or 
equal to 40.00 
Gy2 
Greater than 40.00 Gy2 
but less than or equal 
to 56.25 Gy2 
Greater than 56.25 
Gy2 
Maximum Dose to 
Brainstem (0.03 cc) 
Less than or 
equal to 52.80 
Greater than 52.80 Gy2 
but less than or equal 
Greater than 75.00 
Gy2 

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Gy2 
to 75.00 Gy2 
Scenario (2): No previous radiation to the local area or critical organs at risk 
Maximum Dose to 
PRV for Optic 
Nerves and Chiasm 
(0.03 cc) 
Less than or 
equal to 96.11 
Gy2 (the 
prescription 
dose) 
Greater than 96.11 Gy2 
but less than or equal 
to 104.28 Gy2 
Greater than 104.28 
Gy2 
Maximum Dose to 
Brainstem (0.03 cc) 
Less than or 
equal to 96.11 
Gy2 (the 
prescription 
dose) 
Greater than 96.11 Gy2 
but less than or equal 
to 104.28 Gy2 
Greater than 104.28 
Gy2 
 
Tables 8 and 9 give the phase 1 and phase 2 normal tissue dose constraints in absorbed 
doses, respectively. 
 
Table 8. MARS-Glio phase 1 normal tissue dose constraints (given as absorbed 
dose) 
 
 Dose Metric 
 Per Protocol 
Variation Acceptable 
Deviation 
Unacceptable 
Scenario (1): Previous radiation to the local area including critical organs at risk 
Maximum Dose to 
PRV for Optic 
Nerves and Chiasm 
(D0.03 cc) 
Less than or 
equal to 16.05 
Gy 
Greater than 16.05 Gy 
but less than or equal 
to 19.96 Gy 
Greater than 19.96 
Gy 
Maximum Dose to 
Brainstem (0.03 cc) 
Less than or 
equal to 19.18 
Gy 
Greater than 19.18 Gy 
but less than or equal 
to 23.87 Gy 
Greater than 23.87 
Gy 
Scenario (2): No previous radiation to the local area or critical organs at risk 
Maximum Dose to 
PRV for Optic 
Nerves and Chiasm 
(0.03 cc) 
Less than or 
equal to 27.75 
Gy 
Greater than 27.75 Gy 
but less than or equal 
to 29.14 Gy 
Greater than 29.14 
Gy 
Maximum Dose to 
Brainstem (0.03 cc) 
Less than or 
equal to 27.75 
Gy 
Greater than 27.75 Gy 
but less than or equal 
to 29.14 Gy 
Greater than 29.14 
Gy 
 
Table 9. MARS-Glio phase 2 normal tissue dose constraints (given as absorbed 
dose) 
 
 Dose Metric 
 Per Protocol 
Variation Acceptable 
Deviation 
Unacceptable 
Scenario (1): Previous radiation to the local area including critical organs at risk 
Maximum Dose to 
Less than or 
Greater than 4.48 Gy 
Greater than 5.93 

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PRV for Optic 
Nerves and Chiasm 
(D0.03 cc) 
equal to 4.48 
Gy 
but less than or equal 
to 5.93 Gy 
Gy 
Maximum Dose to 
Brainstem (0.03 cc) 
Less than or 
equal to 5.63 
Gy 
Greater than 5.63 Gy 
but less than or equal 
to 7.43 Gy 
Greater than 7.43 
Gy 
Scenario (2): No previous radiation to the local area or critical organs at risk 
Maximum Dose to 
PRV for Optic 
Nerves and Chiasm 
(0.03 cc) 
Less than or 
equal to 8.98 
Gy 
Greater than 8.98 Gy 
but less than or equal 
to 9.54 Gy 
Greater than 9.54 
Gy 
Maximum Dose to 
Brainstem (0.03 cc) 
Less than or 
equal to 8.98 
Gy 
Greater than 8.98 Gy 
but less than or equal 
to 9.54 Gy 
Greater than 9.54 
Gy 
 
See Section 6.5 below for specifics regarding when to implement a dose reduction. The 
final prescription dose will be reported specifically to the study coordinator and recorded 
on a patient-by-patient basis. 
 
