The Effect of Dexamethasone on Symptoms in Patients With Advanced Cancer
Phase: PHASE2
Conditions: Solid Tumors
Sponsor: M.D. Anderson Cancer Center

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Proposal To: American Cancer Society     Mentored Research Scholar Grant  
Title (Applicant): Effect of Dexamethasone on symptom distress in patients with advanced cancer 
(Yennurajalingam, Sriram) 
 
 
Proposal To: American Cancer Society     Mentored Research Scholar Grant  
Title (Applicant): Effect of Dexamethasone on symptom distress in patients with advanced 
cancer (Yennurajalingam, Sriram) 
 
 
Project Title Effect of Dexamethasone on symptom distress in patients with advanced cancer 
 
Is this proposal in response to a Request for Application (RFA)? 
No 
   
RFA Title: N/A 
 
Total Amount Requested: 
  
Start Date:  
  
End Date:   
  
Is this proposal for a new grant or renewal of an existing grant? New 
 
Proposal Type  
  
ACS Grant#:  N/A.  
  
Have you submitted this proposal to ACS for funding consideration before? No 
  
Prior application number: N/A.  
  
First or second resubmission?  If this application is a resubmission, please select if this is your 
first or second resubmission.  
 
Title: Effect of dexamethasone on symptom distress in patients with advanced cancer(66 
Characters) 
Project Abstracts & Coding 
  
Please provide a General Audience Summary below (< 3,000 characters. Text only. No special characters or 
formatting. See instructions for details.). 
Attach the Technical Abstract as a file at the bottom of this page. 
 
8.General Audience Summary  
Most patients with advanced cancer develop 
devastating physical and psychosocial symptoms. These symptoms decrease the quality 
of life of patients and produce severe distress in their families. At present there are 
limited treatment options to treat these symptoms. Corticosteroids such as 
Dexamethasone have been widely used in the treatment of symptoms such as fatigue, 
nausea, anorexia and pain in advanced cancer patients.  
 
Despite widespread use of steroid therapy in cancer symptom management, the data is 
still inadequate to draw definitive conclusions of the efficacy of these compounds in the 
management of pain and other symptoms. Previous studies by our group and other 
investigators on steroids suggested beneficial effects of steroids on these symptoms. But 

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the studies were done using not validated assessment tools, different types of steroids, 
administration routes and dosages. Steroids have potentially severe side effects, 
especially on prolonged use including immunosuppression, osteoporosis, Cushing’s 
syndrome, myopathy, and hyperglycemia. Some of these effects can be particularly 
serious in patients with advanced cancer. Therefore it is important to better determine the 
symptomatic effects relative to the potential side effects of these drugs. None of studies 
described the underlying mechanism of action of steroids on symptoms. 
In recent years, it has become evident that many cytokines have powerful effects on the 
brain.  Animal models of symptoms such as pain and cachexia, and clinical studies of 
immunotherapy in which pro-inflammatory cytokines are administered to patients with 
various cancers have provided important insight into the central effects of these agents. 
Sickness behavior is typically associated with behavioral changes seen in humans and 
laboratory animals suffering from microbial infections and includes symptoms of 
cognitive dysfunction, anxiety, psychomotor slowing, fatigue, anorexia, sleep alterations 
and increased sensitivity to pain. Relevant to their mediation by cytokines, symptoms of 
sickness behavior can be reliably reproduced in both laboratory animals and humans by 
administration of each of the cytokines that induce the pro-inflammatory cytokine 
cascade (TNF-α, IL-1, IL-6). The cytokines and pro inflammatory mediators are elevated 
in advanced cancer patients, are associated with these symptoms. Dexamethasone and 
other steroids could potentially decrease the symptoms specifically, fatigue, nausea, 
anorexia and pain by decreasing these cytokines and inflammatory substances. 
At present, the association between the effects of dexamethasone on symptoms and its 
effects in decreasing cytokines and inflammatory substances has not been established 
using validated assessment instruments and laboratory correlates in a randomized 
controlled trial. Our study will be the first to provide an association. By linking 
symptomatic response to dexamethasone with the circulating cytokines we will be able 
to better establish the role of cytokines in the frequency and severity of symptoms. The 
finding in the study will help in development of cytokine specific suppressive therapies 
that could be used to prevent and treat these troubling symptoms.  
 
 
Selected Research Areas  
Cachexia 
Clinical Practice 
Immunomodulation 
Interleukins 
Supportive Care of Cancer Patients 
Tumor Necrosis Factor 
 
Please select two priority areas that are applicable to this project. Then provide a % weighting 
indicating the relative emphasis of the project for all selected priority areas. Please refer to the ACS 
Instructions appendix with regard to the common scientific outline terms which are requested below. 
 
 
Selected Priority Areas  
% of Project  
6.6-End of Life Care 
 
 
0 
 
Please select any organ site applicable to this project. For each selection, provide a relative weighting 
(total must equal 100% or 0%). 
 
 
Selected Organ Sites  
% of Project  
Brain 
 
  
0 
 
Project Abstracts & Coding 
 

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10.STRUCTURED TECHNICAL ABSTRACT 
 
Name of Applicant: 
Sriram Yennurajalingam 
 
1. Title of Project: Effect of Dexamethasone on symptom distress in patients with advanced cancer: a 
randomized controlled trial vs. placebo. 
 
 
 
 
 
In the 7 x 7-inch space below, summarize concisely your proposed research, outlining 
background, objective/hypothesis, specific aims, study design, and relevance to the 
cancer problem.  You will prepare the abstract as a separate file when you electronically 
submit your application.  Refer to Application Instructions.  If the application is funded, 
this Abstract will become public information.   
 
 
 
 
 
 
10.1 BACKGROUND 
Approximately 50% of patients diagnosed with cancer die of progressive disease. 
Patients with advanced cancer experience clusters of physical and psychosocial 
symptoms including pain, fatigue, nausea, anorexia/cachexia, depression, and sleep 
disorders [Walsh D, et al, 2000, Paice, 2004; Dodd, et al., 2001; Trask, et al., 2004; 
Cleeland, 2002]. The prevalence rates of the many different symptoms reported by 
advanced cancer patients vary as follows: pain 41%-76%, depression 33%-40%, anxiety 
57% - 68%, nausea 24%-90%, constipation 65%, sedation/confusion 46%-60%, 
dyspnea 12%-58%, anorexia 85% and Fatigue 90%[Walsh D, et al., Bruera et al., 2004]. 
In cancer patients, symptom expression is a multidimensional construct that results from 
different mechanisms of production and brain perception. There is a complex interaction 
between the tumor and the host that depends mostly on the tumor mass, the tumor 
function, the immune status of the host, co-morbidities, and the type of anti-neoplastic 
treatments being given. It has been noted that somatic nerves deliver afferent 
information related to symptoms such as pain. The cytokines can influence the 
stimulation of such afferent nerves at the periphery and some of the central synaptic 
activity at the dorsal horn and in the brain cortex [Cleeland et al., 2003].  Visceral nerves 
deliver information regarding symptoms such as dyspnea, nausea, and anorexia and 
these nerves are also under the influence of cytokines both centrally and peripherally 
[Cleeland et al., 2003].  Tumor by-products can produce abnormalities that are linked 
with cancer cachexia [Argiles et al., 2003]. The relationship between tumor by-products 
and host response has not been completely established. Finally, circulating cytokines 
and inflammatory proteins have been thought to be directly associated with pain, and 
cognitive impairment [Lee et al., 2004; Cleeland et al., 2003], depression [O’Brien et al., 
2004], fatigue [Kurzrock 2001], cachexia [Bruera 1999], and sleep disorder [Haack et al., 
2004]. 
 
 

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These symptoms decrease the quality of life of patients. At present there are limited 
treatment options to treat these symptoms clusters. Corticosteroids such as 
Dexamethasone have been widely used in treatment of symptoms fatigue, nausea, 
anorexia, and pain in advanced cancer patients. Despite widespread use of steroid 
therapy in cancer symptom management, the data is inadequate to draw definitive 
conclusions about the efficacy of these compounds in the management of pain and other 
symptoms. Previous studies by our group and other investigators on steroids[Bruera and 
Roca et al 1985; Tannock I, etal 1996; Kim JH, Fainsinger et al., 1994; A.B. Ettinger et al 
1988; T. Popiela, et al, 1989; Della Cuna, et al, 1989; Twycross, 1992; Mercadante, et al 
2001; Vecht ChJ, et al 1989; Moertel C, et al., 1974; Stiefel FC, Breitbart WS, et al, 
1989].   suggested beneficial effects of steroids on these symptoms in advanced cancer. 
But the studies were done using assessment tools that were not validated; various 
different steroids, routes of administration and dosages were used. There was no 
attempt to understand the pathophysiology using laboratory correlates. The role steroids 
on cancer related fatigue, pain, appetite and nausea (which are the most common 
symptoms in advanced cancer), their effects on cytokines need to be defined through 
randomized controlled studies using updated and validated and laboratory correlates. 
 
10.2 Objective/ Hypothesis: 
We hypothesize that dexamethasone decreases the intensity of symptoms namely 
Fatigue, nausea, anorexia and pain that occur frequently in advanced cancer and one 
of the mechanisms it exerts such effects by decreasing a cytokines levels (namely IL-
1, IL-6, TNF-, IL-10, IL-8) that mediate these symptoms. 
 
 
        10.3 Specific Aims: 
 
 
We intend to test the effect of dexamethasone on symptoms in advanced cancer 
patients by pursuing the following three specific aims: 
 
 
• 
Primary objective:  To determine the effect of Dexamethasone on the intensity of 
Fatigue 
• 
Secondary objective-1:  To determine the effect of Dexamethasone on the intensity 
of Pain, anorexia and nausea.  
• 
 Secondary objective–2:  To determine the changes in cytokines (IL-1, IL-6, TNF-, 
IL-10, IL-8, activated monocytes and corresponding receptor levels) and C-reactive 
protein before and after treatment with dexamethasone. 
• 
Secondary objective-3:  To determine association of cytokines (IL-1, IL-6, TNF-, 
IL-10, IL-8, activated monocytes and corresponding receptor levels) and C-reactive 
protein and Fatigue, Pain, Anorexia and nausea. 
• 
Secondary objective – 4:  To collect pilot data on the quality of sleep and cortisol 
levels in ten subjects 
 
 
 
 
 
 
 
       
 

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   10.4 Study Design 
We will conduct a prospective, randomized, double blind, placebo controlled study 
comparing Dexamethasone 4mg orally two times per day for 14 days versus placebo. 100 
Eligible patients who agree to participate in the study and provide written informed consent 
will be randomized to either group A, in which patients will receive Dexamethasone orally, 
4mg two times a day for 14 days; or group B, in which patients will receive placebo orally, 
two times a day for 14 days. On day 15, all patients will be receive 4mg of dexamethasone 
twice a day on a open label basis till Day 21,From Day 22 to Day28 the dose of 
dexamethasone is to be tapered to 2mg orally twice a day. Subsequently patients would 
be off study with dose tapered to the minimum tolerated dose.  All study patients will be 
asked to return to the clinic for follow-up assessments 2 weeks after the study 
medication is discontinued ( day 43  3 days) for a safety and toxicity assessment. 
The reason to have open label design after Day15 is to observe the descriptive trends. 
 
Exam (including history including FACIT-F, FAACT, HADS, ESAS, BPI, physical exam 
and toxicity assessment will be done day 0(baseline), Day 8 3, Day 153, Day 
223, Day 293.  GSE on days 8 3, 223 and 293. Patients will also be 
assessed by the research nurses for any signs and symptoms of infection while 
on the study drug.   Laboratory correlates including cytokine levels- IL-1, IL-6, TNF-, 
IL-10, IL-8, activated monocytes and corresponding receptor levels, complete blood 
counts, chemistry (electrolytes), C-reactive protein on day 0(baseline), Day 8, Day 15, 
Day 22, Day 29. The ESAS and Toxicity evaluation on Day 4 would be done through the 
phone. 
 
A subset of ten patients will be asked to complete the Pittsburg Sleep 
Quality Index at baseline and Day 15 [+ 3].  These patients will also collect 
saliva cortisol specimens at baseline and Day 15 [+ 3].  We will select the 
subset of 10 patients sequentially. Every patient will be approached 
regarding the optional procedure of participating in the quality of sleep 
questionnaires and the cortisol levels, We will collect the pilot data on the 
first 10 patients that consent. 
 
10.5 Cancer Relevance 
 
Approximately 50% of patients diagnosed with cancer die of progressive disease.  The 
overwhelming majority of patients develop devastating physical and psychosocial 
symptoms.  Those symptoms decrease the quality of life of patients. Circulating 
cytokines and inflammatory proteins have been thought to be directly associated with 
pain, and cognitive impairment, depression, fatigue, cachexia, and sleep disorder. 
Steroids decreases the intensity of symptoms namely Fatigue, nausea, anorexia and 
pain that occur frequently in advanced cancer and one of the mechanisms it exerts such 
effects by decreasing a cytokines levels that mediate these symptoms. Despite 
widespread acceptance and frequency of steroid therapy in patients with cancer 
symptom management, the data is inadequate to draw definitive conclusions about the 
efficacy of these compounds in the management of pain and other symptoms. The role 
steroids on cancer related fatigue, pain, appetite and nausea (which are common 
symptoms in advanced cancer), their effects on cytokines need to be defined through 
randomized controlled studies using updated and validated Symptom assessment tools 
and laboratory correlates (which were lacking in the previous studies on corticosteroids 
for symptoms). Our findings will also allow investigators 1) To effectively treat the 

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symptoms clusters in advanced cancer patients and improve their quality of life. 2) 
Establish Cause and effect relationship between symptoms and cytokines. 3) To 
establish the use of dexamethasone for symptom control in advance cancer patients 
through randomized controlled studies using updated and validated Symptom 
assessment tools and laboratory correlates 4) Development of cytokine specific 
suppressive therapies that could be used to prevent and treat these troubling symptoms. 
 
 
 
 
 
Assurances & Certifications 
  
Human Subjects 
 
Does the proposed project involve Human Subjects? Yes 
  
If Yes, Status of IRB Approval Pending 
 
Approved or Pending Date  
 
Human Subjects Assurance Number  
FWA363  
This assurance number cannot be entered on this screen – it will appear only if properly entered in the 
institution profile (for the institution you selected in the institution section of the proposal). If no assurance 
number appears here, please contact your institution’s grants and contacts office to have them add the 
assurance numbers to the institution profile. If you need assistance, contact proposalCENTRAL customer 
support.  
  
Does the proposed project involve Vertebrate Animals? No 
 
If Yes, status of IACUC approval  
 
Approved or Pending Date  
 
Animal Welfare Assurance Number  
A-3343-1  
This assurance number cannot be entered on this screen – it will appear only if properly entered in the 
institution profile (for the institution you selected in the institution section of the proposal). If no assurance 
number appears here, please contact your institution’s grants and contacts office to have them add the 
assurance numbers to the institution profile. If you need assistance, contact proposalCENTRAL customer 
support.  
 
Does the Proposed project involve Recombinant DNA? No 
  
If Yes Status of Approval  
 
Approved or Pending Date  
 
Are hazardous materials used or produced in the project? No 
 
If yes Explain:  
 
Animal species  
 
If vertebrate animals will be used, please list all species, separated by commas.  
 

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Assurances & Certifications 
CONTENTS 
Cover Pages – (Signature Page, Contact Page, Assurances and 
Certification, General Audience Summary) 
Structured Technical Abstract 
PART I 
 
Table of Contents .......................................................................................................................................... 1 
 
Budget ........................................................................................................................................................... 2 
 
Justification of Budget ................................................................................................................................... 3 
 
Biographical Information of Applicant ........................................................................................................... 
 
Biographical Information of Key Personnel .................................................................................................... 
 
Other Support .................................................................................................................................................. 
 
Experience ....................................................................................................................................................... 
 
Work Accomplished by You and/or Others .................................................................................................... 
 
Specific Aims .................................................................................................................................................. 
 
Rationale and/or Significance .......................................................................................................................... 
 
Statement of Cancer Relevance ....................................................................................................................... 
 
Plan of Attack  
 
Facilities .......................................................................................................................................................... 
 
