The Current Pediatric Oncology Landscape

Transcription

1 The Current Pediatric Oncology Landscape An Imperative for Change Smita Bhatia, MD, MPH UAB Department of Pediatrics at Children s Hospital of Alabama

2 Five-year Observed Survival Rates for Two Time Periods, Ages % % 80% 70% 60% 50% 63% 83% 500, 000 childhood cancer survivors by in 530 individuals between 20 and 39 years of age is a childhood cancer survivor 40% all cancer sites

3 US Childhood and Adolescent Cancer Survivors by Cancer Site, as of Jan 1, 2010 Bone, 13,132 Ovary, 17,092 AML, 8,267 N=379,112 <20y 20+y 300, ,330 NBL, 19,452 ALL, 60, , ,000 Testes, 20,645 NHL, 22,743 CNS, 59, , , ,782 Wilms, 23,538 50,000 STS, 31,448 HL, 35,253 0 all tumors Cancer Facts & Figures 2014

4 Landmarks in Pediatric Oncology by Decade 1970s Recognition that cure was possible Proliferation of clinical trials Effective multi-modality protocols 1990s Understanding relation of dose to late effects Initiating efforts to track and educate survivors Large and medium-sized cohorts 1980s Tailoring therapy to risk factors Identifying late effects Reducing radiation dose Substituting effective drugs for radiation 2000s Defining late effects from cohorts Understanding dose-effect relation Developing infrastructure to understand pathogenesis of late effects

5 Landmarks in Pediatric Oncology by Decade 2010s Defining late effects from cohorts Understanding dose-effect relation Developing infrastructure to understand pathogenesis of late effects Developing risk prediction models Developing targeted intervention for risk reduction

6 Childhood Cancer Survivorship 1. Describing current landscape of morbidity/ premature mortality 2. Understanding the pathogenesis of the morbidity 3. Identifying childhood cancer survivors at highest risk 4. Developing targeted interventions to reduce morbidity 5. Optimizing long-term health by partnering with parents/ patients

7 Childhood Cancer Survivorship 1. Describing current landscape of morbidity/ premature mortality 2. Understanding the pathogenesis of the morbidity 3. Identifying childhood cancer survivors at highest risk 4. Developing targeted interventions to reduce morbidity 5. Optimizing long-term health by partnering with parents/ patients

8 Long-term Sequelae in Childhood Cancer Survivors Growth and development linear growth skeletal maturation intellectual function emotional/social maturation Vital Organ Function Cardiac Pulmonary Renal Endocrine Health-related Quality of Life sexual development Gastrointestinal Vision/Hearing Fertility and Reproduction Fertility Health of Offspring Second Neoplasms Benign Malignant

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11 Chronic Conditions in Adult Survivors of Childhood Cancer Grade 1-5 The implications of cure are not trivial Cumulative Incidence Grade 3-5.Burden of morbidity in survivors of childhood cancer is substantial N Engl J Med, 2006; 355:

12 Late Mortality in Survivors of Childhood Cancer US Female US Male CCSS Female CCSS Male

13 Cumulative Cause-specific Mortality in Survivors of Childhood Cancer Relapse-related mortality Non-relapse-related mortality Mortality due to external causes

14 Childhood Cancer Survivorship 1. Describing current landscape of morbidity/ premature mortality 2. Understanding the pathogenesis of the morbidity 3. Identifying childhood cancer survivors at highest risk 4. Developing targeted interventions to reduce morbidity 5. Optimizing long-term health by partnering with parents/ patients

15 Therapeutic Exposures and Adverse Events Anthracyclines Chest Radiation Radiation Alkylating agents Topoisomerase II inhibitors Heart failure Second cancers Steroids Radiation Radiation Osteonecrosis Stroke

16 TRADITIONAL EPIDEMIOLOGY Therapeutic Exposure Adverse Outcome MOLECULAR EPIDEMIOLOGY Exposure Internal dose Biologically effective dose Altered structure/ function Preclinical disease Clinically Overt Outcome Susceptibility

17 COG ALTE03N1 Goals Identify key adverse events in childhood cancer survivors (cases) Second Cancers Osteonecrosis Congestive Heart Failure Stroke Identify childhood cancer survivors without adverse events (controls) Bank DNA and RNA from cases and controls Explore role of genetic susceptibility in development of outcomes Leukemia Lymphoma Society R01 CA

18 COG ALTE03N1 Methods Cases and Controls Therapeutic Summary Self-reported questionnaire Blood Opened: Institutions with IRB Approval 129 Samples ~5000 Saliva

19 Anthracycline-related cardiomyopathy 35 Inter-individual variability J Clin Oncol, 2012;30: Cases Controls Odds Ratio Anthracycline dose Dose dependent association

