late effects in pediatric cancer survivors · wilms tumor (nephroblastoma) neuroblastoma soft...
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Late Effects in Pediatric Cancer Survivors
L I S A K O P P , D O
A S S O C I A T E P R O F E S S O R
T H E U N I V E R S I T Y O F A R I Z O N A
D E P A R T M E N T O F P E D I A T R I C S
D I V I S I O N O F H E M A T O L O G Y / O N C O L O G Y / B M T
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Objectives Review Childhood Cancer and Childhood Cancer Survivor Statistics
Recognize some of the common side effects of childhood cancer therapy
Be familiar with the resources available for monitoring side effects of childhood cancer therapy
Review the most common late effects that you will likely encounter in your office
Recognize the modifiable risk factors of childhood cancer therapy
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Childhood Cancer
Approximately 12,400 children and young adults are diagnosed with cancer each year in the US
Cancer remains the leading cause of death among children between 1-19 years of age in the US
With the introduction of new treatments over the past 50 years the survival has increased dramatically
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Ware, E Childhood and adolescent cancer statistics, 2014, CA: a cancer journal for clinicians
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Ware, E Childhood and adolescent cancer statistics, 2014, CA: a cancer journal for clinicians
Overall Survival Rate is >80%
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Why is this important to the Family Physician?
There are over 325,000 survivors in the US = 1 in 570 adults
Over 60% of survivors have a long term side effect as a consequence of the therapy they received
Childhood cancer survivors will be in your clinic
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Childhood Cancer SurvivorsPrevious to the 1990s the only reports on the late effects of therapy consisted of small cohorts of patients
These reports did indicate excessive mortality rates in 5-year survivors of childhood cancer survivors
In 1994 the Childhood Cancer Survivor Study was began which is a component of the Long Term Survivor Study
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Collaborative, multi-institutional study funded by the National Cancer Institute
31 participating centers - coordinated though St. Jude Children’s Research Hospital
Individuals have survived more than 5 years after diagnosis of cancer during childhood or adolescence
Retrospective cohort consisting of 36,000 childhood cancer survivors diagnosed between 1970 and 1999
Approximately 5,000 siblings are also included who serve as matched controls
More than 170 publications to date from this data base
https://ccss.stjude.org
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Childhood Cancer Survivor CohortDiagnoses:◦ Leukemia◦ Central Nervous System cancers◦ Hodgkin's Lymphoma◦ Non-Hodgkin’s Lymphoma◦ Wilms Tumor (Nephroblastoma)◦ Neuroblastoma◦ Soft tissue sarcomas◦ Bone Tumors
Late Effects Evaluated: ◦ Death◦ Secondary malignancies◦ Organ system problems◦ Impaired growth and development◦ Impaired cognitive function◦ Psychosocial problems◦ Infertility◦ Overall reduction in quality of life
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The cumulative incidence of severe, disabling, lift-threatening and fatal events compared to siblings◦ Graded 3 – 5 as per CTCAE (Common Toxicity Criteria Adverse Events)
Median 24 years from diagnosis; Age 35 – 62 years of age
Among survivors 35 years – 26% experienced a grade 3 – 5 Event within 10 years compared to 6% matched siblings
Armstrong et. al JCO 2014
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Armstrong et. al JCO 2014
Leukemia
Hodgkin Lymphoma
Kidney Tumors
Soft Tissue Sarcomas
Central Nervous System Tumors
Non-Hodgkin Lymphoma
Neuroblastoma
Bone Tumors
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Armstrong et. al JCO 2014
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Nathan et al. JCO 2008
Cross-section study of > 8,000 childhood cancer survivors
Assessed prior 2 years medical visits:◦ Were these visits related to prior cancer therapy?◦ Did you receive advice on how to reduce long term effects?◦ Were any screening tests discussed or ordered?
