A Diagnosis of Childhood 21/03/2017 Objectives
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21/03/2017 Objectives A Diagnosis of Childhood Cancer Lasts a Lifetime To review the advances made in childhood cancer therapy over the last 60 years. To understand the many disease and therapy-specific complications of childhood cancer treatment. To recognize that childhood cancer survivorship may be accompanied by chronic medical and psychosocial issues which require specialized knowledge for optimal care. To discuss future directions of childhood cancer therapy and late effects research. Gregory M.T. Guilcher MD, FRCPC, FAAP Assistant Professor of Oncology and Paediatrics University of Calgary Disclosures Relationships with commercial interests: Collaborative Research for Childhood Cancer An example for clinical research across all medical disciplines Over 80% of children and adolescents diagnosed with cancer will be cured Consulting fees for interviews for drug development and marketing Patient Access Solutions Canada Market Research Better use of established agents To a lesser extent use of novel agents Supportive care measures have improved significantly Childhood Cancer, 1971-2010 One-, Five- and Ten-Year Actuarial Survival (%), Children (Aged 0-14), Great Britain But our work is not done All childhood cancers includes all malignant tumours (ICD-10 codes: C00-C97), and all benign, uncertain or unknown behaviour brain, other central nervous system (CNS) and intracranial tumours (ICD-10 codes: D32-D33, D35.2-D35.4, D42-D43 and D44.3-D44.5). No significant progress over the last 30 years for Many central nervous system tumours Sarcomas Osteosarcoma Rhabdomyosarcoma These tumours account for over 25% of childhood cancer diagnoses Adolescents and young adults have not seen major improvements in survival despite progress for children and older adults Please include the citation provided in our Frequently Asked Questions when reproducing this chart: http://info.cancerresearchuk.org/cancerstats/faqs/#How Prepared by Cancer Research UK Original data sources: 1. National Cancer Intelligence Network. National Registry of Childhood Tumours Progress Report, 2012. Oxford: NRCT; 2013. 2. Ten-year actuarial survival, children aged 0-14 years, Great Britain, 1971-2005 data were provided by Charles Stiller at the National Registry of Childhood Tumours on request in 2013. cancerresearchuk.org 1 21/03/2017 Aftermath of childhood cancer treatment Cytotoxic chemotherapy Targeted therapy thiessenteam.com; science.howstuffworks.com How big is the problem? ~40 000 survivors of childhood cancer in Canada We want these survivors to live for decades With good quality of life Without living dependent on a caregiver Able to achieve educational and vocational goals Able to have meaningful social and romantic relationships curesearch.org We are good at curing childhood cancerbut the price of cure is still too high. Childhood CNS tumours Medulloblastoma Survivors Most common solid tumours in children (Childhood Cancer Survivor Study) Medulloblastoma is the most common malignant CNS tumour Late onset hearing loss- HR 36 Stroke- HR 33.9 Seizures- HR 12.8 Poor balance- HR 10.4 University degree- RR 0.49 Marry- RR 0.35 Live independently- RR 0.58 King et al. Neuro Oncol 2016 So we go from… brightonteachingenglish.com; kidscancercare.ab.ca But we are not in the habit of giving up easily. kidscancercare.ab.ca/get-involved We’ve got work to do. Let’s get started. First we have to know the extent of the challenge we are facing We must also acknowledge that we fully learn about the late effects of our treatments decades later Many treatments have changed significantly over that time We are always playing “catch-up” But there is still much to learn from our experiences dailymail.co.uk 2 21/03/2017 What are unique aspects of childhood cancer treatment and survivorship? It takes a village Childhood cancer diagnosis and treatment often interferes with development in the following domains Social Educational Recreational Children