So…What Happens Now?—

Taking On Life After Cancer

Joel C. Thompson, MD

Director, Taking on Life after Cancer (TLC) Program

Assistant Professor of Pediatrics

Pediatric Hematology/Oncology

Disclosure

I have no relevant financial relationships or affiliations with

commercial interests to disclose.

Learning Objectives

At the end of the

presentation, the audience

should be able to:

1. Recognize the need for

continual, comprehensive

surveillance of survivors of

childhood cancer.

2. Compare health outcomes for

survivors of childhood cancer

with their siblings and the

general population.

3. Discuss the importance of

survivorship care plans in the

appropriate care of childhood

cancer survivors. https://commons.wikimedia.org/wiki/File%3AWikipedia_-_Cancer_Survivor.jpg

By Mike E. Perez from Dallas, Texas, USA (Wikipedia - Cancer Survivor Uploaded by Adrignola) [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons

What is a Survivor of Childhood Cancer?

Patient alive without evidence of cancer 5 years from diagnosis

5 year mark is somewhat arbitrary

Relapses are uncommon after 5 years but still do happen

In general, priorities of care shift during journey of cancer

therapy:

At diagnosis: CURE→ acute toxicities → late effects

End of therapy: Detect relapse → subacute toxicities → late effects

2-5 years off therapy: Detect relapse → late effects

5+ years off therapy: Detect relapse → late effects

After 5 years (sometimes before), generally seen yearly in

survivorship (TLC) clinic

Childhood Cancer Survivorship

In 2014 in USA—estimated 15,780 new cases of cancer in

children, birth-19yo

Estimated 1,960 cancer deaths (12.4%)

13,820 childhood cancer survivors1

Childhood cancer survivors in USA (estimated)2:

328,000 in 2005

379,000 in 2010

420,000 in 2013

~500,000 in 2020

Currently, 1 in 750 individuals in USA is childhood cancer

survivor

1. Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. CA. Cancer J. Clin. 2014;64(2):83–103.

2. Robison LL, Hudson MM. Nat. Rev. Cancer. 2014;14(1):61–70.

How Did We Get Here?

From: Robison LL, Hudson MM. Nat. Rev. Cancer. 2014;14(1):61–70.

Cancer treatment is hard

Combinations of surgery, chemotherapy, and/or radiation

Chemo and radiation work in non-specific fashion

Leads to cancer cell kill AND organ damage

Which organs and how severe variable based on drugs, doses, timing, etc.

Many acute and long-term toxicities—can be severely life-altering or fatal

May not become clinically apparent until years after therapy is finished

Psychosocial challenges—don’t end when you are “cured”

Very late relapse and treatment-related cancers

Risk-benefit balance—what price will you pay for a chance at a cure?

Price will be paid both in short-term and long-term

Why Worry about Cancer Survivors?

“I’m more willing and able to accept

intimacy and love and care from the people

that have no idea that I ever had serious

health issues because I don’t have it in the

back of my head that the only reason they’re

behaving this way is because they’re caring

for or pitying over the fact that I was sick.”

-21yo male, lymphoma survivor

“You know, [I started] out high school bald

and in a wheelchair and heavier than I ever

had been before. I felt like I was the “cancer

girl” for probably all of high school.”

-22yo female, osteosarcoma survivor

“I just remember feeling like I had to grow

up really fast and I felt like I didn’t get to

be a teenager ‘cause now I had to worry

about health stuff and go to all these

appointments and do all this stuff.”

-19yo female, neuroblastoma survivor

The Challenges of Survivorship

From: Robison LL, Hudson MM. Nat. Rev. Cancer. 2014;14(1):61–70.

Comprehensive Guidelines

Published by many cooperative groups

Children’s Oncology Group (COG)—USA

Dutch Childhood Oncology Group (DCOG)

Scottish Intercollegiate Guideline Network (SIGN)

United Kingdom Children’s Cancer and Leukemia Group (UKCCLG)

PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup)

Effort to form consensus international guidelines

International Guideline Harmonization Group (IGHG; ighg.org)

All attempt to address:

Who is at risk? Highest risk?

How, when, and how frequently should they be monitored?

What should be done if late effects are discovered?

COG Guidelines

Available publically at survivorshipguidelines.org

Most recent version October 2013

Update coming any day now

Meant to apply at least 2 years after completing treatment

Does not address monitoring for relapse of original cancer

Lists long-term effects based on exposures (chemotherapy drug, radiation, surgery)

Lists exposure → potential late effect → risk factors → evaluation and management considerations

241 pages → a reference, not bedtime reading

Helps answer the question from pediatricians: “Could this new/worsening medical problem be related to this patient’s cancer or cancer therapy?”