References ....................................................................................................................................................... 
 
Letters of Recommendation ............................................................................................................................ 
 
PART II 
 
Faculty or Scientific Apointment of Candidate ............................................................................................... 
 
Program Goals and Proposed Training ............................................................................................................ 
 
Institutional Resources and Environment ........................................................................................................ 
 
Abbreviated CV of Mentor(s) ......................................................................................................................... 
 

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Support of Mentor(s) ....................................................................................................................................... 
 
Appendix:  List: 

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BUDGET 
 
A. Personnel 
 (indicate percent effort, salary, and names of personnel) 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Percent of effort: 
S Yennurajalingam   FTE 60% 
 
 
 
 
 
Research nurse   FTE   40% 
 
 
 
 
 
Data Manager FTE 20% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fringe Benefits Total 
 
 
 
 
 
Category Total 
 
 
 
 
 
B. Permanent Equipment (Itemize) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Category Total 
 
 
 
 
 
C. Supplies (Group into major categories) 
 
 
 
 
 
Drug 
 
 
 
 
 
 HADS forms (100 x 4 x $ 1.00) 
 
 
 
 
 
 Cytokine assay 
 
 
 
 
 
 C- Reactive protein 
 
 
 
 
 
 
 
 
 
 
 
Category Total 
 
 
 
 
 
D. Travel (Domestic only) 
 
 
 
 
 
 1,500 x 2  for presentation of 2 papers that are planned to be 
written based on the study 
 
 
 
 
 
 
 
 
 
 
 
Category Total 
 
 
 
 
 
E. Miscellaneous 
 (List specific amounts for each item)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Category Total 
 
 
 
 
 
F. Subcontracts (Categorize on continuation page) 
 
 
 
 
 
 
Category Total 
 
 
 
 
 
 
Total Direct Costs  
 
 
 
 
 
G. Indirect Costs:       %) (Excluding permanent equipment) 
Total Indirect Costs 
 
 
 
 
 
Total Annual Costs 
 
 
 
 
 
 
Total Amount Requested 
(Sum of all years including indirect costs; transfer this   amount 
to the budget section of the on-line form) 
  
 
_______________ 
 
 

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JUSTIFICATION OF BUDGET 
 
Justify all items of equipment costing over $500, and the need for personnel, supplies, 
travel, and other items. 
 
           PERSONNEL 
 
 
 
• 
Eduardo Bruera, M.D., Co-Investigator and Mentor (10% FTE) Dr. Bruera is a medical 
oncologist who specializes in palliative care. Dr. Bruera is the F. T. McGraw Chair in the 
Treatment of Cancer and heads the Department Palliative Care and Rehabilitation 
Medicine.  Dr. Bruera has Mentored in design the study and will oversee all aspects of 
the execution and analysis of the protocol.   
• 
Saroj Vadhan-Raj, Co-investigator and additional Mentor  (5% FTE) Dr. Vadhan is a 
medical oncologist who is a section chief of Medical Supportive Care in the Department 
of Palliative Care and Rehabilitation Medicine at UTMDACC. Dr. Vahdan collaborates 
with us in research currently conducted at UTMDACC.  She will be responsible, 
primarily, for conducting and evaluating cytokine measuring. She has mentored and 
helped design and write this application, will collaborate in the interpretation of the 
results and the preparation of manuscripts resulting from this study. 
• 
Sriram Yennurajalingam, MD, principal Investigator (60% FTE) Dr. Yennurajalingam is 
an Symptom control and Palliative care specialist who completed his doctoral fellowship 
in the Department of Palliative Care and Rehabilitation Medicine at M. D. Anderson 
Cancer Center, and became an assistant professor and attending physician in the 
department in 2004. He has great interest in the relationship between symptom clusters 
and cytokine production and symptom management. 
       Dr Yennurajalingam has designed the study and will oversee all aspects of the 
execution and analysis of the protocol.  He will be responsible for the presentation of the 
study in peer-reviewed meetings and for the publication of the final manuscript.   
 
• 
Lynn Palmer, Ph.D., Co-investigator and additional mentor  (20% FTE) Dr. Palmer is 
Associate Professor of Biostatistics in the Department of Palliative Care and 
Rehabilitation Medicine and in the Department of Biostatistics. Dr. Palmer has 24 years 
experience as a biostatistician, has designed and analyzed a large number of clinical trials 
and other studies related to the treatment of cancer, and has authored or co-authored 
numerous publications, including many manuscripts in palliative care. Dr. Palmer will 
contribute to the design of the study and be responsible for all bio statistical aspects of the 
study. She will analyze and interpret the data from the clinical trial and assist in 
manuscript preparation. 
 
• 
Jie Willey, R.N., MSN, Research Nurse Manager (30% FTE) Ms. Willey is a research 
nurse manager in the Department of Palliative Care & Rehabilitation Medicine.  She has 
extensive clinical, administrative, and supervisory experience in research development, 
implementation and administration in the area of breast cancer and symptom 
management.  She will coordinate this research study by supervising the research staff, 
reassuring patient accrual, study implementation, and data collection and monitoring. She 
will maintain protocols according to institutional guidelines, monitor study progress, and 
prepare progress reports for the institution and funding source. 
 
 

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• 
Mary Abanto, RN BSN, (40% FTE) Ms. Abanto is a research nurse in the Department of 
Palliative Care & Rehabilitation Medicine.  She will be responsible for patient screening 
and recruiting. She will administrate the assessment measures during clinic visit, and will 
ensure the blood collection for cytokine levels. She will maintain contact with the 
patients to ensure all study related data are accurately collected. 
 
• 
Karen Zhang, MS, Data Manager, (20% FTE) Ms. Zhang will be responsible for all 
aspects of data management of the project. She will develop databases for the data 
collected.  She will perform data entry and manage the databases.  She will assist the 
statistician in data analyses. 
 
NON-PERSONNEL BUDGET ITEMS 
 
Supplies 
Drug 
HADS 
CYTOKINE ASSAY 
 
BIOGRAPHICAL INFORMATION OF APPLICANT 
(Do not exceed two pages for total biographical information.) 
 
Last name, First name     YENNURAJALINGAM, SRIRAM 
 
Education 
Degree/Year Conferred 
Institution/Location 
Field of Study 
M.B.B.S. (Bachelor of 
Medicine and Bachelor 
of Surgery) 
 
Osmania Medical College, University of 
Health Sciences, Hyderabad, India, 1995 
Medicine 
Training 
Title 
Mentor 
Institution 
Dates 
Fellowship in Symptom 
control and Palliative Care 
 
Fellowship in Geriatrics 
 
 
Residency in Internal 
Medicine 
 
 
Eduardo Bruera 
MD 
 
Dharmarajan MD 
 
 
Ida Ashley MD 
 UT M. D. Anderson Cancer Center, 
Houston, TX, 07/2003-06/2004 
 
University Hospital of New York Medical 
College, Our lady Mercy Medical Center, 
Bronx, NY 
 
Mount Sinai Services (Affiliated to Mount 
Sinai School of Medicine), Queens 
Hospital Center, Queens, NY 
2003 – date 
 
 
07/2002 – 06/2003 
 
07/1999-06/2002 
Appointments 
Title 
Institution 
Dates 
 
Department of Palliative Care and Rehabilitation Medicine, 
The University of Texas M.D. Anderson Cancer Center, 
7/2004 – 8/2004 

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Temporary Director 
 
Assistant Professor of Medicine 
 
 
 
 
Houston, Texas 
 
Department of Palliative Care and Rehabilitation Medicine, 
The University of Texas M.D. Anderson Cancer Center, 
Houston, Texas 
 
 
9/2004- to date 
 
Justification of Eligibility (if appropriate) 
 
Junior Faculty in 1st year of appointment. 
 
 
Eligibility Status 
 
Year last degree conferred:                                                  MBBS____________ 
Year of first independent position:                                        __2004_________ * enter date in appropriate box on 
                                                                                                                           Title page  
 
BIOGRAPHICAL INFORMATION OF APPLICANT 
 
CERTIFICATIONS: 
ECFMG Certification (Steps I, II & III passed), 1995-indefinite  
Internal Medicine Board Certified, 08/2002. 
Geriatrics Board Certified, 11/2003. 
Palliative Care Board Certified, 11/2004 
 
 
 
 
 
 

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PROFESSIONAL ACTIVITIES: 
 
Rotating Intern, Osmania General Hospital and affiliates, in Hyderabad, India, 1994-1995  
Internship consisting of practical experience in Medicine & Dermatology (3 months), General 
Surgery, Ophthalmology & Orthopedic Surgery (3 months), Gynecology & Obstetrics (2 
months), Pediatrics (1 month), Infectious Diseases (1 month), Emergency Medicine (1 month), 
Social & Preventive Medicine (1 month). 
Senior House Officer, Department of General Medicine and Psychiatry, Osmania General Hospital 
and affiliates, Hyderabad, India, 1995-1997 
Voluntary Clinical Externship, Ambulatory Care (ER), VA Medical Center,  
Dallas, TX, 1997-1998 
Voluntary Clinical Externship, Internal Medicine, Conemaugh Memorial Hospital, 
Johnstown, PA and Queens Hospital Center, Queens, NY, 1998-1999 
Resident, Internal Medicine, Mount Sinai Services (Affiliated to Mount Sinai School of Medicine), 
Queens Hospital Center, Queens, NY, 07/1999-06-2002 
Fellowship, Geriatrics at University Hospital of New York Medical College, Our lady Mercy 
Medical Center, Bronx, NY, 07/2002-06/2003 
Fellowship, Symptom Control and Palliative Care, The University of Texas M. D. Anderson 
Cancer Center, TX, 06/2003-07-2004 
 
HONORS AND AWARDS 
National Merit Scholarship, 1986 
 
PUBLICATIONS (if partial list is given, indicate total number of publications): 
Sharma U, Mojab H, Yennurajalingam S, Chokhavatia S, Opran A. Systemic vasculitis presenting 
with abdominal pain and metabolic acidosis.  American Journal of Gastroenterology 2002; 97 (9): 
S164-S164 
Noel D, Yennurajalingam S, Reich D, Sachmechi I. Four-Year Retrospective Analysis Examining 
Adherence to Five of The American Diabetes Association (ADA) Guidelines for Diabetic Care. 
The Mount Sinai J of Med. 2004:212 
Yennurajalingam S, Peuckmann V, Bruera E.  Recent Developments in Cancer Pain Assessment 
and Management.  Supportive Cancer Therapy 2004; 1(2): 97-110. 
Yennurajalingam S, Braiteh, F, Bruera E.  Pain and Terminal Delirium Research in the Elderly.  
Clin Geriatr Med 2005; 21:93-119. 
 
 
 
BIOGRAPHICAL INFORMATION OF KEY PERSONNEL 
(Do not exceed two pages per person for total biographical information.) 
 
Last name, first name 
 
Education 
Degree/Year 
Conferred 
Institution/Location 
Field of Study 
 
 
 
Appointments 
Title 
Institution 
Dates 

2005-0816 
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Publications 
(If partial list is given, indicate total number of publications.) 
 
 
 
 
 
 
OTHER SUPPORT 
(Current and pending) 
 
Provide details of: Current and Pending support for all professionals listed in the Budget, and Institutional 
Support to the applicant, as described in the INSTRUCTIONS FOR APPLICATION FOR A MENTORED 
RESEARCH SCHOLAR GRANT. 
 
Current Support: none 
 
Pending: none. 
 
PLANS FOR WORK UNDER THE GRANT: 
RESEARCH PLAN (Sections A-E):   
 
 
 
A. Experience 
I am an Assistant professor of Medicine in Symptom control and Palliative care in the 
Department of Palliative care and rehabilitation Medicine at M.D. Anderson Cancer 
Center. I currently devote 90% of patient care and 10% in clinical research. Receipt of 
this award would enable me to increase my research effort to 60%. I would use this 
opportunity to understand the pathophysiological process of symptoms that are severe 
and prevalent in advanced cancer patient. 
After graduation Osmania Medical College, India in 1995, my career goal was to 
alleviate the suffering in most vulnerable elderly patients cancer patients. Hence I 
pursued further studies in Internal Medicine in Mount Sinai, Queens Hospital center and 
Geriatrics in New York Medical College. Subsequently I underwent Training in symptom 
control and palliative care fellowship in M.D Anderson Cancer Center where I had an 
opportunity to work with many well-known Medical oncologists and symptom control/ 
Palliative care specialists. During my training in fellowship I learned clinical skills and 
medical management of symptoms in wide variety of malignancies. In additions to the 
clinical experience my training included teaching to the residents and visitors and 
presentations. My Research experience include clinical research in the form of 
retrospective studies on symptom management by symptom control and palliative care 
consult team, role of family conference in enhancing end of life care in advanced cancer 
patient and review of challenges involved in the management of cancer pain. I am also 
involved as a co-investigator for the study of thalidomide. In addition I have been a 
collaborator in various studies which include A Multicenter, Randomized, Double-Blind, 
Placebo-controlled Study of Darbepoetin Alfa for the Treatment of Anemia of Cancer, 
2004-0255, PI Vadhan, Saroj, M.D., 2005, A Double-Blind Placebo Controlled Study of 
Methylnaltrexone (MNTX) for the Relief of Constipation due to Chronic Opioid Therapy in 
Patients with Advanced Cancer, DM03-0026, PI Zhukovsky, Donna S., M.D., 2005, The 
Effect of Methadone on QTc Intervals, 2005-015, PI Reddy, Suresh, M.D., 2005, 

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Validation study the revised Edmonton symptom assessment scale, 2005. In addition I 
am actively involved in publication of articles in peer-reviewed journals and Oncology 
and palliative care textbooks. 
 
Career goals  
My immediate career Objective is to develop the knowledge and skills necessary to 
compete for independent research support 
My specific interest is the role of cytokines and other inflammatory substances in the 
causation of symptoms.  The short-term goal is to establish the use of dexamethasone 
for symptom control in advance cancer patients through randomized controlled studies 
using updated and validated Symptom assessment tools and laboratory correlates. The 
long-term goal is to the goals to develop strategies based on pathophysiology (by using 
laboratory correlates) to effectively treat the symptoms clusters in advanced cancer 
patients and improve their quality of life.   This includes development of cytokine specific 
suppressive therapies that could be used to prevent and treat these troubling symptoms. 
With a strong clinical background and being motivated, focused and perseverant, I am 
confident to make significant difference in reducing the symptoms in cancer patients and 
thereby their quality of life. This award will enable me to receive high quality, 
multidisciplinary didactic training so that I will be well grounded the principles and 
techniques for the research on human subjects. In addition, it would release me from 
more routine aspects of patient care responsibilities so that I can focus on investigator- 
initiated research. 
 With my strong background in patient care and further training in patient-oriented 
research, I will be better positioned to develop therapies, specifically symptom clusters in 
cancer patients. 
 
Career Development Activities during Award Period 
 
To achieve the goal of being an independent clinical investigator, I propose a 
comprehensive didactic training program with focus on biostatistics and clinical trial 
methodology. The major portion of my didactic training program is to obtain Master of 
Sciences (MS) in Clinical Research Program at UT Health Science Center at Houston 
Medical School (MD Anderson is part of UT Health Science Center). This MS degree 
program is designed as a focused and flexible program to train clinical investigators in 
designing and conducting patient-oriented research of exemplary. The courses are 
concentrated on Wednesday afternoons. The degree can be completed in minimum of 2 
years. The MS Clinical Research Curriculum Topics include (Please see attached 
appendix 3 for the Master of Science in Clinical Research Degree Program Catalog 
Addendum): 
 
1. Clinical Epidemiology (14 weeks) 
2. Clinical Trials (13 weeks) 
3. Seminars in Clinical Research (13 weeks) 
4. Use of Computers in Clinical Research (lab course, flexible schedule) 
5. Scientific Writing (8 weeks) 
6. Biostatistics for Clinical Research (15 weeks) 
7. Literature Appraisal (8 weeks) 
8. Ethical Aspects of Clinical Research (5 weeks) 
9. Introduction to Translational Research (7 weeks) 
10. Clinical Research Design Workshop (12 weeks) 
11. Evaluating Costs and Benefits in Clinical Research (Elective) 
12. Using Research to inform Health Care Policy and Practice (Elective) 
13. Molecular and Cellular Approaches to Human Genetics (Elective) 

2005-0816 
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14. Genetics and Human Disease (Elective) 
 
Advanced Course for Master’s Program (required) 
• 
Advanced Epidemiology (Wednesday afternoon) 
This course covers the analysis of complex observational studies with emphasis 
on the identification of interaction and control of confounding variables. Other 
topics include the use of matching, selection of appropriate control groups, and 
identification of potential sources of bias. A problem-based approach is used in 
which students are asked to solve design and analysis problems using existing 
data sets. 
 
