Keto-Brain: Investigating the Use of Ketogenic Diets in Brain Metastases
Phase: NA
Conditions: Brain Metastases, Adult
Sponsor: Ohio State University Comprehensive Cancer Center

Keto Brain: Investigating the Use of 
Ketogenic Diets in Brain Metastases 
 
The Ohio State University 
 
IRB Approval   13 April 2022 
 
IRB# 2020C0046 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB Approved  
1. BRAIN METASTASES 
Neurological tissues are among the most common (>10% of cancer patients) and debilitating sites 
for metastatic disease to develop (1). The brain is a ‘sanctuary site’ for many cancer cells and 
remains a challenging site to treat. Surgery and radiation therapies are the most common treatments. 
We hypothesize that the metabolic adaptations associated with a well-formulated ketogenic diet that 
induces nutritional ketosis will significantly improve the response to surgery and radiation in 
patients with brain metastases.  
 
2.0 STANDARD OF CARE RADIOTHERAPY 
Over 200,000 patients a year will be diagnosed with brain metastases (BM) and the incidence of 
BM is predicted to grow due to improvement in survival with newer systemic therapies effective 
for various primary cancer diseases. (2) Overall survival has also improved significantly over the 
years for patients with BM, so the morbidity of radiation is becoming more important. Whole brain 
radiation therapy (WBRT) is the most common treatment for BM to date. The majority of patients 
treated with WBRT suffer neurocognitive deterioration by 6 months. RTOG 0614, randomized trial 
of WBRT +/- memantine, found patients treated with WBRT alone had an 80% rate of cognitive 
deterioration at 6 months. (3) For WBRT we can reduce neurocognitive decline by using IMRT to 
spare the hippocampus, but even with HA, 50% of the patients will still develop neurocognitive 
failure based on NRG-CC001. Nonetheless, for patients who present with extensive (>4 lesions) 
BMs, WBRT is considered the standard approach and the latent challenge is to both control 
intracranial disease but simultaneously preserve neurocognition and prevent decline in quality of 
life. Moreover, SRS is the standard of care for patients with limited number (1-4) of BM. RTOG 
1270 showed similar overall survival but less neurocognitive decline at 6 months using SRS vs. 
WBRT with patients up to 4 BM. (4) The obstacle in the use SRS for extensive BM is the time 
under treatment if each lesion is treated with a separate radiation plan. Therapy choices for this 
population are currently guided by the available technologies and little to no relevant information 
on normal tissue toxicity exist. Specifically, in vivo mapping of ultrastructure damage is still 
unrevealed in the context of BM.  Here we have chosen to select BM patient candidates for SRS 
who are willing to adopt either a ketogenic or guidelines-based mixed diet to explore the clinical 
course of disease following radiation treatment. We purposely chose a highly sensitive cohort to 
study the overlapping benefits of using advanced radiation delivery, the SRS, in synergy with the 
potential neuro rejuvenating aspects of nutritional ketosis. We hypothesize that a sustained 
ketogenic diet has neuroprotective effects that can aid in neurocognitive preservation in patients 
treated with SRS.  
 
3.0 Metabolic Adaptations to a Ketogenic Diet and Relevance to Metastatic Cancer 
A ketogenic diet causes accelerated fat metabolism, which results in production of specific 
metabolites called ketones. The principal ketone body beta-hydroxybutyrate (BOHB) is now 
recognized as both a preferred metabolite for the brain and other extrahepatic tissue as well as a 
potent signaling molecule with epigenetic effects that favorably affect cellular function (5, 6). Over 
the last 15 years, our research group has established the superiority of very low-carbohydrate 
ketogenic diets over traditional low-fat diets in managing insulin resistant conditions (7, 8), which 
now includes over half the adults in the US (9). The metabolic state of nutritional ketosis is 
associated with a robust shift to almost exclusive reliance on fatty acids and ketones for fuel. 
Interestingly, highly competitive national caliber ultra-endurance athletes are also increasingly 
switching to ketogenic diets. We recently published the first paper showing that keto-adapted 
athletes have extraordinary fat burning capabilities at least 50% higher than the highest rates ever 
recorded (10). The reduced reliance on carbohydrate oxidation and insulin- mediated glucose 

uptake has beneficial effects on satiety, weight loss, insulin sensitivity and glycemic control. There 
is also decreased inflammation and oxidative stress, improvements in cholesterol and lipoprotein 
profile, fatty acid composition, and overall cardio-metabolic risk.  
Importantly, the state of nutritional ketosis should provide a favorable environment to nourish the 
body while deterring tumor growth through less glucose flux, insulin stimulation, and 
inflammation. One central tenant of tumor metabolism is an almost exclusive uptake and 
utilization of glucose for energy derivation. An ability to control blood glucose and insulin, 
without additional medication, may inherently decrease tumor   viability.   The   reliance   on   
glucose   as   a   fuel   substrate   is   exploited   via   18- flourodeoxyglucose positron emission 
tomography (FDG-PET), the gold standard for cancer diagnosis and prognostic characterization. 
Evidence that targeting insulin sensitivity and improved glucose management is beneficial to 
cancer comes from the recent discovery that metformin, the most widely used anti-diabetic 
medication to improve insulin sensitivity, results in decreased risk of cancer occurrence (11). 
Nutritional ketosis resulting from a ketogenic diet consistently reduces circulating plasma glucose 
levels and increases insulin sensitivity (12-14). 
 
Only a few human studies have investigated the effects of a ketogenic diet on cancer.  Two small 
clinical trials that investigated the effectiveness of a ketogenic diet in advanced stage cancer 
patients both demonstrated slowed disease or partial remission in several patients (15, 16). A recent 
study reported that a patient with breast cancer with PET avid metastasis in both lung and bone 
experienced complete remission after adoption of a ketogenic diet (17). The same authors further 
demonstrated that 60% of the adopters experienced improvements in tumor biology or prognosis, 
with diet adherence associated with better outcomes (17). These findings provide a strong 
scientific rationale for a larger and tightly controlled study in advanced cancer patients that 
incorporates more sophisticated methods of inducing and monitoring nutritional ketosis. 
 
It is well understood that cancer results in a state of chronic inflammation, in which the tumor 
thrives. Ketogenic diets have clinically demonstrated improved systemic inflammation status, 
specifically decreased concentrations of several proinflammatory cytokines (e.g., IL-6 and IL-8) 
(18), both of which are significantly increased in advanced stage breast cancer patients (19). This 
may significantly improve patient well-being and quality of life, as cancer related fatigue in 
patients with breast cancer has been linked with chronically elevated concentrations of the pro-
inflammatory cytokine IL-6 (20). IL-6 increases have also been linked with an induction of the 
genes SNAIL and TWIST. SNAIL and TWIST are two of the major genetic regulators of 
epithelial-mesenchymal transition (EMT), the initial step of metastasis (21). Nutritional ketosis 
reduces the amount of cancer stem cells, a cell population that is theorized to be the root cause for 
metastasis and cancer recurrence (22). Further in vivo evidence has demonstrated the ability of a 
ketogenic diet to improve mood of individuals undertaking a weight loss program (23). In vitro 
research has demonstrated the ability of ketosis to decrease tumor viability and improve survival 
time (24). 
One potential pathway for the discord in energy metabolism of cancer may result from PTEN and 
phosphoinositide 3-kinase (PI3K) pathway mutations. Within the past two decades the tumor 
suppressor capabilities of the phosphatase and tensin homologue (PTEN) gene have been well 
documented (25). Either PTEN inhibition or PI3K activation via insulin-mediated processes causes 
metabolic deregulation and result in a Warburg-like Effect. Loss of PTEN results in 
phosphatidylinositol-3,4,5-triphosphate 
dephosphorylation, 
as 
well 
as 
an 
increased 
phosphorylation of AKT via PDK1 further activating and enhancing the PI3K/AKT pathway. Since 

insulin is a primary activator of the PI3/AKT pathway, tumor growth could reasonably be inhibited 
by therapeutic interventions that lower insulin concentration and action. One of the fundamental 
adaptations associated with a ketogenic diet is decreased insulin concentration and signaling, 
increased reliance on fatty acids and ketones as energy substrates, and dramatically reduced 
reliance on glucose uptake and oxidation (10, 26). Fatty acids and ketones do not require insulin-
dependent PI3K signaling for transport and oxidization in cells, and thus should result in decreased 
action of PI3K and downstream effectors including mTOR inhibition (22). 
 