6.2 
Technical Factors 
 
6.2.1 RT will be delivered with megavoltage equipment at energies ≥6 MV.  Any FDA cleared 
external beam radiation delivery system may be used (including conventional linear 
accelerators).  All treatment fractions (as specified above in Table 1) will be delivered on 
consecutive treatment days.  All patients will be positioned via a combination of rigid 
immobilization and daily image guidance to ensure positioning accuracy of 3 mm or 
better, and of a magnitude that justifies the PTV margin applied (the treating radiation 
oncologist must document the immobilization and localization methods applied). 
 
6.3 
EBRT Localization, Simulation, and Immobilization 
 
6.3.1 Simulation will be CT- and/or MRI-based (if available) in all cases. The use of contrast at 
the time of simulation is not required.  Participants will be positioned on a flat tabletop 
with a customized immobilization for stabilization and setup reproducibility, with the 
patient in the same position and immobilization device as for treatment.  CT images 
should be acquired at a slice thickness of ≤3 mm.  Target volumes (Section 6.4.1) and 
normal critical structures (Section 6.4.1.5) will be defined in the slices in which they are 
visualized.  
 
6.4 
Treatment Planning/Target Volumes 
 
6.4.1 The definition of volumes will be in accordance with the ICRU Report #50: Prescribing, 
Recording, and Reporting Photon Beam Therapy. 
 

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6.4.1.1 
The Gross Tumor Volume (GTV) is defined will be defined using a CT and/or 
contrast-enhanced MRI (obtained prior to the initiation of re-irradiation).  If no 
residual enhancing tumor is noted, the post-operative resection cavity will be 
outlined. 
 
6.4.1.2 
The Clinical Target Volume (CTV) is the GTV plus areas considered to contain 
microscopic disease.  A CTV expansion of no more than 5 mm is optional for lesions 
measuring less than 3.5 cm in maximum diameter or if this is a new lesion, but must 
be reported when used.  Otherwise, no CTV expansion is expressly recommended. 
 
6.4.1.3 
The Planning Target Volume (PTV) will provide a margin around the CTV to 
compensate for the variability of treatment set up and internal organ motion. A range 
of 1-5 mm around the CTV is required to define each respective PTV. As noted above 
in Section 6.3.1, daily image guidance to ensure positioning accuracy of 3 mm or 
better. 
 
6.4.1.4 
The ICRU Reference Points are to be located in the central part of the PTV and, 
secondly, on or near the central axis of the beams. Typically these points should be 
located on the beam axes or at the intersection of the beam axes. 
 
6.4.1.5 
The PTV forms the entire target as described. 3D-conformal, intensity modulated 
radiation therapy (IMRT), Volumetric Arc Therapy (VMAT), and/or fractionated 
stereotactic radiotherapy (SRT) are all acceptable modalities of radiation treatment 
delivery.  If IMRT or SRT are intended, to avoid delays resulting from unplanned 
equipment availability, photon therapy may be administered using 3D-conformal 
radiotherapy at the discretion of the treating radiation oncologist. 
 
6.5 
Critical Structures  
 
Critical structure dose constraints shall remain consistent with Tables 7-9 above. While 
every effort should be made to deliver prescription doses to the PTV as specified while 
adhering to these constraints, it is recognized that certain anatomical factors may prevent 
this. 
 
For purposes of compliance, up to a 5% absolute increase in the volume of critical 
structure receiving greater than the specified dose will be considered “variation 
acceptable,” without a protocol deviation. Any increase in critical structure volume 
greater than 5% receiving more than the specified dose will be considered a “deviation 
unacceptable.”  It is at this point that a dose reduction should be considered. 
 
6.6 
Quality Assurance 
 
6.6.1 Documentation Requirements 
 
The institution will archive treatment prescription and verification images for later review 
by the study chair if requested. At least one port film or pretreatment alignment film per 

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field along with the digital reconstructed radiographs (DRRs) from the treatment 
planning program or, alternatively, a simulation verification radiograph shall be acquired 
and kept for evaluation if requested except where geometrically impractical. 
 
6.6.2 Radiation Quality Assurance Reviews  
 
The study chair will oversee quality assurance reviews for patients treated on this study. 
RT quality assurance reviews will be ongoing and performed remotely. RT quality 
assurance reviews will be facilitated by study chair. 
 
