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The Application of Evidence-Based Medicine to Achieve Progress in Pediatric Oncology. Malcolm Smith, MD, PhD Pediatric Section, Clinical Investigations Branch 12 September, 2000. Outline. Introduction and historical perspective

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    1. The Application of Evidence-Based Medicine to Achieve Progress in Pediatric Oncology Malcolm Smith, MD, PhD Pediatric Section, Clinical Investigations Branch 12 September, 2000

    2. Outline • 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

    3. Childhood 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

    4. Breast 14.7% Lung Prostate 14.2% 17.1% Colorectal 11.0% Bladder 4.1% NHL Other 3.9% 32.2% Uterus 2.8% Age-Adjusted SEER Cancer Incidence, 1991-95, Reflecting Cancers Occurring among Adults

    5. Childhood 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

    6. Justification for Separate Studies for Children 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.

    7. Survival Rates Have Dramatically Improved 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, 1973-96

    8. Remarkable Past Progress Leukemia Mortality 1950-96 Age < 20 Years

    9. Childhood Acute Lymphoblastic Leukemia (ALL) Survival Rates:1960-1996 Age < 15 Years SEER (9 areas)

    10. Childhood Lymphoma Mortality 1950-97 Age < 20 Years

    11. Remarkable Past Progress NHL Survival Rates:1960-1996 Age < 15 Years SEER (9 areas)

    12. 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

    13. Why Randomized Phase III 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!

    14. Why Randomized Phase III 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).

    15. Selection Bias in High-dose Chemotherapy (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)

    16. NCI-Supported Clinical Research for Children 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

    17. NCI-Supported Clinical Research for Children 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

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

    19. From Phase I to Phase III--Ifosfamide/Etoposide for Ewing’s Sarcoma • 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

    20. Randomized Trials for Pediatric Cancers - Ewing’s Sarcoma

    21. Randomized Trials for Pediatric Cancers - 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

    22. Results from Recent Phase III Trials for Children 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

    23. Study Questions for Recently Completed/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

    24. 100 Years of Number of DIagnosis Children % Survival 1989-93 3,080 80 1983-89 3,712 1978-83 2,979 60 1972-75 1,313 1972-75 936 40 1970-72 499 20 C C G Bleyer 1968-70 402 Total Number of 12,921 0 2 6 8 10 4 Patients Treated: Years from Diagnosis CCG: Survival of Children with Acute Lymphoblastic Leukemia

    25. Risk-Adjusted Therapy:Classifying 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

    26. Risk-Adjusted Therapy:Classifying 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. Poor Prognosis Group Favorable Prognosis Group Patients destined to survive Patients destined to have poor outcome

    27. Risk-Adjusted Therapy: Assigning Treatment 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.

    28. Risk-Adjusted Therapy Requires the Identification 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

    29. Scope of NCI-Supported Pediatric Clinical 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

    30. Pediatric Clinical Trials Cooperative Groups • 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

    31. 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.

    32. Pediatric Cooperative Group Clinical Trials Program --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

    33. Pediatric Cooperative Group Clinical Trials 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

    34. Pediatric Cooperative Group Clinical Trials 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.

    35. Pediatric Cooperative Group Clinical Trials Program --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.

    36. Survivors 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

    37. Childhood Cancer Survivor Study (CCSS): - Study Design Retrospective Cohort n ~ 13,000 Newly Diagnosed 1970-1986 <21 yrs at Diagnosis Survived 5 yrs. from Diagnosis English-, Spanish-speaking Reside in U.S. or Canada Surveyed for long-term health and psychosocial status

    38. Selected 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

    39. Unmet 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

    40. Distribution of Cancer Mortality in Children 0-19 Years Leukemia 33%

    41. Moving 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”??

    42. Molecularly Targeted Therapies for Childhood Cancers--2000 • BCR-ABL positive ALL • Tyrosine kinase inhibitors • Monoclonal antibody therapies: • Acute lymphoblastic leukemia • Non-Hodgkin’s lymphomas • Neuroblastoma • Growth factor receptor inhibitors • EGF, PDGF, TRK

    43. Bcr-Abl as Target for Treatment of Philadelphia 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, 1996 Blood 90:4947,1997 & Clin Can Res 4:1661,1998

    44. Mechanism of Action STI571 9;22 translocation bcr-ablfusion protein bcr- ablfusion protein Ph+ ALL Normal hematopoiesis

    45. Bcr-Abl as Target for CML and Ph+ 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

    46. 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.

    47. 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