Regional Research Partnership
The BTFC recently made a $50,000 grant to Duke University, to help fund a project by Dr. Katy Peters.
Effects of Low-Dose Naltrexone on Quality of Life in High-Grade Glioma Patients: A
Placebo, Double-Blind Randomized Controlled Trial
A. Specific Aims
Individuals who are diagnosed with high-grade gliomas (HGGs) are immediately confronted
with two serious health issues. First, there is a new diagnosis of cancer that will require serious
therapies such as brain surgery, brain irradiation, and chemotherapy. Secondly, they face the
symptoms and signs of neurological dysfunction. Having both immediate oncologic and
neurological concerns is unique to brain tumor patients such that they have more challenges in
their search for a positive and productive quality of life (QOL). In fact, when compared to
matched patients with other types of cancer, HGG patients exhibit more dysfunction with
physical function, neurocognition, and QOL.
are few options to improve QOL, functional capacity, and neurocognition during the course of
treatment for newly diagnosed HGG.
approaches, are needed to treat and evaluate multi-dimensional aspects of QOL. Naltrexone is
a commonly used opioid antagonist, but in very low doses, its action can increase the
expression of opioid receptors and increase met-enkephalin and
signaling changes and endogenous compounds can decrease inflammation, improve mood, and
as multiple sclerosis and fibromyalgia and has been shown to improve QOL.
is well-tolerated at this lower dosage. In light of its utility in other neurological disorders, we
have embarked on a study to evaluate LDN and its effects on QOL in HGG patients. In this
grant proposal, we have designed a placebo-controlled, double-blind randomized trial of 72
newly diagnosed postsurgical HGG patients to evaluate if LDN in comparison to placebo can
improve QOL during standard chemoradiation and adjuvant chemotherapy.
likely have farther reaching implications on how we measure QOL and improve QOL in all
cancer patients that are undergoing treatment.
QOL in HGG patients.
We hypothesize that QOL will be improved in newly diagnosed HGG patients when taking LDN
in comparison to placebo.
We hypothesize that functional capacity in newly diagnosed HGG patients will differ depending
on whether the patient is on LDN or placebo.
We hypothesize that neurocognition in newly diagnosed HGG patients will differ depending on
whether the patient is on LDN or placebo.
We hypothesize that LDN will be safe and well-tolerated therapy in HGG patients.
Primary brain tumors represent 1% of all diagnosed cancers.
newly diagnosed high-grade gliomas (HGGs) involves surgical resection followed by
temozolomide concurrently with and after radiotherapy. Before and during treatment for HGG,
adult patients experience a decline in perceived quality of life (QOL).
concept that encompasses the multidimensional well-being of a person and reflects an
Page 2 of 9
individual’s overall satisfaction with life.”
dysfunction, whether cognitive or physical, fatigue associated with treatment, symptoms such as
nausea and anorexia associated with treatment, and other common symptoms such as
insomnia, seizures, and headaches all have negative impacts on QOL. Overall functionality
and QOL are particular important in brain tumor patients since they experience more
dysfunction than age-matched controls with non-small lung cancer patients.
prospective study by Budrukkar and colleagues on QOL in brain tumor patients, they found that
QOL, as rated by questionnaire scores, was low before initiating any type of treatment.
Factors associated with poorer QOL included poor performance status, illiteracy, and more
aggressive nature of tumors.
neurocognition such that HGG patients with better physical function and better neurocognitive
function reported having higher levels of QOL.
symptoms and signs are interrelated and should not be studied alone such that cognitive
decline/dysfunction was associated with increased fatigue and poorer performance status.
During concurrent chemoradiation, brain tumor patients experience a decline in relative QOL
particularly due to fatigue and changes in cognition.
not be studied alone, but in concert with neurocognition and physical function. Because of this,
we have designed a multidimensional approach to look at the subjective aspects of QOL and
objective findings in physical function and neurocognition.