• 
Advanced Biostatistics for Clinical Investigators (Wednesday afternoon) 
This course will focus on the mechanics of applying biostatistical techniques in a 
research setting. Emphasis will be placed on assumption testing and techniques 
of model fitting. Students will be expected to critically evaluate, develop, and 
execute analysis plans using descriptive analysis and regression techniques. 
 
 
 
The following table is a sample two-year completion schedule for MS in Clinical 
Research Program  
 
 
Sample Two-Year Completion Schedule  
 Patient-Based Clinical Research Track  
Academic 
Year  
Course 
Type  
Fall  
Spring  
Summer  
   
   
 2006-
2007  
CRCA  
(Wed: 
5:00-6:30)  
Biostatistics for 
Clinical 
Investigators  
   
 
Literature 
appraisal 
Ethical Aspects 
of Clinical 
Research  
Introduction to 
Translational 
Research 
Seminars in 
Clinical 
Research  
Use of 
Computers in 
Clinical 
Research 
(flexible 
schedule)  
Advanced  
(Wed: 
1:00-4:30)  
Evaluating Costs 
and Benefits 
in Clinical 
Research  
Advanced 
Biostatistics  
   
Other  
Practicum  
Practicum  
Practicum  
   
   
2007-
2008  
CRCA  
(Wed: 
5:00-6:30)  
Clinical 
Epidemiology  
Clinical Trials  
Clinical Trials 
(cont)  
Clinical 
Research 
Design 
Workshop  
Scientific Writing  

2005-0816 
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Advanced  
(Wed: 
1:00-4:30)  
Using Research 
to Inform 
Health Care 
Policy and 
Practice  
Advanced 
Epidemiology  
   
Other  
Thesis  
Thesis  
Thesis  
 
 
Besides MS program training, I will participate in a variety of scientific meetings and 
seminars, including: 
 
• 
Grand Rounds at the Division of Medicine (Tuesdays) and M. D. Anderson 
(Fridays): Nationally recognized researchers and investigators from M. D. 
Anderson are invited to give lectures on cancer research and treatment at both 
Grand Rounds. 
 
• 
Multidisciplinary Conferences in Symptom control and Palliative care l Tuesdays, 
and Thursdays: In each conference, a multidisciplinary team, discusses the 
complicated and challenging cases and plan for optimal treatment. 
 
• 
Research Seminars (Thursdays): The Dept. of symptom control and Palliative 
care has a weekly research seminar.  
 
 
 
• 
Phase I and II Meeting (Wednesdays): This weekly meeting is chaired by Dr. 
Razelle Kuszrock(Phase I) and Dr. Hagop Kantargen (Phase II). Investigators 
from the institution discuss progress and opportunities available from NCI-
sponsored phase I and II clinical trials. Every month, investigators give 
presentations about ongoing clinical trials, study design, and progress in relevant 
research fields. 
 

2005-0816 
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Page 18 of 60 
 
B.Specific Aims: 
 
Previous research has shown that patients with advanced cancer develop clusters of 
physical and psychosocial symptoms [1-4].  The brain is the ultimate organ where 
symptoms are perceived [5].   In recent years a number of cytokines and other pro-
inflammatory mediators produced by the host in response to the presence of cancer 
have been associated with a number of these symptoms including pain [5,6], cognitive 
impairment [5-6], depression [7], fatigue [8], cachexia [9], and sleep disorder [10]. 
 
A number of pharmacological interventions have been found to be capable of reducing 
some of the severe symptoms associated with cancer, AIDS, and other chronic 
infections where cytokines have been identified as playing a major role [11,12].  Our 
group [13] and others [14-27] have found that corticosteroids are capable of improving 
symptoms such as fatigue, anorexia, pain, and anorexia/cachexia in patients with 
cancer.  
 
Dexamethasone has been found to exert complex effects on a number of major 
cytokines [28-33] 
 
Our long-term goal is to better understand the role of cytokines in the frequency and 
severity of symptoms. The objective of the study is to find association between the 
effects of dexamethasone on symptoms and its effects in decreasing cytokines and 
inflammatory substances. We hypothesize that dexamethasone decreases the intensity 
of symptoms namely Fatigue, nausea, anorexia and pain that occur frequently in 
advanced cancer and one of the mechanisms it exerts such effects by decreasing a 
cytokines levels (namely IL-1, IL-6, TNF-, IL-10, IL-8) that mediate these symptoms. 
The rationale for the proposed research is despite the prevalence of severe symptom 
clusters in patients with advanced cancer there has been limited research on treatment 
of these symptom clusters. Corticosteroids such as Dexamethasone have been widely 
used in treatment of symptoms fatigue, nausea, anorexia, and pain in advanced cancer 
patients. Despite widespread use of steroid therapy in cancer symptom management, 
the data is inadequate to draw definitive conclusions about the efficacy of these 
compounds in the management of pain and other symptoms. Previous studies by our 
group and other investigators on steroids suggested beneficial effects of steroids on 
these symptoms in advanced cancer. But the studies were done using assessment tools 
that were not validated; various different steroids, routes of administration and dosages 
were used. 
 
We intend to test the effect of dexamethasone on symptoms in advanced cancer 
patients by pursuing the following three specific aims: 
 
 
• 
Primary objective:  To determine the effect of Dexamethasone on the intensity of 
Fatigue 
• 
Secondary objective-1:  To determine the effect of Dexamethasone on the intensity 
of Pain, anorexia and nausea.  
• 
Secondary objective-2:  To determine the changes in cytokines (IL-1, IL-6, TNF-, 
IL-10, IL-8, activated monocytes and corresponding receptor levels) and C-reactive 
protein before and after treatment with dexamethasone. 
• 
Secondary objective-3:  To determine association of cytokines (IL-1, IL-6, TNF-, 
IL-10, IL-8, activated monocytes and corresponding receptor levels) and C-reactive 
protein and Fatigue, Pain, Anorexia and nausea. 

2005-0816 
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Page 19 of 60 
 
• 
Secondary objective – 4:  To collect pilot data on the quality of sleep and cortisol 
levels in ten subjects 
 
 
C. Background: 
 
Approximately 50% of patients diagnosed with cancer die of progressive disease. 
Patients with advanced cancer experience clusters of physical and psychosocial 
symptoms including pain, fatigue, nausea, anorexia/cachexia, depression, and sleep 
disorders [1-4,34]. The prevalence rates of the many different symptoms reported by 
advanced cancer patients vary as follows: pain 41%-76%, depression 33%-40%, anxiety 
57% - 68%, nausea 24%-90%, constipation 65%, sedation/confusion 46%-60%, 
dyspnea 12%-58%, anorexia 85% and Fatigue 90%[34,35]. In cancer patients, symptom 
expression is a multidimensional construct that results from different mechanisms of 
production and brain perception. There is a complex interaction between the tumor and 
the host that depends mostly on the tumor mass, the tumor function, the immune status 
of the host, co-morbidities. 
 
It has been noted that somatic nerves deliver afferent information related to symptoms 
such as pain, and cytokines can influence the stimulation of such afferent nerves at the 
periphery and some of the central synaptic activity at the dorsal horn and in the brain 
cortex [6].  Visceral nerves deliver information regarding symptoms such as dyspnea, 
nausea, and anorexia and these nerves are also under the influence of cytokines both 
centrally and peripherally [6].  Tumor by-products can produce abnormalities that are 
linked with cancer cachexia [36]. The relationship between tumor by-products and host 
response has not been completely established. Finally, circulating cytokines and 
inflammatory proteins have been thought to be directly associated with pain, and cognitive 
impairment [5,6], depression [7], fatigue [37], cachexia [38], and sleep disorder [10]. 
Fig. 1 
 
 
 
          Tumor      
 
Tumor Function 
          Mass 
 
− 
 
 
 
 − 
 
 
 
Immune response 
 
Autonomic nerves 
IL-1, IL-6, and TNF- 
 
 
 
− 
 
 
 
 
Somatic nerves 
 
 
 
Tumor Byproducts 
 
Dexamethasone 
 
 
 
 
 
 
 
 
+ 
               + 
 
                    + 
  + 
 
− 
 
 

2005-0816 
April 5, 2011 
Page 20 of 60 
 
                                                   PAIN  
                                              FATIGUE                                                         Brain 
                                             ANOREXIA 
                                    COGNITIVE FAILURE 
                                              NAUSEA 
                                                FEVER 
  
 
 
 
The Role of Cytokines and Pro-inflammatory Mediators on Symptom Production 
 
As shown in Figure 1, cytokines have been associated with the presence of the tumor, 
co-morbidities such as infections, and the effects of cancer treatments including 
radiation therapy and cytotoxic therapy. 
In recent years, it has become evident that many cytokines have powerful effects on the 
brain.  Animal models of symptoms such as pain and cachexia, and clinical studies of 
immunotherapy in which pro-inflammatory cytokines are administered to patients with 
various cancers have provided important insight into the central effects of these agents 
[6]. 
 
Sickness behavior is typically associated with behavioral changes seen in humans and 
laboratory animals suffering from microbial infections and includes symptoms of 
cognitive dysfunction, anxiety, psychomotor slowing, fatigue, anorexia, sleep alterations 
and increased sensitivity to pain [39]. Relevant to their mediation by cytokines, 
symptoms of sickness behavior can be reliably reproduced in both laboratory animals 
and humans by administration of each of the cytokines that induce the pro-inflammatory 
cytokine cascade (TNF-α to IL-1 to IL-6) [40].  
     
One of the mechanisms cytokines mediate symptoms is through an array of signals 
through the hypothalamic-pituitary-adrenal axis or circardian axis. Laboratory studies 
show that administration of IL-6 increases serum glucocorticoid levels through 
hypothalamic pathways [41]. TGF- mediates hypothalamic signaling for circardian 
regulation of motor activity, sleep, and body temperature[42]. Data taken together in the 
form of cortisol circadian rhythms, symptoms and poor prognosis suggest close 
relationships[43]. In patients with chronic stress from cancer, altered patterns of cortisol 
rhythmicity are associated with poor prognosis [41]. 
 
Cytokines and fatigue 
Fatigue is the most common symptom associated with cancer and cancer treatment. 
Researchers have proposed that one possible explanation for the development of 
fatigue in cancer patients is the increased secretion of pro inflammatory cytokines in 
response to both the disease itself and the treatment [8,44]. Fatigue symptoms are 
multifactorial. It has been reported that pro inflammatory cytokines can act at the level of 
mood, muscle mass and strength, and metabolic status to induce fatigue [5,8]. Studies in 
rats and mice showed that increased signs of fatigue when infection and other conditions 
associated with an increase in pro inflammatory cytokines were present [45,46]. Drugs 
such as IFN- α, IL-2 and TNF- α have been associated with symptoms such as fatigue, 
mood changes, sleep disturbance, and cognitive changes [47]. Cytokine associated 
symptoms including anorexia/cachexia, chronic nausea, fever, depression, pain, and 
sleep disorders can also contribute to fatigue [48-49]. Previous studies showed that 
cytokines have been implicated in the pathophysiology of fatigue on the basis of several 
lines of evidence, including: 1) their increased levels in non-oncologic conditions 

2005-0816 
April 5, 2011 
Page 21 of 60 
 
characterized by fatigue, such as chronic fatigue syndrome [50-53]; 2) the occurrence of 
fatigue as a major side effect of cytokines (interleukins, TNF, and interferon) used in the 
treatment of cancer patients [54-58]; and 3) the up regulation of pro-inflammatory 
cytokines and their correlation with fatigue in several malignancies [44,59,60) 
Chemotherapy treatment of cancer results in elevation of cytokines [61]  
 
Cytokines and pain 
A variety of recent research has uncovered a role for immune-to-brain communication 
and brain cytokines in aspects of sensory processing. Animal models of hyperalgesia 
suggested that cytokines might contribute to cancer-related pain [62]. Cytokines such as 
IL-1 and TNF-α have been associated with aggravation of pain in experimental models 
[63]. Research has demonstrated that simply attracting immune cells that release pro-
inflammatory cytokines in the regions of the nerve produces long-lasting pain 
enhancement [64], and that blocking IL-1 receptors can reverse ongoing chronic 
exaggerated pain [65]. In cancer treatments, increased release of cytokines (IL-1, IL-6, 
IFN-α, TNF-α) was observed in patients receiving cisplatin [66], taxol [67], vincristine [68] 
and irradiation [69,70], and who showed clinical manifestation of neuropathic pain-like 
syndromes.  
 
Cytokines and anorexia, cachexia and chronic nausea 
Cancer anorexia/cachexia syndrome is often observed in patients with advanced stages 
of cancer. Patients with this wasting syndrome experience diverse symptoms such as 
progressive bodyweight loss, chronic nausea, fatigue, sleep disorders and a decreased 
sense of well being [71]. In recent years, cancer cachexia has been recognized as a 
result of major metabolic disarray because of complex mechanisms involving tumor by-
products and host cytokine release, in particular TNF- α, rather than a simple increase in 
energy consumption by the tumor and starvation by the patient. Cytokines, such as TNF-
α, IL-1, IL-6 and IL-8 have been shown to induce anorexia/cachexia by lipolysis and 
other metabolic effects, and by direct action in the central nervous system (CNS) [72-
74]. Researchers measured various specific components of the cytokine-induced 
anorectic reaction, and found that IL-1β, TNF-α, and IFN-γ messenger RNA were 
detected in the tumor tissue of anorectic tumor-bearing rats [75]. This suggests that IL-
1β and its receptor may play a significant role in this model of cancer-associated 
anorexia. IL-6 has been revealed as a key mediator of food intake in an experimental 
sepsis model in mice [Leon et al., 1998]. It is likely that close interrelation among these 
mediators (IL-1, IL-6, TNF-α and IFN) exists in the hypothalamus, decreasing food intake 
and leading to cachexia [76]. 
 
Cytokines and cognitive impairment 
The pro-inflammatory cytokines have been considered as immune-to-brain signaling 
molecules [63]. Interleukin 1 α and β  (IL-1 α and β), tumor necrosis factor- α (TNF- α), 
and IL-6 are key elements signal the brain. A number of observations suggest that 
immune-to-brain communication and the consequent induction of cytokines might 
produce cognitive disturbances that include interference with the formation of memories 
[77,78].  Further evidence from women with breast cancer indicates that the hormone-
ablative agent tamoxifen affects several neurotransmitters and cytokines (e.g. IL-1, IL-6, 
IFN- α, TNF-α) implicated in cognitive functioning [78]. 
 
 
Cytokines and sleep disorders 
Studies have shown that by crossing the blood-brain barrier and through peripheral 
autonomic efferent nerves, the peripheral cytokines can communicate and signal the 
brain to elicit central nervous system manifestation, e.g. sleepiness [79]. In Vgontzas’ 

2005-0816 
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Page 22 of 60 
 
study, it was evident that the reduction of sleepiness was found to be associated with 
decreased IL-6 levels in patients with excessive daytime sleepiness [80]. Other 
researches have found that the deterioration in the quality and quantity of nighttime 
sleep is associated with alterations of IL-6 and TNFα [10,80].  
 
Cytokines and fever 
The mechanism of neoplastic fever is thought to involve inflammatory cytokines such as 
TNF- α, IL-1, IL-6 that are produced either by host macrophages in response to the 
tumor or by the tumor itself [Leon et al., 1998]. Cytokines such as IL-1, TNF-α, and IFN, 
which are released by neoplastic cells (i.e. renal carcinoma, lymphomas, and acute 
myelogenous and chronic myelogenous leukemia) are pyrogenic [81]. 
 
