Late Effects in Pediatric Cancer Survivors · Wilms Tumor (Nephroblastoma) Neuroblastoma Soft...

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

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

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

Ware, E Childhood and adolescent cancer statistics, 2014, CA: a cancer journal for clinicians

Ware, E Childhood and adolescent cancer statistics, 2014, CA: a cancer journal for clinicians

Overall Survival Rate is >80%

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

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

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

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

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

Armstrong et. al JCO 2014

Leukemia

Hodgkin Lymphoma

Kidney Tumors

Soft Tissue Sarcomas

Central Nervous System Tumors

Non-Hodgkin Lymphoma

Neuroblastoma

Bone Tumors

Armstrong et. al JCO 2014

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?

Nathan et al. JCO 2008

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

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

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…....

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

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?

Fertility

■ 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

Barton et al. Lancet Oncology 2013

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

Wasilewski-Masker et al. Journal of Cancer Survivors 2014

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

Chow et al. Lancet Oncology 2016

Chow et al. Lancet Oncology 2016

Case Study Is Suzie at Risk?

◦ Therapy included: ◦ Ifosfamide and Cyclophosphamide◦ Radiation therapy to right pelvis

Secondary Cancers

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

Meadow et al. JCO 2009

Meadow et al. JCO 2009

Choi et al. IJC 2014

Choi et al. IJC 2014

Choi et al. IJC 2014

Case Study Is Suzie at Risk?

◦Therapy included: ◦ Ifosfamide and Cyclophosphamide◦ Etoposide◦ Doxorubicin ◦ Radiation therapy to right pelvis

Cardiovascular Disease

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

Cardiotoxic TherapyChemotherapy◦ Anthracyclines◦ Alkylating agents◦ Vinca alkaloids◦ Antimetabolites◦ Biologic agents

Radiation therapy◦ Cardiac radiation dose > 1500cGy

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

Cumulative Doxorubicin Dose

Swain, S et al. Cancer 2003

> 450 mg/m2 ~ 10% heart failure> 500mg/m2 ~ 20% heart failure

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

Childhood Cancer Survivors -Netherlands

Van der Pal, H. et al JCO 2012

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

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

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

10,724 5-year survivors

3,159 siblings

Reviewed prevalence:◦ Hypertension◦ Diabetes mellitus◦ Dyslipidemia ◦ Obesity

Armstrong et al. JCO 2013

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

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

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

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

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

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

Resourceshttp://www.survivorshipguidelines.org

Thank You!