11

The Application of Evidence-Based The Application of Evidence-Based Medicine to Achieve Progress in Medicine to Achieve Progress in Pediatric OncologyPediatric Oncology

Malcolm Smith, MD, PhDMalcolm Smith, MD, PhD

Pediatric Section, Clinical Investigations BranchPediatric Section, Clinical Investigations Branch

12 September, 200012 September, 2000

http://ctep.info.nih.gov/

OutlineOutline

Introduction and historical perspective Importance of phase III randomized

clinical trials to progress Importance of risk-adjusted therapy to

developing better treatment strategies Clinical trials research infrastructure Unmet needs and future directions

Childhood CancerChildhood Cancer

8700 new cases diagnosed annually in children younger than 15 years of age and 12,400 cases in persons younger than 20 years

Approximately 1700 children younger than 15 years and 2300 children/adolescents younger than 20 years die each year in U.S.

Most of the cancers of children differ from those of adults in their histology and in their biological characteristics

Age-Adjusted SEER Cancer Incidence, 1991-95, Age-Adjusted SEER Cancer Incidence, 1991-95, Reflecting Cancers Occurring among AdultsReflecting Cancers Occurring among Adults

Prostate17.1%

Breast14.7%

Lung14.2%

Colorectal11.0%

Bladder4.1% NHL

3.9%Uterus2.8%

Other32.2%

Distribution of Cancer Diagnoses: 0-14 Years

ALL23.5%

AML4.7%

Brain22.1%

Neuroblastoma7.9%

Wilms' tumor6.0%

NHL5.7%

Hodgkin's3.6%

Rhabdomyosarcoma3.6%

Non-RMS3.5%

Germ cell (gonadal)3.5%

Retinoblastoma3.2%

Osteosarcoma2.6%

Other 10.1%

Childhood Cancer Clinical ResearchChildhood Cancer Clinical Research

National efforts are essential for studying specific childhood cancers because of the limited numbers of children with individual cancer types

The NCI has supported since the 1950s a nationwide clinical research program specifically designed to improve the outcome and quality of life for children with cancer

Justification for Separate Studies for Justification for Separate Studies for Children with CancerChildren with Cancer

The cancers of children are generally biologically distinctive from those occurring in adults.• The response of childhood cancers to anti-cancer

treatments may be qualitatively or quantitatively different from that of adult cancers

The ability of children to tolerate anti-cancer treatments may differ from that of adults.

Investigators with special expertise in pediatric oncology are best qualified to prioritize, design, and implement clinical trials for children with cancer.

Survival Rates Have Dramatically Survival Rates Have Dramatically Improved for Children with CancerImproved for Children with Cancer

Small minority of children cured of their cancer in 1960

Current 5-year survival rates for children with cancer < 15 years = 75%

Childhood cancer mortality rate decreased nearly 50% from 1973-96

The decrease in childhood cancer mortality continued in the 1990s at rate of 2.7% per year

SEER Cancer Statistics Review, 1973-96http://www-seer.ims.nci.nih.gov/Publications/

Remarkable Past Progress Leukemia Mortality 1950-96

0

5

10

15

20

25

30

35M

orta

lity

per

mill

ion

1950 1955 1960 1965 1970 1975 1980 1985 1990 1995

Year

Age < 20 Years

Childhood Acute Lymphoblastic Leukemia (ALL) Survival Rates:1960-1996Survival Rates:1960-1996

3%

34%

69%

82%

0%

20%

40%

60%

80%

100%5-

Yea

r S

urv

ival

%

1960-63 1970-73 1979-82 1989-96

Age < 15 Years SEER (9 areas)

http://www-seer.ims.nci.nih.gov/

Childhood Lymphoma Mortality 1950-97

0

1

2

3

4

5

6

7

8M

orta

lity

per

mill

ion

1950 1955 1960 1965 1970 1975 1980 1985 1990 1995

Year

Age < 20 Years

Remarkable Past Progress NHL Survival Rates:1960-1996Survival Rates:1960-1996

18%

45%

62%

78%

0%

20%

40%

60%

80%

100%

1960-63 1974-76 1980-82 1989--96

Age < 15 Years SEER (9 areas)

http://www-seer.ims.nci.nih.gov/

Contributions of NCI-Supported Nationwide Clinical Trials System to Improved Outcome