It is remarkable that a relatively small number of cytokines are repeatedly associated 
with a large number of symptoms in patients with advanced cancer. In particular, IL-1, 
IL-6, TNF-α, and IFN are most commonly associated with the symptom clusters that are 
most frequently observed in advanced cancer. 
 
Cytokines and depression 
Clinical and experimental studies on animals indicate that depression is associated with 
increased plasma cytokine (IL-1, IL-6 and TNF-α) acute phase protein concentrations 
and hypothalamic-pituitary-adrenal axia (HPA) activation [7]. Previous studies have 
suggested that hyper secretion of cytokines in response to stress or to endogenous 
trigger factors may induce depressive symptoms [77]. The role of cytokines in 
depression was first considered when IFN resulted in “sickness behavior,” the symptoms 
of which are similar to those of major depression [7]. 
Table I shows the main cytokines identified as associated with a number of specific 
symptoms. 
 
It is remarkable that a relatively small number of cytokines are repeatedly associated 
with a large number of symptoms in patients with advanced cancer. In particular, TNF, 
IL-1, IL-6, and interferon are most commonly associated with the symptom clusters that 
are most frequently observed in advanced cancer. 
 
 
 
 
 
 
 
Symptoms 
 
 
Associated Cytokines 
 
 
 
 
Fatigue 
 
 
IL-1, IL-6, IFN-α, TNF-α 
 
 
 
Anorexia/cachexia 
 
IL-1, IL-6, IFN-α, TNF-α 
 
 
 
Fever  
 
 
IL-1, IL-2, IL-6, IL-12, IFN-α, TNF-α 
 
 
 
Depression 
 
 
IL-1, IL-6, IFN-α, TNF-α 
 
 
 
Sleep disorder 
 
IL-6, TNF-α 
 
 
 
Cognitive impairment  
IL-1, IFN- α 
 
 
 
Pain 
 
 
 
IL-1, IL-6, TNF-α 
 
 
 
 
 
 
Role of Corticosteroids on Symptoms  
 
Dexamethasone is a synthetic glucocorticoid. It exhibits potent anti-inflammatory, 
immunosuppressant activity with minimal mineralocorticoid properties. 
Preliminary Studies by our group and other investigators have found that Corticosteroids in 
cancer population can improve transiently pain, appetite, nausea, fatigue and overall 
quality of life. There are a number of different mechanisms have been proposed for these 
effects. These include reduction of the tumor mass [82-85]. Corticosteroids modulate 

2005-0816 
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Page 23 of 60 
 
adrenergic activity in the dorsal horn [86]. Corticosteroid also can effect tumor function and 
decrease peritumoral edema (87].Corticosteroids also have analgesic properties [13-23], 
Central antiemetic and euphoric effects [(13,24-27]. Dexamethasone also suppresses 
abnormal discharges produced by injured somatic and autonomic nerves [88]. 
Dexamethasone decreases several inflammatory cytokines including IL-1, IL-6, IL-8 TNF-
α, IFN, TGF-. [28-33].  
 
Fatigue 
 
Fatigue is the most common symptom in patients with cancer or its treatment [89]. It is 
also a most undertreated symptom in patients with cancer [90]. Cancer-related fatigue 
results in substantial adverse physical, psychosocial, and economic consequences for 
both patients and caregivers [90].  This is a multidimensional syndrome resulting from a 
combination of factors including tumor by-products, host cytokines, cachexia, depression, 
anxiety, sleep disorders, and the effects of drugs or radiation therapy  [91,92]. 
Corticosteroids decrease fatigue. The proposed mechanisms include (1) Decrease of the 
cytokines IL-1, IL-6, TNF-alpha and IFN- gamma that are involved in the causation of 
fatigue. [13-16,37,71,93-95], (2) Corticosteroids have an effect on on HPA axis function, 
as disturbances in HPA axis function have been observed in other chronic inflammatory 
and fatigue-related disorders [32,96]. 
Nausea and Anorexia: 
Corticosteroids decrease nausea in advanced cancer patients [13]. The mechanisms by 
which steroids exert their antiemetic activity are not fully understood. When used in 
combination with other anti-emetics, they exert a booster effect in raising the emetic 
threshold. They decrease the peritumoral edema, thus the intracranial pressure, a 
known cause of vomiting. It is not evident that there is any difference between the 
different steroids, but dexamethasone appears to be the most intensively investigated. 
For prevention of acute emesis an 8 mg single dose of dexamethasone for moderately 
emetogenic chemotherapy and 20 mg for highly emetogenic chemotherapy should be 
the doses of choice. [24-27, 97-99].  
Improvement in nausea, appetite and food intake potentially benefit in the management 
of cachexia. Several double –blind randomized controlled trials have demonstrated the 
symptomatic effect of different types and dosages of corticosteroids for cancer cachexia. 
[13,16-18,22, 100,101]. 
Pain 
 Corticosteroids such as Dexamethasone are beneficial in the management of many 
different types of pain in the palliative care settings. Based on extensive clinical 
experience, the accepted pain-related indications are refractory neuropathic pain, bone 
pain, pain associated with capsular expansion or duct obstruction, pain from bowel 
obstruction, pain caused by lymphedema, and headache due to increased intracranial 
pressure. Corticosteroids are also effective in managing pain and symptoms from 
metastatic spinal cord compression [Greenberg HS, et al, 1980; The analgesic effects of 
corticosteroids presumely result from a variety of mechanisms (1) Mass effect from 
expanding neoplasm could be lessened by the reduction of peritumoral edema (102),  
(2) antiinflammation. (13-23) and (3) immunosuppressant action. The effects of 
dexamethasone upon hyperalgesic activities of carrageenin, bradykinin, TNF-α. IL-1β, 
IL-6, IL-8, PGE2, and dopamine were investigated in a model of mechanical hyperalgesia 

2005-0816 
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Page 24 of 60 
 
in rats. The hyperalgesic responses to Pl. injections of carrageenin, bradykinin, TNF-α, 
IL-β and IL-6, but not IL-8, PGE2 and Dopamine were inhibited by pretreatment with 
dexamethasone (103). 
 
Role of Corticosteroids on Cytokines 
 
Patients with advanced cancer experience clusters of physical and psychosocial 
symptoms including pain, fatigue, nausea, anorexia/cachexia, depression, and sleep 
disorders. Cytokines and other pro-inflammatory mediators are elevated in patients with 
advanced cancer as a consequence of the presence of the tumor, the host response and 
co-morbidities such as infections or treatment interventions including drugs, radiation 
therapy and chemotherapy [6].  Several cytokines and pro-inflammatory mediators have 
been implicated in causing or amplifying some of these symptoms.   Dexamethasone 
relieves symptoms associated with advanced cancer. These symptoms include pain, 
fatigue, anorexia/cachexia, and nausea.  Dexamethasone decreases several cytokines 
including IL-1, IL-4, IL-6, IL-8 TNF-α, IFN, and TGF-. [28,33,101,104,105]. The effects 
of dexamethasone upon hyperalgesic activities of carrageenin, bradykinin, TNF-α. IL-1β, 
IL-6, IL-8, PGE2, and dopamine were investigated in a model of mechanical hyperalgesia 
in rats. The hyperalgesic responses to Pl. injections of carrageenin, bradykinin, TNF-α, 
IL-β and IL-6, but not IL-8, PGE2 and Dopamine were inhibited by pretreatment with 
dexamethasone (103). 
 
Author 
Patients 
Patient Treatment 
Duration 
(Study Design) 
Daily Dosing scheme 
(equivalent study 
design) daily dose of 
Dexamethasone(DM) 
Bruera et al 1995 
40 
14 days 
MP* 32 mg (6mg) 
(Randomized double 
blind crossover) 
Della Cuna 1989 
40 
8 weeks 
MP* 125mg (23.44mg) 
(Randomized double 
blind placebo – 
controlled parallel) 
Popiela et al 
173 
8 weeks 
MP* 125mg (23.44mg) 
(Randomized double 
blind placebo – 
controlled parallel) 
Cassileth et al 1983 
22 
56 trials 
10mg (Randomized 
Controlled Trial 
Parallel) 
Italian group for 
antiemetic research 2000 
708 
5 days 
8mg (Randomized 
double blind placebo – 
Controlled, parallel) 
Akira Inoue 2003 
68 
6 days 
8mg (Randomized 
double blind placebo – 
Controlled, parallel) 

2005-0816 
April 5, 2011 
Page 25 of 60 
 
Koo and Ang 1996 
98 
 
8mg (Randomized 
double blind placebo – 
Controlled, parallel) 
JR Hardy 2001 
160 
21.5 days 
12mg (survey) 
Mercadante 
376 
26 days 
4-16mg (survey) 
Bruera 2004 
51 
7 days 
20mg (Randomized 
double blind placebo – 
Controlled, parallel) 
Vecht 1994 
96 
28 days 
4-16mg (Randomized 
double blind placebo – 
controlled parallel) 
*MP= Methylprednisolone 
 
Significance: 
At present there are limited treatment options to treat these symptoms clusters. In clinical 
practice there is widespread acceptance of use of steroid therapy in treatment of 
advanced cancer patients with symptoms specifically pain, nausea, fatigue and anorexia.  
Preliminary research by our group and other investigators has found that Dexamethasone 
in cancer population can decrease transiently pain, appetite, nausea, fatigue and overall 
quality of life [Bruera and Roca et al 1985; Tannock I, etal 1996; Kim JH, Fainsinger et al., 
1994; A.B. Ettinger et al 1988; T. Popiela, et al, 1989; Della Cuna, et al, 1989; Twycross, 
1992; Mercadante, et al 2001; Vecht ChJ, et al 1989; Moertel C, et al., 1974; Stiefel FC, 
Breitbart WS, et al, 1989].   
Despite it, the data is inadequate to draw definitive conclusions about the efficacy of the 
steroids in the management of pain and other symptoms in advanced cancer. The data 
collection and methodology was inadequate. Assessment tools were not validated, 
especially the term ‘Activity’ may not the accurate measure for fatigue. There was no 
attempt to understand the pathophysiology using laboratory correlates. The role steroids 
on cancer related fatigue, pain, appetite and nausea (which are the most common 
symptoms in advanced cancer), their effects on cytokines need to be defined through 
randomized controlled studies using updated and validated and laboratory correlates 
(which were lacking in the previous studies on corticosteroids for symptoms). Our 
findings will also allow investigators  
• 
To effectively treat the symptoms clusters in advanced cancer patients and 
improve their quality of life. 
• 
Establish cause and effect relationship between symptoms and cytokines. 
• 
Development of cytokine specific suppressive therapies that could be used to 
prevent and treat Fatigue, nausea, anorexia and pain. 
 
 
D. Preliminary studies 
Studies on Symptom Management 
Our group has conducted multiple studies on the treatment of difference symptoms in 
patients with advanced cancer. Specifically, we have conducted clinical trials of pain 
management using opioids [106], and adjuvant drugs [107]; fatigue using corticosteroid 
[13], methylphenidate [108], and donepezil [Bruer109]; cognitive failure using 
methylphenidate [108]; and anorexia/cachexia using megestrol acetate [110], fish oil 
[111], and thalidomide [112]. In the course of conducting these studies, we learned that 
patients presented with symptom clusters rather than using the main symptom target for 
our intervention. 

2005-0816 
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A. Experiences in the Assessment of Symptoms in Advanced Cancer Patients  
Our group has conducted multiple studies of symptom assessment in patients with 
advanced cancer.  We developed the Edmonton Symptom Assessment System [113], a 
tool that has undergone independent validation [114] and is currently being widely used 
in acute care hospitals, hospices, and palliative care units.  We have also developed the 
Edmonton Staging System for Cancer Pain [115], the Edmonton Functional Assessment 
Test [116]. 
 
Using these and other tools we conducted a number of studies on the frequency and 
severity of symptoms. In an outpatient setting, we evaluated 138 consecutive patients 
with advanced cancer referred to multidisciplinary palliative care clinic at M.D. Anderson 
Cancer Center, a cluster of symptoms was observed and the median symptoms intensity 
(0= no symptom, 10=worst symptom) was ranked as fatigue 7 (4.5-8), pain 6 (4-8), 
anorexia 6 (4-8), sleep problems 6 (4-8), drowsiness 5 (1.5-8) and anxiety 5(1-8)[117].  
We retrospectively reviewed 320 patients referred to our palliative care inpatient unit, we 
observed that the main referral symptoms by the primary physicians were pain (44%), 
nausea (41%), fatigue (39%) and dyspnea (38%), the mean intensity ranked as fatigue 
6.7 ± 2.7, pain 5.7 ± 3.5, anorexia 5.4 ± 3.4, sleep problems 5.0 ± 3.3[118].  In a tertiary 
acute care hospital, we retrospectively reviewed 100 consecutive cancer patients who 
had been referred to a palliative care consult team, we found that the most intense 
symptoms were fatigue, appetite and well-being [119].  We also found higher frequency 
and severity of symptoms in patients admitted to the community-based hospices [120]. 
 
Table IV summarizes the frequency of the main symptom clusters observed in different 
settings and also the frequency of patients who developed severe (≥ 3/10 intensity of 
these symptoms) [120]. 
 
Frequency of Severe Symptoms (ESAS  ≥ 3/10) in the Different Settings 
Symptom 
TPCU(%) 
Acute Care 
(%) 
Hospices (%) 
p-value 
Pain 
117/157 (75) 
295/642 (46) 
244/425 (57) 
<0.0001 
Fatigue 
139/155 (90) 
559/625 (70) 
367/449 (82) 
0.0006 
Nausea 
56/153 (37) 
127/638 (20) 
92/382 (24) 
0.0001 
Depression 
88/149 (59) 
247/568 (43) 
183/408 (45) 
0.0026 
Anxiety 
103/153 (67) 
285/578 (49) 
213/420 (51) 
0.0003 
Drowsiness 
112/155 (72) 
397/623 (64) 
321/434 (74) 
0.0011 
Well-being 
119/148 (80) 
382/536 (71) 
274/422 (65) 
0.0013 
Appetite 
117/153 (76) 
503/617 (82) 
327/444 (74) 
0.0083 
Shortness of 
breath 
77/154 (50) 
203/633 (32) 
156/409 (38) 
0.0007 
Overall 
928/1377 (67) 
1998/5460 
(55) 
2177/3793 
(57) 
<0.0001 
P -values determined using chi-square test. Significance was accepted at the p<0.0055 
level to take into account the Bonferroni correction for multiple comparisons. 
 
    Our findings show that symptom clusters as extremely frequent and that we have the 
methodology to appropriately determine the frequency, severity and relationship of those 
symptoms and the change over time and as a result of different treatment interventions. 
   By using the results of this study the Investigator would have a better understanding of 
the biological mechanisms of the symptom clusters. Hence treat the symptom clusters in 

2005-0816 
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advanced cancer patients and thereby improve their quality of life. The understanding of 
the mechanisms would enable the Investigator in the future to develop cytokine specific 
suppressive therapies that could be used to prevent and treat these troubling symptoms. 
 
 
 
Studies on cytokines  
In our clinical studies with a number of cytokines in cancer patients, symptoms such as 
fatigue and constitutional symptoms such as pain, malaise, depression, and sleep 
disorders are commonly observed. Because many of the hematopoietic cytokines 
activate immune cells including monocytes, we examined the numbers and functions of 
monocytes and measurements of cytokines [121-124]. Our findings have shown that 
with cytokines that activate monocytes such as GM-CSF or PIXY-321 (fusion molecule 
of GM-CSF and IL-3), there is a significant increase in the levels of stimulated release of 
TNF-α and IL-1β, which can explain constitutional symptoms such as fever, myalgia, 
bone pain, and fatigue experienced by these patients [121,122]. Interestingly, in vivo 
administration of IL-1 which causes severe symptom distress including high fever, 
myalgia, pain, and cognitive impairment, results in induction of more cytokine in vivo as 
evidenced by an increase in the intra-cellular transcripts of IL-1 mRNA and an increase 
in the levels of cytokine in the supernatant of cells as measured by an ELISA assay (Fig 
2a and b) [124]. 
 