Aside from direct effects on tumor-based outcomes, nutritional ketosis may counteract undesirable 
side effects associated with drugs commonly used to manage different types of cancer. In efforts 
to combat inflammation associated with chemotherapeutic agents, patients are frequently 
administered glucocorticoids. Glucocorticoids function by binding the glucocorticoid receptor, 
activating transcription factors, and effecting target genes (27). While high doses glucocorticoids 
strengthen anti-inflammatory defenses and combat adverse reactions to chemotherapeutic drug 
infusion, they promote insulin resistance and weight gain (27). In fact, approximately two-thirds 
of individuals with a high dose of glucocorticoids exhibit hyperglycemic conditions (28). 
Glucocorticoid-induced insulin resistance manifests in a similar fashion to that of Type II diabetes. 
The resultant hyperglycemia is associated with increased proteolysis, de novo lipogenesis, and 
hepatic fatty acid accumulation. These unfavorable metabolic outcomes to glucocorticoids are 
targeted by ketogenic diets (7, 8). Thus, nutritional ketosis would be expected to decrease the need 
for glucocorticoids owing to its anti-inflammatory effects and decreased dependency on glucose 
metabolism. In more aggressive cases, nutritional ketosis may also permit the use of higher doses 
of glucocorticoids, when needed, by mitigating untoward side effects. 
 
Thus, there are several metabolic adaptations to a ketogenic diet that should benefit patients with 
brain metastases including decreased fat mass, decreased glucose flux into tumors, less insulin 
burden, less inflammation and oxidative stress, improved tolerance to chemotherapy and radiation, 
and mitigation of side effects to medications. 
 
3.1 Non-Metabolic Roles of Ketones and Relevance to Cancer 
A defining feature of a well-formulated ketogenic diet is that circulating levels of BOHB increase 
by an order of magnitude. A remarkable new perspective on BOHB was published in Science just 
a few years ago (29). This paper showed that BOHB is a potent histone deactylase (HDAC) 
inhibitor and regulator of a group of genes that protect cells  from oxidative  stress. Specifically, 
it  was  demonstrated that  at  physiological  levels characteristic of nutritional ketosis, BOHB 
switched on specific genes that protect cells  from free radical damage. Shortly after this research 
was published, others reported that the same mechanism of action by BOHB also potently and 
directly reduced insulin resistance. Since oxidative stress is prominent in the pathophysiology of 
aging, it has been hypothesized that BOHB may be a longevity metabolite, which is now supported 
by two recent papers (5, 30). 
 
It is highly probable that the nontoxic, epigenetic, drug-like effect of naturally-produced BOHB 
on HDAC inhibition has relevance to cancer metabolism and management. HDAC inhibitors are 
currently used as novel anti-cancer agents, and have been shown to arrest tumor growth and induce 
apoptosis in cancer cells in vitro and in vivo (31). Paclitaxel (taxol) is used as a first line standard 
of care chemotherapeutic drug. Two recent papers (31, 32) demonstrated a potent synergistic effect 
of combining paclitaxel with an HDAC inhibitor on two different cancer cell lines. The HDAC 
inhibitor used in these studies was phenethyl isothiocyanate (PEITC), found in a wide variety of 

 
cruciferous vegetables with much less relative potency compared to BOHB. Further evidence 
demonstrating a therapeutic role of HDAC inhibitors has been the clinical success of Vorinostat in 
combating triple negative breast cancer and sensitizing the malignancy to more common 
treatments (33). Vorinostat is a broad spectrum HDAC inhibitor that selectively targets similar 
HDACs as BOHB (29, 33). Thus it may be likely that a ketogenic diet provides a non-toxic 
pathway for improving patient-related outcomes and increase tumor sensitivity to radiation. In our 
proposed study, we will customize the diet such that we optimize ketones in the same range shown 
to result in HDAC inhibition (29). We expect this unique synergistic combination will yield overall 
favorable patient effects (e.g., less tumor growth, decreased treatment dose to maintain 
effectiveness, decreased toxicity of treatment). 
 
3.2 Current Knowledge of Ketogenic Diets in Cancer 
There currently exist several basic science papers and animal studies pointing to positive effects 
of ketogenic diets in different types of cancers (24, 34, 35), and this is now moving into human 
clinical trials. Our current on-going Keto-CARE trial is the world’s first and only clinical trial 
investigating the feasibility and efficacy of a well-formulated ketogenic diet in women with 
metastatic breast cancer. To date, this trial has demonstrated high levels of tolerance and feasibility 
as evidenced by mean blood ketones above 0.5mmol, the threshold for nutritional ketosis. Two 
previous studies also found a high degree of feasibility of the ketogenic diet in human patients 
with advanced stage cancers (15, 16). Both research teams successfully demonstrated that a 
ketogenic diet is feasible and well tolerated with no adverse events in advanced stage cancer 
patients. In a cohort analysis Fine (2012) demonstrated that participants with the highest ketosis 
levels exhibited either stable disease, or partial remission. While findings were promising, the 
sample and effect sizes were small, the diets lacked sophistication and were at the lower end of 
nutritional ketosis, and they were not done in combination with chemotherapy. The patients 
studied in Fine (2012) were also later stage 4 and thus represented a population that may be more 
difficult to treat effectively than patients initially diagnosed with BM. A larger study with better 
control over dietary parameters is needed to determine the response to a ketogenic diet in patients 
with brain metastases. Despite the sample size limitations, interpretation of the Fine (2012) study 
reveals that the highest responders to ketosis were most likely to succeed. This finding 
corroborates results from Schmidt (2011) that showed participants who completed the intervention 
had higher levels of stable disease or partial remission. There currently exist approximately ten 
registered clinical trials investigating a ketogenic diet in cancer patients, the majority of which are 
focused on head, neck, lung and brain primary tumor sites. None of these trials are investigating 
patients with brain metastasis. Due to the unique etiology and most common tumorigenic 
pathways, brain metastasis presents a myriad of potential therapeutic mechanisms through which 
ketosis may target. 
 
Thus, the next logical step is to perform a larger study in patients with brain metastasis that 
incorporates principles of a personalized well-formulated ketogenic diet. Our research group 
includes experts in ketogenic diets and medical and radiation oncologists. Thus, we are uniquely 
suited to perform such a study. 
 
4. RATIONALE AND FEASIBILITY 
 
To date, numerous preclinical studies have demonstrated the ability of nutritional ketosis and 
caloric restriction to augment the therapeutic efficacy of radiotherapy (36, 37). Use of a ketogenic 
diet is known to decrease the protein expression of HIF-1a and VEGFR2, and may increase radio 

 
sensitivity by normalizing tumor vasculature and increasing facilitated oxygen delivery to tumor 
cells. Several additional proposed mechanisms exist for enhancing radiosensitivity of the 
malignancy including: HDAC dependent mechanisms, ATP deprivation, mitochondrial ROS 
production and downregulation of IGF-1 receptor.  Short-term fasting, a way to increase ketones 
acutely, has been demonstrated to speed up mitotic rates and thus facilitate a DNA damage 
sensitization. Lastly, a recent study showed that glucose restriction lowered Ki-67 expression, 
clonogenic frequency and rate of proliferation in gliomaspheres in vitro.   
 
Our research team has an established expertise in conducting ketogenic diet interventions. Many 
individuals have adopted a low-carbohydrate diet for health reasons, yet there is scarce 
professional support available to provide guidance and support, especially for ketogenic diets. We 
have scientific expertise and practical knowledge of both ketogenic and current standard of care 
cancer diets combined with a passion to empower people with the tools to implement these eating 
approaches into their lifestyle. This project is highly patient-centered. We will support patients 
who are randomized into either one of the intervention groups and provide them with a 
personalized eating plan designed to have maximal therapeutic impact and positively impact their 
lives. To that end, this project is unique in that it is highly patient-centered while also designed to 
have a substantial scientific and practical impact on medical management of brain metastasis 
treatments. 
 
5.0 OBJECTIVES 
We propose to conduct a highly controlled feeding study for 16 weeks to examine the effects of an 
individualized ketogenic or American Institute of Cancer Research (AICR) dietary approach on 
tumor response to targeted radiation therapy, as well the neural preservation in non-targeted areas 
of the brain. Our specific aims are as follows: 
Primary objective: Assess the feasibility of maintaining a ketogenic versus AICR diet in 
patients with brain metastasis selected for radiosurgery. Endpoints: 
• Circulating glucose (primary endpoint) 
• Circulating ketones (primary endpoint) 
• Retention 
• Side-effects 
Secondary objective: Assess the preliminary efficacy of the ketogenic versus AICR diet on 
tumor response to targeted radiation therapy. Endpoints: 
• RECIST v. 1.1 will be utilized to evaluate responses to therapy  
Exploratory objective: Assess the preliminary effects of the ketogenic versus AIRC diet on 
cognitive function and quality of life in BM individuals undergoing radiation therapy. 
 
6.0 STUDY DESIGN 
This pilot study will be a single center, randomized controlled study of 24 participants with 
diagnosed BM (various primary disease sites) comparing the effect of a ketogenic (n=12) and AICR 
(n=12) diet. Randomization will be balanced by blocks of random sizes but no stratification due to 
the small sample size. Both groups will undergo a 16-week diet intervention. In an effort to maintain 
a patient centric focus and monitor changes in quality of life (QOL) all patients will complete 
psychosocial and behavioral inventories. These inventories aim to capture a holistic view on the 
proposed nutritional intervention during treatment. Primary outcomes will be determined at 
baseline, 8 weeks, and 16 weeks (see section 13 – Study Calendar) while patient-centric outcomes 
will be assessed every four  weeks. 
 