Research in Survivorship

1970’s and early 1980’s—single institution reports, small

consortia, some cooperative clinical trials group reports

Limited by small samples sizes, incomplete data, limited follow-up

1994—Childhood Cancer Survivor Study (CCSS) funded by

National Cancer Institute

Created a large, multicenter, prospective cohort of childhood cancer

survivors to:

Better identify adverse health and QOL outcomes

Quantify magnitude of these outcomes

Quantify risk factors for these outcomes

Not designed to look at prospective interventions

Selection bias?

Self-reported outcomes

Childhood Cancer Survivor Study

Cohort consists of:

~14,000 childhood cancer survivors (>5 years)

3,800 age-matched siblings

Diagnosed with cancer between 1970 and 1986

Later expanded to include 1987-1999 (additional ~20,000 subjects)

Diagnosed with leukemia, CNS cancers, Hodgkin lymphoma, non-

Hodgkin lymphoma, Wilms tumor, neuroblastoma, soft tissue

sarcoma, or bone tumor

Initial (comprehensive) survey at enrollment with follow-up surveys

in 2000, 2003, 2005, and 2007

Additional more focused surveys

Biorepository of DNA and cells lines from survivors and siblings

St. Jude Lifetime Cohort Study

Initiated in late 2007

Eligibility:

Diagnosis of pediatric cancer treated or followed at SJCRH

≥18 years of age

≥5 more years survival from primary diagnosis

Both retrospective and prospective cohort

Return to SJCRH at least once every 5 years for evaluation

Over 4000 cancer survivors enrolled

Premature Aging as a Paradigm Cancer treatments sap physiologic reserve and leads to early

aging

Supported by observation that cancer survivors develop chronic health

conditions typically seen in people decades older:

Cataracts

Congestive heart failure

CAD/Stroke

Cognitive decline

Osteoporosis

Hypogonadism/premature ovarian

failure

Secondary cancers

Ness et al. Premature Physiologic

Aging as a Paradigm for

Understanding Increased Risk of

Adverse Health Across the

Lifespan of Survivors of Childhood

Cancer.

JCO 2018.

Mechanisms of Aging

Cellular senescence—loss of cell’s ability to replicate and grow

Telemere shortening—leads to DNA damage response and senescence or apoptosis

Hypermethylation in normally hypomethylated areas—leads to gene silencing

Somatic mutations—lead to cancer and tissue degeneration

Michochondrial DNA fidelity—mtDNA has higher rates of mutation than somatic DNA; mtDNA pathology associated with reduced physiologic reserve and premature aging (mice)

Alkylator-based regimens lead to mtDNA mutations; cisplatin preferentially accumulates in mitochondria

Ness et al. Premature Physiologic Aging as a Paradigm for Understanding Increased Risk of Adverse Health Across the

Lifespan of Survivors of Childhood Cancer. JCO 2018.

Frailty Phenotype Frailty—loss of physiologic capacity that interferes with

normal function

Usually seen in older adults

Characterized by 3 or more of:

Low lean muscle mass

Reduced strength

Slow walking speed

Low energy expenditure

Fatigue

In CCS, associated w/XRT

Those NOT exposed to XRT also had increased risk, however

Relationship between frailty and chemotherapy yet to be explored

Ness et al. Premature Physiologic Aging as a Paradigm for Understanding Increased Risk of Adverse Health Across the

Lifespan of Survivors of Childhood Cancer. JCO 2018.

Frailty in CCS SJLIFE Study1—1,922 CCS were assess for frailty phenotype

≥3 criteria = frail; 2 criteria = pre-frail

1. Ness et al. Physiologic Frailty As a Sign of Accelerated Aging Among Adult Survivors of Childhood Cancer: A Report From the St

Jude Lifetime Cohort Study. JCO 2013.

2. Ness et al. Premature Physiologic Aging as a Paradigm for Understanding Increased Risk of Adverse Health Across the

Lifespan of Survivors of Childhood Cancer. JCO 2018.

Frail survivors → 2.2-fold increased risk of new-onset chronic condition; 2.6-fold increased risk of death

Similar to elderly population with frailty2

Issues of Concern with Survivors

Late mortality

Chronic disease

Subsequent neoplasm (SN)

Other outcomes

Late Mortality Cumulative mortality of:

6.5% at 10 years from dx

11.9% at 20 years from dx

18.1% at 30 years from dx

Mortality rates (in deaths/1000 person-years—standardized mortality ratio, SMR):

Most common causes: secondary malignant neoplasms (SMN), cardiac, pulmonary

Armstrong GT, Liu Q, Yasui Y, et al. J. Clin. Oncol. 2009;27(14):2328–2338.