 
 
 
 
Figure 2a 
 
 
 
 
Figure 2b 
Before Treatment
After Treatment
IL-1Administration in Cancer Patients 
Induction of IL-lmRNA in Monocytes
 
Cytokine levels by Luminex method: 
Recently, simultaneous measurement of multiple cytokines with a small sample size 
is made possible with the use of Luminex method. We have examined the levels of 
multiple cytokines in plasma of chemo-naïve patients with sarcoma. As shown figure 3 
below, the preliminary results of these assays in a cohort of 8 patients showed that prior 
to treatment with chemotherapy, a number of endogenous cytokines are measurable in 

2005-0816 
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the plasma of these cancer patients. After one cycle of chemotherapy, there is a marked 
decrease in the levels of Th-1 type of cytokines such as IL-2, IFN-gamma, and TNF-
alpha. In contrast, the levels of IL-6, IL-8 and IL-10 were increased. We also examined 
the levels of IL-6 by ELISA to see if there was a correlation in the levels. As shown in the 
fig. 3 below, IL-6 levels were increased post treatment by both Luminex and ELISA 
methods. We plan to further examine the correlation between symptom distress 
experienced by these patients and the circulating levels of cytokines as patients undergo 
cytotoxic treatment. In the present proposal, we wish to examine the cytokine profile 
before the initiation of treatment with Dexamethasone and during treatment and at the 
end of the study with Dexamethasone vs. placebo, and sought correlation between the 
cytokine levels, symptom clusters, and response to Dexamethasone treatment.  
 
 
 
E. Research design and Methods. 
 
 
We will conduct a prospective, randomized, double blind, placebo controlled study 
comparing Dexamethasone 4mg orally two times per day for 14 days versus placebo. 
Eligible patients who agree to participate in the study and provide written informed consent 
will be randomized to either group A, in which patients will receive Dexamethasone orally, 
4mg two times a day for 14 days; or group B, in which patients will receive placebo orally, 
two times a day for 14 days. On day 15, all patients will be receive 4mg of dexamethasone 
twice a day on a open label basis till Day 21,From Day 22 to Day28 the dose of 
dexamethasone is to be tapered to 2mg orally twice a day. Subsequently patients would 
be off study with dose tapered to the minimum tolerated dose. 
The reason to have open label design after Day15 is to observe the descriptive trends. 
Exam (including history including FACIT-F, FAACT, HADS, ESAS, BPI, GSE (on days 8, 
22, and 29),physical exam and toxicity assessment will be done day 0(baseline),  Day 8 [ ± 
3 days], Day 15 [ ± 3 days], Day 22 [ 3 days] Day 29 [ ± 3 days].  ESAS and Toxicity will 
be done on day 4.  A physician will do a physical exam on the patient on day 0, 15, and 
Day 29; and the nurse will do a nursing assessment on days 8, and day 22.    If patient is 
unable to return to clinic on Day 8, 15, 22, or 29 the assessments will be done by the 
research nurse by phone.   Laboratory correlates including cytokine levels- IL-1, IL-6, TNF-
, IL-10, IL-8, activated monocytes and corresponding receptor levels, C-reactive protein, 
complete blood counts, chemistry (electrolytes) within 7 days of baseline, Day 8 [ ± 3 
days], Day 15 [ ± 3 days], Day 22 [ ± 3 days], and Day 29 [ ± 3 days].  If patients are 
unable to return to clinic on Day 8, 15, 22, or 29 the laboratory correlates will not be done.  
Patients will also be assessed by the research nurses for any signs and symptoms 
of infection while on the study drug.   All study patients will be asked to return to 
the clinic for follow-up assessments 2 weeks after the study medication is 
discontinued ( day 43  3 days) for a safety and toxicity assessment.  If the patient 
is unable to return to the clinic on day 43, the safety and toxicity assessment will 
be done by the research nurse by telephone. 
  The electrolytes measured will include chloride (Cl), carbon dioxide (CO2), Potassium 
(K) and Sodium (Na). 

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Treatment plan is illustrated in Figure 2.  
 
 
 
 
                            Eligible patients 
 
 
                                         Provide Written Consent 
 
 
                                          Randomization 
 
 
 
 
 
 
 
 
Group A 
 
 
Group B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                               
 
 
 
 
 
 
 
 
 
 
 
 
 Figure 2. 
 
 
 Dex 4mg 
orally BID 
for 14 days 
Matching 
Placebo 
orally BID 
Start open label 
4mg orally BID till 
Day 21 
Initiate a dose of 
2mg orally BID 
from Day 22 to 
Day 28 
Taper to minimum 
tolerable dose 

2005-0816 
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Page 30 of 60 
 
 
X = assessment, Y=phone evaluation, PE= MD assessment, A= RN assessment 
 
Table. 1 Clinical and Laboratory Evaluation During Study 
 
Recruitment 
H. Screening Measures 
Symptom clusters and intensity: Patient must have 3 or more symptoms (fatigue, Pain, 
nausea, anorexia/cachexia, sleep problems, depression) based on Edmonton Symptom 
Assessment System, and the average intensity of each symptom during last 24 hours 
must be >/= 4 on a 0 to 10 scale (0 is no symptom, 10 is worst possible symptom). 
Target symptoms chosen for this study were based on previous research by our group 
and others, suggesting that Dexamethasone has potential effects on these symptoms. 
According to NCCN guideline, symptoms such as pain and fatigue are measured on a 0 
to 10 numerical scale (0 is no symptom, 10 is worst symptom imaginable) can also be 
measured on categorical scale, none (0), Mild (1-3), Moderate (4-6) and Severe (7-10). 
We will include patients with symptom intensity >/=  4 (moderate or severe).   
 
Clinical setting  
Patients will be recruited from the Palliative Care and Rehabilitation Medicine, Pain 
center, and Thoracic center at M.D. Anderson Cancer Center. Patients will also be 
Assessments 
Baseline 
Day 
4+ 
Day 8 
[± 3 
days] 
Day 
15 [ ± 
3 
days] 
Day 
22 
[ ± 3 
days] 
Day 29  
[ ± 3 days] 
Day 43 [± 3 
days] 
MDAS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BPI 
X 
 
X 
X 
X 
X 
 
FACIT-F 
X 
 
X 
X 
X 
X 
 
FAACT 
X 
 
X 
X 
X 
X 
 
HADS 
X 
 
X 
X 
X 
X 
 
r-ESAS 
X 
Y 
X 
X 
X 
X 
PE or Y 
GSE 
 
 
X  
 
X 
X 
 
Toxicity 
X 
Y 
X 
X 
X 
X 
PE or Y 
Demographics 
X 
 
 
 
 
 
 
Cytokine, 
Activated 
monocytes 
and 
corresponding 
receptor 
levels 
Within 7 
days 
 
X 
X 
X 
X 
 
C-reactive 
protein 
Within 7 
days 
 
X 
X 
X 
X 
 
Electrolytes 
(Cl, CO2, K, & 
Na), CBC 
Within 7 
days 
 
X 
X 
X 
X 
 
MD physical 
exam 
PE 
 
 
PE 
 
PE 
 
RN 
assessment 
 
 
A 
 
A 
 
 

2005-0816 
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recruited from LBJ hospital and at Four Seasons Hospice in Flat Rock, North Carolina. 
The physicians will identify potential eligible patients to participate in this study.  
 
The Pain, and Symptom Care Palliative Care Clinics from which patients will be recruited 
at U.T. M.D. Anderson Cancer Center, operates out of the Pain and Palliative Care 
Center.  There are 13 examination rooms staffed by 14 physicians and 5 clinical nurses, 
and 1 advanced practice nurse. Patients will be recruited from the Palliative Care 
Outpatient Clinic, which serves, on average, 227 patients a month, and the Pain Clinic, 
which serves about 464 patients a month.  Patients will also be recruited from the 
Thoracic Clinic, which serves about a 1,000 patients a month.   Services available 
through this clinic include thoracic and cardiovascular surgery, thoracic oncology, and 
radiation oncology.  There are a total of 14 examination rooms staffed by 19 physicians 
and 11 clinical nurses, 7 advanced practice nurses.   
 
Research staff 
The research staff in the Department of Palliative Care and Rehabilitation Medicine at 
UT M.D. Anderson Cancer Center includes a research nurse manager, a biostatistician, 
two senior research nurses, one research nurse and one clinical data coordinator. Our 
group has conducted multiple clinical trials related to symptom management, quality of 
life and communications between patients and physicians. 
 
Eligibility Requirements 
Inclusion Criteria.  Patients will be eligible to participate in this study if they meet the 
following criteria: 
1. Present with 3 or more symptoms during the last 24 hours (pain, fatigue, chronic 
nausea and anorexia/cachexia, sleep problems, depression or poor appetite) 
with average intensity of >/= 4 on a 0 to 10 scale, in which 0=no symptom, and 
10=worst possible symptom.  
2. No clinical evidence of cognitive failure as evidenced by MDAS score of 13 or 
less at baseline. 
3. Must be 18 years or older. 
4. No longer a candidate for aggressive anticancer therapy such as receptor 
blockers (Iressa, etc.).   Patients on oral or palliative chemotherapy are eligible 
for study if approved by primary oncologist prior to inclusion.  Patients who are 
receiving IV chemotherapy are eligible for study if approved by primary 
oncologist and they have completed 1st cycle of chemotherapy and are deemed 
stable by primary oncologist. PI will obtain approval from patient’s primary 
oncologist. 
5. Life expectancy ≥ 30 days. 
6. Must understand and sign written informed consent. 
7. Patients on topical, or inhaled corticosteroids are eligible for study.  If patients 
have been on oral corticosteroids for </= 7 days prior to inclusion of study they 
are eligible for study. 
8. Patients currently taking Megestrol must be off drug for > 7 days prior to study 
inclusion 
 
 
 
 
Exclusion Criteria.  
1. Allergy to Dexamethasone, 
2. Inability to complete the baseline assessment forms 
3. Patients currently taking Megestrol, and not off drug   for > 7 days 

2005-0816 
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4. Anemia as defined as a hemoglobin of < 9 
5.  Known history of HIV 
6. Neutropenia as defined by an absolute neutrophil count (ANC) of < 1500 
cells/mm 
7. Patients with a history of diabetes will be excluded. 
8. All major surgeries such as thoracotomy etc., that requires wound healing within 
last 2 weeks. 
9. Those who are currently receiving oral corticosteroid therapy or who have been 
on corticosteroid therapy >/= 8 days prior to study inclusion 
10. Sepsis and/or acute, chronic, or ongoing infections 
 
 
 
Randomization 
Patients will be randomized to one of two treatment arms.  One arm would have 50 
eligible patients and would receive Dexamethasone and another would also have 50 
eligible patients will receive matching placebo.  The randomization schema will be based 
on parameters input into RANLST, a randomization program developed at MDACC and 
supported by an NCI grant.  A randomization list containing order information for both 
arms will be made.  Patient names in sequence will be recorded on each list as the 
patients are entered and both lists will match patient name and identification number.  
Only the primary statistician and Investigational Pharmacy will know the complete list of 
the order of randomization into the two arms until the end of the study.  However, the 
code for an individual patient as to drug treatment group may be disclosed early and the 
patient removed from the study in the case of a request by the primary treating physician 
due to adverse events. Otherwise, no other persons will know about the assignment of 
patients to treatment arms until the end of the study.   
 
 
Outcome measures  
 
Specific aim #1: To determine the effect of Dexamethasone on the intensity of Fatigue 
We hypothesize that dexamethasone decreases the intensity of symptoms namely 
Fatigue, nausea, anorexia and pain that occur frequently in advanced cancer as 
compared with those receiving placebo 
 
1. Measures of Fatigue  
The patient will rate symptom scores at baseline, day 8 [ ± 3 days], day 15 [ ± 3 days], day 
22 [ ± 3 days], and day 29 [ ± 3 days], by using the Functional Assessment of Chronic 
Illness Therapy-Fatigue (FACIT-F) (Appendix x): The FACIT-F fatigue subscale has been 
used primarily in cancer patients to measure fatigue. The subscale consists of 13 items. 
Patients rate the intensity of fatigue and its related symptoms on a scale of 0-4, from 0 “not at 
all” to 4 “very much”. Test-retest reliability coefficients for the fatigue subscale have ranged 
from 0.84-0.90. This scale has demonstrated strong internal consistency (alpha=0.93-0.95) 
[125].  
The patient will rate symptom scores at baseline, day 8 [ ± 3 days], day 15 [ ± 3 days], day 
22 [ ± 3 days], and day 29 [ ± 3 days],  by using the Edmonton Symptom Assessment 
System (ESAS) (Appendix x): This tool is designed by our group [Bruera et al., 1991] to 
assist in the assessment of nine symptoms common in cancer patients: pain, fatigue, nausea, 
depression, anxiety, drowsiness, shortness of breath, appetite, feelings of well-being and a 
line labeled “Other Problem”.  The severity at the time of assessment of each symptom is 
rated from 0 to 10 on a numerical scale, 0 meaning that symptom is absent and 10 that it is of 
the worst possible severity. The instruments and techniques are both valid and reliable in the 

2005-0816 
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assessment of the intensity of symptoms in cancer populations [114]. The instrument is 
designed for both patient and caregiver (if the patient is cognitively impaired or for other 
reasons cannot independently do the ESAS) to complete [113]. 
 
Specific aim #2: To determine the effect of Dexamethasone on the intensity of Pain, 
anorexia and nausea 
 
Measures of pain : Brief Pain Inventory (BPI) Pain severity and pain interference 
will measured with the BPI. The patient will rate symptom scores at baseline, day 8 [ 
± 3 days], day 15 [ ± 3 days], day 22 [ ± 3 days], and day 29 [ ± 3 days].   The BPI 
asks patients to rate their pain for the last week on 0-10 scales at its “worst,” “least,” 
“average,” and “now.” The scales are presented in a 10 cm line, with each number 
equidistant from the next. Each scale is bounded by the words “no pain” at 0 end and 
“pain as bad as you can imagine” at the other. Using the same type of scales, 
patients are also asked to rate how their pain interferes with several quality of life 
domains including activity, walking, mood, sleep, work, and relations with others. 
These scales are bounded by “does not interfere” at the 0 end and “interferes 
completely” at the other. Patients are also asked to estimate the pain relief they are 
receiving from their pain treatment (in percent), to locate areas of pain on a human 
figure, and to estimate the cause of their pain (cancer disease, cancer treatment, or 
non-cancer). Issues of the validity and reliability of the BPI have been examined in 
detail [126,127]. 
 
Measure of anorexia: Symptom Measure (Cachexia/ Anorexia): Functional 
Assessment of Anorexia/Cachexia Therapy (FAACT). The patient will rate symptom 
scores at baseline, day 8 [ ± 3 days], day 15 [ ± 3 days], day 22 [ ± 3 days], and day 
29 [ ± 3 days]. This 12 item Symptom-specific subscales in addition to FACIT-G is to 
measure patients additional concerns about their anorexia /cachexia. The FAACT 
has internal consistency and a reliability coefficient (Cronbach’s alpha) of 0.88 for its 
12 components [125]. Patients rate the intensity of anorexia/cachexia and its related 
symptoms on 0 to 4 numerical scales from 0 “not at all” to 4 “very much”.   
 
Measure of anorexia: the ESAS tool that was used for the measurement of fatigue 
also measures nausea. 
 
Specific aim # 3: To determine the changes in cytokines (IL-1, IL-6, TNF-, IL-10, IL-8, 
activated monocytes and corresponding receptor levels) and C-reactive protein before 
and after treatment with dexamethasone. 
We hypothesize that dexamethasone decreases the intensity of symptoms namely 
Fatigue, nausea, anorexia and pain that occur frequently in advanced cancer and one 
of the mechanisms it exerts such effects by decreasing a cytokines levels (namely IL-
1, IL-6, TNF-, IL-10, IL-8, activated monocytes and corresponding receptor levels) 
and C-reactive protein that mediate these symptoms. 
 
