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

Long-Term Toxicities in Survivors of Pediatric Cancer

Gregory T. Armstrong, MD, MSCE Principal Investigator, Childhood Cancer Survivor Study Department of Epidemiology and Cancer Control

The Childhood Cancer Survivor Study

Cancer Survival, 0-14 Years of Age SEER Program 1973-2012

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

Survivorship Statistics

• >83% of children with a malignancy will

achieve five-year survival

• In 2013, estimated 420,000 survivors of

childhood cancer in the U.S.

• By 2020, estimated 500,000 survivors
• 1 in 750 in US is a childhood cancer survivor

0 5 10 15 20

100 80 60 40 20

1975-79 1980-84 1985-89 1990-94 1995-99 2000-04 2005-11

Years from Diagnosis Proportion Surviving

• Funded in 1994
• Retrospective cohort, recent expansion

includes survivors diagnosed 1970-1999

• 31 contributing centers
• 5-year survival
• Leukemia, lymphoma, CNS, bone,

Wilms, NBL, soft-tissue sarcoma

• Detailed treatment data
• Wide range of self-reported outcomes

Childhood Cancer Survivor Study (U24 CA55727)

35,923 Eligible 20,690 (1970-86) 15,233 (1987-99)* 24,368 Participants 14,364 (1970-86) 10,004 (1987-99)* 11,889 Stored DNA

* indicates expansion cohort population, now available to investigators

Late Mortality Among 5+ Year Survivors All-cause Mortality

An NCI-funded Resource

Survival function estimate

US Female US Male Female Male 1.00 0.70 0.95 0.90 0.85 0.80 0.75 5 10 15 20 25 30 35

Years since diagnosis

US Female US Male Female Male Mertens et al, J Clin Oncol., 2000

Survival function estimate

US Female US Male Female Male 1.00 0.70 0.95 0.90 0.85 0.80 0.75 5 10 15 20 25 30 35

Years since diagnosis

Mertens et al, J Natl Cancer Inst., 2008

Late Mortality Among 5+ Year Survivors All-cause Mortality

An NCI-funded Resource

Armstrong GT, et al, J Clin Oncol, 2009

Cause-specific Mortality Among Aging Survivors

Standardized Mortality Ratio SMN =15.2 Cardiac = 7.0

Years from Initial Cancer Cumulative Incidence 5 10 20 30 5 10 15 20 25 Years from Initial Cancer Cumulative Incidence

Second Neoplasms Among 5+ Year Survivors of Childhood Cancer

• Cumulative incidence of second

neoplasm at 30 years = 22%

• Cumulative incidence of second

malignancy at 30 years = 11%

N= 14,359 five-years survivors of leukemia, lymphoma, neuroblastoma, CNS, bone, soft-tissue and kidney cancer Second Neoplasm Second Malignant Neoplasm

(SEER defined)

JNCI, 98:1528-37, 2006

10 20 30 40 50 60 10 20 30 40 60 70 80 90 200 400 1000 10 20 30 40 50 60 50 600 800 1200 Glioma Meningioma

Relative Risk Dose in Gy

10 20 30 40 50 60

5 10 15 20 25 30 35 Lancet, 365:2014-23, 2005

Thyroid - Linear Exponential

Dose in Gy

Dose-Risk Relationship for Tissue-Specific Radiation Exposure and CNS Tumors and Thyroid Cancer

• Linear dose-response for

secondary CNS tumors

• Distinct slopes for

meningioma compared to glioma

• Linear exponential fit for

secondary thyroid cancer, consistent with a cell kill model

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

Armstrong GT, et al, J Clin Oncol, 2013

11.8% 6.8% 5.0% 0.3%

At 45 Years

Clinical Heart Failure: CTCAE Grades 3-5

An NCI-funded Resource

CCSS

An NCI-funded Resource

Modifiable Risk Factors & Major Cardiac Events

Armstrong GT, et al, J Clin Oncol, 2013

Evaluate relative contribution of CVRFs to development of CHF

• Longitudinal evaluation
• 10,724 survivors, CCSS
• Is risk simply additive?
• Hypertension potentiates

anthracycline-associated risk for CHF

• Multiple traditional CV risk factors

increase risk

Congestive Heart Failure

180 160 80 60 40 20 100 Rate Ratio RR=34.1 HTN, No Anthracycline RR=8.3 Anthracycline, No HTN RR=88.5 HTN + Anthracycline

Relative excess risk due to interaction = 44.5

An NCI-funded Resource

Communicating Health Issues & Improving Coordination with Primary Care

Principal Investigator: Eric Chow, M.D. (Fred Hutchison Cancer Institute) Award: Scored 2nd 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

The CHIIP Study

Reduction in Late Mortality Among Five Year Survivors of Childhood Cancer:

A Report from the Childhood Cancer Survivor Study

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

N Engl J Med, 2016 Mar 3:374(9):833-42

Cause-specific Mortality: Treatment-related Causes

1970s 3.1% (2.7 – 3.5) 1980s 2.4% (2.2 – 2.7) 1990s 1.9% (1.6 – 2.2)

P<0.001

15-Year Cumulative Mortality

Cumulative Mortality (%) 25 30 35 20 15 10 5

Years since diagnosis

10 15 5

Armstrong GT et al, N Engl J Med., 2016

Treatment-related Cause Late Mortality: 15 Years from Diagnosis

Era Health- related Cause Subsequent 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

Cranial RT Chest RT Abdominal RT % Receiving RT 87%

Armstrong GT et al, N Engl J Med., 2016

Temporal Changes in Anthracycline Exposure (mg/m2)

Mean Cumulative Dose (mg/m2) 289 217 158

Armstrong GT et al, N Engl J Med., 2016

1970s 1980s 1990s −3 −2.5 −2 −1.5 −1 −0.5 0.5 1 1.5 2 2.5 3 3.5 4

Treatment Intensity Score Treatment Era

ALL: Reduction in Treatment Intensity and Treatment Related Cause Late Mortality

RR 95% CI Treatment Era 1.0 0.8-1.2 Cranial RT None ≥20 Gy 1.0 2.3 1.4-3.5 Anthracycline None 150-299 mg/m2 300-449 mg/m2 450-599 mg/m2 >600 mg/m2 1.0 2.1 1.2 1.9 3.1 1.0-4.4 0.7-2.1 0.7-5.1 1.2-8.2

Model unadjusted for therapy, Treatment era: RR = 0.88 (95% CI 0.81-0.95)

1 1.5 2 2.5 3

15-year Cumulative Mortality (%)

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

• f 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 1970s 10.7% (10.1 - 11.4) 1980s 7.9% (7.4 - 8.3) 1990s 5.8% (5.4 - 6.3)

P<0.001 Cumulative Mortality (%) 25 30 35 20 15 10 5

Years since diagnosis

10 15 20 25 5

15-Year Cumulative Mortality 15-Year Cumulative Mortality

Armstrong GT et al, N Engl J Med., 2016

Cause-specific Mortality: Recurrence or Progression of Primary Cancer

1970s 7.1% (6.6 – 7.6) 1980s 4.9% (4.5 - 5.2) 1990s 3.4% (3.1 – 3.7)

P<0.001

Cumulative Mortality (%) 25 30 35 20 15 10 5

Years since diagnosis

10 15 5

15-Year Cumulative Mortality