Conducting randomized phase III clinical trials that reliably identify superior new treatments

Providing children with cancer throughout the United States and Canada access to state-of-the-art treatment protocols that are developed by national experts and that have multiple levels of review for scientific quality and multiple levels of review for patient safety

Providing central review of pathology and imaging leading to improved diagnosis and staging

Supporting research studies leading to the identification of reliable clinical and biological prognostic factors

Why Randomized Phase III Why Randomized Phase III Clinical Trials??Clinical Trials??

Because what is logical and should work often doesn’t:• Identifying new superior treatments is an empirical,

not a deductive process

Example: Anti-arrhythmic therapy to prevent mortality from fatal arrhythmias

1. Elevated VPBs are associated with early death

2. Encainide and flecainide suppress VPBs

3. Therefore, encainide and flecainide should reduce mortality in patients with VPBs

WRONG!

Why Randomized Phase III Why Randomized Phase III Clinical Trials??Clinical Trials??

Need reliable answers to questions of therapy:• Example: Accepting a more toxic therapy as superior when

it is not better than standard therapy has serious consequences for future patients.

Conclusions from single arm (non-randomized) clinical trials have limited reliability:• Apparent improvements ascribed to treatment are often

due to patient selection (selection bias)– Historical control populations may differ from current study

populations

• Improvement ascribed to one intervention may be due to second uncontrolled factor (supportive care, XRT, surgery).

Selection Bias in High-dose Selection Bias in High-dose Chemotherapy (HDCT) TrialsChemotherapy (HDCT) Trials

Single arm trials suggested higher response rates and survival rates for HDCT in women with breast cancer

Outcome for 1581 patients with metastatic breast cancer treated with conventional doxorubicin-based regimens, not HDCT: (J Clin Oncol 15:3171,1997)

CR% MedianPFS

5-YrSurvival

HDCTEligible

27% 16 mos 21%

HDCTIneligible

7% 8 mos 6%

NCI-Supported Clinical Research for NCI-Supported Clinical Research for Children with Cancer--Phase III TrialsChildren with Cancer--Phase III Trials

Phase III trials generally require 100s of patients to reliably identify clinically meaningful differences between treatments being compared

Patients randomized to receive “best available” therapy or to receive a new treatment• The new treatment is prioritized for evaluation based on

preliminary data suggesting its potential for improving outcome (i.e., increase survival, diminished toxicity)

Address important questions of therapy for which the answer is not known

NCI-Supported Clinical Research for NCI-Supported Clinical Research for Children with Cancer--Phase III TrialsChildren with Cancer--Phase III Trials

Participation in Phase III trials is considered an appropriate “standard of care” for children with cancer:• Rationale: Many current treatments are sub-optimal because

of limited efficacy and/or excessive toxicities• Safeguards for patient protection: multiple levels of scientific

review and review for patient safety, and appropriate informed consent/assent

• Given the above, it is felt appropriate in most circumstances to ask families to consider participation in phase III trials

Phase III trials available for most types of childhood cancer • ~ 25 phase III trials at any given time

Randomized Trials for Pediatric Acute Randomized Trials for Pediatric Acute Lymphoblastic Leukemia: CCG-1922Lymphoblastic Leukemia: CCG-1922

S ta nd a r d R isk A L L

P red nisoneO ra l 6M P

O P

P red nisoneIV 6M P

IP

D exam ethasoneO ra l 6M P

O D

D exam ethasoneIV 6M P

ID

N ew ly D iagnosed A L LS tand ard R isk

CCG-1922 EFS FROM ON STUDY (RANDOMIZATION) BY REGIMEN

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6

YEARS

PR

OB

AB

ILIT

Y

OP

IP

OD

ID

(N=270)

(N=260)

(N=274)

(N=256)

From Phase I to Phase From Phase I to Phase III--Ifosfamide/Etoposide for Ewing’s III--Ifosfamide/Etoposide for Ewing’s SarcomaSarcoma