5-9 years

from dx

10-19 years

from dx

20-29 years

from dx

30+ years

from dx

Survivors 13.57 6.00 6.52 14.22

Age-adjusted

expected

0.66 1.03 1.44 2.07

Late Mortality Cancers with highest late

mortality rate:

Ewing sarcoma (13.3 SMR)

CNS tumors (12.9 SMR)

Medulloblastoma (17.7 SMR)

AML (11.5 SMR)

Cancers with lowest late mortality rate:

Neuroblastoma (5.6 SMR)

Renal tumors (4.6 SMR)

Non-Hodgkin lymphoma (4.4 SMR)

Radiation therapy:

2.9x risk of death from SMN

3.3x risk of death from cardiac

2.0x risk of death from pulmonary

Armstrong GT, Liu Q, Yasui Y, et al. J. Clin. Oncol. 2009;27(14):2328–2338.

Late Mortality—Good News!

Armstrong GT, Chen Y, Yasui Y, et al. N. Engl. J. Med. 2016;160113140012003

Chronic Disease Cardiac → dilated cardiomyopathy, MI, valvular disease, pericarditis,

arrhythmia

Pulmonary → fibrosis, chronic cough, pleurisy, exercise dyspnea

Endocrine → thyroid dz, growth disorders, obesity/metabolic syndrome, puberty disorders

Neuro → seizures, CVA (including >5 yrs from dx), neurocognitive impairment, coordination/motor control

GI → enterocolitis, adhesions/strictures, ulcerations, intestinal fibrosis

Renal → CKD, tubular dysfunction, electrolyte abnormalities, HTN

MSK → AVN, osteopenia/osteoporosis, scoliosis, leg length discrepancies

Grades

1 = Mild

2 = Moderate

3 = Severe

4 = Debilitating/Life Threatening

5 = Fatal

Chronic Disease—Grade 3-5 Conditions

Armstrong GT, Kawashima T, Leisenring W, et al. J. Clin. Oncol. 2014;32(12):1218–1227.

Cumulative incidence

at 20 years of age:

Survivors = 16.0%

Siblings = 3.3%

24yo survivors had

same cumulative

incidence as 50yo

siblings

Age 50 → 22.5% of

survivors had ≥2

grade 3-5 conditions

vs 4.3% of siblings

Chronic Disease

Adapted from Diller L, Chow EJ, Gurney JG, et al. J. Clin. Oncol. 2009;27(14):2339–2355.

0

1

2

3

4

5

6

7

8

9

10

Rela

tive R

isk

Relative Risk of Chronic Health Conditions Compared with Siblings

Grade 1-4

Grade 3-4

Mean age of survivors: 26.5 years

Mean interval from primary cancer diagnosis : 17.5 years

Subsequent Neoplasms (SN)

Includes secondary malignant neoplasm (SMN), non-

melanoma skin cancer (NMSC), and meningioma

SMN → Defined as histologically distinct malignancy

developing at least 2 months after completion of treatment

for primary malignancy

Cumulative incidence at 30 years post-dx:

All SN: 20.5%

SMN: 7.9%

Most frequent SMN’s were breast and thyroid cancer

Friedman DL, Whitton J, Leisenring W, et al. J. Natl. Cancer Inst. 2010;102(14):1083–1095.

Secondary Malignant Neoplasms

0

1

2

3

4

5

6

7

8

9

10

Sta

ndard

ized Incid

ence

Rati

o (

SIR

)

Incidence of Secondary Malignant Neoplasms, By Primary Diagnosis

Adapted from Friedman DL, Whitton J, Leisenring W, et al. J. Natl. Cancer Inst. 2010;102(14):1083–1095.

Subsequent Neoplasms

Friedman DL, Whitton J, Leisenring W, et al. J. Natl. Cancer Inst. 2010;102(14):1083–1095.

XRT and SMN

Most significant risk for

SMN

Dose-dependent, organ

dependent

“If radiation touches

it, it can become

cancerous”

Most non-hematologic

SMNs have latency of

15-30 years

Turcotte et al. Risk, Risk Factors, and Surveillance of Subsequent Malignant Neoplasms in Survivors of Childhood Cancer: A Review.

JCO 2018.

Other Outcomes

Reproductive

Higher incidence of nonsurgical premature menopause in survivors vs siblings (8% vs 0.8%, RR = 13.21)1

Associated with higher ovarian radiation, higher alkylator usage, dx of Hodgkin lymphoma

No evidence for increased rate of congenital malformations

Higher incidence of erectile dysfunction in survivors vs siblings (12.3% vs 4.2%, RR = 2.63)2

Associated with testicular radiation (≥10 Gy), spinal cord/sympathetic nerve surgery, prostate surgery, pelvic surgery

Social

Survivors have similar high school graduation rates to siblings3

Survivors are:

More likely to require special education services

Less likely to attend college

More likely to be unemployed and unmarried as young adults

1. Green DM, Sklar CA, Boice JD, et al. J. Clin. Oncol. 2009;27(14):2374–2381.

2. Ritenour CWM, Seidel KD, Leisenring W, et al. J. Sex. Med. 2016;13(6):945–954.

3. Gurney JG, Krull KR, Kadan-Lottick N, et al. J. Clin. Oncol. 2009;27(14):2390–2395.

Survivorship Care Plans (SCPs)

