Kara Kelly, M.D.Associate Professor of Clinical PediatricsDivision of Pediatric OncologyColumbia University Medical CenterNew York
Research Methods: Clinical Trials and Lessons Learned
Research Challenges Many patients with cancer perceive a
benefit to the use of CAM therapies Most have not been adequately tested
for safety, efficacy, and interactions with chemotherapy and radiation
ISSUE: CAM therapies are available over the counter without the regulatory oversight or quality controls that govern conventional medications
Research-Design Issues
Sufficient preclinical data often does not exist
Adequate justification is needed beyond claiming that patients are already using a CAM therapy for a particular purpose
Plausible data-based hypotheses about the possible clinical effects of the CAM therapy of interest are needed
Do the Ground Work First Before Initiating a Phase III Trial!
But How Do You Get Started with Clinical Research??
STEP 1:Develop plausible data-
based hypotheses Assessment of
Risk/Benefit Ratio Best Case Series Systematic Literature
Reviews
Assess the Risk-Benefit Ratio
What is the known about the effectiveness of the CAM therapy?
Is there any reported toxicity of the CAM therapy?
How effective is the conventional anti-cancer therapy?
Are there any known interactions?
NCI Best Case Series Program
Independent review of medical records and medical imaging from patients treated with unconventional cancer therapies
Primary goal of this program is to obtain and review sufficient information to determine if NCI-initiated research on a specific intervention is warranted
What the NCI Best Case Series Program IS…
Retrospective data collection involving patients who receive an alternative therapy for the treatment of cancer that results in significant tumor reduction or complete tumor remission
An opportunity to receive feedback on the quality of data submitted for review
A pathway to possible NCI-initiated research and advances in scientific knowledge
An avenue for cancer CAM therapies to gain scientific rigor supported by conventional medicine
From http://www.cancer.gov/cam/bestcase_toolbox.html
Systematic Reviews
Synthesis of the results of multiple primary investigations by using strategies that limit bias and random error
Comprehensive search of all potentially relevant articles using explicit, reproducible criteria in the selection of articles for review
Primary research designs and study characteristics are appraised, data are synthesized, and results are interpreted
Meta-analysis is a systematic review that uses statistical methods to combine the results of two or more studies
Used to summarize existing data, refine hypotheses, estimate sample sizes, and help define future research agendas
Cook, D. J. et. al. Ann Intern Med 1997;126:376-380
Copyright ©1997 BMJ Publishing Group Ltd.
Greenhalgh, T. BMJ 1997;315:672-675
Fig 1 Methodology for a systematic review of randomised controlled trials1
Research Example:
Antioxidant Supplementation During Chemotherapy
TumorProtection
ImprovedTreatmentEfficacy
0
10
20
30
40
50
60
GeneralPopulation
Early StageBreastCancer
Multivitamin
AntioxidantMixture
Vitamin E
Vitamin C
Carotenoid
%
Antioxidant Use Increases with Diagnosis of Cancer
Rock et al. J Nutr 2004;134:31948
Chemotherapy/Antioxidant Interactions
Patients with cancer frequently use antioxidant supplements in an effort to minimize side effects of chemotherapy or to have a direct effect on the tumor
Although there is a lot of evidence from in vitro studies, there is limited evidence from clinical studies
AnthracyclinesPlatinum-complexes High Alkylating agents
EpipodophyllotoxinsCamptothecins
Purine/PyrimidineAntimetabolites
Low TaxanesVinca alkaloids
Reasons for Antioxidant Supplements
Excessive chemotherapy or radiotherapy induced reactive oxygen species may prevent apoptotic death through interference with cell cycle
Treatment related toxicity may necessitate chemotherapy or radiotherapy dosage reduction or treatment delays
Reasons Against Antioxidant Supplements
Protective mechanisms of antioxidants may not distinguish between normal and malignant cells
Radiation and some chemotherapy agents rely on oxidative mechanisms for their antitumor effects
Coagulation cascade may be affected by some antioxidants (e.g. vitamin E) increasing risk of hemorrhage
Conventional Protectants
Dexrazoxane Amifostine Mesna
ASCO clinical guidelines are based on clinical trials showing evidence of improvement of specific side effects, with a lack of evidence of adverse impact on outcome
Antioxidants and Cancer Therapy: A Systematic Review
Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM
Journal of Clinical Oncology 2004; 22(3):517-528.