1986: Ifosfamide reported as active agent for Ewing’s sarcoma

1987: Ifosfamide/etoposide (IE) combination reported as active for Ewing’s sarcoma

1988: Phase III trial evaluating IE for Ewing’s sarcoma begins

1994: Phase III trial closes 1995: Phase III trial results reported: IE

improves outcome for Ewing’s sarcoma

Randomized Trials for Pediatric Randomized Trials for Pediatric Cancers - Ewing’s SarcomaCancers - Ewing’s Sarcoma

IN T -0 0 9 1 - In te r g r o up E w ing ’s S a r c o m a S tud y

V cr + D ox + C ycT reat q 3 w eeks

V cr + D ox + C ycA ltern atin g w ithIf osf am id e + E top osid eT reat q 3 w eeks

L oca lized E w in g 's S arcom a

Randomized Trials for Pediatric Randomized Trials for Pediatric Cancers - Ewing’s SarcomaCancers - Ewing’s Sarcoma

Trial Results: Patients receiving the ifosfamide/etoposide combination (n=198) had superior 3-yr EFS rates compared to pts receiving standard therapy (n=200): • 69% 3-yr EFS vs 50% 3-yr EFS (p = 0.0005)

Significance: The INT-0091 defined a new standard therapy for Ewing’s sarcoma that includes ifosfamide + etoposide.

Determining this required a commitment of resources for over a decade from the time of the initial evaluation of ifosfamide in children

Results from Recent Phase III Trials for Results from Recent Phase III Trials for Children with CancerChildren with Cancer

ABMT is superior to intensive conventional therapy as consolidation therapy for children with neuroblastoma

Cis-retinoic acid maintenance therapy following ABMT improves outcome for children with neuroblastoma

Reducing the dose of craniospinal radiation for children with medullblastoma increases the relapse rate

Pulse-intensive short courses of therapy have similar efficacy as more burdensome, long courses of therapy for children with Wilms’ tumor

Study Questions for Recently Study Questions for Recently Completed/Ongoing Phase III TrialsCompleted/Ongoing Phase III Trials

High-dose methotrexate for T-cell ALL Dexrazoxane as a cardioprotectant for children with T-cell

ALL and children with Hodgkin’s disease Dose-intensive therapy for Ewing’s sarcoma Ifosfamide and MTP-PE for osteosarcoma Triple intrathecal therapy for children with ALL Defining optimal thiopurine for children with ALL MDR-reversal agent for children with AML Ch14.18 (anti-GD2 monoclonal antibody) for children with

neuroblastoma following ASCT Topotecan + cyclophosphamide for rhabdomyosarcoma

CCG: Survival of Children withAcute Lymphoblastic Leukemia

8080

6060

4040

2020

100100 Years of Years of Number of Number of

1972-751972-751972-751972-75

00 22 44 8866 1010

Years from DiagnosisYears from Diagnosis

%%

SSuurrvviivvaall

1989-931989-93

1983-891983-891978-831978-83

1970-721970-72

1968-701968-70

3,0803,080

3,7123,7122,9792,9791,3131,313

936936

499499

402402

DIagnosisDIagnosis ChildrenChildren

12,92112,921Total Number ofTotal Number ofPatients Treated:Patients Treated:

C C GC C GBleyerBleyer

Risk-Adjusted Therapy:Risk-Adjusted Therapy:Classifying Patients by PrognosisClassifying Patients by Prognosis

The approach to treatment (and to clinical trial design) differs based on the anticipated outcome for the population.

Patients destined to survive

Patients destined to have poor outcome

Risk-Adjusted Therapy:Risk-Adjusted Therapy:Classifying Patients by PrognosisClassifying Patients by Prognosis

If prognostic factors can be identified that allow identification of which patients do well with current therapy and which do poorly, this allows treatment intensity/risk to be better tailored to likely outcome.

Patients destined to survive

Patients destined to have poor outcome

Poor Prognosis Group

Favorable Prognosis Group

Risk-Adjusted Therapy: Assigning Risk-Adjusted Therapy: Assigning Treatment Based on PrognosisTreatment Based on Prognosis

Patients who have low survival rates with current treatments may benefit from novel, more aggressive therapeutic approaches that are associated with greater risk.