6.6.3 Compliance Criteria 
 
Cases that meet criteria as stated in Section 6.1.1 will be scored as per protocol.  See 
Table 2 and Table 3 for target and normal tissue compliance criteria respectively.  
 
6.7 
Radiation Adverse Events 
 
All participants will be seen weekly by their treating radiation oncologist while 
undergoing therapy. Any observations with respect to symptoms/side effects that are 
possibly, probably, or definitely related to recurrent glioblastoma or irradiation to the 
brain will be followed for adverse event (AE) reporting.  
 
Clinical discretion may be used in managing radiotherapy-related side effects. 
 
6.8 
Radiation Adverse Event Reporting 
Any observations with respect to symptoms/side effects that are possibly, probably, or 
definitely related to recurrent glioblastoma or irradiation to the brain will be followed for 
AE reporting. See Section 9 for listing of particular AEs that will be monitored. This is 
not an all-inclusive list, and any AE that is considered by the treating physician to be 
related to recurrent glioblastoma and/or irradiation to the brain will be followed with 
attributions and grading according to CTCV 4.0. Routine solicited AEs not considered by 
treating physicians to be related to recurrent glioblastoma or irradiation to the brain will 
be treated according to institutional guidelines and managed by the patient’s oncology 
team in the best clinical judgment of the responsible physician. 

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6.9 
Criteria for Discontinuation  of Protocol 
Disease progression 
 
Unacceptable toxicity to the participant (at the discretion of the treating physician).  
Reasons for removal must be clearly documented on the appropriate case report 
form/flowsheet. 
 
The participant may withdraw from the study at any time for any reason. 
 
If protocol treatment is discontinued, follow-up and data collection will continue as 
specified in the protocol  
 
 
7. DRUG THERAPY 
 
This protocol does not specify any investigational drug therapy.  Participants receiving re-
irradiation may not receive concurrent cytotoxic chemotherapy (i.e. temozolomide, CCNU, 
vincristine, procarbazine) or concurrent immunotherapy (i.e. pembrolizumab, nivolumab).  
Participants may receive sequential systemic therapy before or after radiation without limitation.   
Participants may receive concurrent corticosteroid and/or anti-angiogenic therapy (i.e. 
bevacizumab) if clinically indicated.   
 
 
8. SURGERY  
 
This protocol does not mandate neurosurgical resection prior to receipt of re-irradiation.  
Participants may undergo a planned neurosurgical resection prior to registration and receipt of 
re-irradiation at the discretion of the treatment multidisciplinary team.  Such participants will be 
required to have recovered from the acute effects of neurosurgery prior to initiating re-irradiation 
at the judgment of the treating radiation oncologist.  There is no maximum or minimum interval 
from the time of prior surgery to initiation of re-irradiation.  If participants underwent a 
preceding neurosurgical resection, the target volume for re-irradiation will include the surgical 
cavity plus any residual enhancing disease.  
 
 

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9. ADVERSE EVENTS 
 
Toxicity assessments will be performed using the active version of the NCI CTCAE which is 
available at:  http://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
 
Grade 1-2 fatigue will be managed supportively. Activity will be encouraged. 
Grade 3 fatigue can be managed per above, with the additional of low-dose dexamethasone 
and/or methylphenidate 2.5-5.0 mg daily, as needed.  
 
Grade 1-2 nausea can be managed with as-needed antiemetics such as Zofran 8 mg prn, steroids 
(dexamethasone preferred, e.g. 2 mg PO BID), and hydration. 
Grade 3 nausea can be managed per above with the addition of intravenous fluids and electrolyte 
repletion. Hospitalization and a treatment break can be considered. 
 
Grade 1 headache can be managed with Tylenol 650 mg BID and consideration of low-dose 
dexamethasone (2 mg PO BID) 
Grade 2 headache can be managed per above, with narcotics as needed. 
Grade 3 headache can be managed per above, with consideration of high-dose dexamethasone (4 
mg PO TID) and a treatment break. 
 
Symptomatic edema can be managed with dexamethasone (2 mg PO BID) at discretion of 
treating physician.  
 