Specific aim #4:  To collect pilot data on the quality of sleep and cortisol levels in ten 
subjects. 
Measure of sleep quality:  The Pittsburg Sleep Quality Index (PSQI) will be used to 
measure subjects’ sleep quality.  The PSQI (Appendix N) is a 9-question, 19 item self-
report instrument designed to measure sleep quality.  PSQI questions 1-4 request 
specific respondent information that is filled in by hand, such as customary bed time and 
length of time to fall asleep. PSQI questions 5-8 are answered on a 0-3 scale with 0 

2005-0816 
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indicating no symptom presence and 3 representing symptom presence 3 or more times 
the past week. Question 9 is answered on a 0-3 scale with 0 meaning “very good” and 3 
representing “very bad.” All scores are combined according to the scoring criteria 
included with the form to produce a Global PSQI Score. Scores above 5 indicate 
clinically meaningfully disturbed or poor sleep.  
Cronbach’s alpha coefficient produced an average internal consistency reliability 
estimate of .80 for the Global PSQI Score across numerous patient populations with a 
variety of different physical ailments. Additionally, the PSQI is more highly correlated 
with sleep problems (r =.69-.77) than with unrelated constructs, such as mood symptoms 
and depression (r =.22-.65).  Additionally, Global PSQI Scores above 5 resulted in a 
sensitivity of 98.7 and specificity of 84.4 to persons with sleep disturbances versus 
controls.  (http://www.bmedreport.com/archives/6559) 
Salivary cortisol levels were assessed by enzyme immunoassay (Salimetrics, State 
College, PA http://www.salimetrics.com/products 
and_services/salivary_assays/specifications/cortisol.php ). This assay has a lower 
detection limit of less than 0.003/dL. The mean intraassay coefficient was 5.5 (range, 4–
6%) and the mean interassay coefficient was 8.2 (range, 7–11%).  All samples from a 
participant were analyzed in duplicate in the same assay to minimize variability. 
Appendix O explains the testing protocol. 
      Cytokine Measures  
 
Cytokine-antagonists that inactivate pro-inflammatory cytokines such as TNF (e.g. 
Ethanercept), IL-1 (e.g.IL-1ra), and IL-6 (anti-IL-6 antibody) have been investigated in 
trials in which an aberrancy in cytokines has been found [121]. Cytokines such as IL-1, 
IL-6, TNF-α, and IFN-α have been reported to be correlated with other symptoms such 
as pain, anorexia/cachexia, depression, cognitive impairment and sleep disorders in 
cancer patients.  Thus, measuring levels of cytokines and examining them for a possible 
correlation with symptom clusters, and the response to Dexamethasone may provide 
insight into the pathophysiology of symptom clusters experienced by patients with 
cancer and may reveal novel strategies to overcome these distressing symptoms.  
 
In this study, we will measure the levels of IL-1β, IL-6, TNF-α, IL-10, IL-8, activated 
monocytes and corresponding receptor levels) and C-reactive protein at baseline, 8 [ ± 3 
days], 15 [ ± 3 days], 22 [ ± 3 days], day 29 3 days. The serum samples will be stored 
frozen for subsequent cytokine profile. Serum samples will be assayed. The cytokine 
profile will be correlated with the degree of symptoms and for the responsiveness or 
failure to respond to Dexamethasone. As high levels of plasma IL-1 , TNF-, IFN-γ and 
IL-6 are associated with sleep disturbance, nausea, and weight loss, any significant 
reduction in these cytokines will result in appreciable reduction in these symptoms. 
 
Pro-inflammatory cytokines (IL-1, IL-6, TNF-α) will be measured in the serum of patients 
using commercially available Luminex kit (Biosource Inc.). The Multiplex Bead 
Immunoassay will be used to measure serum/plasma levels of IL-1, IL-6, IL-10, IL-8, 
activated monocytes and corresponding receptor levels, and TNF-alpha. This assay 
sensitivity for the cytokines is 3-6 pg/mL. The Multiplex Bead immunoassay represents 
the development of a Multiplex Assay designed to work in conjunction with the Luminex 
100 analyzer (Luminex Corp., Austin, TX), associated software and fluorescently 
encoded microspheres.  In this assay, each microsphere is labeled with a 
distinguishable fluorophore that allows it to be assigned or gated to a particular region by 

2005-0816 
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the scanner.  Antibodies, specific for the cytokine or protein of interest (purchased from 
Biosource International, Camarillo, CA) are covalently linked to individually beads of a 
different fluorescent marker.  When the beads are reacted with sera or plasma 
containing cytokines, the cytokines bind to the bead coated with the complementary 
antibody, and its unique fluorescent signature can detect cytokine-bead complex by the 
Luminex 100 analyzer.  These assays have been performed in our laboratory in support 
of our ongoing trials. 
 
If the levels of any or all of the inflammatory cytokines are found to be elevated and 
significantly correlated with the degree of symptoms and correlation with the response or 
failure to respond to dexamethasone treatment, it may provide directions for future 
strategies to be explored such as cytokine blockers or antagonists in combination with 
dexamethasone or other novel agents. We would be interested in designing such study 
based on the rationale from laboratory investigations 
 
The absence of elevated levels of cytokines in circulation may not rule out their possible 
role in the cytokines in pathophysiology of symptom clusters. It is possible that local 
cellular production of cytokines may be responsible for symptoms. In the absence of a 
conclusive correlation between plasma cytokines, magnitude of symptoms, and 
response to Dexamethasone, we will separate the mononuclear cells and freeze cell 
lysate for future analysis of intra-cellular measurements of cytokines.  
 
 
Specific aim #4: To determine association of cytokines (IL-1, IL-6, TNF-, IL-10, IL-8, 
activated monocytes and corresponding receptor levels)) and C-reactive protein and 
Fatigue, Pain, Anorexia and nausea. 
 
We will also investigate how cytokines and C-reactive protein are related in 
combination to the symptoms of fatigue, pain, anorexia, and nausea.  These 
analyses will be made separately for each symptom.  We will use a repeated 
measures analysis with the change in symptom score between baseline and two 
weeks as the dependent variable, with the cytokines (IL1, IL6, TNF-, IL-10, IL-8, 
activated monocytes and corresponding receptor levels) and C-reactive protein as 
independent variables, over three time points.  Differences overall between 
groups will also be tested by this model, in addition to a test of a time effect and a 
group by time interaction effect.   
 
Other Assessments 
 
 
• 
Symptom Measure (Depression): Hospital Anxiety and Depression Scale 
(HADS): This 14 item questionnaire has been validated in a number of clinical 
situations and has been widely used in medically ill patients [129], Although its 
use in cancer patients has been somewhat limited, we believe its proven validity 
in the clinical setting makes it well-suited for our study. 
• 
Global Symptom Evaluation. This instrument is to estimate the minimal 
important difference in symptoms before treatment and after treatment.  Patients 
will be asked about their symptoms (worse, about the same, or better) after 
starting new medication. If their answer is better, patients will be asked to rate 
how much better their symptoms are (almost the same, hardly any better at all, a 
little better, somewhat better, moderately better, a good deal better, a great deal 
better, a very great deal better). If their answer is worse, patients will be asked to 
rate how much worse their symptoms are (almost the same, hardly worse at all, a 

2005-0816 
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little worse, somewhat worse, moderately worse, a good deal worse, a great deal 
worse, a very great deal worse) [130,131]. 
 
• 
Toxicity Assessment: The potential side effects of Dexamethasone will be 
assessed using the side effects recording sheet based on NCI common toxicity 
criteria. 
 
• 
Demographic variables. The variables of age, gender, education, race, and 
ethnicity, cancer diagnosis will be assessed at baseline. 
 
 
 
 
STATISTICAL CONSIDERATIONS 
Prior to inferential procedures, extensive descriptive statistical analyses of the outcome 
and predictor variables will be conducted.  Standard descriptive statistics including 
means, standard deviations, ranges, and frequencies, together with 95% confidence 
intervals, will be computed where appropriate.  Distributional characteristics of relevant 
variables will also be more closely examined using boxplots and histograms. If the data 
do not appear to be approximately normally distributed, transformations will be made to 
the data. Bivariate associations will be explored using Pearson’s Product Moment 
correlation coefficients, scatterplots, and contingency tables. 
 
The primary objective of this study is to determine the effectiveness of dexamethasone 
as compared to placebo after two weeks for the management of cancer-related fatigue. 
Fatigue will be measured using the Functional Assessment for Chronic Illness Therapy- 
Fatigue (FACIT-F), previously described.  The FACIT-F has been validated in the 
assessment of fatigue in cancer patients. The current study will determine if the average 
decrease in fatigue from baseline to day 15 in patients who receive dexamethasone is 
greater than for patients who receive placebo.  
 
In a pilot study testing the effectiveness of methylphenidate for the management of 
cancer-related fatigue in 30 patients, the variable fatigue was also measured at baseline 
and one week using the FACIT-F. The study showed that the baseline average of fatigue 
for 30 patients using the FACIT-F was 17.5 (11.3 standard deviation), and this average 
improved to 34.7 (10.0 SD) at day 7. This is an improvement of more than 1.5 standard 
deviations. The average difference score (matched by patient) was 17.1 with a standard 
deviation of 13.95.  Therefore the change, by patient, between baseline and 7 days was 
about 1.2 standard deviations. 
 
However, we are investigating a different drug in this study, and we also assume that 
there may be a placebo effect. Patients who receive placebo may improve in their 
fatigue scores. We propose to detect a decrease in fatigue in the dexamethasone group 
over and above that in the placebo group of ½ standard deviations, or approximately 7 
on the FACIT-F scale. In order to declare this difference to be statistically significant, 
assuming a one-sided significance level of 0.05 and 80% power, we will need to enter 50 
evaluable patients per group into this study. Twenty patients will be recruited at Four 
Seasons Hospice. We will enter a total of up to 160 patients to allow for a possible 37% 
dropout rate. A t test will be used to evaluate the difference between groups unless the 
data appear to be non-normally distributed, in which case a Wilcoxon rank-sum test will 
be used to evaluate the difference between groups. We will add performance status as a 
covariate in analysis if there are differences between the two groups. 
 

2005-0816 
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Fifty evaluable patients per group will also allow us to detect a difference between 
groups for other symptom variables (of pain, anorexia and nausea) of approximately 
one-half a standard deviation (assuming a one-sided significance level of 0.05 and 80% 
power), or approximately 0.57 standard deviations for two-sided tests.  Analyses will be 
made as above for fatigue.  The variable pain will be assessed using the BPI, anorexia 
will be assessed using the FAACT, and nausea will be assessed using the ESAS.  
 
Given that we will also have measurements available at 8 days (in addition to baseline and 
two weeks later), we will also conduct a repeated measures analysis of variance on each 
of the symptom variables. These analyses will include main effects of group and time (with 
three time points) and an interaction term of group by time.  In addition, information will be 
graphically summarized by group for all days, including days 22 and 29, when 
dexamethasone will be provided open label.   
 
The third objective will determine if there is more of a change over time in cytokines for the 
group that receives dexamethasone as compared to the placebo group.  Analyses will be 
similar to those made for the symptom variables. We will initially analyze difference scores 
between baseline and two weeks later by use of a t test if the data are approximately 
normally distributed and by a Wilcoxon test if not. We will also conduct analyses using a 
repeated measures analysis of variance with time points of baseline, 8 days and two 
weeks later. As above these analysis will include main effects of group, time, and a group 
by time interaction.    
 
The associations between symptom and cytokine change scores at two weeks from 
baseline will also be explored.  We will determine the correlations between all 
combinations of the symptoms of fatigue, pain, anorexia and nausea, the cytokines IL1, 
IL6, TNF-, IL-10, IL-8, activated monocytes and corresponding receptor levels, and C-
reactive protein.  If the data are approximately normally distributed we will use a 
Pearson’s correlation coefficient to measure these associations, and otherwise will use a 
Spearman’s correlation coefficient.  If necessary, we will transform the data to achieve 
approximately normal distributions.  Our initial hypothesis is that when symptoms 
increase in severity, cytokine levels also increase.  We will be able to declare correlation 
coefficients greater than 0.39 as statistically significant with a two-sided significance 
level of 0.05 and 80% power.  
 
We will also investigate how cytokines and C-reactive protein are related in combination 
to the symptoms of fatigue, pain, anorexia, and nausea.  These analyses will be made 
separately for each symptom.  We will use a repeated measures analysis with the 
change in symptom score between baseline and two weeks as the dependent variable, 
with the cytokines (IL1, IL6, TNF-, IL-10, IL-8, activated monocytes and corresponding 
receptor levels) and C-reactive protein as independent variables, over three time points.  
Differences overall between groups will also be tested by this model, in addition to a test 
of a time effect and a group by time interaction effect.   
 
Summary information on the global symptom evaluation by group will also be provided at 
each of the assessed time points.  Differences in distributions between groups will be 
analyzed using a chi-square analysis.   
 
When a total of 50 patients (one-half of total number of evaluable patients) have been 
entered and evaluated, the statistical collaborator will conduct an interim monitoring of 
efficacy and toxicity.  Results will be presented overall and by arm retaining the blinding 
as to arm assignment. The PI and other collaborators (other than the statistical 
collaborator) will remain blinded as to the arm assignments of patients. We plan to stop 

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the trial at the time of interim analysis if the two groups differ in their reduction in fatigue 
from baseline to day 15 with a significance level less than 0.001. This would occur if 
differences in the reduction in fatigue were greater than twice the standard deviations of 
the groups, with 80% power. Toxicity is not expected in either group, but will also be 
summarized and monitored.  
 
We will also determine on an exploratory basis whether patients increase or 
decrease their symptom levels from the end of the second week to the end of the 
third and fourth week. After week two patients will be aware that they are 
receiving the drug and not possibly a placebo. These analyses will be made 
separately by treatment group and summarized graphically. We will also conduct 
analyses at 3 and 4 weeks using the patient’s 2-week score as a baseline. These 
analyses will consist of a t test or a Wilcoxon test as appropriate. If there is no 
carry-over effect, there should be no difference between the two groups in these 
analyses.  
 
As a preliminary analysis repeated-measures analysis of variance will be used to 
examine correlation between salivary cortisol, cancer related fatigue (FACIT-F), 
sleep quality (PSQI) and cytokines (IL-1B, IL-6, TNF-A, IL-8, IL-10 and their 
receptors. 
 
Missing Data 
In order to allow for up to 37% of the patients to potentially drop out before completing 
the study for 15 days, we will recruit a total of approximately 80 patients per arm, or a 
total of up to 160 patients. After 7 days of our open pilot study of methylphenidate [37] 
we found that 30 out of 31 eligible patients were evaluable (97%).  By day 28, only 21-30 
patients remained evaluable (70%).  Therefore, we estimate that the drop out rate could 
increase from 3% by day 7 to 30% by day 28.  Since the duration of this study is of 15 
days, we conservatively estimate that the dropout rate will be approximately 15% upon 
completion of the double-blind phase. However, as the study progresses, we are finding 
an actual dropout rate of 37% (43 out of 115).  
 
Information from the intervention phase (days 15-29), where all willing patients will 
receive study drug, will be summarized and exploratory analyses conducted to 
determine if patients in the treatment group continue to experience reduced fatigue and 
if patients previously assigned placebo improve.  However, the dropout rate after 15 
days could be greater than 30% and sicker patients may be more likely to drop out early. 
Therefore the conclusions from these analyses may be preliminary only. However, this 
data set will also be used to determine the impact of different methods of taking into 
account data that may not be missing at random. 
 
As an alternative analysis, subjects who drop out during the study will have their last 
available scores from the outcomes measures carried forward.  This procedure will be 
used because subjects may in some cases drop out because of worsening disease, 
which may be reflected in their fatigue measures.  Failure to account for this might 
otherwise bias the treatment effect estimate.  
 
We will initially assume that missing data will give unbiased estimates of the intervention 
effects provided that the probability of having missing data depends only on the 
covariates in the model. We will check this assumption by looking at predictors of 
missing data. If the assumption is violated we will perform sensitivity analyses to 
determine the effect of varying the assumptions about the mechanisms for missing data. 
Other methods of accounting for missing variables will also be employed in sensitivity 

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analyses (132).   
 
a. Human Subjects   
This application is to obtain support for a clinical trial that will determine whether 
Dexamethasone at low doses can improve symptom clusters in patients with advanced 
cancer as compared to placebo; to determine whether the levels in serum of cytokines (IL-
1, IL-6, TNF-α, IL-10, IL-8, activated monocytes and corresponding receptor levels) and 
pro-inflammatory marker CRP are associated with the symptom cluster score, before and 
after treatment with Dexamethasone. 
 