For subjective QOL measures, we have utilized multiple standardized questionnaires to
evaluate issues with fatigue, cognition, physical function, sleep, and mood. The Functional
Assessment of Cancer Therapy-Brain (FACT-Br) has been used extensively and has been
documented to identify key QOL problems for brain tumor patients.
questionnaires include Functional Assessment of Cancer Therapy-Fatigue, Functional
Assessment of Cancer Therapy-Cognition, Beck Medical Outcomes Survey, Epworth
Sleepiness Scale, Pittsburgh Sleep Quality Index and Zung Self-Rating Depression Scale.
Since these are subjective measures, we have also employed objective measures of physical
function and neurocognition using six-minute walk test and neurocognitive testing with CNS
Vital Signs®, respectively. These measurements have been validated and are being used
extensively in our research in not only brain tumor patients but also in patients with other forms
In a recent published study in the Journal of Neuro-Oncology, physical fitness using the
6- minute walk test and QOL using patient-reported outcomes were obtained in recurrent highgrade
glioma patients. This study revealed that patients that had very poor physical fitness as
objectively measured with the 6-minute walk test had poorer patient-reported QOL measures in
comparison to patients with better performance on the 6-minute walk test.
walk test is a validated and useful test in determining functional capacity in GBM patients and
correlates with patient-reported QOL. In a recent article by Jones, Peters, and colleagues, we
examined objective physical functioning and patient-reported QOL, fatigue, and cognitive
function in low grade glioma and HGG patients.
surgery to 6 months after surgery. Again, changes in physical functioning were associated with
similar changes in patient-reported QOL, fatigue, and cognitive function measures. Additionally
findings showed that three distinct sets of patients could be delineated based on their physical
functioning. These results point further to a necessity for interventions to improve QOL in HGG
patients during their treatment course.
Interventions to improve QOL in brain tumor patients have included stimulants such as
methylphenidate and modafinil. Clinical trials with methylphenidate in brain tumor patients
undergoing radiation therapy were discontinued in early stages because interim analysis did not
show any evidence of effectiveness.
QOL in brain tumor patients, but the study was not placebo-controlled.
Page 3 of 9
approaches and more clinical studies are needed to evaluate interventions in regards brain
tumor patient QOL.
Naltrexone is orally semisynthetic opiate antagonist that has been licensed by the FDA
for the treatment of heroin and alcohol addiction. Doses for this treatment are usually in the
range of 50 mg to 100 mg. The main role of naltrexone is to counteract the effects of opioids
by blocking opiate receptors.
less than 5 mg/day), works much differently than naltrexone at higher, conventional doses.
The proposed mechanism for LDN is that by transiently inhibiting opioid receptors it stimulates
the expression of mu, delta, and epsilon opioid receptors, circulating met-enkephalin and
energy, mood, and well-being. There has been recent interest in the use of LDN for the
treatment of fatigue in other neurological conditions such as multiple sclerosis and fibromyalgia.
In a single-blind, crossover study in fibromyalgia patients, LDN was shown to lower symptoms
of fatigue and stress.
included vivid dreaming in two subjects and transient insomnia and nausea in one subject.
Three pilot trials have been performed in multiple sclerosis and its effects on QOL.
most recent study by Cree and colleagues, they evaluated eighty multiple sclerosis patients in a
single-center, double-masked, placebo-controlled crossover study. In self-reported QOL
measures, LDN (at dose of 4.5 mg orally nightly) improved scores significantly in several
different scales. In particular, outcomes on the Medical Outcomes Survey were significantly
improved with 3.3-point increase at 8 week for LDN in comparison to placebo. Most common
toxicities were vivid dreaming as seen in seven placebo patients and ten LDN patients. Other
adverse events include sinus infection (1 in LDN group), anorexia (1 in LDN group), insomnia (1
in placebo group), flu-like symptoms (1 in placebo group), and fatigue (2 in LDN group and 1 in
placebo group). Moreover, this treatment was deemed easily tolerated while multiple sclerosis
patients were on disease modifying therapies such as interferon-
this information, LDN is a provocative agent with little to no toxicity that can positively impact
QOL in patients with neurological disease. Therefore, we have designed a clinical trial to
explore this possibility in brain tumor patients.