6.1 Eligibility Criteria 

 
 
Inclusions: 
• 
Ages 18-75 years old 
• 
Measurable brain lesions noted on baseline MRI imaging  
• 
Graded Prognostic Assessment > 1.5 
• 
Body mass index (BMI) ≥18 kg/m2 
• 
Eastern Cooperative Oncology Group (ECOG) Performance status of 0-1 (0=participant has 
either normal activity, 1= participant has some symptoms but is nearly full ambulatory) 
• 
Able and willing to follow prescribed diet intervention 
• 
Scheduled to receive SRS  
  
Exclusion criteria: 
• 
Undergoing whole brain radiation therapy 
• 
BMI <18 kg/m2 
• 
Pregnant or nursing women 
• 
Not willing to be randomized into either of the dietary interventions 
• 
Unable to provide Informed Consent 
• 
No previous diagnosis of small cell lung carcinoma 
• 
No previous or suspected leptomeningeal disease 
• 
Type 1 diabetes or insulin-dependent Type II diabetes 
• 
Abnormal renal function (GFR < 55 mL/min, creatinine >2.0, urinary albumin >1 g/day) 
Not MRI eligible 
 
7.0 TREATMENT PLAN 
Participants will have counseling by the attending physician for additional applicable medications 
for any treatment related side effects or toxicities. The intervention groups will undergo their 
randomized dietary regimen for 16 weeks.   
 
7.1 Treatment considerations 
7.1.1 Prior to Treatment 
After informed consent is obtained from the patient and prior to randomization, baseline QOL 
and functional independence assessments must be completed. 
The SRS dose has been selected in order to provide a high rate of local control with minimum 
risk of radionecrosis. The SRS dose is decreased modestly for larger lesions in order to account 
for the volume effect on complication rates. While prior SRS to other lesions is allowed, repeat 
SRS to the same lesion/location is NOT allowed. 
Treatment Timing:  Patients must initiate radiosurgery treatment ≤14 days after registration. 
Treatment should occur within 14 days of the MRI for treatment planning. 
Cytotoxic Chemotherapy is not allowed 3 days before SRS, the same day as the SRS, or 3 days 
after the completion of the SRS.  
 
7.2 Stereotactic Radiosurgery (SRS) to Surgical Bed Guidelines: (Fractionated SRS) 
For unresected brain metastases see Section 7.3.   
For unresected brain metastases see section 7.3. If all lesions cannot be treated on the same 
day, all lesions MUST be treated with ≤8 days of completing treatment of the first legion.  
 
For any questions regarding dose and volumes physicians may contact the study radiation 
oncology PI, Joshua Palmer, for guidance 

 
For unresected brain metastases see Section 7.3.  If all lesions cannot be treated on the same 
day, all lesions MUST be treated within ≤8 days of completing treatment of the first lesion.  
 
7.2.1 
Medications 
Patients may be given a short steroid taper over 1-2 weeks, 2-4 mg of dexamethasone twice 
daily for 5 days, then 2-4 mg daily for 5 days. Concurrent use of a proton pump inhibitor or H2 
receptor antagonists are encouraged if on steroids for an extended period.   
 
7.2.2 
Equipment 
Modality: Gamma knife or X-rays with nominal energy of 4 megavoltage (MV) or greater for 
accelerator-based treatments, including isocentric conical collimators, mini-multi-leaf (5 mm 
or less) technology, single isocenter mutli-target technique, or linear accelerators mounted on 
robotic arms will be used. 
 
7.2.3 
Target Volume Definitions 
The volumes shall be defined by a planning MRI brain scan.   ICRU-91 and AAPM TG-263 
nomenclature target volumes are defined as follows and will include laterality and tumor 
location (ie. GTV(#)_frontal_L and PTV(#)_cerebellum_R): 
• Gross Tumor Volume (GTV):  Pre-operative MRI post-contrast volumetric imaging, post-
operative MRI post-contrast volumetric imaging and CT simulation or treatment planning MRI 
of the brain will be used. The surgical bed is defined as the entire surgical cavity noted on T1 
post-contrast volumetric imaging, including blood products and postsurgical changes if these 
are limited to the surgical bed. For deep lesions this does not include the entire surgical tract 
through the brain.  In addition, this does not include edema. However, the GTV will include 
the adjacent meningeal surfaces which were shown on the pre-operative MRI imaging and any 
adjacent meningeal surfaces adjacent to the resection bed. GTV will not extend outside of the 
calvarium (CT simulation bone window is preferred if available).  
• Clinical Tumor Volume (CTV):  This is defined as the GTV with a 2 mm margin as seen on 
planning MRI.  However this 2 mm margin does not need to expand into structures that 
typically are not at risk of tumor infiltration from brain metastases such as air or bone.   
• Planning Target Volume (PTV): Typically, PTV will equal CTV with no expansion. However, 
an optional 1mm expansion of CTV is allowed when defining PTV.  
• Contouring will be reviewed by the radiation oncology PI, Joshua Palmer.  
 
7.2.4 
Target Dose: 
Prescription Specification: The dose should be prescribed to the highest isodose line 
encompassing the PTV (surgical cavity plus 2 mm – see section 7.334), which can range from 
45% to 95% of the maximum dose. 
Dose Definition:  Dose is specified in Gray (Gy). 
Prescription Dose: The total prescribed dose is determined by the GTV.  The volume 
determines dose due to the often irregular shape of surgical cavities: 
 
Fractionated SRS 
Lesions <30 cc receive 27 Gy /3 fractions 
Lesions ≥ 30 cc to < 5 cm receive 30Gy /5 
fractions 
 
Dose Conformity: The ratio of the prescription isodose volume to the target volume should be 
between 1.0 and 2.0.  Preferably, the conformity index should be between 1 and 1.2. It is 

 
understood that this ratio may be difficult to achieve with some very small lesions. For lesions 
less than 5 mm in size, a ratio up to 3.0 is acceptable.  
 
7.2.5 
Treatment Technique 
An immobilization/patient localization system is mandatory for this study. Single isocenter, 
multi-target, multiple isocenter and non-isocentric techniques are permitted. 
 
7.2.6 
Normal Tissue/Critical Structures 
The treatment parameters should be modified to optimize the fit of the prescription volume to 
the target volume while minimizing dose to critical structures. Normal Tissue tolerances are 
based on AAPM TG 101.  
• 3 (three) Fraction Dose Constraints.  The maximum point dose to the optic pathway should 
be less than 17.4 Gy, and <0.2cc will receive 13.8 Gy. No more than 0.5 cc of the brain stem 
should exceed 18 Gy, maximum point dose 23.1 Gy.  
• 5 (five) Fraction Dose Constraints.  The maximum point dose to the optic pathway should be 
less than 23 Gy, and <0.2cc will receive 20 Gy. No more than 0.5 cc of the brain stem should 
exceed 23 Gy, maximum point dose 28 Gy. 
 
7.3 Guideline for Unresected Brain Metastases 
If all lesions cannot be treated on the same day, all lesions MUST be treated within ≤10 days 
of treatment of the first lesion.  
 
7.3.1 
Medications 
If single fraction SRS, patients may be given an intravenous bolus dose of 4 to 16 mg of 
dexamethasone or 40 to 80 mg of SoluMedrol at the time of SRS, at the discretion of the 
treating physician. Patients in both arms may alternatively be given a short steroid taper over 
1-2 weeks, 2-4 mg of dexamethasone twice daily for 5 days, then 2-4 mg daily for 5 days. 
Concurrent use of a proton pump inhibitor or H2 receptor antagonists are encouraged while on 
steroids. See Section 8.1 for ancillary/concomitant therapy.  
 
7.3.2 
Equipment 
Modality: Gamma knife or X-rays with nominal energy of 4 megavoltage (MV) or greater for 
accelerator-based treatments, including isocentric conical collimators, mini-multi-leaf (5 mm 
or less) technology, single isocenter mutli-target technique, or linear accelerators mounted on 
robotic arms. 
 
7.3.3 
Target Volume Definitions 
The volumes shall be defined by typical standard of care MRI brain scan (recommended MR 
protocol included in Appendix B: IMAGING).   ICRU-91 and AAPM TG-263 nomenclature 
target volumes are defined as follows and will include laterality and tumor location (ie. 
GTV(#)_frontal_L and PTV(#)_cerebellum_R): 
• Gross Tumor Volume (GTV): This is defined as the contrast enhanced tumor seen on planning 
MRI. The maximal cross-sectional diameter must be < 3.0 cm. 
• Clinical Tumor Volume (CTV):  The CTV will equal the GTV with no expansion.    
• Planning Target Volume (PTV): This is defined as the CTV for this study. Typically there will 
be no expansion of CTV to create PTV, but an optional 1-2 mm expansion of CTV is allowed 
when defining the PTV determined by the treating physician based on immobilization and 
treatment technique. 
 