Objective
Systematic review of the published trials and observational studies investigating: The effects of conventional chemotherapy with
or without radiation on antioxidant status The effects of antioxidant supplementation in
combination with conventional chemotherapy with or without radiation on antioxidant status
The effects of antioxidant supplementation on treatment-related toxicities and survival
Methods
Human studies published in English were identified by repeated literature searches of MEDLINE and Cochrane database and reference lists from studies reviewed from July 2000 to January 2002
Keyword terms: antioxidants, supplements, vitamins, diet, nutrition, cancer, chemotherapy, chemotherapy toxicity, cancer survival
Studies reporting vitamin C, E, selenium, or β-carotene (studies of other antioxidant nutrients not required from the diet were excluded)
Results
> 100 citations reviewed; 52 met criteria
ObservationalStudiesInterventionTrials
2131
Only 6 of 21 Intervention Trials are RCTs
0
10
20
30
40
50
60
70
# Patients Enrolled
Observational Studies: The Effect of Cancer Therapy on Antioxidant Levels (n=31)
0
2
4
6
8
10
12
Vitamin C Vitamin E Selenium beta-carotene
TRAP
Antioxidant
# o
f S
tud
ies
INCREASE
DECREASE
NO CHANGE
No specific chemotherapy treatment was associated with changes in individual antioxidant micronutrients
0
1
2
3
4
Vitamin C Vitamin E Selenium beta-carotene
TRAP
Antioxidant
# o
f S
tud
ies
INCREASE
DECREASE
NO CHANGE
The Effect of Supplementation with Antioxidants in combination with Cancer Therapy on Antioxidant Levels (n=9)
Recurrence/Overall Survival No effect (n=3)
Vitamin E β-carotene Vitamin C, E, β-carotene
Improved overall survival (n=2) Vitamin E, β-carotene, Selenium, Vitamin C
Improved 1-year survival; No improvement in overall survival (n=1) Vitamin E, Vitamin C
Do these results translate into absence of tumor protection?Study design issues preclude this conclusion at the present time
Conclusions
Studies investigating changes in vitamins C and E, selenium, and beta carotene found no consistent patterns associated with chemotherapy
Existing studies are too small and have too many variables to guide clinical practice
Additional studies are needed
STEP 2: What Kind of Study Design?
Observational Studies Case-control studies Prospective cohort studies
Intervention Trials Pilot studies Randomized controlled
Research Example:Antioxidant and Oxidative Status of Children on Treatment for ALL
Design: Prospective multi-center cohort study of newly diagnosed children with ALL followed for approximately 6 months
Subjects: 103 newly diagnosed children with ALL between the ages of 1-18 years
Measurements: Antioxidants: Plasma vitamin A, C, E, total
carotenoids and lipids, ORAC, 8-oxo-dG adducts Dietary: Nutrient intake by YA FFQ and 24-hour
recall; Intake of vitamins and herbs Clinical: Toxicity, QOL Am J Clin Nutr 79:1029-36, 2004
Integrative Cancer Therapies 3:301-9, 2004 Pediatric Blood and Cancer 44:1-8, 2005
Plasma Concentrations Vary By Phase of Therapy
0
20
40
60
80
100
120
0 IM DI
Pla
sma
leve
l m
icro
mo
l/L
Vitamin C Vitamin E Total carotenoid Vitamin A
Total Antioxidant Capacity Declines with Chemotherapy
0.817
0.690.619
0
0.2
0.4
0.6
0.8
1
1.2
0 IM DI
OR
AC
pca
Plasma Concentrations of Micronutrient Vitamins
0
10
20
30
40
50
60
70
80
Vit A Carotenoids Vit C Vit E
DiagnosisIMDI
% C
hild
ren
D
efici
en
t
Dietary Intakes of Micronutrient Vitamins
0
1020
3040
50
6070
8090
Vit A Carotenoids Beta-carotene
Vit C Vit E
DiagnosisIMDI
%
Child
ren
D
efici
en
t
Associations with Clinical Outcomes
Lower antioxidant plasma levels were associated with increased risk of toxicity (dose reductions, infections, chemotherapy delays, days spent in the hospital, decreased quality of life)
Lower dietary intake of antioxidants were associated with increased risk of toxicity (chemotherapy delays, infection, days spent in the hospital
Next Steps: DFCI ALL Consortium
Companion study to current Phase III trial (n=540)
Objective: To investigate the association of dietary
antioxidant micronutrient intake, including vitamin C, vitamin E, vitamin A, ß-carotene and total carotenoids with the rate of infections (episodes of bacteremia and disseminated fungal infections) during remission induction and continuation therapy
Intervention Trials
Do we know enough from observational studies to move forward?