Protection of Human Subjects 
1. Permission to conduct the study under this grant will be obtained from the 
Institutional Review Board of M.D. Anderson Cancer Center. The Protection of 
Human Rights Guidelines will be followed during all study-related activities. 
2. The proposed clinical trial will enroll patients. The inclusion criteria include the 
following: patients present with 3 or more symptoms (pain, fatigue, appetite 
(anorexia/cachexia), and nausea) during the preceding 24 hours, have an 
average intensity ≥4 on a 0 to 10 scale, in which 0=no symptom, and 10=the 
worst possible symptom;; have no clinical evidence of cognitive failure, have 
normal Memorial Delirium Assessment Scale [MDAS] 13 or > is considered as 
normal); must be 18 years or older; have life expectancy ≥ 6 weeks; have a 
negative pregnancy test if women with childbearing potential; must understand 
and sign written informed consent; have no concurrent steroids or be off steroids 
for at least 7 days prior to inclusion into study; Exclusion criteria include patients 
have major contraindication to Dexamethasone, i.e. allergic reaction; are not able 
to complete the baseline assessment forms and are pregnant or lactating.  
3.  Data collected for the clinical trial will be from patient medical charts, assessment 
tools and laboratory results. Data will be collected specifically for this research 
purposes, and existing data from medical charts will be incorporated (i.e., 
demographic data). 
4. Patients will be informed that refusing to participate in the study or deciding to 
terminate their participation will not affect their current treatment plan. The 
patients will be given a written and verbal description of the study during the 
informed consent teaching interview. Guidelines regarding Institutional Review 
Board, Human Rights Protection will be strictly followed. 
 
5.  Study subjects will sign an IRB-approved written informed consent form after 
having the study explained to them in person by the physician. Included in this 
explanation will be a reassurance that lack of participation in the study will not 
bear a relationship to their care for cancer or its symptoms. Circumstances of 
obtaining informed consent will be documented in patient medical records. 
Informed consent will be obtained in the language preference of the potential 
subject. When necessary, professional translators, and not family members, will 
obtain written informed consent. 
 
6. The most serious side effects known with dexamethasone is Cardiovascular: 
Edema, hypertension, arrhythmias, cardiomyopathy, myocardial rupture (post-MI), 
syncope, thromboembolism, thrombophlebitis, vasculitis. Central nervous system: 
Insomnia, nervousness, vertigo, seizures, psychosis, pseudotumor cerebri (usually 
following discontinuation), headache, mood swings, delirium, hallucinations, 
euphoria. Dermatologic: Hirsutism, acne, skin atrophy, bruising, hyperpigmentation, 
pruritus (generalized), perianal pruritus (following I.V. injection), urticaria.Endocrine & 

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metabolic: Diabetes mellitus, adrenal suppression, hyperlipidemia, Cushing's 
syndrome, pituitary-adrenal axis suppression, growth suppression, glucose 
intolerance, gynecomastia, hypokalemia, alkalosis, amenorrhea, sodium and water 
retention, hyperglycemia, hypercalciuria, weight gain. Gastrointestinal: Appetite 
increased, indigestion, peptic ulcer, nausea, vomiting, abdominal distention, 
ulcerative esophagitis, pancreatitis, intestinal perforation. Genitourinary: Altered 
(increased or decreased) spermatogenesis. Hematologic: Transient leukocytosis. 
Hepatic: Transaminases increased, hepatomegaly. Neuromuscular & skeletal: 
Arthralgia, muscle weakness, osteoporosis, fractures, myopathy (particularly in 
conjunction with neuromuscular disease or neuromuscular blocking agents), tendon 
rupture, vertebral compression fractures, neuropathy, neuritis, parasthesia. Ocular: 
Cataracts, glaucoma, exophthalmos, intraocular pressure increased. Miscellaneous: 
Infections, anaphylactoid reaction, anaphylaxis, angioedema, avascular necrosis, 
secondary malignancy, Kaposi's sarcoma, intractable hiccups, impaired wound 
healing, abnormal fat deposition, moon face. Topical:<1%: Itching, dryness, 
folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, 
allergic contact dermatitis, skin maceration, skin atrophy, striae, miliaria, local 
burning, irritation. secondary infection 
 
8.  We will maintain confidentiality by assigning a study number to all study subjects. 
Data collected will be identified and tracked using this number. No names or 
other identifying information will be attached to the data collection.  
 
Benefits: Several potential benefits may result. The study may provide data that will 
help us further understanding of symptom clusters, pro inflammatory mediators and 
symptom management.  
 
Inclusion of women and minority 
The subject selection procedure provides equal access to both genders. M.D. Anderson 
Cancer Center data suggest approximately equal gender distribution for the Pain clinic, 
Palliative Care & Rehabilitation Medicine clinic and thoracic clinic. Eligibility criteria do 
not exclude by race or ethnicity. We will collect detailed information on race and ethnicity 
by asking the subjects to self-identify or self-report ethnicity. Subjects will be ethnically 
diverse. All of the patients will be recruited at The University of Texas M. D. Anderson 
Cancer Center or Lyndon Baines Johnson Hospital in the breast surgical oncology clinic. 
During 2004, the population was approximately 71% Anglo-American, 11% African-
American, 11% Hispanic, and 7% Asian/other. We believe that our sample will reflect the 
ethnic and racial, and gender demographics of the patients seen at MD Anderson and 
LBJ Hospital. 
 
Target/Planned Enrollment Table: Total of 100 patients will be enrolled.  
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
5 
6 
11 
Not Hispanic or Latino 
43 
46 
89 
Ethnic Category: Total of All 
Subjects 
48 
52 
100 
Racial Categories 
 
 
 
Asian and other 
4 
3 
7 
Black or African American 
5 
6 
11 
Caucasian 
40 
42 
82 

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Racial Categories: Total of 
All Subjects 
49 
51 
100 
 
 
 
 
Data and Safety monitoring  
The Institutional Review Board (IRB) of the University of Texas M. D. Anderson Cancer 
Center (MDACC) reviews and approves the Data and Safety Monitoring Plan for all 
clinical trials. In addition to ongoing monitoring by the PI and research staff, data and 
safety monitoring for this project will be conducted by two independent MDACC entities 
set up specifically to address these issues, the IRB and the Data Monitoring Committee 
(DMC). Plans and procedures for maintaining data integrity, defining and reporting 
adverse events/experiences, and IRB and DMC oversight and monitoring of this project 
are described below. These procedures include monitoring of participant eligibility and 
accrual, adverse events, interim data analyses, etc. The procedures for monitoring by 
the IRB and DMC are described in separate sections below, followed by a section 
defining and further describing procedures for reporting adverse experiences, for 
assuring that any action resulting in a temporary or permanent suspension of the trial is 
reported to the grant program director, as well as procedures for ensuring data quality 
and integrity. 
 
Monitoring the Progress of Trials and the Safety of Participants 
Monitoring by IRB During the protocol review and approval process, the IRB determines 
the level of safety monitoring required for each protocol. The minimum monitoring 
requirements include investigator monitoring of participant safety, adverse event (AE) 
reporting in compliance with IRB, NIH, and FDA guidelines, and participation in the 
Continuing Review process with the IRB. The Data Monitoring Committee (DMC) also 
monitors clinical trials. The outcomes of IRB and DMC reviews are conveyed to the PI via 
the administrative support staff in the Office of Protocol Research (OPR). 
 
For all protocols conducted at the MDACC, the PI is responsible for submitting AEs to 
the IRB. The MDACC’s policy for AE submission has been defined and approved by the 
IRB and must be included as an appendix to all protocols. AEs are submitted to OPR, 
entered into the Protocol Data Management System (PDMS) and forwarded to the 
designated IRB vice chairperson for review. Attached to each AE, is a listing of all prior 
AEs submitted for that protocol. Any comments, questions or changes the IRB requests 
to the protocol as a result of this review are conveyed to the PI. The PI response and 
protocol modification process is monitored by the IRB vice chairperson and OPR support 
staff. The vice chairperson presents the report on AE review to the full committee at the 
next IRB meeting. 
 
All protocol participants must be registered in the Protocol Data Management System 
(PDMS). PDMS is a clinical trials database designed to meet the regulatory needs of the 
MDACC clinical research enterprise, allow PIs to collect their protocol data electronically, 
and allow electronic data transfer to NIH and industry sponsors. The Office of Protocol 
Research (OPR) creates a file in PDMS of each human subjects protocol submitted for 
review and approval. After the title, PI, collaborators and other protocol specific information 
is entered, the system assigns the protocol a unique number that will be used to track the 
protocol through review and approval, participant registration, adverse event collection, 
continuing review and participant data collection processes.  
 

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The system tracks the reviewers and the committee dates and outcomes of each 
protocol through the scientific review and IRB review processes. Once the protocol has 
IRB approval and all other issues are satisfied, the protocol may be “activated”. The 
Activation Process involves entering into PDMS the eligibility criteria, any dose 
information, and the date of the most current IRB approved informed consent document. 
Once activated, participants may be registered in the database. Activation is an 
independent step in the review and approval process and must be specifically requested 
by the PI.  
 
It is the MDACC policy that all participants in a clinical trial must be registered in PDMS. 
To register a participant, the PI or research coordinator must enter some demographic 
data and then answer all the eligibility criteria that are specific for that protocol. The 
system is programmed with the logic to determine which eligibility criteria are not met 
based on the Yes/No response of the person registering the participant. For protocols 
sponsored by NIH, no participant may be registered unless they completely meet all 
eligibility criteria. This real time, continuous monitoring of participant eligibility increases 
participant safety by ensuring that only individuals that meet the criteria are enrolled. 
 
PDMS also contains a field that is visible during the participant registration process that 
indicates the date of the current IRB approved informed consent document. The OPR 
staff updates this field each time the IRB approves a modification to an informed consent 
document. The IRB approved informed consent document is stamped dated and signed 
only when a protocol is activated. No document without the stamp can be used. 
Stamping, signing and dating the document are the final step in the activation process. 
Comparing the date on the informed consent document with the date in PDMS enables 
the registering individual to make sure the correct informed consent document was used.  
 
OPR also uses PDMS as a tool for monitoring participant safety using menus designed 
for reporting, tracking and reviewing adverse events. All adverse events (AEs) submitted 
to the IRB are submitted to OPR, which provides the administrative support to the 
committee. Each AE for a participant treated at MDACC is entered into PDMS in the 
electronic file for the protocol upon which the participant was enrolled. The AE form and 
any additional information supplied to OPR are forwarded to an IRB Vice Chair who is 
responsible for reviewing AEs. In addition to the submitted information, a report is 
generated from PDMS summarizing all previous AEs submitted for that protocol and 
supplied to the IRB Vice Chair. This allows the reviewer to see the entire safety history 
of the protocol and identify trends much sooner than in situations where the safety 
information is reviewed together only once a year during an IRB review. 
 
It is during this continuous AE review that the IRB requests PIs to make modifications to 
informed consent documents if new safety issues arise, or to request dose modification 
to reduce potential toxicity to the participant or any other protocol modification to 
enhance participant safety. This real time, continuous AE review and protocol/informed 
consent modification process is an important component of the MDACC continuous 
monitoring of participant safety. 
 
Part of the information in the database for each protocol is the maximum accrual 
approved by the IRB. Since each participant is registered on the protocol in the 
database, monitoring the progress of the research by examining protocol accrual is a 
simple and routine process carried out by OPR. Every six months reports are generated 
for categories of Low, Slow, No Accrual and Approved but not yet activated. The PI of 
any protocol that falls in one of these categories is sent a memo requesting input on why 
the protocol is not accruing at the expected rate. Depending on the response, the 

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outcome is either closure of the protocol, or the protocol may continue for six months 
and be re-reviewed at that time. 
 
In addition, PDMS sends an automatic email message to OPR who in turn notifies the PI 
when a protocol is within 5 participants of reaching maximum accrual. The system sends 
another email message when accrual is reached and OPR then closes the protocol to 
new participant entry. With this system, protocols cannot accrue participants in excess of 
the numbers approved by the IRB. 
 
PDMS is also used in other ways as an audit tool by OPR. In addition to auditing 
eligibility, the evaluability, on-study dates, and off-study dates are all required entry fields 
and can be tracked on all research subjects through this computer system. 
 
OPR performs audits on both a random and for-cause basis although its major focus is 
the operation of an elaborate and intense training program for research coordinators. It 
is the belief of the Office of Research Administration that while auditing can identify 
problems, education can prevent them. That is why that office has used OPR to stress 
an educational, proactive approach to research quality.  
 
In addition, OPR contains an ombudsman function that confidentially assists research 
personnel who believe that a study may not be operating in a manner consistent with 
Good Clinical Practice. A report to this function may trigger an audit or some other type 
of investigation. Every report is investigated fully and confidentially to assure no 
repercussions to the reporter or to the research team performing the research in 
question unless a true violation is identified.  
 
Most Phase 1 and 2 trials at M.D. Anderson are monitored on a day-to-day basis by the 
research teams performing the research. In addition the IRB may require frequent 
reporting on toxicity of any trial the IRB identifies as having risks warranting an increased 
monitoring frequency.  
 
The requirements for AE reporting are extensively reviewed with all key personnel on 
grant applications during the mandatory IRB-sponsored training. In addition, every 
protocol must have the AE reporting requirements attached to it prior to IRB approval.  
 
Every AE report is reviewed by a Vice Chairperson of the IRB and duly reported to the 
entire IRB at the next meeting. IRB meetings occur every two weeks. If immediate action 
is required (protocol closure, information dissemination to other PI’s doing studies with 
similar agents) that is done by the IRB Vice Chair via the Office of Protocol Research. All 
of these actions are coordinated through the PDMS computer system. 
 
Plans for assuring that that any action resulting in a temporary or permanent suspension 
of an NIH-funded clinical trial is reported to the NIH grant program director responsible 
for the grant. 
 
For the most part, the closure of the trial will occur due to actions coordinated within the 
OPR, whether this is due to a poor audit, an IRB action, or unexpected AEs. OPR will work 
with the IRB to notify all parties requiring such notification (e.g., NIH, FDA, sponsor). 
 
Audits are performed by the OPR on individual trials and accrual is monitored every six 
months on all trials.  
 
Monitoring of data at additional sites 

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Since neither the UTMDACC IRB nor the OPRQA monitoring teams provide oversight or 
monitoring for the conduct of clinical trials conducted outside of UTMDACC, we will 
monitor the conduct of this trial at Four Seasons Hospice. The Four Seasons Hospice 
has submitted the protocol, and their IRB has already reviewed and approved the 
protocol. Data and safety monitoring at Four Seasons Hospice is consistent with the 
approved Data and Safety Monitoring Plan outlined in the protocol. The UTMDACC 
DMC will be used, and all data will be submitted to UTMDACC. 
 
In order to uphold good quality research and monitor safety and quality data from 
outside institutions, we have established departmental procedures that will be 
implemented in these collaborations. With study activation, we plan to have orientation 
via teleconference, with involvement of the P.I., research data coordinator, research 
nurse and data manager, and plan for a future site visit by a member of the research 
team in order to provide for sufficient review of the protocol. CRF’s will be submitted to 
UTMDACC in a timely fashion. With close monitoring of adverse event reporting, we 
would be able to maintain safe and quality study conduction with additional sites. 
 
MONITORING BY THE DATA AND SAFETY MONITORING BOARD:  
  
The Data Monitoring Committee(DMC) is an officially constitueted committee of 
MDACC designed to oversee the data and safety monitoring of clinical trials. The 
primary objectives of DMC are to: 
    
• 
Ensure that participants in a trial are protected; 
• 
Ensure that participants’ interests are not made secondary to the interests of the 
scientific investigation; and 
• 
Monitor all clinical trials that originate at MDACC or that are coordinated or analyzed 
by the MDACC. 
The DMC has the following responsibilities to accomplish the above objectives: 
• 
To review interim analyses of outcome data (prepared by the study Statistician or 
other responsible person at the time points defined in the protocols approved by the 
IRB), and to recommend, if necessary, whether the study needs to be changed or 
terminated based on these analyses; 
• 
To determine whether and to whom outcome results should be released prior to the 
reporting of study results from this trial at the time specified in the protocol; 
• 
To review interim toxicity data and efficacy of treatment; 
• 
To review major modifications to the study proposed by the PI prior to 
implementation (e.g., termination, dropping an arm based on toxicity results from this 
trial or results of other trials, increasing target sample size); 
• 
To communicate information and recommendations to appropriate persons at 
MDACC regarding the assessment of issues or problems and effective resolutions 
for educational purposes and improved participant care and risk prevention. 
 