Seizures will be managed with antiepileptic drugs, consideration of a treatment break, and 
referral to Neuro-oncology or admission, depending on the nature and severity of the episode. 
 
Any observations with respect to symptoms or side effects that are possibly, probably, or 
definitely related to brain metastases or radiation to the brain will be followed for AE reporting. 
 
 
10. PARTICIPANT ASSESSMENTS 
 
Table 10 presents the schedule of treatment and follow up visits. Visits should occur within 2 
weeks of the scheduled day. If a participant fails to appear for a visit, the investigator will make 
every attempt to contact them and determine the reason for the missed visit.  A participant will 
be deemed lost to follow-up only after at least 3 attempts to contact him/her have been made 
over a 4-week period. For participants who present with significant transportation or other 
barriers that would prevent them from being followed at the Dana-Farber/Brigham and Women’s 
Cancer Center clinics, they may be followed closer to home at outside institutions by local 
oncologists, and clinical notes will be requested by the study team. 
 
The primary endpoint (feasibility of receipt of fractions) will be assessed at the completion of all 
treatment fractions.  
 
Medical history and physical exam, which includes general questions about health, medications 
being taken, current allergies, and assessment of the development of seizures will be taken at 

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screening, at each weekly visit during radiation therapy, at 4 + 2 weeks after completion of 
radiation, and at subsequent follow-up visits every 1-3 months thereafter per usual clinical 
practice.  
 
Karnofsky Performance Status (KPS) will be assessed at screening, at each weekly visit during 
radiation, at 4 ± 2 weeks after completion of radiation, and at subsequent follow-up visits every 
2-4 months thereafter per usual clinical practice.   
 
Toxicity review will consist of a history at each visit to monitor for relevant toxicity as described 
in section 9.Toxicity will be assessed at each weekly visit during radiation therapy, at 4 + 2 
weeks after completion of radiation, and at subsequent follow-up visits every 2-4 months 
thereafter per usual clinical practice. 
 
Quality of life, as per the MDASI-BT: M. D. Anderson Symptom Inventory – Brain Tumor 
survey) will be assessed at baseline, at 4 ± 2 weeks after completion of radiation, and at 
subsequent follow-up visits every 2-4 months thereafter per usual clinical practice.  The MDASI-
BT is performed as part of an institution-wide effort to collect patient-reported outcomes. This is 
the usual care pattern for such patients. Patients who have significant transportation limitations 
may follow-up with their local oncologist and forgo the questionnaire. 
 
Head imaging will be obtained at baseline, at 4 ± 2 weeks after completion of radiation, and at 
subsequent follow-up visits every 2-4 months thereafter per usual clinical practice.  Typically, 
this will consist with an MRI of the brain with contrast (although CT Head and non-contrast 
scans will be permitted if participants cannot receive standard MRIs).  Head imaging will be 
used to define response as outline in section 12.7. 
 
Follow-up data from these visits will continue to be collected after active participation in the 
study concludes. Therefore, participants will be followed per protocol for 6 months after 
completion of radiation treatment. Additional clinical follow up per standard of care will 
continue until death or loss to follow up, and relevant outcome data will be collected 
retrospectively during that time.  
 
The length of follow up for the primary outcome measure (feasibility of receipt of fractions) will 
be 1 month after treatment completion.  The length of follow up for all other endpoints will be 
until death or loss to follow up.  This is because the usual clinical care for patients with brain 
metastases involves a radiation or neuro-oncology visit, history, and an MRI brain every 2-6 
months until death or other loss to follow up.  
 