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Nathan et al. JCO 2008
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Case StudySuzie is a 27 y/o young lady who is a new patient you are seeing today in clinic
CC: new patient – came for a preventive care check as she has a new insurance; she has no specific concerns today
◦ PMHx – History of right pelvic Ewing’s sarcoma when she was 16 years old◦ Therapy included: Ifosfamide, Etoposide, Cyclophosphamide, Doxorubicin, and Vincristine; Radiation therapy to right pelvis
◦ PSHx – tumor biopsy; port-a-cath placement and removal
◦ Social History – works at CVS as a pharmacy tech; married - no children; does not have time to exercise; non-smoker; drinks alcohol 1-2 x per month; no substance abuse
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Case Study (continued)Physical Exam ◦ Vitals: T: 97F R: 16 HR: 85 BP: 140/85◦ Height: 5’5” Weight: 170 lbs◦ Gen: overweight, A&O x 3◦ HEENT: EOMI, PERRL, nares patent, mouth clear◦ Lungs: CTAB◦ CVS: RRR, +S1, S2; no murmurs◦ GI: soft, NT/ND, no HSM◦ MKS: limb salvage right femur; slight limp, FROM x 4, ◦ Neuro: CN II – XII grossly intact; sensation intact
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Case (continued)As you ask the last question that you always regret asking prior to walking out the room “Do You have anything else I can help you with today?”
Suzie says – oh yeah: ◦ She is worried because she has been off her OCP for 1 year and has not gotten pregnant. She is
wondering if she should be worried and what she should do about it…....
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Labs return a few days later…..Labs◦ CBC – normal◦ BMP – normal◦ HbA1C – 6◦ Lipids
◦ LDL – 150◦ HDL – 55◦ Triglycerides – 180
https://en.wikipedia.org/wiki/Blood_test
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Case Study Assessment ◦ 30 y/o female with mild hypertension and obesity (history of Ewing’s sarcoma) (and possibly infertility)
Plan◦ What are her risks due to her chemotherapy?◦ Should you be more concerned about her obesity, mild hypertension, and slightly elevated HbA1C and
lipids than you would be with a 27 y/o with no history of cancer?◦ Is her infertility linked at all to her cancer therapy?
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Fertility
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■ 3,531 survivors and 1,366 female sibling controls
■ Survivors had an increased risk of infertility
■ Most pronounced at early reproductive ages
■ Increasing doses of uterine radiation and alkalyating chemotherapy were strongly associated with infertility
Barton et al. Lancet Oncology 2013
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Barton et al. Lancet Oncology 2013
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Male survivors who wanted to become pregnant - 938 survivors, 174 sibs
Prevalence was 46% versus 17.5% in sibs
37% of survivors who met definition of infertility – reported at least one pregnancy which resulted in a live birth
Wasilewski-Masker et al. Journal of Cancer Survivors 2014
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Wasilewski-Masker et al. Journal of Cancer Survivors 2014
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10,938 survivors and 3,949 matched siblings
Significant decrease in male and female survivors compared to siblings◦ Siring or having a pregnancy◦ Having a livebirth
Chemotherapy affected each sex differently regarding risk of infertility ◦ Males: higher doses of cyclophosphamide, ifosfamide, and cisplatin◦ Females: highest doses of cyclophosphamide, busulfan, lomostine
Chow et al. Lancet Oncology 2016
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Chow et al. Lancet Oncology 2016
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Chow et al. Lancet Oncology 2016
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Case Study Is Suzie at Risk?
◦ Therapy included: ◦ Ifosfamide and Cyclophosphamide◦ Radiation therapy to right pelvis
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Secondary Cancers
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Secondary Malignancies are the leading cause of nonrelapse late mortality◦ 20.5%◦ 6 fold increase in secondary malignancies compared with the general population
Multifactorial etiology ◦ Primary cancer diagnosis ◦ Cancer therapy ◦ Presence of genetic conditions
Meadow et al. JCO 2009
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Meadow et al. JCO 2009
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Meadow et al. JCO 2009
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Choi et al. IJC 2014
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Choi et al. IJC 2014
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Choi et al. IJC 2014
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Case Study Is Suzie at Risk?