In this pilot clinical trial, we will test the effectiveness of LDN in improving QOL in HGG
patients that are receiving standard chemoradiation. The primary objective of this pilot study is
to compare patient-reported measures of QOL in HGG patients on either LDN or placebo.
Using a multidimensional approach, secondary measures will include functional capacity (as
measured by the six-minute walk test) and neurocognitive function (as measured by CNS Vital
Signs®). Safety of LDN in this population will also be a secondary outcome with standard
monitoring with complete blood counts with differential and comprehensive metabolic panels.
This data will be used to design large studies in regards to cancer-related QOL and the use of
C. Experimental Design/Brief Methods of Procedure
C.1 Setting and Patient Participants
The proposed study will be conducted at the Preston Robert Tisch Brain Tumor Center
(PRT-BTC) at Duke. All subjects will be patients that will be undergoing standard
chemoradiation with radiotherapy and daily oral temozolomide for the treatment of high-grade
Inclusion criteria for this study are:
1) Written informed consent prior to beginning specific protocol procedures
2) Histologically proven high-grade glioma
3) Planned treatment with concurrent radiotherapy and daily oral temozolomide
Page 4 of 9
5) Karnofsky performance index >70%
6) No documented cardiac or pulmonary disease
7) No contraindications to six-minute walk test
8) Primary neuro-oncologist approval
10) Serum creatinine < 1.5 times upper limit of normal, serum SGOT < 2.5 times upper
limit of normal and bilirubin < 2.0 times upper limit of normal
11) If sexually active, patients will take contraceptive measures for the duration of the
Exclusion criteria for this study are:
1) Prior therapy with naltrexone or naloxone
2) Co-medication that may interfere with study results; e.g opioids
3) Known hypersensitivity to any component of naltrexone
4) Pregnant (positive pregnancy test) or lactating
5) Life expectancy of < 12 weeks.
C.2 Study Design and Procedures
The proposed study is a placebo-controlled, double-blind randomized clinical trial.
Potential participants will be identified via clinical protocol chart review of patients scheduled to
attend their pre-determined follow-up consultations at PRT-BTC after evaluation of treatment for
newly diagnosed high-grade gliomas. We will identify high-grade glioma patients that will
receive standard chemoradiation (radiotherapy with daily temozolomide dosed at 75 mg/m2).
After obtaining written informed consent, all participants will be scheduled for baseline study
assessments before starting radiotherapy. Patients will be randomized to receive either placebo
or LDN dosed at 4.5 mg orally to be taken every evening before going to bed. Patients will be
assessed at the following timepoints:
1. Baseline (before chemoradiation)
2. After chemoradiation (approximately 8 weeks from initial assessment)
3. 2 months after standard chemoradiation (approximately 16 weeks after initial
4. 4 months after standard chemoradiation (approximately 24 weeks after initial
assessment). (See Figure 1 for study design)
Treatment with LDN or placebo will begin on first day of chemoradiation and will be
continued for a total of 16 weeks. Last assessment at 24 weeks will occur 8 week after
discontinued of LDN or placebo. All visits will be linked to patients’ clinical management visits.
All testing will be performed at PRT-BTC and at Duke University Medical Center. LDN and
placebo will be compounded and distributed by the Duke University Compounding Pharmacy
Page 5 of 9
Quality of Life
(FACT-BR) scale. The FACT-BR (version 4) contains subscales for physical (7-items),
functional (7-items), emotional (6-items), and social/family (7-items) well-being. In addition, this
instrument contains an 23-item brain cancer subscale (BCS) which assess symptoms
commonly reported by brain cancer patients.
13-item Fatigue Scale using the Functional Assessment of Cancer Therapy-Fatigue (FACITFatigue)
subscale, version 4.
Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) subscale.
subscales for perceived cognitive impairments (20 items), comments from others (4 items),
perceived cognitive abilities (9 items), and impact of quality of life (4 items). Using CNS Vital
Signs, we have included the following batteries: Medical Outcomes Survey (MOS), Epworth
Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Zung Self-Rating
Depression Scale (ZSDS). These questionnaires will be computerized and delivered as part of
the cognitive testing. They will be viewed and completed after the neurocognitive testing
portion. MOS is a 36-item scale using to assess general health, well-being, and quality of life,
and we will be using the short form for this assessment.
item scale used to assess self-rating of depression.
used to evaluate for underlying depressive symptoms. We will used the revised version (BDI-II)
and the scores will range from 0 (no depression) to 63 (severe depression).
21 questions in regards to mood symptoms and is multiple-choice and self-reported.
Figure 1: Study Design. Yellow areas are for standard chemoradiation time and orange areas are
for adjuvant chemotherapy. A1, A2, A3, and A4 are indicative of assessments and number.
(XRT=irradiation, mg=milligrams, po=orally, qhs=at night)
Page 6 of 9
instructed to walk at their fastest pace and to cover the longest possible distance over 6 minutes
under supervision of an American College of Sports Medicine certified exercise specialist.
Distance walked will be determined in a measured corridor and performed according to ATS
guidelines. Oxyhemoglobin saturation (SpO
using pulse oximetry (BCI, Hand-Held Pulse Oximeter, Waukesha, WN).
computerized battery CNS Vital Signs®.
verbal and visual memory, finger tapping, symbol digit coding, the Stroop Test, a test of shifting
attention, continuous performance test. Verbal memory test will assess verbal learning,
memory for words, immediate recall, and delayed recall. Visual memory tests will assess visual
learning, memory for geometric shapes, immediate recall, and delayed recall. Finger tapping
test will assess motor speed and fine motor control. Symbol digit coding test will evaluate
complex attention, visual-perceptual speed, and information processing speed. Stroop Test will
assess executive function, simple and choice reaction time, speed-accuracy trade-off,
information processing speed, and inhibition/ disinhibition. Shifting attention test will assess
executive function, reaction time, and information processing speed. Continuous performance
test will assess sustained attention and choice reaction time. Normative data is available for
this testing through CNS Vital Signs® and patients’ performance will be compared to this
Medical and Demographic Information
(e.g., education, employment, smoking status). Medical information will be abstracted from
medical records and study questionnaires.
Monitoring for adverse events will be included along with routine testing with
comprehensive metabolic panel, complete blood cell counts with differential, and thyroid
function testing including thyroid stimulating hormone and free thyroxine.
C.4 Location and facilities:
PRT-BTC at Duke is an internationally known center for the treatment of primary brain
tumors. Each week, we see approximately 12 to 20 new primary brain tumor patients in our
outpatient clinic with a majority of those being newly diagnosed HGG. Because of the
excellence and experience of
service for the PRT-BTC has approximately 5 to 6 newly diagnosed primary brain tumor patients
that will be undergoing surgery at Duke University Medical Center every week. All of the
testing has been designed to be amendable to the inpatient and outpatient setting. The QOL
questionnaires, neurocognitive testing, and 6-minute walk testing are all easily performed at the
bedside, on the clinical ward, or in the clinic outpatient setting. Because of our resources, in
particular multitude of patients, inpatient services, and outpatient services, we feel that this
study can be performed successfully at the PRT-BTC.
C.5. Study Personnel and Expertise
Surgery) am a board-certified neurologist with a background in cognitive neuroscience and
neuro-oncology. My unique backgrounds in both neurology and cancer biology (PhD work from
Stanford University) provide me with the appropriate criteria to author and lead this study. As
one of the new attending for the PRT-BTC, I work with world-renown clinician scientists in
neuro-oncology such as
continuation of collaboration with
Radiation Oncology) who is a preeminent exercise scientist and Director of the Cancer
Survivorship Center at Duke. I have written several protocols with
will continue to benefit from his knowledge and support.