 
7.3.4 
Target Dose: 
Prescription Specification: The dose should be prescribed to the highest isodose line 
encompassing the PTV, which can range from 45% to 95% of the maximum dose. 
Dose Definition: Dose is specified in Gray (Gy). 
Prescription Dose: For unresected metastases the fractionation schedule should match the 
fractionation schedule for the surgical bed as treating all lesions at the same time. 
 
Single Fraction SRS. The total prescribed dose is determined by treatment arm and 
tumor size (maximal diameter). 
SSRS Unresected Metastasis: 
  Lesions < 1.0 cm receive 24 Gy 
  Lesions ≥ 1.0 to ≤ 2.0 cm receive 
22 Gy 
 
Three Fraction SRS. 
FSRS Unresected Metastasis: 
Lesion >2.0 cm receive 27 Gy /3 
fractions 
 
Five Fraction SRS. 
Arm B (FSRS) Unresected 
Metastasis: 
Lesion >3.5 cm receive 30Gy /5 
fractions 
Dose Conformity: The ratio of the prescription isodose volume to the target volume (PTV) 
should be between 1.0 and 2.0. It is understood that this ratio may be difficult to achieve with 
some very small lesions. For lesions less than 5 mm in size, a ratio up to 3.0 is acceptable.  
 
7.3.5 
Treatment Technique 
An immobilization/patient localization system is mandatory for this study. Single isocenter, 
multitarget, multiple isocenter and non-isocentric techniques are permitted. 
 
7.3.6 
Normal Tissue/Critical Structures 
The treatment parameters should be modified to optimize the fit of the prescription volume to 
the target volume while minimizing dose to critical structures.   The dose constraints depend 
on the fractionation schedule utilized. 
• Single (one) Fraction Dose Constraints.  The maximum point dose to the optic pathway should 
be less than 9 Gy. No more than 1cc of the brain stem should exceed 12 Gy. 
• 3 (three) Fraction Dose Constraints.  The maximum point dose to the optic pathway should be 
less than 17.4 Gy, and <0.2cc will receive 13.8 Gy. No more than 0.5 cc of the brain stem 
should exceed 18 Gy, maximum point dose 23.1 Gy.  
• 5 (five) Fraction Dose Constraints.  The maximum point dose to the optic pathway should be 
less than 23 Gy, and <0.2cc will receive 20 Gy. No more than 0.5 cc of the brain stem should 
exceed 23 Gy, maximum point dose 28 Gy. 
 

 
Please refer to the table in Section 7.2.6 for the standard naming convention for critical 
structures. 
 
Dietary Interventions (16 weeks): Four to seven days prior to the baseline testing, participants in 
both the Ketogenic and AICR Diet groups will be provided with meals consistent with their diet 
group that will provide 100% of caloric needs to assist  participants with their dietary transition and 
to ensure participants in the ketogenic arm get into nutritional ketosis by the time of baseline 
treatment. Food for both diet groups will be provided by a 'ready to eat' meal delivery company 
along with supplemental snacks. After baseline testing  both groups will be provided individualized 
counseling and support to follow guidelines for each respective eating pattern to maintain their 
respective diet for the remainder of the study.  The Ketogenic Diet will consist of <50 g carbohydrate 
(personalized based on level of ketones checked daily by finger stick), ~15-20% protein and ~70-
75% fat. Total energy intake will be ad libitum to permit overweight/obese participants to restrict 
caloric intake to induce weight and fat loss for those who are overweight. Participants will be 
provided with a handheld glucometer (Precision Xtra, Abbott Nutrition) and ketone test strips in 
order to check the concentration of BOHB from a finger stick.  Normal levels of ketones in a person 
consuming more than 100 grams of carbohydrate per day is <0.1 mmol/L. The goal of the diet will 
be to induce a state of nutritional ketosis defined as blood ketones >0.5 mmol/L.  We believe that a 
level  of ketones above 1.5 mmol/L will enhance the metabolic therapy and deliver better outcomes 
based on preliminary studies in women with breast cancer (Fine et al., 2012; Schmidt et al., 2011) 
and blood BOHB concentrations shown to inhibit histone deacetylases (Shimazu et al., 2013b).The 
carbohydrate level required to induce nutritional ketosis will vary from person to person and thus 
objective feedback provided by testing blood ketones is a novel tool we will use to personalize the 
diet by titrating the carbohydrate and protein intake to the participant’s individual ketosis threshold. 
We will encourage consumption of a wide range of ketogenic-appropriate whole foods including 
non- starchy vegetables, fruits (berries, olives, tomatoes, lemons/limes), meats (beef, chicken, pork, 
fish, lamb), nuts and seeds, oils (olive, canola, coconut), cheese, butter, cream, and eggs. Contrary 
to the misconception that the diet is boring or overly restrictive, it is noteworthy that even the most 
carbohydrate intolerant person can choose from a wide range of whole foods including berries and 
a wide assortment of vegetables.  
 
Participants randomized into the AICR arm will follow the “Model plate for a cancer preventative 
diet” which is outlined as follows: “Aim for meals made up of 2/3 (or more) vegetables, fruits whole 
grains or beans and 1/3 (or less) animal protein. If you are overweight, consider gradually reducing 
that number. Controlling portion size at home and in restaurants makes a long-lasting difference in 
controlling your weight.” 
 
Adherence and Retention: Achieving good adherence and retention is one of the most challenging 
aspects of prospective diet intervention studies. Most studies of low- carbohydrate ketogenic diets 
have poor compliance because of poor understanding of proper formulation and implementation 
challenges. Historically we have had excellent compliance and satisfaction to a ketogenic diet in 
both feeding and free-living studies. Ketogenic diets should not be forced on people so we carefully 
explain details of the diet (including meal plans, acceptable and non-acceptable foods, etc.) so that 
individuals are knowledgeable about what to expect and can make an informed choice whether to 
enroll in a study. We have performed multiple ketogenic feeding experiments including a recently 
completed study at OSU where we observed excellent adherence as determined by daily capillary 
BOHB measurement over a 10-week period and another ongoing trial in patients with metastatic 
breast cancer. The proposed study will be the first time we work specifically with cancer patients 
who are undergoing radiation therapy. We acknowledge there may be unique challenges in regard 

 
to compliance in this population of patients with metastatic cancer due to their cancer diagnosis 
and/or drug-induced effects on appetite and preferences for food.   
 
Due to the small sample size proposed (n=24), we will have an enhanced researcher/participant 
relationship to promote individualized education and counseling to facilitate nutritional ketosis and 
perceived benefit. We have developed extensive educational materials and resources to help 
participants successfully make the behavior change to eating a very low-carbohydrate diet and an 
AICR diet. Well-formulated ketogenic diets are unique when compared to other diets in that there 
exists an ability to receive direct feedback on participant adherence via finger prick and handheld 
glucometer that measures the biomarker BOHB. Enrolled participants will be in daily correspondence 
with research staff throughout the duration of the study to provide a personalized nutrition approach 
and optimize the amount of time spent in nutritional ketosis and to provide continued support and 
education for the AICR cohort. 
 
8.1 Clinical assessments 
 
Standard of Care Clinic Visits 
Participants will be evaluated in the clinic prior to the start of therapy and study intervention, as well 
as at monthly intervals for history, physical examination for vitals, height, and weight. Hearth Hope 
Index (HHI), SF-36, cancer specific FACT-surveys, Brief Pain Inventory, and Brief Fatigue 
Inventory, and self-report diaries (adverse events, adherence and palatability surveys) will be 
completed to evaluate QOL and will be administered at baseline, monthly during the intervention 
and at study terminus. Serum or plasma-based biological markers will also be collected at baseline, 
and midpoint and study terminus. Standard of care brain imaging will be utilized at baseline, 8 and 
16 weeks to evaluate disease status and progression. Body composition and bone mineral density 
will be assessed at baseline and 16 weeks using dual energy x-ray absorptiometry (DXA). 
 
