Pediatric Oncology Research:The Impact of

Collaborative Clinical Trials

Mary Lou Schmidt, MDHead, Division of Pediatric Hematology/Oncology

Department of PediatricsUniversity of Illinois at Chicago

College of Medicine

Important Concepts Pediatric Oncology Partnerships have led to

dramatic gains against childhood cancer: (age <15 yrs: survival 80%)

2/3 of survivors of childhood cancer have a major disability by 25 years of age

15-45 year olds have had NO improvement in their survival from cancer in the last 30 years.

Childhood Cancer’s Impact

The leading cause of death by disease for children < 15 years of age

(greater than HIV, heart disease, cystic fibrosis, infection combined)

12,000 US cases/year, 160,000 cases worldwide

20% death rate in Western World (1 in 5 die)65% of survivors have a major disability25% of survivors have 3-4 disabilities/one of

which is life-threatening

Pediatric Oncology World Goal Improve the survival rates for childhood

cancer Reduce the immediate and long-term side

effects causing deficits/disabilities:

cognitive musculoskeletal pulmonary fibrosis cardiomyopathy renal insufficiency infertilityEndocrinopathies second cancersvision loss hearing loss

Specific types of childhood cancer

Hematologic: acute leukemias-33%lymphomas-12%

Solid tumors: brain tumors-20% muscle or bone tumors- 12%

Solid Tumors in children < 8yrs: 16% retinoblastoma, Wilm’s tumor, neuroblastoma, hepatoblastoma

The patients and families……

5-Year Cancer Survival RatesU.S., 1960-1993

%%5-Year5-Year

SurvivalSurvival

Modified from Landis SH et al, CA - Cancer J Clin 48:6-29. 1998Modified from Landis SH et al, CA - Cancer J Clin 48:6-29. 1998

5050

7070

3030

1960-31960-3 1970-31970-3 1974-61974-6 1980-21980-2 1983-51983-5

<15 Year-<15 Year-OldsOlds

1986-931986-931977-91977-9

AdultsAdults

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Potential Areas for Cancer Research

Epidemiology: causes of cancerPre-clinical studies Biology studies from clinical specimensClinical Trials: Phase I, II, IIIQuality of Life StudiesLate Effects StudiesDisparities StudiesEnd of Life Studies

Improvement in Annual Cancer Mortality Rate among U.S. Children <15 Years of Age: 1950-2000

( )

1950 1960 1970 1980 1990

2

4

6

8

Mortality per

100,000, Age-

Adjusted

CCG

NWTSG

IRSG

POG

CALGB Pediatric Division

SWOG Pediatric Division

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OO..C. GG

Oncology Group

1960 1970 1980 1990

CCG

NWTSG

IRSG

POGCALGB Pediatric Division

SWOG Pediatric Division

2000

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The Children’s Oncology Group

250 institutions: US, Australia, Canada, Switzerland, the Netherlands and New Zealand including:

St. Jude, Sloan-Kettering, Mayo Clinic, Harvard, Stanford, MD Anderson

7 Chicagoland COG programs: UIC + Rush (+ Stroger);

CMH, U of C, Loyola, Lutheran General, Christ

Children’s Oncology Group Clinical Trials Research Program

Goal: improve survival & decrease toxic side effects bycomparing new experimental therapy to current standard of care

150 clinical trials currently available

Each trial enrolls: 30-2000 patients

Trials frequently randomize patients between 2-4 different arms

Each trial must be locally approved and managed, With high quality data entered on time and on-line,And institutional audits passed every 3 years

Results are published collaboratively

Children’s Oncology GroupClinical Trials Research Program Succeeds because of

Full participation by all US Pediatric Oncologists in a

Collaborative Spirit, using scarce shared resources which has led to amazing forward progress

Fueling further research & education

COG Members Pediatric Oncologists Nurses Clinical Research Associates Radiologists Surgeons (ophtho, ortho, neuro, peds) Pathologists (cytogenetics, surgical) Radiation Therapists Pharm D’s (clinicians, researchers) Social Workers, psychologists Researchers: MD, PhD, MD/PhD’s