20 CBR genotype and anthracycline-related cardiomyopathy DOX DOXol 10 CBR3 activity (nmol doxol./h.mg) CBR3 V244 (G) 3.22 CBR3 M244 (A) Cardiotoxic CBR3:GG CBR3:GA/AA Drug Metab and Disp, 2005 J Clin Oncol, 2012;30:

21 Genes associated with de novo cardiovascular disease ITMAT/Broad/CARe (IBC) cardiovascular SNP-array HD anthracyclines + DM HD anthracyclines + HTN HD anthracyclines Blood, 2011;118: Odds Ratio 0-log10 (p-value) of SNPs rs *anthracycline, p=5.3x10-7 Successfully replicated in an independent cohort Reduced gene expression associated with A allele in health hearts SNP rs on gene HAS3 GG GA AA Chromosomes J Clin Oncol, 2014; 32: AA: OR=56.5 AA: OR=56.5 GA: OR=6.0 GA: OR=6.0 GG: OR= Cumulative Anthracycline Dose (mg/m 2 ) GG: OR=0.6

22 Genome-wide association study G x E interaction GG CELF4/BRUNOL4 is a protein encoded by CELF4 gene (chromosome 18) Regulates pre-mrna alternative splicing Implicated in developmentally regulated alternative splicing of cardiac troponin T (ctnt) ctnt is a biomarker of myocardial injury. Odds Ratios SNP rs on gene CELF4 AA GA GG Anthycycline Dose GA AA Coexistence of >1 ctnt variants results in a temporally split myofilament response to Ca 2+ decreased myocardial contractility Abnormal ctnt splicing variants are found in failing hearts with dilated cardiomyopathy Findings from healthy hearts suggest an association between rs GG genotype and co-existence of embryonic form of ctnt with the adult form (P=0.02)

23 Anthracycline Prescribed dose ctnt Internal dose CBR3 NAD(P)H NAD(P)H oxidase multienzyme complex NAD(P) + Dox-quinone Dox-semiquinone* Dox-ol CELF-mediated alternative splicing of ctnt >1 isoforms of ctnt HAS 3 HA Anti-oxidant activity O 2 */H ROS Mitochondrial dysfunction CELF4 CELF4 Protein Myocyte apoptosis Maladaptive LV Remodeling Asymptomatic LVEF/FS Modified: Pharmacol Rev, 2004; 56:185 Pharmacol Rep, 2009; 61: 154 Heart Failure Decreased myocardial contractility

24 Childhood Cancer Survivorship 1. Describing current landscape of morbidity/ premature mortality 2. Understanding the pathogenesis of the morbidity 3. Identifying childhood cancer survivors at highest risk 4. Developing targeted interventions to reduce morbidity 5. Optimizing long-term health by partnering with parents/ patients

25 Risk scores (sex, age at cancer diagnosis, and anthracycline and chest radiotherapy doses) AUC of 0.74 and concordance statistic of 0.76 at or through age 40 years. Validation cohort estimates ranged from 0.68 to Risk scores collapsed to form distinct risk groups with cum inc of heart failure at age 40 y Low risk group: 0.5% Moderate risk group: 2.4% High risk group: 11.7%

26 False-Positive Rate (100%-specificity) Anthracycline-related cardiomyopathy Combined clinical and genetic risk prediction model 1.00 True-Positive Rate (sensitivity) Br J Haematol, 2013 Oct;163(2): AUC 95% CI SNPs only Clinical only SNPs and Clinical

27 Childhood Cancer Survivorship 1. Describing current landscape of morbidity/ premature mortality 2. Understanding the pathogenesis of the morbidity 3. Identifying childhood cancer survivors at highest risk 4. Developing targeted interventions to reduce morbidity 5. Optimizing long-term health by partnering with parents/ patients

28 Moving Research through Translational Pipeline Cumulative inc 0.30 Radiation-related breast cancer Phase II clinical trials to reduce the risk of radiation-related breast cancer J Clin Oncol, 2003 NEJM, % Low dose Tamoxifen vs. placebo (R01 CA140245) Age in years 30% 20% 10% 0% 6MP adherence and relapse risk J Clin Oncol, 2012 Adherence < 95% p= Adherence 95% Comprehensive Approach to Improve Medicine Adherence in Pediatric Leukemia Text messaging, directly supervised therapy, education (R01 CA174683)

29 Moving Research through Translational Pipeline Unrelated Related Autologous Quadrivalent Human Papillomavirus (HPV) Vaccine in Cancer Survivors Safety, immunogenicity, efficacy Overall 5.8 R01 CA Odds Ratio Anthracycline-related CHF J Clin Oncol, 2011 Phase II clinical trial to reduce the risk of anthracycline-related CHF Carvedilol vs. placebo Leukemia Lymphoma Society, R01

