Pediatric Cancer The Childhood Cancer Survivor Study Gregory T. - PowerPoint PPT Presentation

Long-Term Toxicities in Survivors of Pediatric Cancer The Childhood Cancer Survivor Study Gregory T. Armstrong, MD, MSCE Principal Investigator, Childhood Cancer Survivor Study Department of Epidemiology and Cancer Control

Cancer Survival, 0-14 Years of Age SEER Program 1973-2012 100 Survivorship Statistics 2005-11 80 2000-04 • >83% of children with a malignancy will 1995-99 1990-94 Proportion Surviving achieve five-year survival 1985-89 1980-84 60 1975-79 • In 2013, estimated 420,000 survivors of childhood cancer in the U.S. 40 • By 2020, estimated 500,000 survivors 20 • 1 in 750 in US is a childhood cancer survivor 0 0 5 10 15 20 Years from Diagnosis Howlader N, SEER Cancer Statistics Review 1975-2012 Phillips et al, CEBP , 2015 NCI Office of Cancer Survivorship Robison L. & Hudson MM, Nature Reviews Cancer 2014

Childhood Cancer Survivor Study (U24 CA55727) • Funded in 1994 35,923 Eligible 20,690 (1970-86) • Retrospective cohort, recent expansion 15,233 (1987-99)* includes survivors diagnosed 1970-1999 • 31 contributing centers 24,368 Participants • 5-year survival 14,364 (1970-86) • Leukemia, lymphoma, CNS, bone, 10,004 (1987-99)* Wilms, NBL, soft-tissue sarcoma • Detailed treatment data 11,889 Stored DNA • Wide range of self-reported outcomes * indicates expansion cohort population, now available to investigators

Late Mortality Among 5+ Year Survivors All-cause Mortality An NCI -funded Resource 1.00 US Female US Female US Male US Male 0.95 Survival function estimate 0.90 Female 0.85 Male 0.80 Female 0.75 Male 0.70 5 10 15 20 25 30 35 Years since diagnosis Mertens et al , J Clin Oncol. , 2000

Late Mortality Among 5+ Year Survivors All-cause Mortality An NCI -funded Resource 1.00 US Female US Male 0.95 Survival function estimate 0.90 0.85 0.80 Female 0.75 Male 0.70 5 10 15 20 25 30 35 Years since diagnosis Mertens et al , J Natl Cancer Inst. , 2008

Cause-specific Mortality Among Aging Survivors Standardized Mortality Ratio SMN =15.2 Cardiac = 7.0 Armstrong GT, et al, J Clin Oncol, 2009

Second Neoplasms Among 5+ Year Survivors of Childhood Cancer N= 14,359 five-years survivors of leukemia, 25 lymphoma, neuroblastoma, CNS, bone, soft-tissue and kidney cancer 20 Cumulative Incidence Cumulative Incidence • Cumulative incidence of second Second Neoplasm 15 neoplasm at 30 years = 22% Second • Cumulative incidence of second 10 Malignant Neoplasm malignancy at 30 years = 11% (SEER defined) 5 0 5 10 20 30 Years from Initial Cancer Years from Initial Cancer

Dose-Risk Relationship for Tissue-Specific Radiation Exposure and CNS Tumors and Thyroid Cancer JNCI, 98:1528-37, 2006 • Linear dose-response for Lancet, 365:2014-23, 2005 secondary CNS tumors 35 1200 1000 800 600 30 400 200 • Distinct slopes for 25 90 meningioma compared to 80 Relative Risk 20 70 glioma Meningioma 60 15 50 40 10 • Linear exponential fit for 30 Thyroid - Linear Glioma Exponential secondary thyroid cancer, 5 20 consistent with a cell kill 10 0 0 model 0 10 20 30 40 50 60 0 0 10 10 20 20 30 30 40 40 50 50 60 60 Dose in Gy Dose in Gy

Meningioma after Cranial Radiotherapy • 4,221 survivors exposed to CRT • 199 meningiomas in 169 survivors • Overall cumulative incidence 5.6% at 40 years of age • Increased risk attributable to • ↑ CRT dose • Female sex Bowers et al, J Clin Oncol, 2017

Morbidity Associated with Meningioma Survivors >5 years from diagnosis reporting meningioma had an increased risk for: seizures (HR 10.0, 95% CI 7.0-15.3) and focal neurological dysfunction (HR 4.9, 95% CI 3.2-7.5). Bowers et al, J Clin Oncol, 2017

Clinical Heart Failure: CTCAE Grades 3-5 An NCI -funded Resource At 45 Years 11.8% 6.8% 5.0% 0.3% Armstrong GT, et al, J Clin Oncol, 2013

CCSS Modifiable Risk Factors & Major Cardiac Events An NCI -funded An NCI-funded Resource Resource Congestive Heart Failure Evaluate relative contribution of CVRFs to 180 development of CHF RR=88.5 Relative excess risk 160 due to interaction • 100 Longitudinal evaluation = 44.5 • 10,724 survivors, CCSS 80 RR=34.1 • Rate Ratio Is risk simply additive? 60 • 40 Hypertension potentiates anthracycline-associated risk for CHF RR=8.3 20 0 • Multiple traditional CV risk factors HTN, Anthracycline, HTN + increase risk No Anthracycline No HTN Anthracycline Armstrong GT, et al, J Clin Oncol, 2013