Page 7 of 9
aforementioned colleagues, I have been able to design an innovated study to evaluate,
for the first time, at the use of LDN in HGG and how it impacts QOL during
The focus of the time line will be initially on patient recruitment in the first 5 months and will
shift to data collection and patient follow-up in the later months. Because of our patient volume,
we anticipate recruiting and randomizing 72 patients within 5 months. Essentially, this will be
approximately 15 patients recruited per month for the study. Because the study time is 24
weeks total we will need to complete recruitment by month 5. Therefore, all data collection and
follow-up information will be obtained at month 11. This will be suitable for data analysis in
month 12. Reporting of finding will include communication to granting organization, professional
meetings, and likely publication.
Months 1-5 Months 6-11 Month 12
Patient Recruitment/Data Collection Data Collection Final Data
Months 6-11 Analysis
Follow-up on Patients
D. Statistical Analysis
Seventy-two (72) patients newly diagnosed with high-grade glioma will be randomized
with equal probability to receive either LDN or placebo with standard chemoradiation treatment
consisting of temozolomide, radiotherapy, and possibly bevacizumab. Randomization will be
stratified by the inclusion of bevacizumab in the chemoradiation treatment plan. Though this
study is comparative, the goal of this randomized double-blinded pilot study is to determine
whether LDN is worthy of further investigation, and not to make definitive statements about its
effectiveness relative to placebo. Though the basis for sample size determination will focus on
treatment differences in QOL at week 16 as measured by FACT-Br, other factors such as
treatment differences in QOL at week 8 and treatment differences in cognition and fatigue at all
follow-up assessments will be considered in the final decision-making.
The universal importance of a half standard deviation change or difference has been
previously reported for health-related quality of life measures.
detect a half standard deviation difference in QOL scores measured at week 16.
Being a phase II study, there is a need to constrain the sample size requirements at the
expense of either an increased false negative or false positive rate. As proposed by Ratain and
Sargent, a false-positive rate of 0.2 will be used to test this hypothesis.
patients per arm in this screening study, the power of a 1-tailed two-sample t-test conducted at
the 0.2 level of significance to detect a half standard deviation difference in QOL scores
measured at week 16 is 90% (SAS 9.2, Cary, NC). Assuming that approximately 10% of
patients withdraw from study participation prior to week 16 assessment, approximately 66
patients are expected to provide a week 16 assessment. With 33 patients per arm, the test
described above will have approximately 88% power to detect the noted difference.
Descriptive statistics (e.g. means and standard deviations) will be used to summarize
within-group changes from baseline in each patient-reported outcome and cognition scale and
subscale at each follow-up assessment. Analysis of covariance will be used to compare groups
with respect to changes between baseline and week 16 in each of these subscales, with the
baseline measure included as a covariate. Generalized linear models for repeated measures
which accounts for correlations among serial measurements obtained from the same patient will
be used to compare treatment patterns of response over time in cognition and patient-reported
Page 8 of 9
outcomes from questionnaires. Adjustments to the intended analysis plan will be made if
patients withdraw from study participation before the completion of the week 16 assessment.
Options include a focus on repeated measures obtained during the first 8 weeks, as well as
more complicated models such as pattern mixture models. An intent-to-treat philosophy will be
followed in all analyses.