 
 
 
 
 
 
 
 

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Table 10. Study Calendar 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Every 2-4 
months* 
 
Screening Radiation 
Planning 
Radiation 
Start 
Week 1 
Visit 
Week 2 
Visit 
4-week 
follow up* 
Informed Consent  
X 
 
 
 
 
 
 
Medical History 
(including 
assessment of 
development of 
seizures) & Physical 
Exam 
X 
 
 
X 
X 
X 
X 
Neurologic Exam 
X 
 
 
X 
X 
X 
X 
Karnofsky 
Performance Status 
(KPS) 
X 
 
 
X 
X 
X 
X 
CT or MRI 
X 
X 
 
 
 
X 
X 
MDASI-BT 
X 
 
 
 
 
X 
X 
Toxicity Assessment 
X 
 
 
X 
X 
X 
X 
Radiation Planning 
 
X 
 
 
 
 
 
Radiation Treatment 
 
 
X 
X 
X 
 
 
*Patients who have significant transportation limitations may follow-up with their local oncologist and 
also forgo the MDASI-BT 
 
Abbreviations: MDASI-BT: M. D. Anderson Symptom Inventory – Brain Tumor survey 
 

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11. DATA COLLECTION 
11.1 
Summary of Data Submission 
Item 
Due 
Demographic Form 
Initial Evaluation Form 
Pathology Report 
Head Imaging Report 
 
Within 2 weeks after registration 
Treatment Form 
 
Within 2 weeks of the end of radiotherapy 
MDASI-BT 
Within 2 weeks of each follow up as above 
Follow-Up Form 
 
Within 2 weeks of each follow up as above 
 
Within 2 weeks of progression/relapse and 
death 
 
11.2 
Summary of Dosimetry Data Submission for Protocol Treatment 
Item 
Due 
Final Dosimetry Information 
Radiotherapy Form  
Daily Treatment Record 
Within 1 week of RT end 
 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
 
Primary Endpoint 
The primary outcome measure is the feasibility of delivering a model-adapted radiation 
fractionation schedule. Feasibility is defined as successful completion of radiation therapy for at 
least 13 of 14 patients. Successful completion of radiotherapy is defined as receipt of all 
scheduled fractions of daily radiotherapy within 24 hours of once daily fractions and within 1 
hour of three-times daily fractions.   
 
A sensitivity analysis has been performed on the mathematical model, which revealed no 
significant effect on tumor kill from the timing of once daily radiotherapy.  This analysis did 
reveal the importance of the timing of three-times daily radiation therapy, for which feasibility 
was defined as treatment within 1 hour of the scheduled time.  
 
Secondary Endpoints 
Secondary outcomes and analytic techniques to assess these outcomes will include: 
1. Quality of life, as determined by the MDASI-BT index (Appendix B), ascertained at the time 
of study enrollment, 4 weeks after completion of reirradiation, and every 2-4 months 
thereafter. We will conduct a longitudinal / repeated measures analysis to assess quality of 
life (mean MDASI-BT score for items 1-22 in APPENDIX B between 0-24 weeks) 
2. Incidence (exact binomial distribution with 95% confidence intervals) 

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and time to the development of Grade 3+ acute or delayed CNS toxicity 
3. Incidence and time to development of radiation necrosis (Kaplan-Meier plot, Cox regression) 
4. Incidence and time to the development of seizures (Kaplan-Meier plot, Cox regression) 
5. Performance status (longitudinal regression) 
6. Overall survival, defined as the interval from registration to death from any cause (Kaplan-
Meier plot, Cox regression) 
7. Progression-free survival, defined as the interval from registration to progression or death, 
whichever occurs first (Kaplan-Meier plot, Cox regression) 
8. Local recurrence, defined as the interval from registration to local recurrence (Kaplan-Meier 
plot) 
9. Incidence and time to salvage craniotomy (Kaplan-Meier plot, Cox regression) 
10. Incidence and time to additional systemic treatments after reirradiation (Kaplan-Meier plot) 
 
12.2 
Sample Size and Power Justification 
 
The final target accrual for this study will be 14 cases. 
 
A recent trial attempted to deliver 90 fractions of radiation therapy to glioblastoma patients in 6 
to 7 weeks, 5 days per week, 3 fractions per day (32). The schedule was successfully 
administered in 22/27 (81%) patients who started radiation therapy. The one-sided 95% upper 
limit (exact binomial distribution) for the population non-adherence was, therefore, 35%. Based 
on this adherence rate delivery of the schedule was deemed feasible. 
 
The schedule proposed in this protocol is substantially simpler to deliver. If 13 out of 14 patients 
are able to complete the proposed schedule (86%), this study would demonstrate that the one-
sided 95% upper limit (exact binomial distribution) for the population non-adherence is 30%. 
This non-adherence rate, or lower, would be deemed acceptable to progress to a subsequent 
efficacy trial. If all patients are able to complete the proposed schedule, this study would 
demonstrate that the one-sided 95% upper limit for the population non-adherence is no higher 
than 20%. 
 