8.2 Adherence 
Participant adherence with the study intervention will be encouraged and monitored in several ways. 
All participants will be provided a handheld glucometer (Precision Xtra, Abbott Nutrition) and 
reagent strips that measure BOHB from a small amount of blood obtained by finger stick. Although 
there is variability between people, BOHB levels in individuals consuming more than 100 grams of 
carbohydrate per day are usually ≤0.1 mmol/L. A primary goal of the initial diet intervention is for 
each participant to enter nutritional ketosis, which starts at 0.5 mM and extends up to approximately 
3.5 mmol/L. This is a strong indication that fat is being used as one’s primary fuel, and there may 
be other therapeutic benefits associated with ketones in this range. Transient increases in ketones 
above 3.5 mmol/L may occur after exercise, but regulatory feedback systems keep ketones from 
elevating to dangerous levels that are seen in uncontrolled type-1 diabetics who have insufficient 
insulin (i.e., >10 mmol/L). Participant’s information will be kept private and only made available to 
IRB approved research staff.  During the intervals between research- based visits participants will 
report their ketone levels daily to the research coordinator and lead RD on the team and adjustments 
to the diet made accordingly.  
We will counsel patients to aim for a level > 1.0 mM while following principles of a well-formulated 
ketogenic diet. If ketone readings are lower than 0.5 mM, we will individually work with the patient 
to identify appropriate changes to their diet/lifestyle to achieve nutritional ketosis. The monitoring 
of daily ketones for patients on the ketogenic diet provides a gold-standard biofeedback marker that 
is objective and quantifiable for adherence. Deviation from the dietary standards of a well-
formulated ketogenic diet will cause rapid decreases in ketones and elevations in blood glucose, 

 
which will be identified in the patient:researcher interaction.  For the standard diet arm, this will 
present a greater challenge.  We will ask participants to inform us of dietary deviations and these 
will be identified and logged.  The monthly self-report diaries will be used for tracking any minor 
adverse effects (GI distress, bloating, gut distension, diarrhea etc.). If participants do not experience 
any side effects, it is possible they will not have a self-report diary to share monthly.   
 
8.3 Data and Records 
Primary source documents will include forms routinely used at the James Comprehensive Breast 
Center, namely the Breast Patient Information Form, clinic and office notes as well as laboratory and 
radiology reports. 
 
8.4 Safety Monitoring 
Adverse events will be monitored by self-reporting of signs and symptoms. Patients will maintain 
weekly contact with researchers and any possible ill effects will be noted and discussed with the 
attending physician or Research Nurse to discuss and manage any possible side effects. Patients will 
be counseled with regard to potential signs of treatment toxicity and should immediately contact the 
PI, study coordinator or treating physician in the event such a problem arises. 
 
8.5 Accountability 
All interventional testing will be provided at no cost to the patient. Further, as a result of the time-
intensive nature of the study participants in the intervention group will receive a completion stipend 
of $500. 
 
9.0 BIOCHEMICAL, COGNITIVE AND PSYCHOSOCIAL TESTING 
 
Activity Monitor: 
Physical activity during a course of radiation therapy can be associated with decreased fatigue and 
may potentially mitigate other side effects. An activity tracker will be worn around the wrist daily for 
heart rate and step counting.  
 
Peripheral Blood Samples: 
Additional lab samples, which are not part of standard care, will be obtained at baseline and paid 
for as a research cost. Blood will be collected at baseline and every 8 weeks throughout the study 
duration until terminus. 
 
Continuous Glucose Monitoring (CGM)/ Continuous Ketone Monitoring (CKM): 
In order to more accurately quantify the glycemic control and diet adherence of patients using either 
the AICR or Ketogenic diet we will use three 10-14 day recording periods of CGM/CKM at baseline, 
midpoint and post-testing. A small Bluetooth compatible unit will be affixed to either the triceps or 
adipose located near anterior superior iliac spine.  CGM/CKM will be analyzed for glucose 
excursions, mean glucose levels and other markers of glycemic control.  
 
Insulin Resistance and Pre-Diabetes Panels 
Due to the high correlation between insulin resistance, diabetes and breast cancer 
occurrence/prognosis, we will examine the effects of the two diets on several biomarkers including 
HbA1c, Insulin, Glucose, and Sex hormone binding globulin (SHBG). 
Inflammation Panel 
Due to the fact that anti-cancer therapies result in increased inflammation, we will examine a panel 

 
of inflammation markers. Each of the following markers is associated with either prognosis or 
quality of life. The markers to be assessed will be: TNF-α IL-6, IL- 8, CD-14, and CD-16. 
 
Collection and Handling of Specimens 
At baseline, and on a monthly basis until study terminus blood will be collected from the participant. 
Prior to testing all vacutainers will be labeled per study requirements. Blood will be collected into 
vacutainers, inverted and then stored depending on requirements for each assay. 
 
Cognitive Testing 
The current trial will build on the successes of RTOG 0614 and NRG-CC001 in utilizing the same 
neurocognitive function (NCF) measures with the addition of the PROMIS Cognitive Function Short 
Form 8a self-report assessment. There are a number of advantages of such an approach including 
familiarity and acceptance of these measures by clinical research staff, the well-established use and 
validation of these measures in brain metastasis research, and the possibility of future post-hoc 
analyses between studies.   
 
The NCF tests to be used in this study (the Hopkins Verbal Learning Test – Revised (Benedict 1998), 
Trail Making Test (Tombaugh 2004), and the Controlled Oral Word Association (Ruff 1996) are the 
same tests as were used in RTOG 0614, NRG-CC001, NCCTG/Alliance N0574, and 
NCCTG/Alliance N107C, and that are being used in numerous ongoing brain met trials (e.g., NRG-
CC003, SWOG S1827).   
 
While NCF outcomes have been recognized as being crucial in the brain metastasis population (Lin 
2013), there is also interest in evaluating the impact of treatment arm on patient-reported outcomes. 
PROMIS Cognitive Function Short Form 8a measures perceived cognitive abilities (e.g., memory, 
attention, and decision making) and the application of such abilities to everyday tasks (e.g., planning, 
organizing, calculating, remembering and learning). The PROMIS-8, assessment is brief and 
therefore not a significant burden for patients to complete.  
 
The Hopkins Verbal Learning Test – Revised (Benedict 1998), Trail Making Test (Tombaugh 2004), 
and the Controlled Oral Word Association test (Ruff 1996) are widely used and standardized 
psychometric instruments that have been shown to be sensitive to the impact of cancer and the 
neurotoxic effects of cancer treatment in other clinical trials (Gilbert 2014; Meyers 2004; Wefel 
2011). The tests have published normative data that account for age and, where appropriate, education 
and gender. The NCF assessments will be administered at baseline, 8 and 16 weeks.  
 
The established metric for clinically-significant change is the Reliable Change Index (RCI; Jacobsen 
1991). The RCI is derived from the standard error of measurement of each test and represents the 
90% confidence interval for the difference in raw score from baseline to the next assessment that 
would be expected if no real change occurred: 
 
RCI = 1.64(standard error of difference), where standard error of difference  
 
 
  = [2(standard error of measure2)]1/2,  and standard error of measure  
 
 
  = standard deviation1[(1 − rxy)1/2] 
 
 
 
This yields the following RCI values for each test in the Clinical Trial Battery: 
NCF Test 
RCI Value 
HVLT-R Total Recall 
5 
HVLT-R Delayed Recall 
3 

 
HVLT-R Delayed Recognition 
2 
TMT Part A 
12 
TMT Part B 
26 
COWA 
12 
 
At each assessment, change in raw test score relative to baseline are calculated, and declines in a score 
that meets or exceeds the RCI value is categorized as a failure. Cognitive failure (CF) is defined as 
a decline on at least one of the Clinical Trial Battery tests (HVLT-R, TMT, COWA) that meets or 
exceeds the RCI value. 
 
PROMIS Cognitive Function Short Form 8a v2.0: This measure is a 8-item questionnaire that assesses 
patient-perceived cognitive concerns over the past 7 days.  The 8-item short form has demonstrated 
excellent internal consistency reliability and has criterion validity related evidence for measuring 
cognitive concerns but not cognitive performance. This measure asks the patient to rate the frequency 
of the following cognitive complaints over the preceding 7 days. Each question has five response 
options ranging in value from one to five (with lower scores indicating more severe cognitive 
concerns). The total raw score for a short form would be the sum of the values of the response to each 
question (therefore, for a short form which all questions are answered, the lowest possible score is 8 
and the highest possible raw score is 40).  
 
Collection of Psychosocial and Behavioral Inventories 
Psychological effects of the combinatory therapy will be evaluated using several inventories. The 
Hearth Hope Index is a 12-item adapted version of the Hearth Hope Scale designed to assess feelings 
of ‘hope’ within the patient.  The Short Form-36 is a 36-item patient reported survey of patient health 
status. Each scale is transformed into a 0-100 score and includes eight sections: vitality, physical 
functioning, bodily pain, health perceptions, role functioning, emotional functioning, social 
functioning and mental health. Brief Pain Inventory is a short form used for clinical trials that rapidly 
evaluates the severity of pain and impact on body functioning, and the Brief Fatigue Inventory is 
used to evaluate the severity and impact cancer-related fatigue. To more directly assess the 
emotional and behavioral response to the diet initiation and maintenance we will employ the 
Functional Assessment of Anorexia/cachexia Treatment. The FAACT measures the general aspects 
of quality of life as well as specific anorexia and cachexia related concerns. These surveys will help 
to determine the individual’s psychosocial response to the eating changes. Additionally, participants 
will be asked to maintain an event diary to determine diet palatability and any adverse event 
reporting. Inclusion of these surveys and diaries will provide important data on the feasibility of a 
ketogenic diet in patients with brain mets. Expected time for completion of the surveys is 
approximately 30 minutes.  
 