and growing and developing Exposure of chemotherapy and radiation to tissues which are still maturing carries different risks Brain- neurocognition Heart- myocytes Childhood Cancer Survivor Study Retrospective cohort study 10 397 survivors (mean age 26 years) 3 034 siblings (mean age 29 years) Cardiovascular disease Most common organ system affected 62% of survivors had at least one chronic health condition Sevenfold increase in risk of cardiac death compared to general population Antracycline exposure 27.5% had a severe or life threatening condition Mediastinal radiation Cumulative incidence of a chronic health condition was 73.4% at 30 years post cancer diagnosis, 42.4% for a severe, life-threatening or disabling condition Young age at treatment Females higher risk Oeffinger et al. NEJM 2006 etsy.com; Armenian et al. ASCO University 2015 Educational Book Important points about cardiovascular disease for childhood cancer survivors Long latency between exposure and clinical cardiovascular disease Sometime years or decades Screening at risk populations important 5 year survival after heart failure develops is less than 50% Cardiomyopathy is of particular concern Coronary artery disease Valvular abnormalities Conduction abnormalities Pericardial disease Armenian et al. ASCO University 2015 Educational Book Endocrine Dysfunction Childhood Cancer Survivor Study Hypothyroidism- RR 6.6 Thyroid nodules- RR 6.3 Thyroid cancer- HR 9.2 Growth hormone deficiencyHR 5.3 Mostoufi-Moab S et al. JCO 2016; biologyclass7thgrade.blogspot.jp 3 21/03/2017 Infertility Lungs Consider Pulmonary Function Testing Surveillance if Hx of: After survival, one of the most important concerns for adolescent and young adult cancer survivors Fertility preservation options are expanding Bleomycin Such (non-experimental) options should be offered routinely Nitrosurea compounds Risk factors for infertility Gonadal radiation or radiation to uterus/ovaries/pituitary Alkylating agents, typically greater than 5-8 g/m2 Tumour/surgical disruption of reproductive structures Lomustine Busulfan Lung radiation Thoracotomies Fertility may be preserved, but window for childbearing may be reduced survivorshipguidelines.org Carmustine Premature ovarian failure 1200 cGy or greater rarehistoricalphotos.com; survivorguidelines.org Any organ system can be affected Important to review the patient’s treatment exposure history to determine what organs are at risk and how to screen Kidneys- platinum agents, calcineurin inhibitors, high dose methotrexate Hearing- platinum agents, radiation therapy Liver- most chemotherapy can be hepatotoxic, graft-versus-host disease Skin- radiation, many chemotherapy agents Bone health (osteopenia/osteoporosis/avascular necrosis)- corticosteroids, methotrexate survivorshipguidelines.org Neurocognition Children are learning and developing Radiation is a major risk for neurocognitive deficits Especially children under 3 years of age Combined with high dose methotrexate, cytarabine or corticosteroids Brain tumours and neurosurgery are also risk factors Time in hospital, missed school, family and social time are also important Family history of learning difficulties and socioeconomic status are important predictors Neurocognitive Function www.meresearch.org.uk/our-research/ongoing-studies/neurocognitive-performance/ survivorshipguidelines.org 4 21/03/2017 PSYCHOLOGICAL LATE EFFECTS OF CHILDHOOD/ADOLESCENT CANCER Neurocognitive Difficulties Post-Therapy for Acute Lymphoblastic Leukemia CNS prophylaxis is necessary Data shows mean IQ is in the normal range for those with intrathecal chemotherapy + systemic therapy (no radiation) Problems include difficulties with Psychosocial/QOL Effects • Social withdrawal • Educational problems • Relationship problems • Under-employment • Dependent living Radiation is more toxic with similar efficacy to intrathecal chemotherapy However, when compared to sibling controls, most studies show significant differences between survivors and siblings (which may or may not be clinically