12.3 
Sample Size, Accrual Rate and Study Duration 
 
This study is expected to accrue 8-10 cases per year.  Therefore, the target accrual should be 
completed within 22 months of study activation, allowing slow accrual in the first 6 months.  If 
the average accrual over two months (6 months after trial activation) is less than 1 case, the study 
will be re-evaluated with respect to feasibility.  
 
The study duration will be approximately 28 months; 22 months of accrual and 6 months of 
follow-up on the last participant enrolled.  
Accrual should be well-balanced for males, females, and minorities. 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
1 
+ 
1 
= 
2 

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12.4 
Stratification Factors 
 
No stratification factors will be used in this non-randomized study. There will be no dose 
escalation in this cohort. 
  
 
12.5 
Interim Monitoring Plan 
Futility: If two or more patients experience non-adherence events no further patients will be 
recruited. 
 
12.6 
Analysis of Primary Endpoints 
 
Specified above 
 
12.7 
Analysis of Secondary Endpoints 
 
Specified above 
 
Local control will be defined as the interval from registration to local recurrence as determined 
by the Response Assessment in Neuro-Oncology (RANO) working group (33).  
Not Hispanic or Latino 
6 
+ 
6 
= 
12 
Ethnic Category: Total of all subjects 
7 
(A1) + 
7 
(B1) = 
14 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
1 
+ 
1 
= 
2 
Black or African American 
1 
+ 
1 
= 
2 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
5 
+ 
5 
= 
10 
Racial Category: Total of all subjects 
7 
(A2) + 
7 
(B2) = 
14 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 

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Response/Progression Categories  
 
Complete response (CR). All of the following criteria must be met: 
o Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, 
this scan will be considered only stable disease. 
o No new lesions. 
o All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
o Participants must be on no steroids or on physiologic replacement doses only. 
o Stable or improved non-enhancing (T2/FLAIR) lesions. 
o Stable or improved clinically, for clinical signs and symptoms present at baseline 
and recorded to be disease related. 
Participants with non-measurable disease cannot have a complete response. The best 
response possible is stable disease. 
 
Partial response (PR). All of the following criteria must be met: 
o ≥50% decrease compared to baseline in the sum of products of perpendicular 
diameters of all measurable enhancing lesions sustained for at least 4 weeks. In 
the absence of a confirming scan 4 weeks later, this scan will be considered only 
stable disease. 
o No progression of non-measurable disease. 
o No new lesions. 
o All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
o The steroid dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan. 
o Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
o Stable or improved, for clinical signs and symptoms present at baseline and 
recorded to be disease related clinically. 
Participants with non-measurable disease cannot have a partial response. The best 
response possible is stable disease. 
 
Progressive disease (PD). The following criterion must be met: 
> 25% increase in sum of the products of perpendicular diameters of enhancing 
lesions (over best response or baseline if no decrease) on stable or increasing doses of 
corticosteroids and/or one or more of the of the following: 
o Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing 
doses of corticosteroids steroids compared to baseline scan or best response 
following initiation of therapy not due to co-morbid events (radiation therapy, 
demyelination, ischemic injury,infection, seizures, post-operative changes, or 
other treatment effects). 
o Any new lesion 

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o Clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g. seizures, medication side effects, complications of therapy, cerebrovascular 
events, infection, etc.). The definition of clinical deterioration is left to the 
discretion of the investigator but it is recommended that a decline in the 
Karnofsky Performance Score (KPS) from 100 or 90 to 70 or less, a decline in 
KPS of at least 20 from 80 or less, or a decline in KPS from any baseline to 50 or 
less, for at least 7 days, be considered neurologic deterioration, unless attributable 
to comorbid events or changes in corticosteroid dose. 
o Failure to return for evaluation due to death or deteriorating condition  
o NOTE: If there is uncertainty whether the patient has progressed it is permissible 
to repeat the scan in 1 month. If that scan confirms progression, the date of 
progression will be the original date when progression was suspected to deal with 
ambiguities related to pseudoprogression. 
 