Patients who have very good outcome with current therapy should be spared more intensive and toxic treatments.

Risk-Adjusted Therapy Requires the Risk-Adjusted Therapy Requires the Identification of Reliable Prognostic FactorsIdentification of Reliable Prognostic Factors

Identification of reliable prognostic factors:• Requires analyzing outcome for large

numbers of patients, preferably treated in uniform manner.

• For biological prognostic factors, requires collection and analysis of tumor tissue.

Protocol-treated patients and Cooperative Group tumor banks have been invaluable in identifying and confirming prognostic factors

Scope of NCI-Supported Pediatric Scope of NCI-Supported Pediatric Clinical Trials ProgramClinical Trials Program

Approximately 5000 children entered onto treatment trials each year.• 3,800 Phase III entries to ~ 25 trials• 700 Phase II entries to ~ 30 trials• 250 Phase I to ~ 25 trials

Accrual to Phase III by tumor type:• ALL ~ 1,900 (2,300)• AML ~ 410• Wilms ~ 480• Ewing’s ~ 160• Osteosarcoma ~230

Pediatric Clinical Trials Cooperative Pediatric Clinical Trials Cooperative GroupsGroups

Cooperative Groups supported via Cooperative Agreements with the NCI:• Children’s Cancer Group• Pediatric Oncology Group• Intergroup Rhabdomyosarcoma Study Group• National Wilms’ Tumor Study Group

Represent over 200 institutions throughout U.S. and Canada that are involved in the treatment of most children with cancer

Children’s Oncology Group Merger of pediatric clinical trials groups into

single entity: the Children’s Oncology Group• Improved efficiency in developing and conducting

clinical trials for children with cancer.

Pediatric Cooperative Group Clinical Trials Pediatric Cooperative Group Clinical Trials Program --Participating ResearchersProgram --Participating Researchers

Multimodality:• Hematologist/oncologist

• Surgeons (including orthopedic surgeons neurosurgeon, etc.)

• Radiation oncologist

• Pathologist and laboratory researchers

• Nurses

• Epidemiologist

• Radiologist

• Clinical Research Associates (Data managers)

• And others

Pediatric Cooperative Group Clinical Pediatric Cooperative Group Clinical Trials Program --Supported Structures 1Trials Program --Supported Structures 1

Operations Office• Coordinate protocol development & distribution• Organize semi-annual meetings• Distribute funds to member institutions• Regulatory oversight & negotiate contracts with pharmaceutical

companies when appropriate

Statistical Center• Statistical design of protocols• Data collection and management• Assure IRB review prior to protocol entry• Analysis of data from trials• Institutional performance review• Coordinate on-site audit program

Pediatric Cooperative Group Clinical Pediatric Cooperative Group Clinical Trials Program --Supported Structures 2Trials Program --Supported Structures 2

Member Institutions• Principal investigator at institution• Clinical research associates• Partial reimbursement for research costs of

patient accrual (~$1,725 per patient direct costs)

• Support for tissue collection and shipping to central reference laboratory/tumor bank

• Support for submitting radiographs, pathology reports, surgical reports, etc.

Pediatric Cooperative Group Clinical Trials Pediatric Cooperative Group Clinical Trials Program --Supported Structures 3Program --Supported Structures 3

Disease and Discipline Committees• Committees responsible for developing the

questions of therapy for clinical trials• Examples of Disease Committees: ALL, AML,

Neuroblastoma, Bone Tumor, etc.• Examples of Discipline Committees: Surgery,

Radiation Oncology, Nursing, etc.• Study Committees for developing and

implementing individual clinical trials generally assigned by Disease Committees.