E. Cited References
1. Klein M, Taphoorn MJ, Heimans JJ, et al: Neurobehavioral status and health-related
quality of life in newly diagnosed high-grade glioma patients. J Clin Oncol 19:4037-47, 2001
2. Liu R, Page M, Solheim K, et al: Quality of life in adults with brain tumors: current
knowledge and future directions. Neuro Oncol 11:330-9, 2009
3. Weerts EM, Kim YK, Wand GS, et al: Differences in delta- and mu-opioid receptor
blockade measured by positron emission tomography in naltrexone-treated recently abstinent
alcohol-dependent subjects. Neuropsychopharmacology 33:653-65, 2008
4. Zagon IS, Rahn KA, Turel AP, et al: Endogenous opioids regulate expression of
experimental autoimmune encephalomyelitis: a new paradigm for the treatment of multiple
sclerosis. Exp Biol Med (Maywood) 234:1383-92, 2009
5. Cree BA, Kornyeyeva E, Goodin DS: Pilot trial of low-dose naltrexone and quality of life
in multiple sclerosis. Ann Neurol 68:145-50
6. Younger J, Mackey S: Fibromyalgia symptoms are reduced by low-dose naltrexone: a
pilot study. Pain Med 10:663-72, 2009
7. Younger JW, Zautra AJ, Cummins ET: Effects of naltrexone on pain sensitivity and
mood in fibromyalgia: no evidence for endogenous opioid pathophysiology. PLoS One 4:e5180,
8. Ohgaki H: Epidemiology of brain tumors. Methods Mol Biol 472:323-42, 2009
9. Gilbert M, Armstrong T, Meyers C: Issues in assessing and interpreting quality of life in
patients with malignant glioma. Semin Oncol 27:20-6, 2000
10. Budrukkar A, Jalali R, Dutta D, et al: Prospective assessment of quality of life in adult
patients with primary brain tumors in routine neurooncology practice. J Neurooncol 95:413-9,
11. Osoba D, Aaronson NK, Muller M, et al: Effect of neurological dysfunction on healthrelated
quality of life in patients with high-grade glioma. J Neurooncol 34:263-78, 1997
12. Brown PD, Ballman KV, Rummans TA, et al: Prospective study of quality of life in adults
with newly diagnosed high-grade gliomas. J Neurooncol 76:283-91, 2006
13. Taylor BV, Buckner JC, Cascino TL, et al: Effects of radiation and chemotherapy on
cognitive function in patients with high-grade glioma. J Clin Oncol 16:2195-201, 1998
14. Crossen JR, Garwood D, Glatstein E, et al: Neurobehavioral sequelae of cranial
irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 12:627-42,
15. Gregor A, Cull A, Traynor E, et al: Neuropsychometric evaluation of long-term survivors
of adult brain tumours: relationship with tumour and treatment parameters. Radiother Oncol
16. Weitzner MA, Meyers CA, Gelke CK, et al: The Functional Assessment of Cancer
Therapy (FACT) scale. Development of a brain subscale and revalidation of the general version
(FACT-G) in patients with primary brain tumors. Cancer 75:1151-61, 1995
17. Jones LW, Cohen RR, Mabe SK, et al: Assessment of physical functioning in recurrent
glioma: preliminary comparison of performance status to functional capacity testing. J
Neurooncol 94:79-85, 2009
18. Jones LW, Mourtzakis M, Friedman AH, et al: Changes in functional performance
measures in adults undergoing chemoradiation for primary malignant glioma. The Oncologist,
Page 9 of 9
19. Butler JM, Jr., Case LD, Atkins J, et al: A phase III, double-blind, placebo-controlled
prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumor patients
receiving radiation therapy. Int J Radiat Oncol Biol Phys 69:1496-501, 2007
20. Kaleita TA, Wellisch DK, Graham CA, et al: Pilot study of modafinil for treatment of
neurobehavioral dysfunction and fatigue in adult patients with brain tumors., American Society
of Clinical Oncology. Atlanta, GA, Journal of Clinical Oncology, 2006, pp 1503
21. Brown N, Panksepp J: Low-dose naltrexone for disease prevention and quality of life.
Med Hypotheses 72:333-7, 2009
22. Rajashekara V, Patel CN, Patel K, et al: Chronic opioid antagonist treatment dosedependently
regulates mu-opioid receptors and trafficking proteins in vivo. Pharmacol Biochem
Behav 75:909-13, 2003
23. Gironi M, Martinelli-Boneschi F, Sacerdote P, et al: A pilot trial of low-dose naltrexone in
primary progressive multiple sclerosis. Mult Scler 14:1076-83, 2008
24. Sharafaddinzadeh N, Moghtaderi A, Kashipazha D, et al: The effect of low-dose
naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled
trial. Mult Scler 16:964-9
25. Van Belle S, Paridaens R, Evers G, et al: Comparison of proposed diagnostic criteria
with FACT-F and VAS for cancer-related fatigue: proposal for use as a screening tool. Support
Care Cancer 13:246-54, 2005
26. Jacobs SR, Jacobsen PB, Booth-Jones M, et al: Evaluation of the functional assessment
of cancer therapy cognitive scale with hematopoietic stem cell transplant patients. J Pain
Symptom Manage 33:13-23, 2007
27. McHorney CA, Ware JE, Jr., Rogers W, et al: The validity and relative precision of MOS
short- and long-form health status scales and Dartmouth COOP charts. Results from the