10 PROCEDURES FOR PATIENT ENTRY ON STUDY 
This study will be open for accrual at the James Comprehensive Cancer Center at OSU. As part of 
the screening process, interested patients who meet initial eligibility requirements will be contacted 
by research staff and the specific requirements, risks/inconveniences, and other details of the 
research will be explained. Patients will have an opportunity to have all their questions and concerns 
about the research study addressed. The goal of this session is maximum understanding of the 
program requirements and its impact on their life. This process is designed to meet ethical 
obligations to the participant and improve retention by fostering a positive relationship between the 
participant and the research staff. The person obtaining informed consent will tell the patient that 1) 
participation is voluntary, 2) participation or non- participation will not affect their usual care and 
management, and 3) patient confidentiality will be maintained in the event that the results of the 

 
study are published. Patients will be provided with a consent form to review, and all questions 
answered. After signed informed consent has been obtained, a study identification number will be 
assigned to the patient for use on all data collection forms and samples. 
 
11 
POTENTIAL RISKS AND MANAGEMENT 
Because we will be obtaining information about a participant’s medical history, lifestyle behaviors, 
and measuring biomarkers that will become part of the electronic health record, there is a chance 
that we will uncover or discover sensitive information regarding a person’s health status. Although 
unlikely, this information could cause emotional distress, increase personal expense for treatment, 
or, if obtained by insurance companies or employers, could be used as justification to raise insurance 
rates or affect employability.   To ensure privacy/confidentiality, information that is received from 
patients will be kept confidential to the extent allowed by law. Patient data will be entered into the 
electronic health record and hard copies will be kept in a secure filing cabinet on site for the duration 
of the study. We will assign all patients a code number to be used on forms, sample collection 
containers and other research materials. Subject codes will be employed for database management 
and when statistical analyses are performed. There will be a single key to the coded data kept on a 
password protected computer. Computer files containing names, addresses or other identifiers will 
be limited to authorized personnel at the site who have access to the computer data base using a 
password protected program. All investigators, professional medical staff, and technicians are aware 
of the confidentiality involved with the proper conduct of such a study. Consistent with the conduct 
of human research studies, the data will not be available or divulged to anyone outside of the 
experimental research team. The results from the study may be published, but will have no 
identifiers. 
 
Radiation Treatment.   
Possible Side Effects of Radiosurgery (Radiation) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving radiation therapy, 20 to 100 may have: 
• If a head frame is used, temporary (short-term) pain from the 
head frame placement 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving radiation therapy, 4 to 20 may have: 
• Headache 
• Tiredness 
• If a head frame is used, bleeding and/or infection around the 
head frame pin sites 
 
RARE, SOME MAY BE SERIOUS 
In 100 people receiving radiation therapy, 3 or fewer may have: 
• Nausea 
• Reddening of the skin 
• Localized hair loss which may be permanent  
 
 

 
RARE, AND SERIOUS 
In 100 people receiving radiation therapy, 3 or fewer may have: 
• Decreased brain function such as motor function 
(coordination/movement) 
• Swelling of the brain in the treated area which may require 
steroids 
• Severe local damage to or death of normal brain tissue, which 
may require surgery to remove 
• Seizure   
Ketogenic Diet. There are no significant risks associated with consuming a well-formulated 
ketogenic diet. For patients using medication to control blood sugar and blood pressure, there is a 
need to reduce these medications rather quickly at the onset of the diet to prevent low blood sugar 
and hypotension. In this study, we will exclude those patients who have type-2 diabetes using 
insulin. In our prior research we have assessed thousands of metabolic panels in patients assigned 
to ketogenic diets. Abnormal responses are rare, but it is expected that there will be modest changes 
in some metabolic parameters. These markers are expected to remain within normal limits and not 
pose a serious concern. For example, uric acid levels often increase during the first few weeks of a 
ketogenic diet and then return to or below baseline after 1-2 months. This transient increase does 
not exacerbate gout or have other untoward effects, since the elevation is due to competition with 
ketones for renal excretion, in contrast to increased intracellular synthesis of uric acid. Nutritional 
ketosis is associated with natriuresis (increased loss of sodium in the urine) and fluid loss. If the 
extra sodium excreted is not compensated for in the diet, the subsequent contracted plasma volume 
can manifest in side effects and adrenal stress including a hormonal response that disrupts body 
mineral status. Our diets contain adequate sodium and potassium to ensure mineral nutriture. The 
diet intervention may be challenging for participants since it will require them to limit foods, they 
are accustomed to eating. Participants will be made aware of the general dietary requirements 
including lists of foods they will need to restrict (as well as foods that will be permitted) during the 
informational session, so they can make an educated decision to participate. 
 
Body Composition. The DXA scan has a risk that is negligible, as the skin entrance dose of radiation 
due to the application of the exam is very small. In a whole-body scan, which is the mode used in 
this project, the skin entrance dose of radiation per scan is ~0.04 millirem. On average in the US a 
person receives ~0.85 millirem per day of background radiation. For another comparison, a chest 
X-ray delivers ~10-20 millirems per scan. Thus, the level of radiation exposure is extremely low. 
Since we don’t know what effect the radiation could have on an unborn baby, we will perform a 
urine pregnancy test before the scan for all women of child bearing age in the study. 
 
Blood Draws. Blood draws by venipuncture may cause discomfort at the puncture site and the 
development of a slight bruise. Participants may also experience lightheadedness or fainting during 
the blood draw and there is a slight risk of infection. All blood draws will be taken by trained 
phlebotomists. The total blood volume at each testing session will be less than 50 mL, which 
translates into less than 200 mL over 6 months. 
Ketone Testing. Ketone testing will be done daily by finger stick using a small 26G lancet.  There is 
slight transient discomfort associated with this procedure. 
This is a diet intervention study and thus no risk for toxicity exists beyond that normally present 
during typical treatment. Nevertheless, we will record type of modification and toxicity management 

 
in detail for each patient. 
The severity of adverse reactions is categorized as grade 1 to grade 5 in increasing severity. General 
descriptors for the toxicity grades range from none to fatal: 
Grade 1 – Mild (The adverse reaction does not interfere in a significant manner with the subject’s 
normal functioning level. It may be an annoyance.) 
Grade 2 – Moderate (The adverse reaction produces some impairment of functioning but is not 
hazardous to health.  It is uncomfortable and/or an embarrassment) 
Grade 3 – Severe (The adverse reaction produces significant impairment of functioning or 
incapacitation and is a definite hazard to the subject’s health) 
Grade 4 – Adverse reactions that include or lead to either a) a life-threatening event, though acute 
and without permanent effect, b) prolonged inability to resume usual life pattern, or c) impairment of 
ability to adequately deal with future medical problems 
Grade 5 – Death related to AE 
Toxicity will be monitored during study visits and telephone calls using the National Cancer Institute 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) of the National Cancer Institute 
will 
be 
used 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2998-09- 
15_QuickReference_5x7.pdf). Grade 3, 4 and 5 toxicities will be reported as adverse events. Patients 
with Grade 3-4 adverse reactions that are related to the diet will be removed from the study. 
The attribution of each toxicity will be ascertained by treating physician to both standard therapy as 
well as to diet intervention during the study. Treating physicians will manage suspected toxicity for 
dose holds and dose modifications as part of standard of care according to package insert 
recommendations. 
 
12.0 ADVERSE EVENT REPORTING 
12.1 Definition 
 
Adverse event: Any unfavorable and unintended sign (including abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure, 
regardless of whether it is considered related to the medical treatment or procedure; also an 
“unanticipated problem” of any nature (e.g., psychological or social harm) (designated as unrelated, 
definitely related, probably related, or possibly related; see below) 
Serious adverse event: Any adverse event that is fatal or life threatening, is permanently disabling, 
requires inpatient hospitalization or prolongs hospitalization, or results in a congenital anomaly or 
birth defect 
Life-threatening event: Any adverse event in which the subject is at immediate risk of death from 
the reaction as it occurs; does not include a reaction that, if it were to occur in a more serious form, 
might cause death 
Unexpected event: Any adverse event that is not identified in nature, severity, or frequency in the 
investigator brochure, study protocol, consent form, or IND application; or the event was more 
serious than anticipated 
Association: 
 