 
Stable disease (SD). All of the following criteria must be met: 
o Does not qualify for CR, PR, or progression. 
o All measurable and non-measurable sites must be assessed using the same 
techniques as baseline. 
o Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. In the event that the corticosteroid dose 
has been increased, the last scan considered to show stable disease will be the 
scan obtained when the corticosteroid dose was equivalent to the baseline dose. 
o Stable clinically. 
 
Unknown response status.  
• Progressive disease has not been documented and one or more measurable or non-
measurable lesions have not been assessed. 
 
 
These RANO Response Criteria are also summarized in the following table: 
 
Table 11. Summary of RANO Response Criteria 
 
CR 
PR 
SD 
PD 
T1-Gad+ 
None 
≥50% decrease < 50% decrease 
– <25% increase 
≥25% increase* 
T2/FLAIR 
Stable or 
decrease 
Stable or 
decrease 
Stable or 
decrease 
Increase* 
New Lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or 
decrease 
Stable or 
decrease 
NA 
Clinical Status 
Stable or 
increase 
Stable or 
increase 
Stable or 
increase 
Decrease* 
Requirement 
for Response 
All 
All 
All 
Any 
 

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CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease 
 
#: Progression occurs when any of the criteria with * is present 
 
NA: Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioration. 
 
 
12.8 
Reporting and Exclusions 
 
Participants who never start protocol therapy will be considered “inevaluable” and will be 
excluded from analysis of all endpoints.  In terms of grade 3+ toxicity and acute/delayed toxicity, 
all patients receiving any or partial protocol treatment should be included. 
 
12.8.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. Toxicity 
endpoints will be reported separately for participants who complete all prescribed radiotherapy 
per protocol and for those who do not. 
 
We will monitor for the following: 
 
Fatigue 
 
Fatigue is common after brain radiation; it is less common and typically short-lived after shorter 
courses of radiation but can still occur.  
 
Nausea 
Nausea may occur with re-irradiation although typically not commonly. 
 
Headache 
Headache that occurs with re-irradiation is typically mild in severity. 
 
Symptomatic edema 
Symptomatic edema occurs when radiation interacts with the tumor, leading to death of tumor 
cells and resulting inflammation. It may be more common with re-radiation.  
 
Seizure 
Seizures are uncommon in patients receiving fractioned radiation but may be more common 
among patients receiving re-irradiation.  Seizures generally do not stem from infratentorial 
lesions, however.  
 
Intracranial hemorrhage 
Intracranial hemorrhage has never been definitively associated with radiation, although patients 
with glioblastoma may have a propensity to bleed and may display hemorrhage post radiation, 
especially if patients are on anticoagulation for other reasons. Intratumoral hemorrhage will 

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require only close monitoring with MRI. Extratumoral hemorrhage may require referral to 
Neuro-oncology, admission, a treatment break, and possible discontinuation of agents that 
predispose to bleeding, depending on the nature and severity of the bleed. 
 
Radiation necrosis 
Radiation necrosis can occur after re-irradiation. Enhancing lesions that increase in size after 
radiation will be evaluated for the possibility of radiation necrosis using a dual-phase PET scan, 
at the discretion of the primary investigator and the treating neuro-oncologists.  Asymptomatic 
radiation necrosis will be monitored on brain MRI. Symptomatic necrosis will initially be 
managed with a brief (e.g. three week) course of dexamethasone.  If refractory, referral to Neuro-
oncology for consideration of bevacizumab and neurosurgery for consideration of resection will 
be arranged. 
 
12.8.2 Evaluation of the Primary and Secondary Endpoints 
 
All participants who initiate radiotherapy on protocol will be considered “evaluable” and will be 
included in analyses for feasibility.   
 
Survival, progression-free survival, and quality of life endpoints will be reported separately for 
participants who complete all prescribed radiotherapy per protocol and for those who do not. 
 
 
 
13. REGULATORY CONSIDERATIONS 
 
13.1 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 

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the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 

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APPENDIX B 
M. D. ANDERSON SYMPTOM INVENTORY – BRAIN TUMOR SURVEY 
 
 

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