The Committee consists of not more than 15 members (including the Chairman). A 
majority of members attending meetings of the DMC constitute a quorum. Appointments 
are made based on the breadth of backgrounds and experience. The committee 
includes scientists and statisticians from within and outside the institution selected based 
on their experience, reputation for objectivity, absence of conflicts of interest, and 
knowledge of good clinical trial methodology. At least fifty one percent of the voting 
members are not affiliated with MDACC. DMC members represent participant interests, 
and not that of the institution.  
 

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The DMC meets at least once a year, and more often if necessary. Each randomized 
clinical trial protocol has specified interim analyses times. Information provided to the 
DMC include: title of study, PI, date start of study, expected termination date, expected 
total number of participants, number of participants entered currently, data from interim 
analyses, date of interim analyses, toxicity concerns, and the next formal monitoring 
date as specified in the protocol. The PI may prepare a report addressing specific 
toxicity concerns or other concerns about the conduct of the study during the open 
session. A copy of the statistician’s report may be sent to the DMC Chair for 
presentation during the closed portion, but not to any other individuals not on the DMC. 
The report may contain recommendations on whether to close the study, whether to 
report the results, whether to continue accrual or follow-up and whether DMC discussion 
is needed. 
 
The review of each trial may include two parts. The first part will be an open session in 
which members of the study team may be present at the request of the DMC to answer 
questions. In this part, the focus is on accrual, compliance and toxicity issues. Following 
this open session, there will be a closed, executive session in which the DMC discusses 
interim outcome results by treatment arm, what action needs to be taken, and then 
votes. At the executive session, those present are limited, to DMC members, alternates, 
and ex officio members. If a decision is made by the DMC to modify or discontinue a trial 
- recommendations will be made as to whether and how participants are to be informed 
and by whom and communicated to the PI in writing. Copies of such communication will 
be preserved in the official Committee Minutes. 
 
DMC recommendations are based upon results for the current study being monitored as 
well as upon data available to the DMC from other related studies. The PI will assure 
that the DMC is advised about relevant non-confidential results from other related 
studies that become available. It will be the responsibility of the DMC to determine the 
extent to which this information is relevant to decisions to continue or modify the current 
study. The DMC will provide recommendations in writing to the PI to change or stop a 
study, or part thereof (e.g., one arm), or to continue a study unchanged. Special 
consideration will be given to participants already in treatment. 
 
In the event that a study change is recommended for participant safety reasons 
(including early stopping of inferior therapy), the PI acts to implement the change as 
expeditiously as possible to ensure safety of all participants on the study. In the unlikely 
situation that the PI does not concur with the DMC recommendation, then the Vice 
President for Research Administration must be informed of the recommendation of the 
DMC and of the PI’s reason for disagreeing with the recommendation. The Vice 
President for Research Administration and the PI, in consultation with the DMC Chair, 
are responsible for reaching a mutually acceptable decision about the study. 
Confidentiality is maintained during these discussions. In the event that a change in a 
study is recommended for reasons other than participant safety (e.g., to extend accrual 
because of a lower than expected accrual rate), the DMC provides to the PI as much 
rationale for the proposed change as can be made without jeopardizing the conduct of 
the study. The PI is responsible for having an amendment prepared and submitted to the 
IRB the recommendations of the DMC and providing the rationale for the changes. IRB 
approval of the amendment will be required prior to implementation of the change, 
although a decision to override the DMC’s recommendation is made only in the most 
exceptional circumstances. 
 
All documents, investigative reports or information and conversations relating to this 
committee’s work are strictly confidential and are not shared with anyone other than 

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other committee members. Although committee documents are subject to legal 
privileges as set forth in statutory and case law and are not subject to discovery during a 
litigation process, the privilege may be lost if committee documents are given to, shown 
to or discussed with non-committee members without an official DMC request to do so. 
 
No communication of the deliberations or recommendations of the committee, either 
written or oral, is made outside of the committee except as provided for in these policies 
and procedures. All DMC members or alternates will sign statements of confidentiality at 
the beginning of an appointment period. Outcome (efficacy) results are strictly 
confidential and are not divulged to non-members (excepting the PI and Associate Vice 
President for Clinical Investigations) until the recommendation to report the results are 
accepted and implemented. 
 
Individuals invited to serve on the DMC disclose to the Group Chair any potential, real or 
perceived, conflicts of interest. These include professional interest, proprietary interest 
and miscellaneous interest considerations. Potential conflicts that develop during the 
conduct of a trial should also be disclosed to the PI. 
 
COMPLIANCE 
WITH 
REQUIREMENTS 
REGARDING 
THE 
REPORTING 
OF 
ADVERSE EXPERIENCES 
 
Given the non-invasive, minimal risk nature of the proposed research, we anticipate that 
the types of adverse experiences that may occur, if any, will focus on concerns about 
possible distress associated with sensitive issues arising during data collection. The 
study includes procedures to minimize these risks. 
 
Adverse Experiences Requiring Immediate Reporting:  Two types of Adverse 
Experiences require prompt reporting to the IRB and the study sponsor: Serious Adverse 
Experiences and Unexpected Adverse Experiences. For serious or unexpected AEs, a 
written report is submitted to the Office of Protocol Research (OPR) within 10 working 
days of the adverse experience. Unexpected fatal or life-threatening experiences are 
phoned immediately to the OPR and the OPR will notify the appropriate sponsors within 
3 days. For AEs that are not serious or not unexpected, written reports are submitted to 
OPR every month. Serious Adverse Experiences: For the majority of trials performed at 
MDACC, a serious adverse experience is a clinical event occurring subsequent to the 
administration of an agent or intervention which can be characterized as fatal, life-
threatening, permanently disabling, requiring hospitalization, or an overdose. 
 
Unexpected Adverse Experience:  An unexpected adverse experience is a clinical event 
that is not identified in nature, severity, or frequency in the investigator’s brochure, 
protocol, or other pertinent supporting literature. At times, the occurrence of an 
unexpected adverse experience might not be suspected until more than one event has 
occurred. Once the clinical event has been identified, all cases should be reported. No 
degree of unexpected toxicity is specified, but practically, it is unusual to be able to discern 
< grade 2 toxicity.  
 
Adverse Experiences Associated with Participating in the Intervention: Dexamethasone 
may cause  irregular heartbeat, slow heartbeat, sudden stopping of the 
heartbeat, enlarged heart muscle, heart failure, circulatory system failure, build-
up of fluid, often in the legs or arms, high blood pressure , tearing of the walls of 
the heart, fainting, blood clots, inflammation in blood vessels (possible fever 
and/or fatigue), depression, unstable emotions, euphoria (abnormal feelings of 
great happiness, well-being), headache, increased pressure between the skull 

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and brain, difficulty sleeping, weakness, mood swings, inflammation of a nerve, 
personality changes, psychotic disorders, seizures, dizziness, acne, allergic skin 
inflammation, hair loss, tissue swelling, bruising, dry skin, abnormal skin redness, 
lightening and/or darkening of the skin. 
 
Dexamethasone may cause fragile skin, increased hair growth, excessive body 
hair, anal itching, red or purple spots under the skin, skin rash, thinning of the 
skin, skin tests (such as for TB) may not be accurate, stretch marks, hives, 
decreased function of the adrenal glands (which produce hormones to regulate 
stress response), decrease in carbohydrate tolerance , Cushing's syndrome 
(possible obesity), diabetes, stunted growth in children, bleeding in the 
stomach/intestines area, enlarged abdomen , increased appetite, hole in the 
stomach and/or intestines, which may cause the contents to leak, nausea, 
inflammation of the pancreas (possible abdominal pain), sore in the stomach or 
small intestine, inflammation of the esophagus with sores, weight gain, enlarged 
liver, inflammation of the veins, fluid in the lungs (possible shortness of breath) 
 
Dexamethasone may cause abnormal liver tests (possible liver damage), joint 
disease, death of bone tissue, increased risk of broken bone , loss of muscle mass 
, muscle disease that causes weakness, pain or weakness from damage to parts 
of the nervous system, decreased bone density, tickling and/or tingling sensation, 
rip in a tendon , broken bones in the spine , weakness, cataracts (clouding of the 
lens of the eye), bulging eye, increased pressure in the eye (possible loss of 
vision), increased sugar in the urine (possible liver disease), abnormal build-up of 
fat in the back of the neck, severe allergic reaction, loss of blood supply to the 
bones, excessive sweating, hiccups, problems with wound healing , infection, 
malignant skin lesions, moon face, new occurrence of cancerIn addition to the 
monitoring that is conducted by the M. D. Anderson DMC, patients are closely followed by 
the staff of the project.  Patients will be provided the telephone number of the PI and the 
research nurse in case they feel they need to reach someone immediately.   
 
Adverse Experiences Associated with Self-Report Questionnaires:  This study will 
involve the use of questionnaires and interviews that could reveal sensitive information 
(e.g., assessment of mood or other psychiatric disturbance). Procedures are in place to 
protect participant confidentiality. Such instruments are administered only by trained staff 
and after careful explanation to the participants about their purpose and use in this study. 
The instruments are not used to communicate psychiatric diagnosis to the participant. 
However, the PI or one of the co-investigators reviews the results and if in their clinical 
judgment the results reveal a degree of disturbance that requires further professional 
consultation, the participant is contacted. Possible outcomes of this contact include referral 
to the participant’s primary care physician and/or other physician, and/or other mental 
health providers. 
 
ASSURING THAT ACTION RESULTING IN SUSPENSION OF TRIAL IS REPORTED 
TO ACS PROGRAM DIRECTOR RESPONSIBLE FOR THE GRANT 
Any human subjects research that is not being conducted in compliance with applicable 
institutional policy and Good Clinical Practices will be suspended by the IRB.  An IRB 
shall have authority to suspend or terminate approval of research that is not being 
conducted in accordance with the IRB’s requirements or that has been associated with 
unexpected serious harm to subjects.  Any suspension or termination of approval shall 
include the necessary and appropriate notifications of such actions to the institution’s 
administration, funding agency, ACS other sponsor. 

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DATA QUALITY AND INTEGRITY 
Because of the ongoing monitoring of the project, study investigators and staff are 
responsible for ensuring that data quality assurance procedures are developed and 
maintained. Several procedures will be used to maintain the integrity of the data. All 
databases will be stored in a centralized location on one of the departmental servers, 
which is backed up daily, with access limited to specific users at the discretion of the PI. 
The PI will assure that audits of selected subsets of data are performed and that 
appropriate safeguards of participant privacy are maintained. Privacy safeguards will 
include appropriate password protection and physical security for all computer systems.  
Patient names will not be stored in data files; records linking participants’ names with the 
computer identifiers will be kept in a separate file and encrypted. 
 
A relational database will be created in Microsoft ACCESS to store all project-related 
data. ACCESS can accommodate complex relationships among tables, allowing large 
quantities of data to be integrated into a single database. Relational databases such as 
ACCESS also allow for powerful and flexible queries and reports.  ACCESS can be 
easily customized using Visual Basic for Applications (VBA) code, allowing the inclusion 
of many design features ideal for behavioral science research.  These features include 
more user-friendly interfaces, the ability to specify valid ranges for variables, and double-
entry systems for data, all of which help to maintain data integrity.  We will use the built-
in security features of ACCESS to restrict user access. 
 
Additional quality assurance procedures include a data collection protocol documented 
in a protocol manual; a two-stage editing procedure for survey data collection consisting 
of the initial review of the data collection form by a project member immediately following 
data collection, and a second review by a project member who will record any significant 
deviations from the protocol; and regular meetings between the study statistician, the PI, 
data managers, and other project staff to review problems and solutions, and discuss 
concerns. Data entry systems, whether via scannable forms, or hand entry with 
verification, specifically provide field checks, range checks for continuous variables and 
valid value checks for categorical variables; checks for legitimate dates and times and 
logical consistency. A specific audit trail system that identifies the date, time, and 
individual making changes on the database will be part of the data-entry system. During 
data collection, we will either issue reports weekly or following any new data entry, 
depending on the needs of the project. Queries and reports will be provided to the study 
statistician and the PI.  
 
F. Relevance to the cancer problem 
 
Approximately 50% of patients diagnosed with cancer die of progressive disease.  The 
overwhelming majority of patients develop devastating physical and psychosocial 
symptoms.  Those symptoms decrease the quality of life of patients. Circulating 
cytokines and inflammatory proteins have been thought to be directly associated with 
pain, and cognitive impairment, depression, fatigue, cachexia, and sleep disorder. 
Steroids decreases the intensity of symptoms namely Fatigue, nausea, anorexia and 
pain that occur frequently in advanced cancer and one of the mechanisms it exerts such 
effects by decreasing a cytokines levels that mediate these symptoms. Despite 
widespread acceptance and frequency of steroid therapy in patients with cancer 
symptom management, the data is inadequate to draw definitive conclusions about the 
efficacy of these compounds in the management of pain and other symptoms. The role 
steroids on cancer related fatigue, pain, appetite and nausea (which are common 
symptoms in advanced cancer), their effects on cytokines need to be defined through 

2005-0816 
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randomized controlled studies using updated and validated Symptom assessment tools 
and laboratory correlates (which were lacking in the previous studies on corticosteroids 
for symptoms). Our findings will also allow investigators 1) To effectively treat the 
symptoms clusters in advanced cancer patients and improve their quality of life. 2) 
Establish Cause and effect relationship between symptoms and cytokines. 3) To 
establish the use of dexamethasone for symptom control in advance cancer patients 
through randomized controlled studies using updated and validated Symptom 
assessment tools and laboratory correlates 4) Development of cytokine specific 
suppressive therapies that could be used to prevent and treat these troubling symptoms. 
 
G. Facilities:  MD Anderson Cancer Center and Lyndon Baines Johnson Hospital, 
Houston, TX 
 
 
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cancer pain receiving regular opiates. A preliminary report. 
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Bruera E, Strasser F, Shen L, Palmer JL, Willey J, 
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cancer pain: a pilot study. J Pain Symptom Manage 2003; 
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megestrol acetate in patients with advanced cancer: A 
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Amyotte G. Effect of fish oil on appetite and other 
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anorexia/cachexia: a double-blind, placebo-controlled 
study. J Clin Oncol. 2003; 21(1): 129-34. 
 
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Hanson J. Thalidomide in patients with cachexia due to 
terminal cancer. Preliminary report. Ann Oncol. 1999; 
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Chang VT, Hwang SS, Feuerman M. Validation of the 
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2004. 
 
 
 
LETTERS OF RECOMMENDATION 
 
List the name, title, and address of the three individuals whose letters of 
recommendation have been requested.  Each letter of recommendation must be in a 
sealed envelope and attached to the cover page of the original copy of the application 
with a paper clip. 

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Page 59 of 60 
 
 
 
PART II 
 
 
FACULTY OR SCIENTIFIC APPOINTMENT (of candidate): 
 
 
 
 
 
 
 
 
PROGRAM GOALS AND PROPOSED TRAINING: 
 
 
 
 
 
 
 
 
INSTITUTIONAL RESOURCES AND ENVIRONMENT:   
 
 
 
 
 
 
 
 
TRAINING EXPERIENCE OF MENTOR (S) 
 
 
 
ABBREVIATED CURRICULUM VITAE OF MENTOR (S) 
(Do not exceed two pages for total biographical information.) 
 
Last name, first name 
 
Major research interest: 
 
 
Education 
 
 
Institution/Location 
 
Degree/Year Conferred 
 
Field of Study 
 
 
 
 
 

2005-0816 
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Appointments 
 
 
 
Publications 
 
 
 
 
 
SUPPORT OF MENTOR (S) 
(Current and Pending) 
Give source of support, identifying number, project title, name of principal investigator, 
percent effort of each professional named (including collaborators but not consultants), 
dates of entire project period, and direct costs for the entire period and for the current year.