Communicating Health Issues & Improving Coordination with Primary Care The CHIIP Study Principal Investigator : Eric Chow, M.D. (Fred Hutchison Cancer Institute) Award : Scored 2 nd percentile, RO1 Study Aims : Among survivors newly diagnosed, or undertreated for CVRFs (hypertension, dyslipidemia, diabetes), randomized controlled intervention to reduce undertreatment of CVRFs Intervention: provision of lab results, survivorship care plan and remote counseling Data Collection: 800 in-home assessments; 480 randomized to trial

Reduction in Late Mortality Among Five Year Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study N Engl J Med, 2016 Mar 3:374(9):833-42 Gregory T. Armstrong, Yutaka Yasui, Yan Chen, Wendy Leisenring, Todd M. Gibson, Ann Mertens, Marilyn Stovall, Melissa M. Hudson, Kevin C. Oeffinger, Smita Bhatia, Kevin R. Krull, Paul C. Nathan, Joseph P. Neglia, Daniel Green, Leslie L. Robison

Cause-specific Mortality: Treatment-related Causes 15-Year Cumulative 15 Mortality P<0.001 1970s Cumulative Mortality (%) 3.1% (2.7 – 3.5) 10 1980s 2.4% (2.2 – 2.7) 5 1990s 1.9% (1.6 – 2.2) 0 0 5 10 15 20 25 30 35 Years since diagnosis Armstrong GT et al, N Engl J Med., 2016

Treatment-related Cause Late Mortality: 15 Years from Diagnosis Health- related Subsequent Era Cause Neoplasms Cardiac Pulmonary 1970-74 3.5% 1.8% 0.5% 0.5% 1975-79 2.9% 1.5% 0.4% 0.2% 1980-84 2.7% 1.3% 0.3% 0.3% 1985-89 2.2% 1.3% 0.1% 0.2% 1990-94 2.1% 1.0% 0.1% 0.1% P-value <0.001 <0.001 0.001 0.04 Armstrong GT et al, N Engl J Med., 2016

Temporal Changes in Radiotherapy Exposure 87% % Receiving RT Cranial RT Chest RT Abdominal RT Armstrong GT et al, N Engl J Med., 2016

Temporal Changes in Anthracycline Exposure (mg/m 2 ) 289 Mean Cumulative Dose (mg/m 2 ) 217 158 Armstrong GT et al, N Engl J Med., 2016

ALL: Reduction in Treatment Intensity and Treatment Related Cause Late Mortality Model unadjusted for therapy, 4 Treatment era: 3 3.5 3 RR = 0.88 (95% CI 0.81-0.95) 15-year Cumulative Mortality (%) 2.5 Treatment Intensity Score 2.5 2 RR 95% CI 1.5 Treatment Era 1.0 0.8-1.2 1 0.5 Cranial RT 2 0 None 1.0 −0.5 ≥20 Gy 2.3 1.4-3.5 −1 Anthracycline 1.5 −1.5 None 1.0 −2 150-299 mg/m 2 2.1 1.0-4.4 −2.5 300-449 mg/m 2 1.2 0.7-2.1 1 −3 450-599 mg/m 2 1.9 0.7-5.1 >600 mg/m 2 3.1 1.2-8.2 1970s 1980s 1990s Treatment Era Armstrong GT et al, N Engl J Med., 2016

Summary • Survivors in more recent eras have a significant reduction in late mortality attributable to: - Fewer deaths from recurrence of primary cancer - Fewer deaths from treatment-related causes including subsequent malignancies and cardiac death • The strategy of reducing the intensity of therapy to lower the occurrence of late-effects, along with promotion of early detection and improved treatment of late-effects has now translated to extend the lifespan of survivors.

Childhood Cancer Survivor Study A RESOURCE FOR RESEARCH • The Childhood Cancer Survivor Study is an NCI-funded resource to promote and facilitate research among long-term survivors of cancer diagnosed during childhood and adolescence. • Investigators interested in potential uses of this resource are encouraged to visit: www.stjude.org/ccss

All-cause Late Mortality 3,958 total deaths 15-Year Cumulative 15-Year Cumulative Mortality Mortality 25 P<0.001 1970s Cumulative Mortality (%) 20 10.7% (10.1 - 11.4) 15 1980s 7.9% (7.4 - 8.3) 10 5 1990s 5.8% (5.4 - 6.3) 0 0 5 10 15 20 25 30 35 Years since diagnosis Armstrong GT et al, N Engl J Med., 2016

Cause-specific Mortality: Recurrence or Progression of Primary Cancer 15-Year Cumulative 15 Mortality P<0.001 Cumulative Mortality (%) 1970s 7.1% (6.6 – 7.6) 10 1980s 4.9% (4.5 - 5.2) 5 1990s 3.4% (3.1 – 3.7) 0 0 5 10 15 20 25 30 35 Years since diagnosis