2005—Institute of Medicine (IOM) issued “From Cancer

Patient to Cancer Survivor”

Recognized inherent challenges and importance of transition from

active treatment to post-treatment

Made 10 recommendations to improve survivors’ health care and

quality of life

Focused on survivors of adult cancer; has been extrapolated to

survivors of childhood cancer

“The challenge in overcoming cancer is not only to find therapies

that will prevent or arrest the disease quickly, but also to map the

middle ground of survivorship and minimize its medical and social

hazards.”—Fitzhugh Mullan (1985), physician and cancer survivor

“Knowledge is power.”

“Recommendation 2: Patients completing

primary treatment should be provided with a

comprehensive care summary and follow-up

plan that is clearly and effectively explained.

This ‘Survivorship Care Plan’ should be written

by the principal provider(s) who coordinated

oncology treatment. This service should be

reimbursed by third-party payors of health

care.”

Survivorship Care Plans (SCPs)

Landier W, Armenian S, Bhatia S. Pediatric Clinics of North America (2015) 62:275-300

Do They Help?

Lack of evidence for SCPs → acknowledged in IOM’s

recommendations

Committee concluded that some elements ”simply make sense”

Systematic review of literature about health impact of SCPs

published in May 20181

11 nonrandomized and 13 randomized studies

Conclusion: little evidence that SCPs improve health outcomes and

health care delivery

Low likelihood that SCPs alone would do these things

Did seem to positively impact more proximal outcomes: amount of

information received, satisfaction with care, physician

implementation of recommended care

1. Landier W, Armenian S, Bhatia S. Pediatric Clinics of North America (2015) 62:275-300

What Does a SCP Look Like?

Moving Forward Can lead to information overload, but a critical part of the

patient/family educational backbone of survivorship care

Plan to start faxing copies of SCPs to patient PCPs

When patient transitions back to PCP for follow-up care, will call to

discuss ongoing care needs

If you have a patient who is a childhood cancer survivor and

do not have a copy of their SCP for your records, please

contact our clinic

Do not feel you need to review it with the family (that’s

what we do)

Please review it for yourself so you are better able to understand

their experiences, health care needs, and possible questions

Summary

Improvement in outcomes in pediatric cancer lead to more children and adolescents becoming long-term survivors.

Survivors of pediatric cancer require long-term, comprehensive, multidisciplinary monitoring for late effects.

Pediatric cancer therapy can lead to a variety of potentially serious, even fatal, long-term toxicities.

With close multidisciplinary surveillance, early recognition, improved understanding of risk factors, and potentially new interventions, outcomes and quality of life can be significantly improved for childhood cancer survivors.

Survivorship care plans are a vital part of empowering cancer survivors (and their families) to live a long and healthy life.

Taking on Life After Cancer

TLC Clinic Personnel

Joel Thompson, MD (joel-thompson@ouhsc.edu)

Pam Foster, PA-C (pamela-foster@ouhsc.edu)

Cara Hagemann, PA-C (cara-hagemann@ouhsc.edu)

Sunnye Mayes, PhD (sunnye-mayes@ouhsc.edu)

Roiann Musgrove, RN (roiann-musgrove@ouhsc.edu)

Phone: (405) 271-4412

Questions?

https://commons.wikimedia.org/wiki/File%3AWikipedia_-

_Cancer_Survivor.jpg

By Mike E. Perez from Dallas, Texas, USA (Wikipedia -

Cancer Survivor Uploaded by Adrignola) [CC BY 2.0

(http://creativecommons.org/licenses/by/2.0)], via

Wikimedia Commons

https://commons.wikimedia.org/wiki/File%3ATrying_out

_hats_to_wear_after_chemotherapy_-_cropped.jpg

By U.S. Air Force photo/Master Sgt. Lance Cheung [Public

domain], via Wikimedia Commons

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Armstrong GT, Kawashima T, Leisenring W, et al. Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J. Clin.

Oncol. 2014;32(12):1218–1227.

Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-year survivors of childhood cancer: A summary from the childhood cancer survivor study. J. Clin. Oncol.

2009;27(14):2328–2338.

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Clin. Oncol. 2009;27(14):2374–2381.

Gurney JG, Krull KR, Kadan-Lottick N, et al. Social outcomes in the childhood cancer survivor study cohort. J. Clin. Oncol. 2009;27(14):2390–2395.

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Med. 2016;13(6):945–954.

Robison LL, Hudson MM. Survivors of childhood and adolescent cancer: life-long risks and responsibilities. Nat. Rev. Cancer. 2014;14(1):61–70.

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