◦Therapy included: ◦ Ifosfamide and Cyclophosphamide◦ Etoposide◦ Doxorubicin ◦ Radiation therapy to right pelvis
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Cardiovascular Disease
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Cardiovascular DiseaseAlmost seven-fold increase of chronic cardiac conditions in survivors compared to sibling controls◦ Cardiomyopathy associated with anthracyclines◦ Atherosclerotic disease◦ Diabetes mellitus◦ Dyslipidemia◦ Obesity ◦ Metabolic Syndrome
Mody et al. Blood 2008
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Cardiotoxic TherapyChemotherapy◦ Anthracyclines◦ Alkylating agents◦ Vinca alkaloids◦ Antimetabolites◦ Biologic agents
Radiation therapy◦ Cardiac radiation dose > 1500cGy
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Copyright © The American College of Cardiology. All rights reserved.
J Am Coll Cardiol. 2014;64(9):938-945. doi:10.1016/j.jacc.2014.06.1167
r
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Cumulative Doxorubicin Dose
Swain, S et al. Cancer 2003
> 450 mg/m2 ~ 10% heart failure> 500mg/m2 ~ 20% heart failure
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Children’s Cancer Survivor Study (CCSS) Cohort Results
14,358 survivors and 3,899 siblings
Mean age 27 years
Mulrooney, D et al. BMJ 2010
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Childhood Cancer Survivors -Netherlands
Van der Pal, H. et al JCO 2012
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Cardiac Risk Factors - Non-Modifiable
Female sex
Genetics
Pre-existing cardiac disease
Young age (< 4 years)
Older age (> 40 years)
Lipshultz, SE et al NEJM 1995
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Cardiac Genetic Risk Factors
United States ◦ Case control study – 170 patients
◦ Polymorphisms in the gene CBR3
◦ Predicted and increased risk of cardiomyopathy in those patients exposed to < 250 mg/m2 of anthracycline
Blanco JD et al. JCO 2012
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Cardiac Genetic Risk FactorsCanada and Netherlands◦ 156 children from Canada treated with anthracyclines
◦ 2,997 Single nucleotide polymorphisms (SNP) in 220 drug biotransformation genes were evaluated
◦ 9 SNPs were significantly associated with cardiac toxicity
◦ Replicated in second cohort of 188 children from across Canada and third cohort ◦ 96 children in Netherlands
Visscher, H. et al JCO 2012
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10,724 5-year survivors
3,159 siblings
Reviewed prevalence:◦ Hypertension◦ Diabetes mellitus◦ Dyslipidemia ◦ Obesity
Armstrong et al. JCO 2013
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Prevalence of cardiovascular risk factors—(A) hypertension, (B), dyslipidemia, (C), diabetes, (D) obesity, and (E) multiple cardiac risk factors—with increasing age.
Armstrong G T et al. JCO 2013;31:3673-3680
p < 0.01 p = 0.08
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A, B, and CBlue line = RT – RadiationYellow line = no RTGray line = sibling control
Coronary Artery Disease
Valvular Disease
Arrhythmia
Heart Failure
DBlue line = RT + AnthracyclineYellow line = Anthracycline Red line = RT aloneDark Blue line = NoneGray line = sibling control
Armstrong et al. JCO 2013
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Behavioral Risk Factors
Survivors are more likely to be inactive and less likely to meet physical activity than siblings◦ Miller et al. CCSS PB&C 2013◦ Ness et al. CCSS Cancer 2009
Hypertension incidence is 7.8% after 15 years of follow up in childhood cancer survivors ◦ Armstrong et al. JCO 2013
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Monitoring for CardiotoxicityCardiac Echocardiogram◦ Monitor left ventricular fractional shortening
Circulating biomarkers◦ Cardiac troponin T ◦ N-terminal pro-brain natriuretic peptide
http://www.qualitycardiaccare.com/test
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Case Study
Is Suzie at Risk?
◦ Therapy included: ◦ Doxorubicin
Physical Exam ◦ Vitals: T: 97F R: 16 HR: 85 BP: 140/85◦ Height: 5’5” Weight: 170 lbs◦ Gen: overweight, A&O x 3
Labs◦ HbA1C – 6◦ Lipids
◦ LDL – 150◦ HDL – 55◦ Triglycerides – 180
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SummaryAll Childhood Cancer Survivors are at risk of multiple late effects including Metabolic Syndrome and Cardiovascular Disease
Survivors should be monitored closely for these know effects◦ Providers should be aware of potential late effects◦ Providers should educate survivors on modifiable risk factors
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Resourceshttp://www.survivorshipguidelines.org
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Thank You!