Product Issues: Standardization and Quality Control
Specify formulation: Capsule, powder, suspension Need to consider Placebo formulation
Trials with Botanicals: Species Biologic variation
Stability over course of the trial Quality assurance
Independent testing preferred
Product issues: The Antioxidant Example
Type of antioxidant Natural vs Synthetic Class of Antioxidant
Use of Single vs multiple antioxidants
Route of Administration IV vs Oral
Quality assurance Stability
Phase I and II Trials
Phase I testing MTD and Schedule of Administration:
Dose and schedule tend to be based on traditional practice rather than experimental data
MTD may not be achieved Effect on surrogate endpoint
Need for sufficient preclinical data on mechanisms
Risk of Supplement-chemotherapy/radiation interactions
Phase II Trial: Safety of Oral Antioxidants and IV Vitamin C During GYN Cancer Care
Intervention: IV and PO vitamin C; IV glutathione; PO carotenoids, vitamin A, and vitamin E with conventional chemotherapy and/or radiation therapy
Non-Randomized Safety Study in 50 newly diagnosed and recurrent gynecologic cancer patients
Primary Aim: Safety of adding high-dose antioxidants to chemotherapy
Secondary Aims: Tumor response rate, Time to progression, Survival
Study Status: Opened 9/2005; Expected closure 12/2008
http://www.clinicaltrials.gov/ct/show/NCT00284427
PI: Jeanne Drisko, MD, Univ Kansas
Phase II Trial: Antioxidant Effects on the Outcome of Ovarian Cancer
Intervention: IV and PO vitamin C; IV glutathione; PO carotenoids, vitamin A and vitamin E with conventional chemotherapy
Randomized, Double Blind, Safety/Efficacy Study in 40 patients with chemotherapy refractory stage III/IV ovarian cancer
Primary Aim: Safety of adding high-dose antioxidants to chemotherapy
Secondary Aims: Tumor response rate (CA-125), QOL
Study Status: Opened 10/2002; Expected closure 1/2006
http://www.clinicaltrials.gov/ct/show/NCT00228319
PI: Jeanne Drisko, MD, Univ Kansas
Phase III Trials
Experimental arm Selection of an adequate
comparison group Work with a Statistician
Estimates of effect sizes Determination of an adequate
sample size Selection of appropriate outcome
measures Analytic Plan
Phase III Trials
Potential Pitfalls Use of self
prescribed supplements
Compliance with the experimental therapy
Reasonable timeline—Do you have enough patients?
Phase III Studies: Vitamin E in Preventing Chemotherapy-Induced Peripheral Neuropathy
North Central Cancer Treatment Group Concurrent chemotherapy: taxanes, platinum based Goal: 200 patients Primary Aim: Compare the incidence of chemotherapy-
induced sensory peripheral neuropathy ≥ grade 2 in patients undergoing curative neurotoxic chemotherapy for cancer treated with vitamin E vs placebo.
Secondary Aims: Compare the proportion of patients requiring dose
reductions or cessation of chemotherapy secondary to sensory peripheral neuropathy
Toxicity of vitamin E Study Status: Not yet recruiting
http://clinicaltrials.gov/show/NCT00363129
STEP 3: Practical Issues
Regulatory FDA Human Subjects Protection
Clinical trials can be expensive Sources of funding
Product Regulatory Issues
IND application
Animal Pharmacology and Toxicology Studies Manufacturing Information Clinical Protocols and Investigator Information www.fda.gov/cder/regulatory/applications/ind_page_1.htm
Research Pharmacy
Manufacture, package, dispense and manage different dosage forms
Blind and randomize (if appropriate) Manage drug ordering, inventory,
accountability, multicenter drug distribution and return shipment for study drug products
Fee usually associated with these services
Practical Issues
Human Subjects Protection: Institutional Review Board Approval
Are there members on your institution’s IRB with expertise on reviewing CAM trials?
Data Safety Monitoring Board Critical for Intervention trials
List your trials on Clinicaltrials.gov
Funding
Institutional pilot funds
Philanthropy Private foundations NIH Industry
Product Funds
Institute of Medicine ReportJanuary 2005
Healthcare should strive to be both comprehensive and evidence-based
Hold conventional and complementary treatments to the same standards
Use same general research principles in evaluating both types of treatments
Conclusions
Further research of CAM therapies is greatly needed with the use of the same general research principles that are used in evaluating conventional treatments
Strong research designs are necessary to evaluate CAM therapies and ultimately influence clinical practice and public awareness
Integrative Therapies Program
Elena Ladas MS RDMichael Weiner MDDeborah Hughes
Christine Grimaldi PhD(Yoga/Movement Therapist)
Judith Jacobson DrPHStephen Sands PsyDManuela Orjuela MD MScJulia Glade Bender MDOlga Militano PharmDRia Hawks RN MS PNP
Kathy Taromina MS LaC (Acupuncturist)
Diane Rooney MS LaC LMT (Acupuncturist, Massage Therapist)