Medical Outcomes Study. Med Care 30:MS253-65, 1992
28. Ware JE, Jr., Sherbourne CD: The MOS 36-item short-form health survey (SF-36). I.
Conceptual framework and item selection. Med Care 30:473-83, 1992
29. Johns MW: A new method for measuring daytime sleepiness: the Epworth sleepiness
scale. Sleep 14:540-5, 1991
30. Buysse DJ, Reynolds CF, 3rd, Monk TH, et al: The Pittsburgh Sleep Quality Index: a
new instrument for psychiatric practice and research. Psychiatry Res 28:193-213, 1989
31. Zung WW: A Self-Rating Depression Scale. Arch Gen Psychiatry 12:63-70, 1965
32. Beck AT, Steer RA, Ball R, et al: Comparison of Beck Depression Inventories -IA and -II
in psychiatric outpatients. J Pers Assess 67:588-97, 1996
33. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med
34. Gualtieri CT, Johnson LG: Reliability and validity of a computerized neurocognitive test
battery, CNS Vital Signs. Arch Clin Neuropsychol 21:623-43, 2006
35. Norman GR, Sloan JA, Wyrwich KW: Interpretation of changes in health-related quality
of life: the remarkable universality of half a standard deviation. Med Care 41:582-92, 2003
36. Ratain MJ, Sargent DJ: Optimising the design of phase II oncology trials: the importance
of randomisation. Eur J Cancer 45:275-80, 20091 In spite of the recognition of this problem, there2 New innovative therapies, along with new integrative?-endorphins.3,4 These3,4 Low dose naltrexone (LDN) has been used in neurological disorders such5-7 Moreover, LDNMoreover, it willTo compare prospectively effects of LDN versus placebo on patient-reported measures ofTo compare prospectively the effects of LDN versus placebo on functional capacity inTo compare prospectively the effects of LDN versus placebo on neurocognition in HGGTo evaluate the safety of LDN in newly diagnosed HGG patients.8 The standard of care for2,9 Liu defines QOL as “a2 For brain tumor patients, focal neurological1 In a large1010 Moreover, QOL is dependent of the physical function and11 Liu and colleagues discuss how these2,12,1314,15 Based on these studies, QOL should16 Other standardized1717 Thus, the 6-minute18 Patients were followed prospectively after19 Studies with modafinil did show some positive effects on20 Therefore, new3 Interestingly, low-dose naltrexone (LDN), with doses equal to or21?-4,22 All of these changes in neural chemistry in turn can prompt improvements in6,7 Moreover, LDN easily tolerated with minimal toxicity. Toxicities5,23,24 In the? and glatiramer. Based on≥ 18 years of age≥ 29%, Hemoglobin ≥ 9, ANC ≥ 1,500 cells/?l, platelets ≥ 100,000 cells/?l,will be assessed by the Functional Assessment of Cancer Therapy-Brain16 Cancer-related fatigue will be assessed by the25 Cognitive problems will be assessed using version 3 of the26 This includes27,28 ESS is an 8-item scale used to29 PSQI is a 10-item scale used to assess sleep quality.30 ZSDS is a 20-31 Beck depression inventory (BDI) will be32 The BDI containswill be assessed using 6-minute walk test. 33 The patient will be2) and heart rate will be monitored continuouslywill include the performance on the following testing using a34 This battery consists of seven tests that measurewill consist of general demographic informationDr. Allan Friedman in Division of Neurosurgery, the inpatientDr. Katherine B. Peters, MD PhD (Medical Instructor of Neuro-Oncology, Department ofDr. David Reardon, MD and Dr. Henry Friedman, MD. This study is aLee Jones , PhD (Associate Professor, Department ofDr. Jones as my mentor andWith support from my35 Hence, this study is designed to36 With 36 randomized