significant) Processing speed Executive function Attention Memory (visual, sequencing) Mathematics, reading Moleski. Arch Clin Neuropsychol 2000; survivorshipguidelines.org Risk Factors • Female sex • Younger age at Dx • Neuro-cognitive problems • Physical Factors • Low socioeconomic status Slide courtesy of Dr. Fiona Schulte, University of Calgary • Family Hx of mental health challenges Second Malignant Neoplasms Topoisomerase inhibitors Myelodysplastic syndrome/acute myelogenous leukemia (2-3% risk) Usually within 3 years of exposure Cyclophosphamide, ifosfamide, nitrosureas, platinums Depends on dose, field of radiation, sex, age of exposure Alkylating agents Myelodysplastic syndrome/acute myelogenous leukemia Radiation therapy Skin- particularly non-melanomatous skin cancer Thyroid Brain tumours if cranial RT Colorectal Depends on dose, field of radiation, sex, age of exposure Who should care for these survivors? Risk of breast cancer for adolescent females receiving mantle RT for Hodgkin lymphoma 10-40% Armenian et al. ASCO University Educational Book 2015 Most Canadian centres have multi-disciplinary survivor clinics Meningiomas and high grade gliomas Abdominal RT can confer a risk of colorectal cancer comparable to an inherited predisposition by the time survivors reach age 50! Armenian et al. ASCO University Educational Book 2015 Future directions We need to be able to better predict who will develop toxicities Not all can follow these survivors indefinitely Allows for better screening The number of survivors is outgrowing our current models of care Ideally allows to choose therapies which do not cause late effects in individuals at risk A good problem! We need to include and engage primary care providers Risk of breast cancer for adolescent females receiving mantle RT for Hodgkin lymphoma 10-40% Common cancers include Risk Factors • CNS tumor • CNS-directed therapy • Hearing loss • Premorbid learning or emotional difficulties • Bone marrow transplant • Chronic pain Radiation therapy CANCER EXPERIENCE Radiation Therapy and Second Cancers Etoposide Mental Health Disorders • Depression • Anxiety • Post-traumatic Stress • Suicidal Ideation We need to better therapies which cure without acute or late effects Registries needed To access survivors to update them with new guidelines/screening recommendations To allow for good research to improve outcomes Guilcher et al. Pediatr Blood Cancer 2009; dvd.netflix.com 5 21/03/2017 Pediatric Anthracycline Cardiotoxicity Risk Prediction Tool 100% 89% Cardiotoxicity Risk Risk of Cardiotoxicity (%) 90% Aminkeng et al., In Press, 2015 80% PATIENT 70% 60% 45% Cardiotoxicity Risk 50% PATIENT 39% Cardiotoxicity Risk 40% 21% Cardiotoxicity Risk 20% 0% 14% Risk (~23% of population. Risk estimate based upon 139 patients. Includes carriers of protective SLC28A3 variant.) 0% 20% (~2% of population. Risk estimate based upon 11 patients. Includes carriers of 2 RARG risk variants). (~13% of population. Risk estimate based upon 80 patients. Includes carriers of 1 risk variant, or 2 risk + 1 protective variant). 30% 10% (~2% of population. Risk estimate based upon 9 patients. Includes carriers of 1+ RARG and 1+ UGT risk variants). (~60% of population. Risk estimate based upon 356 patients. Includes non‐ carriers, and carriers of 1 risk + 1 protective variant). 40% 60% 80% 100% Patient Anthracycline‐Induced Cardiotoxicity PGx Risk (Percentile) Slide courtesy of Dr. Bruce Carleton, UBC. Used with permission. Aminkeng F et al. Nature Genetics 2015 Terry Fox PROFYLE PRecision Oncology For Young people Canada-wide initiative led by The Hospital for Sick Children Precision medicine platform to choose targeted therapies for ‘hard-to-treat’ tumours Molecular characterizations of tumour and pathways of oncogenesis will allow for drugs to be selected based on an individual’s tumour urbanmoms.com Copyright unknown We can do better We must do better We will do better curesearch.org Acknowledgements: Patients, families, ACH Long-Term Survivor Clinic Photos used with permission 6
