Kara Kelly, M.D. Associate Professor of Clinical Pediatrics Division of Pediatric Oncology Columbia University Medical Center New York Research Methods:

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

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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

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30

40

50

60

70

# Patients Enrolled

Observational Studies: The Effect of Cancer Therapy on Antioxidant Levels (n=31)

0

2

4

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8

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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

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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

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40

50

60

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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)