 
Definitely Related:  An adverse event that has a timely relationship to the administration   of 
the investigational drug/study procedure and follows a known pattern of response which no 
alternative cause is present 
Probably Related: An adverse event that has a timely relationship to the administration the 
investigational drug/study procedure and follows a known pattern of response, but which a 
potential alternative cause may be present 
Possibly Related: An adverse event that has a timely relationship to the administration the 
investigational drug/study procedure, follows no known pattern of response, potential 
alternative cause does not exist 
Unrelated: An adverse event for which there is evidence that it is definitely a related cause 
other than the investigational drug/agent; in general, no timely relationship administration of 
the drug/procedure exists, or if so, the event does not follow a pattern response and an 
alternative cause is present 
The Common Terminology Criteria for Adverse Events v4.0 (CTCAE) of the National Cancer 
Institute will be used. The severity of adverse reactions is categorized as grade 1 to grade 5 in 
increasing severity. Grade 3, 4 and 5 toxicities will be reported as adverse events. General 
descriptors for the toxicity grades range from mild to fatal: 
Grade 1 – Mild (The adverse reaction does not interfere in a significant manner with the subject’s 
normal functioning level. It may be an annoyance.) 
Grade 2 – Moderate (The adverse reaction produces some impairment of functioning but is not 
hazardous to health.  It is uncomfortable and/or an embarrassment) 
Grade 3 – Severe (The adverse reaction produces significant impairment of functioning or 
incapacitation and is a definite hazard to the subject’s health) 
Grade 4 – Adverse reactions that include or lead to either a) a life-threatening event, though acute 
and without permanent effect, b) prolonged inability to resume usual life pattern, or c) impairment of 
ability to adequately deal with future medical problems 
Grade 5 – Fatal 
12.2 
Documentation 
All adverse events must be documented in detail within the medical record. The patient will be 
observed and monitored carefully until the condition resolves, stabilizes, or its cause is identified. All 
adverse events, including laboratory abnormalities, will be followed up according to good medical 
practices. Information to be recorded includes the following: 
a. 
Specific type of reaction. 
b. 
Duration of reaction. 
c. 
Severity/grade of reaction according to the NCI Common Terminology Criteria for Adverse 
Events v4.0 (CTCAE). 
d. 
Suspected cause of the reaction (i.e. possibly or probably related to one of the following: study 
treatment, progression of disease, concurrent medications, concurrent illness, or other factors). 
e. 
Changes made in the administration of the study drugs and other actions taken to alleviate the 
clinical event. 
f. 
Patient’s response to medical interventions. 
 
12.3 Reporting 
According to FDA regulations (21 CFR 312.32), IND safety reports shall address “any adverse 

 
experience associated with the use of a drug that is both serious and unexpected.” The IRB will be 
notified of any adverse event fulfilling the following criteria: 
12.3.1 
The adverse event is SERIOUS (as defined above), 
or 
12.3.2 
The adverse event is not serious, but is UNEXPECTED and its association with the 
study drug, device, or research-related procedure is either DEFINITELY, PROBABLY, or 
POSSIBLY RELATED, or UNKNOWN (as defined above). 
Federal policy [45 CFR 46.116(b)(5)] also requires that investigators inform subjects of any 
important new information that might affect their willingness to continue participating in the 
research. When an adverse event necessitates changes to the consent/assent form(s) and/or protocol, 
or that notification is given to currently or previously enrolled subjects, an amendment request will 
be submitted in conjunction with the adverse event report. The IRB will make a determination 
whether any new findings, new knowledge, or adverse effects should be communicated to subjects. 
In accordance with IRB guidelines, serious adverse events will be reported within 10 days of 
learning of the event to the Office of Research Risks Protection, Room 300, Research Foundation 
Building, 1960 Kenny Road, CAMPUS, 614-688-8457 telephone, 688-0366 fax, Email: 
researchrisksinfo@osu.edu, 
using 
the 
Event 
Reporting 
Form 
(http://orrp.osu.edu/irb/event/documents/EventReportingForm_v2.2.doc ) of The Ohio State 
University Institutional Review Boards. If the adverse event involved the death of a subject, it will 
be reported immediately, usually within 72 hours. Deaths from “natural causes” or underlying 
disease that occur more than 30 days following completion of study interventions (i.e., events not 
temporally associated) need not be reported. Unexpected adverse events that are not serious but may 
be associated with the drug, device, or procedure (see below) should generally be reported to the 
IRB within 30 days of notification of the event. 
In some instances, adverse events or “unanticipated problems” result in social or psychological harm 
rather than physical harm to subjects or others. These events should also be reported to the IRB 
within 30 days, unless they are considered “serious”. A letter format may be used for reporting these 
events instead of the Event Reporting Form, as applicable. 
 
The IRB will review all serious adverse event reports to reevaluate the risks and benefits of the 
research and need for changes. All other reportable adverse events (unexpected and related or 
unknown) will be reviewed administratively, unless IRB review is recommended. All investigators 
will be notified of any action taken, usually within 30 days. 
 
13. CRITERIA FOR RESPONSE ASSESSMENT 
All patients who took the intervention for any period of time will be considered evaluable. 
Participants with only baseline measures and who did not receive the intervention will be 
considered as drop-outs. RECIST v. 1.1 will be utilized to evaluate responses to therapy. 
 
14 
STUDY CALENDAR 
 
 
Week 
Tests & observations 
0 
4 
8 
12 
16 
Signed informed consent 
x 
 
 
 
 
History and Physical Exam 
x 
 
 
 
x 
Height/weight 
x 
x 
x 
x 
x 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
CRITERIA FOR REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
Study patients may voluntarily withdraw at any time from the protocol. If a treating physician 
elects to remove a patient from the study, the Principal Investigator must be notified of withdrawal 
from the protocol. The reasons for discontinuation of the study must be documented in the patient 
record and data collection forms. Patients experiencing irreversible Grade 3-4 toxicity that is 
clearly related to the study treatment will be removed from the protocol. Patients with documented 
progression of disease will be removed from the protocol. 
 
16 ETHICAL AND REGULATORY CONSIDERATIONS 
This trial will be conducted in compliance with the protocol, Good Clinical Practice guidelines, and 
all applicable regulatory requirements. 
 
16. 
1 Institutional Review Board 
The Principal Investigator will have obtained written approval to conduct the study from The Ohio 
State University IRB and the Clinical Scientific Review Committee of the James Cancer Hospital 
and Solove Research Institute. All amendments must be approved by the Institutional Review Board 
of The Ohio State University prior to implementation. 
 
16.2 Informed consent 
All potential candidates for the study will be given a copy to read of the consent form for the study. 
The Principal Investigator and/or designee will explain all aspects of the study in lay language and 
answer all the candidate’s questions regarding the study. If the candidate desires to participate in the 
study, she will be asked to sign the Informed Consent. The study agent will not be released to a 
subject without a signed Informed Consent. 
 
Elements of informed consent include explanations of 1) the purpose of the trial, 2) what the study 
Standard of Care Imaging 
x 
 
x 
 
x 
Continuous Glucose/Ketone Monitoring 
x 
 
x 
 
x 
Ketone Finger Stick 
x 
x 
x 
x 
x 
Activity Tracker  
x 
x 
x 
x 
x 
DXA Bone & Body Fat Quantification 
x 
 
 
 
 
x 
Cognitive Testing 
x 
 
x 
 
x 
Review of medications 
x 
x 
 
x 
 
Performance status 
x 
 
x 
 
x 
SF-36 
x 
 
 
x 
 
Brief Pain Inventory Questionnaire 
(BPI-10) 
x 
 
x 
 
x 
Brief Fatigue Inventory 
x 
 
x 
 
x 
FACT Questionnaire 
x 
 
x 
 
x 
Hearth Hope Index 
x 
 
x 
 
x 
Blood tests 
x 
 
x 
 
x 
FFQ questionnaire/3-day food log* 
x 
 
 
 
 

 
entails, 3) alternate treatments, 4) expenses and inconveniences to be incurred, 5) discomfort and risks 
to the subject, 6) whether she will receive payment for participation in the study, 7) contact person to 
call in the event of an emergency, 8) subject rights as a result of illness or injury from trial 
participation, 9) her right to withdraw from the trial at any time without prejudice, 10) confidentiality 
of trial participation. 
 
16.3 Patient confidentiality 
The information obtained during the conduct of this study is considered confidential and will not be 
released without the written permission of the subject, except as necessary for monitoring by the FDA 
or other regulatory agencies. All laboratory specimens will be labeled with coded identifiers in order 
to maintain confidentiality. Signed consent  forms,  data sheets, and laboratory notebooks will be kept 
in locked cabinets in Dr. Maryam Lustberg’s or Dr. Jeff Volek’s office and/or research laboratories. 
 
16.4 Publication of research findings 
Publications of the research findings will present data in a format that will not reveal the identity of 
the participants. 
 
16.5 Compliance monitoring 
In accordance with IRB guidelines, the study program will be reviewed by the IRB every 12 months 
or less. Deviations from the protocol must be documented in the medical record  and reported 
immediately to the PI. Deviations that meet the criteria for Immediate Event Reporting 
(http://orrp.osu.edu/irb/event/index.cfm) such as those that increase risks to subjects and/or 
compromise scientific integrity will be reported immediately to the IRB. 
 