COG Studies Childhood Cancer Research Network Registry a) track incidence, demographics for all new pediatric cancers

b) Obtain contact info and consent from patient and family to contact for future studies:

Epidemiology Quality of LifeSurvivorship Late EffectsFertility Insurance/EmploymentEducational level Ethics/End of Life Care

Acute Lymphoblastic Leukemia(n=3000)

20 open studies/14 for newly dx’d pts Studies: biology, ethnic differences,

pharmacokinetics, therapeutic Clinical Trials: precursor B-cell ALL:

infant (survival=30%)standard risk-(85%)high risk (65%)very high risk (40%)relapsed (late 50%), early (20%)

T-cell (70%)B-cell (80%)

ALL COG Studies Use clinical/biologic markers to define risk

and eligibility for therapeutic trials

WBC, CSF +/-, testicular involve Leukemia cell cytogenetics Minimal residual disease markers when

BMA shows remission Clinical Trial: alter Rx for best outcome

and least late effects (randomize when possible)

Brain Tumors (n=2000) Medulloblastoma, astrocytoma,

ependymoma, germ cell tumors Prognosis depends on surgical accessibility,

histology, grading (+/-): (surv=0-80%) 13 open studies: bio, epi, banking, qol,

Clinical trial: Radiation Therapy as variable: conformal, reduced dosing, combined with chemo

Chemo: various regimens, temazolomide, intrathecal topotecan, high dose chemo/auto stem cell tx

Neuroblastoma (n=500) Low/intermediate risk: stages 1-4, 4s if age < 18mos,

MYCN-non-amplified(surv=> 90%) with surgery +/- mod dose chemo

Clinical trial: reduce therapy: minimize surgery (neonate, cord); only need 50% reduction in tumor, avoid RT

High risk: stage 3,4 > 18 mos, any tumor with MYCN

amplification(surv=30-50%)

Clinical Trial: chemo/RT/auto transplant 1 vs. 2), retinoic acid, antibody therapy (yes vs no)

Retinoblastoma (n=250) 7 open protocols (epi, biology, therapeutic) Prognosis> 95% survival, 95% vision Clinical Trials:

Unilateral dz: surg/path studyBilateral dz: chemo/thermoRx studyMetastatic dz: chemo/RT/stem cell tx

1st National RB studies in COG Limited institutions includes UIC Goal: Limit radiation, central review by

Ophthalmologists & ocular pathologists

Hodgkins Lymphoma (n=400) 7 open COG studies Biology, tumor banking, quality of life,

therapeutic studies: low (surv=98%), intermediate (90%), high risk dz (80%) and relapsed/refractory dz (11-50%)

Clinical Trial: 1) eliminate radiation for rapid and complete responders2) Intensify therapy for slow responders3) Improve survivorship for relapsed dz

Sarcomas (n=750) Rhabdomyosarcoma:

low risk: young, embryonal histology (surv= >90%)intermediate: older, alveolar (surv=68%)

9 studies-banking, bio, epi, therapeutic Clinical Trial: reduce RT for favorable dz,

intensify therapy for less favorable dz

Ewings Sarcoma

Localized-(surv=70%) with chemo Pulm mets only (surv=40%) with

chemo/RT Bone mets (surv< 10%)

Studies-bio, epi, therapeutic: Clinical Trial: high dose chemo/SCT for pts w/ EWS + pulm mets

When is a kid a kid? Why have children begun to survive at

much higher rates than adults?

Why have patients ages 15-45 had NOimprovement in their survival in 30 years?

How can we improve the survival rate for adolescents and young adults?

AYA Patients

Acute Lymphoblastic LeukemiaDisease Free Survival

16-20 Years (N = 103)

20-29 Years (N = 123)

DFS

CCG-1800 Series 16-21 Year-Olds (N = 175)

68+2%

Stock W Sather H, Dodge RK, Bloomfield CD, Larson A, Nachman J.