Survivors of Childhood CancerSurvivors of Childhood Cancer

At risk for long-term sequelae of therapy and for sequelae of cancer itself:• Cardiac and Pulmonary• Second Neoplasms• Fertility and Offspring• Central Nervous System• Musculoskeletal• Psychosocial

Retrospective Cohort n ~ 13,000Newly Diagnosed 1970-1986<21 yrs at DiagnosisSurvived 5 yrs. from DiagnosisEnglish-, Spanish-speakingReside in U.S. or Canada

Surveyed for long-term health and psychosocial status

Childhood Cancer Survivor Childhood Cancer Survivor Study (CCSS): - Study DesignStudy (CCSS): - Study Design

Selected CCSS Analyses in ProgressSelected CCSS Analyses in Progress

Late mortality in childhood cancer survivors Second malignant neoplasms following

childhood cancer Pregnancy outcomes after treatment for

cancer during childhood or adolescence Cancer in offspring of pediatric cancer

patients Thyroid disease in survivors of childhood

and adolescent Hodgkins disease Smoking among childhood cancer survivors

Unmet NeedsUnmet Needs Over 2000 children and adolescents die

from cancer each year in U.S. Some children who are cured experience

diminished quality of life because of the long-term effects of their cancer diagnosis and treatment

Current therapy is near-maximal intensity, and new treatment strategies are needed to improve outcome for these children

Figure 11

Leukemia 33.0%

CNS 24.0%

Endocrine 9.0%

Hodgkin's 1.0%

NHL 6.0%

Kidney 3.0%

Liver 2.0%

Bone 7.0%

Soft tissue 7.0%

Other 8.0%Distribution of Cancer Mortality in Children 0-19 Years

Leukemia 33%

Moving Towards a New EraMoving Towards a New Era Molecularly targeted therapies:

Treatments based on the specific molecular characteristics of the cancer

In principle, more specific for processes required for tumor cell survival and growth

But: • Will they be less harmful to normal

tissues??• Will there be a therapeutic window for

these “targeted therapies”??

Molecularly Targeted Therapies Molecularly Targeted Therapies for Childhood Cancers--2000for Childhood Cancers--2000

BCR-ABL positive ALLBCR-ABL positive ALL• Tyrosine kinase inhibitorsTyrosine kinase inhibitors

Monoclonal antibody therapies:Monoclonal antibody therapies:• Acute lymphoblastic leukemiaAcute lymphoblastic leukemia• Non-Hodgkin’s lymphomasNon-Hodgkin’s lymphomas• NeuroblastomaNeuroblastoma

Growth factor receptor inhibitorsGrowth factor receptor inhibitors• EGF, PDGF, TRKEGF, PDGF, TRK

Bcr-Abl as Target for Treatment of Bcr-Abl as Target for Treatment of Philadelphia Chromosome Positive ALLPhiladelphia Chromosome Positive ALL

Ph+ ALL with the Bcr-Abl fusion protein has very poor outcome among children

Bcr-Abl fusion protein has an enzyme activity (tyrosine kinase) necessary for leukemogenic effect.

STI571: Inhibitor of the Bcr-Abl, PDGF, and c-KIT receptor protein-tyrosine kinases. • Inhibits proliferation & induces apoptosis

Nat Med 2:561, 1996 & Cancer Res 56:100, 1996Blood 90:4947,1997 & Clin Can Res 4:1661,1998

Mechanismof Action

9;22 translocation

bcr-abl fusion protein

Normal hematopoiesis

Ph+ ALL

STI571

bcr- abl fusion protein

Bcr-Abl as Target for Bcr-Abl as Target for CML and PhCML and Ph++ ALL Therapy ALL Therapy

Phase I trials completed in adults with CML with very high levels of anti-leukemia activity observed

Pediatric phase I trial ongoing Pilot study for newly diagnosed

patients with Ph+ ALL planned for early 2001

Summary 1 The public health of children has been

improved by long-term, sustained NIH support of an ongoing infrastructure for conducting clinical research for children with cancer.

Superior new treatments have been identified based on definitive evidence, and these treatments have been made widely available to children with cancer throughout the United States and Canada.

Summary 2: Progress Depends on Collaboration and Cooperation

Pediatric cancer researchers (clinical and laboratory) and health care professionals

Families and their advocates National Cancer Institute Academic and pharmaceutical developers of

new cancer treatments and the FDA Third party payers Working together so that the most promising

therapeutic approaches are expeditiously evaluated with the ultimate objective of improving outcome for children with cancer