16.6 Biosafety 
This project will involve the use and analysis of human cells and tissues. Specific precautions will be 
taken to protect laboratory personnel and support personnel form possible infective agents from these 
samples, with the goals of containment of biological materials, proper waste disposal, routine 
decontamination of equipment and surfaces, and implementation of procedures for accidents. 
 
16.7 Data Safety Monitoring Plan 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality 
and data timeliness. Investigators will conduct continuous review of data and patient safety at their 
regular Disease Group meetings (at least monthly) and the discussion will be documented in the 
minutes. The Co-PIs of the trial will review toxicities and responses of the trial where applicable at 
these disease center meetings and determine if the risk/benefit ratio of the trial changes. Frequency 
and severity of adverse events will be reviewed by the Co-PIs and compared to what is known about 
the agent/device from other sources; including published literature, scientific meetings and 
discussions with the sponsors, to determine if the trial should be terminated before completion. 
Serious adverse events and responses will also be reviewed by the OSUCCC Data and Safety 
Monitoring Committee (DSMC). The Co-PIs will also submit a progress report biannually that will 
be reviewed by the committee per the DSMC plan. All reportable Serious  Adverse  Events (SAE) 
will also be reported to the IRB of record as per the policies of the IRB. 
 
17.0 STATISTICAL ANALYSES 
 
Analysis Plan 
Unless otherwise specified, all analyses will proceed on an intent-to-treat basis, and hypothesis tests 
will be two-sided and at the 5% significance level. 

 
 
The primary objective is to assess the feasibility of maintaining a ketogenic versus AICR diet in 
patients with brain metastasis selected for radiosurgery. The primary measurements are blood levels 
of glucose and ketones. Measurements will be taken at baseline, 8 weeks, and 16 weeks. These 
biomarker outcomes will be analyzed using mixed effects linear regression with fixed effects for 
timepoint, diet group, their interaction, BMI, and sex. We will use subject-level intercept random 
effects to account for correlation between repeated measurements within subjects. The primary targets 
of inference are the treatment effects at each (post-baseline) timepoint. To test the two primary 
measurements at the two post-baseline timepoints, we will use a 4-way Bonferroni-Holm correction 
to account for multiplicity. Retention at week 8 and 16, as well as side effects, will be summarized 
and compared between diet groups. 
 
To assess the preliminary efficacy of ketogenic versus AICR diet on tumor response to targeted 
radiation therapy, we will use a Chi-squared test for the association between treatment group and 
partial-or-complete response according to RECIST v1.1. 
 
For the exploratory objective assessing the preliminary effects of the ketogenic versus AICR diet on 
quality of life in BM individuals undergoing radiation therapy, we will use the same linear mixed 
effects model as for the primary objective, but with the following quality-of-life endpoints as 
outcomes: Hearth Hope Index, SF-36, FACT-B, Brief Pain Inventory, and Brief Fatigue Inventory. 
Tests will be performed without multiplicity correction. 
 
The mixed models used for the primary analyses are applicable to unbalanced data due to chance 
imbalances, missing data, or drop-out. We will assess the possible impact of non-random missingness 
using sensitivity analyses. 
 
Power Analysis 
We base our power analysis on preliminary data from a single-arm trial involving patients with Stage 
IV disease undergoing treatment plus a ketogenic diet. The changes in blood glucose from baseline 
to 3 months have mean 11.25 mg/dL and standard deviation 1.077 mg/dL, and the changes in blood 
ketone levels have mean 0.6 mmol and standard deviation 0.16 mmol. With 12 completers per arm 
and a significance level of 0.0125 to account for multiplicity, a two-sample t-test has 99% power to 
detect differences in mean changes between diet arms of 2.3 mg/dL in glucose levels and 0.34 mmol 
in ketone levels. We expect our tests based on linear mixed models to have slightly higher power. 
 
17.1 Imaging Response Criteria (for schedule of evaluations see Section X) 
The typical standard of care MRI protocol at each evaluation will be scored as follows:  
 
17.1.1 Unresected Brain Metastases treated with radiosurgery 
The response score will be rated as one of the following (follow-up MRI will be 
compared to the prior MRI scans):   
Stable disease: Absence of disease progression of treated lesion.  
Disease progression:  
For lesions measuring more than 5 mm in the baseline (volumetric) scan: At least 
50% increase in the product of the two largest perpendicular diameters (compared to 
the smallest product measured for the same lesion). 

 
For lesions measuring 5 mm or less in the baseline (volumetric) scan: At least 100% 
increase in the product of the two largest perpendicular diameters (compared to the 
smallest product measured for the same lesion). 
Note: Radionecrosis will not be considered tumor progression.  
17.1.2 Resected Brain Metastasis (i.e. surgical cavity)  
Note: Tumor bed control is defined as the absence of new nodular contrast 
enhancement in the surgical bed. By definition a post-operative MRI brain scan is 
required as a baseline study. If there is questionable development of nodular 
enhancement in the surgical bed, this should be graded as stable disease recognizing 
follow-up studies will make this determination more certain (e.g. questionable area of 
nodular enhancement continues to grow and should therefore be coded as disease 
progression).   If on a subsequent scan or on an additional imaging modality it is 
deemed as progression in the surgical cavity according to the criteria above, the date 
of progression diagnosis will be documented as the first time a new/progressing lesion 
was evident on a scan (i.e. backdated). 
The response score will be rated as one of the following (follow-up MRI brain scans 
will be compared to the prior MRI brain scan):  
Stable disease: Absence of new nodular contrast enhancement in the surgical bed.  
Disease progression: Development of new nodular contrast enhancement in the 
surgical bed.  
Note: Radionecrosis will not be considered tumor progression.  
17.1.3 Distant Brain Status (excludes status of surgical cavity and any unresected lesions 
treated with SRS at time of trial enrollment) 
The response score will be rated as one of the following (follow-up MRI brain scans 
will be compared to the prior MRI brain scan):  
Stable disease: Absence of new lesions.  
Disease progression: Any new lesion, seen on: 
a. 
Two consecutive axial slices, OR 
b. 
At least one slice in two separate planes. 
A lesion is designated “Undetermined” as long as it does not comply with the 
definition of progression due to a new lesion. If on a subsequent scan or on an 
additional imaging modality it is deemed as cerebral progression according to the 
criteria above, the date of progression diagnosis will be documented as the first time a 
new/progressing lesion was evident on a scan (i.e. backdated). 
 
17.1.4 Leptomeningeal Disease (LMD) Status.  
1. The response score will be rated as one of the following (follow-up MRI brain scans 
will be compared to the prior MRI brain scan). It is recommended that if 
leptomeningeal disease progression is suspected, MRI imaging of the spine should be 
performed prior to CSF cytology: 
Stable disease: Absence of new leptomeningeal lesions.  
Leptomeningeal Disease (LMD) progression: Any new lesion: 
a. New enhancement along the cranial nerves with neurologic symptoms 

 
b. New enhancement along the cerebellar folia or pial lining outside of thE 
surgical bed (treated PTV) 
c. Focal or diffuse leptomeningeal enhancement distant from treatment sites 
d. CSF cytology positive 
e. Leptomeningeal enhancement along the spine 
A lesion is designated “Undetermined” as long as it does not comply with the 
definition of progression due to a new lesion. If on a subsequent scan or on an 
additional imaging modality it is deemed as leptomeningeal progression according to 
the criteria above, the date of progression diagnosis will be documented as the first 
time a new/progressing lesion was evident on a scan (i.e. backdated). 
• If there is leptomeningeal disease progression it will be classified as “local” vs. 
“diffuse” as defined below:  
a) Local LMD:  within 3 cm of the surgical bed respecting anatomic boundaries 
(e.g., tentorium, falx, etc.) with absence of evidence of diffuse LMD 
b) Diffuse LMD: any LMD away from surgical bed and/or positive CSF 
• Radionecrosis.  Meeting any of the following criteria will qualify as radiation 
necrosis after prior SRS. 
1. Pathologic diagnosis after either resection or biopsy revealing findings 
consistent with radiation necrosis with the absence of active tumor cells. 
2. Conventional MR 
a. Lesion quotient of < 0.3, where lesion quotient is defined as the proportional 
value of the maximum axial cross-sectional area of the T2-weighted defined lesion 
over the maximum axial cross-sectional area of the contrast-enhancing lesion on 
the T1-weighted post-gadolinium sequence on a comparable axial slice OR 
b. Due to concerns of radiation necrosis, steroids initiated and follow-up scan (>1 
month interval on repeat scan) reveals decrease in both edema and contrast of 
enhancing lesions that were concerning for radiation necrosis. 
3. Centers that normally use PET, MR Perfusion, or MRS to determine a diagnosis 
of radionecrosis are permitted to use these modalities to diagnose radionecrosis as 
according to the local PI’s best practice. 
NOTE: Images for standard restaging time points should continue to use the same imaging modality 
as used at baseline. 
 
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