pediatric oncology research: the impact of collaborative clinical trials mary lou schmidt, md head,...
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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
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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.
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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
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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
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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
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The patients and families……
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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
A Bleyer
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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
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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
A Bleyer
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OO..C. GG
Oncology Group
1960 1970 1980 1990
CCG
NWTSG
IRSG
POGCALGB Pediatric Division
SWOG Pediatric Division
2000
A Bleyer
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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
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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
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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
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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
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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
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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%)
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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)
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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
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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)
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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
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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
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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
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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
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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?
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AYA Patients
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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
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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
A Bleyer
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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
A Bleyer
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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
A Bleyer
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AYA Patients
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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
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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
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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
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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
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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
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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
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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
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Thank You!
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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: [email protected]