30 Childhood Cancer Survivorship 1. Describing current landscape of morbidity/ premature mortality 2. Understanding the pathogenesis of the morbidity 3. Identifying childhood cancer survivors at highest risk 4. Developing targeted interventions to reduce morbidity 5. Optimizing long-term health by partnering with parents/ patients

31 Burden of Morbidity in Childhood Cancer Survivors Substantial burden of morbidity Clearly defined genetic/ therapeutic factors increase risk of long-term complications Need for extended and standardized follow-up of childhood cancer survivors Survivors and healthcare providers need to be aware of at risk populations ~35% of survivors aware of serious health problems from past treatment Impairs survivors ability to seek/receive appropriate long-term follow-up care

32 Health Care Utilization by Young Adult Survivors Percent Survivors with Medical Visits Ann Fam Med 2004;2: Years since Diagnosis Primary care providers are unfamiliar with the problems faced by childhood cancer survivors General Medical Contact (87%) General Physical Examination (72%) Cancer-related visit (42%) Cancer Center Medical Visit (19%)

33 Survivorship Issues Q1 What can clinicians, parents, and patients do to help attenuate longterm complications? Clinicians Increase awareness of long-term complications among clinicians Provide tools for standardized care Parents/ Patients Education regarding long-term complications and Health Promotion

34 Does Tailored Education Delivered in a Survivorship Clinic Improve Childhood Cancer Survivors Awareness of Personal Risk for Therapy-Related Complications? Survivorship clinics provide education to childhood cancer survivors regarding their treatment history/ health risks Impact of this tailored education on survivors awareness of their personal health risks is unclear Survivors awareness of their specific health risks evaluated for 9 therapy-related complications: - Cardiac dysfunction - Pulmonary compromise - Neurocognitive impairment - Low bone mineral density - Sensory impairment (auditory/visual) -Renal impairment - Thyroid problems - Fertility problems - SMNs Education Education Education Education Education Education T0 qq T1 qq T2 qq T3 qq T4 qq T5 qq

35 Personal Health Risks Awareness of Health Risks: At Study Entry and after 3 Education Sessions SMN Fertility Sensory Thyroid Renal Bone Neurocog Pulmonary Cardiac after 3 visits 35% 25% 29% 34% 34% 39% 39% 49% 44% Baseline 63% 59% 69% 67% 67% 68% 72% 82% 81% 0% 20% 40% 60% 80% 100% % of patients aware of health risk % of Personal Risk of Complications Correctly Identified by At-Risk Survivors 70% 60% 50% 40% 30% 38.6% Awareness of Health Risks: Longitudinal trajectory of knowledge gain Predicted p< % p= % Mean P< % 66.7% 66.3% Number of Education Sessions p=0.7 GEE: Adjusted for diagnosis, HCT, race/ethnicity, education

36 Survivorship Issues Are we approaching survivorship in an evidence-based fashion? 1. Described the health and well being of cancer survivors 1. Magnitude of risk of specific complications 2. Associations between therapeutic exposures and specific outcomes 2. Development of Risk Prediction Models (primary prevention) 3. Interventions (Secondary and Tertiary)

37 Magnitude of risk of specific complications Associations between therapeutic exposures and specific outcomes Cumulative Incidence (%) 25% 20% 15% 20.2% 10% 5% 0% Years after Hodgkin lymphoma Odds ratio Breast Cancer Risk by Radiation Dose Radiation-related breast cancer Dose to breast (Gy)

38 Comprehensive Follow-up of Cancer Survivors Summarization of therapy exposures Long-term Follow-up Guidelines End of therapy Follow-up of survivors using evidence-based guidelines 1. Cost-effectiveness of screening guidelines 2. Yield of screening

39 Screening: Therapy-Related CHF Efficacy (decrease in CHF risk): not demonstrated Cost-effectiveness (value for money): unknown Examine efficacy and cost-effectiveness of ECHO screening for cardiac dysfunction 1. COG-recommended screening frequencies 2. Other frequencies: every 1-5 years Modeling and simulation approach Efficacy Gain of 0.15 QALY (1.7 QALM) per CCS 12% reduction in CI of CHF at 50y after cancer dx Cost-effectiveness CCS cohort: $41,000 per QALY 11 risk profiles: $28,000 - $80,000 per QALY Can we improve upon the COG Guidelines? Alternative ECHO frequencies proposed Less frequent screening Cheaper: $23,000 vs $41,000 per QALY Similar efficacy QALY: 0.13 vs 0.14 CI of CHF 50y post-ca dx: 11% vs 12%

40 Therapeutic Exposures Genetic Predisposition Lifestyle Exposures Viral Infections Age/ sex Identification of High Risk Groups Modification of Therapeutic Protocols Screening of High Risk Populations Risk reduction in High Risk Populations Adverse Outcomes Long-term: Intervention Strategies