Pediatric Oncology Research: The Impact of Collaborative Clinical Trials

1
Pediatric Oncology ResearchThe Impact of
Collaborative Clinical Trials

• Mary Lou Schmidt, MD
• Head, Division of Pediatric Hematology/OncologyDe
  partment 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
  lt15 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 Cancers Impact

• The leading cause of death by disease for
  children lt 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 disability
• 25 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 infe
  rtility
• Endocrinopathies second cancers
• vision 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 lt 8yrs 16
  retinoblastoma, Wilms tumor, neuroblastoma,
  hepatoblastoma

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The patients and families
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5-Year Cancer Survival RatesU.S., 1960-1993
lt15 Year-Olds
A Bleyer
70
5-Year Survival
50
30
Modified from Landis SH et al, CA - Cancer J
Clin 486-29. 1998
1960-3
1970-3
1974-6
1980-2
1983-5
1986-93
1977-9
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Potential Areas for Cancer Research

• Epidemiology causes of cancer
• Pre-clinical studies
• Biology studies from clinical specimens
• Clinical Trials Phase I, II, III
• Quality of Life Studies
• Late Effects Studies
• Disparities Studies
• End of Life Studies

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Improvement in Annual Cancer Mortality Rate among
U.S. Children lt15 Years of Age 1950-2000
A Bleyer
8
Mortality per 100,000, Age- Adjusted
6
( )
4
2
1950
1960
1970
1980
1990
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A Bleyer
IRSG
NWTSG
SWOG Pediatric Division
POG
CALGB Pediatric Division
CCG
1960
1970
1980
1990
2000
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The Childrens 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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Childrens Oncology Group Clinical Trials
Research Program

• Goal improve survival decrease toxic side
  effects by
• comparing 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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Childrens 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 Ds (clinicians, researchers)
• Social Workers, psychologists
• Researchers MD, PhD, MD/PhDs

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COG Studies

• Childhood Cancer Research Network Registry
• track incidence, demographics for all new
  pediatric cancers
• Obtain contact info and consent from patient and
  family to contact for future studies
• Epidemiology Quality of Life
• Survivorship Late Effects
• Fertility Insurance/Employment
• Educational level Ethics/End of Life Care

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Acute Lymphoblastic Leukemia (n3000)

• 20 open studies/14 for newly dxd pts
• Studies biology, ethnic differences,
  pharmacokinetics, therapeutic
• Clinical Trials precursor B-cell ALL
• infant (survival30)
• 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 (n2000)

• Medulloblastoma, astrocytoma, ependymoma, germ
  cell tumors
• Prognosis depends on surgical accessibility,
  histology, grading (/-) (surv0-80)
• 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 (n500)

• Low/intermediate risk stages 1-4, 4s if age lt
  18mos, MYCN-non-amplified
• (survgt 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 gt 18 mos, any tumor with
  MYCN amplification
• (surv30-50)
• Clinical Trial chemo/RT/auto transplant 1 vs.
  2), retinoic acid, antibody therapy (yes vs no)

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Retinoblastoma (n250)

• 7 open protocols (epi, biology, therapeutic)
• Prognosisgt 95 survival, 95 vision
• Clinical Trials
• Unilateral dz surg/path study
• Bilateral dz chemo/thermoRx study
• Metastatic 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 (n400)

• 7 open COG studies
• Biology, tumor banking, quality of life,
  therapeutic studies low (surv98), intermediate
  (90), high risk dz (80) and relapsed/refractory
  dz (11-50)
• Clinical Trial
• 1) eliminate radiation for rapid and complete
  responders
• 2) Intensify therapy for slow responders
• 3) Improve survivorship for relapsed dz

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Sarcomas (n750)

• Rhabdomyosarcoma
• low risk young, embryonal histology
• (surv gt90)
• intermediate older, alveolar (surv68)
• 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-(surv70) with chemo
• Pulm mets only (surv40) with chemo/RT
• Bone mets (survlt 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 NO
• improvement 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 Leukemia Disease Free Survival
Stock W Sather H, Dodge RK, Bloomfield CD, Larson
A, Nachman J. Blood 96 467a, 2000.
DFS
16-20 Years (N 103)
CALGB
20-29 Years (N 123)
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Relative Participation of U.S. Children and
Adults with Cancer on Clinical Trials
Participating in Clinical Trials
A Bleyer
100
80
60
40
20
0
Adults
Children
30
Accrual to Cooperative Group Clinical Trials
10/97 to 9/98
A Bleyer
1855
2000
Number of Patients on Clinical Trials
1500
1263
997
1000
761
819
413
500
162
126
0
0-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
Age (Years)
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Estimated Proportion of Adolescent Young Adults
with Cancer on Clinical Trials
A Bleyer
Number of Patients
0-4
5-9
10-14
15-19
20-30
Age (Years)
32
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 AYAs and MDs
• Nurse/CRAs, 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 Trials

• National 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/MDs
• Clinical Research Nurses
• Regulatory Researchers
• Community educator to improve referrals
• Travel Funds to COG meetings
• Supplies-computers, specimen submissions

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COG _at_ 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. Baldricks Foundation

• A thank you note can go a long way!
• 550,000 (2006-2009) _at_ UIC/Rush/Stroger
• Supports salaries for clinical research
  associates, RNs, 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, MD
• Head, Division of Pediatric Hematology/OncologyDe
  partment of PediatricsUniversity of Illinois at
  Chicago
• College of Medicine
• telephone  [phone]
• e-mail mls3_at_uic.edu