Blood 96: 467a, 2000.

CALGB

Relative Participation of U.S. Children and Adults with Cancer on Clinical Trials

Participating in Participating in

Clinical TrialsClinical Trials

0%

20%

40%

60%

80%

100%

AdultsChildren

Therapy at Therapy at Centers Participating Centers Participating

in Clinical Trialsin Clinical Trials

AdultsChildren

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Number of Patients with Cancer

Accrual to Cooperative Group Clinical Trials10/97 to 9/98

1855

1263997

761

126 162413

819

0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39

Age (Years)

0

500

1000

1500

2000Number

of Patients

on Clinical Trials

Only 22 (of 761) entered ontoOnly 22 (of 761) entered ontoadult Cooperative Group trialsadult Cooperative Group trials

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AtAt Cooperative Group Institution; Cooperative Group Institution;notnot on Cooperative Group Trial on Cooperative Group Trial

On Cooperative Group TrialOn Cooperative Group Trial

Estimated Proportion of Adolescent & Young Adults Estimated Proportion of Adolescent & Young Adults with Cancer on Clinical Trialswith Cancer on Clinical Trials

60%60%2%

33% 29%

11%6%

60%

40%

50%10%

Age (Years)Age (Years)0-40-4 5-95-9 10-1410-14 15-1915-19

Number Number of of

PatientsPatients

20-3020-30

The Adolescent-

Young Adult Gap

in Cancer Clinical Trials

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AYA Patients

To improve survival for AYA pts

Improve access to COG clinical trials Interface with oncologists caring for

AYA pts Provide support for AYA’s and MD’s

Nurse/CRA’s, Social Workers, Ped Onc MD back-up

Benefit of inclusion in COG

Push all facets of research forward by improving enrollment on all possible Children's Oncology Group clinical trials at each local institution (biol, therapeutic, epi, QOL, ethics, disparities)

Improve survival rates: esp for adolescents and young adults

Educate the public and community-based practitioners that all patients, esp AYA pts, can have improved survival if referred promptly for enrollment on COG trials

Funding for COG Clinical TrialsNational Institutes of Health $$$ COG:

CureSearch website, tissue banks and research labs, conduct of 150 COG clinical trials, publishing costs for results

auditing 250 COG institutions

Estimated actual cost to the local COG institution:$ 7000/patient enrolled

Each COG hospital/institution receives: ____________________________ $ 2400/patient enrolled

Local Institutional Funding Gap Coverage: who pays? The treating institution and philanthropists

Requirements for maximum participation in COG Clinical Trials

Salary support for:Principal Investigator/MD’sClinical Research NursesRegulatory ResearchersCommunity educator to improve

referrals

Travel Funds to COG meetings

Supplies-computers, specimen submissions

COG @ UIC/Rush/Stroger 2007: UIC and Rush COG members in good

standing (UIC 25 open protocols, Rush 5 open protocols), Stroger not in

8/07: UIC/Rush/Stroger with 55 faculty applied for joint COG membership

8/08: Merger accepted, UIC IRB began to re-review all protocols adding Rush as 2nd performance site

2009: UIC: 40 COG studies/Rush: 8 COG studies/Stroger agreements being finalized

St. Baldrick’s Foundation

A thank you note can go a long way!

$ 550,000 (2006-2009) @ UIC/Rush/Stroger

Supports salaries for clinical research associates, RN’s, travel to COG meetings, supplies

Immediate Impact on Childhood and Adolescent/Young Adult Cancer

Open the broadest pallet of COG clinical trials possible and fully participate in all aspects of COG

Enroll, enroll, enroll all possible patients

Collaborate, collaborate, collaborate

Thank You!

Questions?

MARY LOU SCHMIDT, MDHead, Division of Pediatric Hematology/Oncology

Department of PediatricsUniversity of Illinois at Chicago

College of Medicine

telephone:  (312) 996-1791e-mail: mls3@uic.edu