Sue Lindemulder, MD, MCR
Medical Director, Childhood Cancer Survivorship Program
September 12, 2013

After this presentation, participants should be able to:
• Identify late effects common in children who are survivors of childhood cancer and stem cell transplant
• Know how to screen patients for common late effects of treatment.
• Identify resources available to aid providers in screening for late effects

Majority of childhood cancer survivors have late effects
Majority of children with cancer become long term survivors

• Multi-institutional collaborative study (26 centers)
• Diagnosed with cancer in childhood or adolescence and survived at least 5 years
• Diagnoses: Leukemia, Kidney, Bone, Soft Tissue
Sarcoma, Neuroblastoma, Hodgkin’s or non-
Hodgkin’s lymphoma, and primary CNS malignancy.
• Diagnoses between January 1, 1970 and December
31, 1986

• 17,565 eligible survivors not lost to follow-up,
4855 eligible siblings
• Baseline questionnaire: 24 pages with demographic variables, medical conditions, surgical procedures and other health outcomes
• 14,362 (81.8%) survivors and 3901 (80.4%) siblings completed the questionnaire
• 12,480 survivors had complete treatment data abstracted

Oeffinger KC et al. 2006

Oeffinger KC et al. 2006

Oeffinger KC et al. 2006

• 1713 participants diagnosed between 1962-2001
• Follow-up between Oct 1, 2007 and Oct 31, 2012
• Median time from Diagnosis: 25 years
• Screened per Children’s Oncology Group Long-
Term Follow-Up Guidelines
(www.survivorshipguidelines.org)
• Chronic health Condition: 98.2% (97.5%-98.8%)
• Serious or life-threatening condition: 67.6%
(65.3%-69.8%)

Nathan PC et al. 2008.

Taken from Oregonian, April 27, 2012

Diagnosis: Acute lymphoblastic leukemia; Relapse (left occular & CNS) 6/7/2004
Date of Diagnosis: 1/03/2003 Date of Bone Marrow Transplant: 9/15/2004
Protocol: POG 9906; followed by relapse therapy CCG 1951
Chemotherapy exposures (cumulative dose): Anthracycline (72 mg/m2), Cytoxan (4.7 g/m2), 6-MP, Vincristine, Dexamethasone, Cytarabine, L' asparginase, Peg-Asparaginase,
Methotrexate (IV, PO & IT), Ifosfamide (9 g/m2); Etopophos (allergy to Etoposide) (2.2 g/m2);
Triple intrathecals x 4, Tacrolimus, Prednisone (ended 11/11/2005). Off immunosuppressives since 10/01/2006.
Radiation Therapy: 2400 cGy to the left eye & 1200 cGy cranial & 1200 cGy TBI (2004)
Last ECHO: (2012) FS 29%; EF 56%
Last PFT: (2011) Improved from previous
Surgeries: Line placement x 2 (2004 & 2005); Right hip replacement (2006); Bilateral cadaveric knee allografts (2007)
Blood Products/year: 2004 on file - presumed 2003
Problem List from History: History of low shortening fraction on echo from 2004 treated with digoxin & lisinopril until 9/2004; History of hyperlipidemia; History of iatrogenic hypertension;
Decreased vision left eye; Avascular necrosis; History of chronic GVHD of the skin and gut;
Gonadal failure; Hypothryroid; Severe influenza requiring ICU hospitalization shortly after transplant.
Neuropsych testing: (8/21/2004) (pre-transplant)- Intellectual functioning intact; normal on all examinations

Late Effect: Cardiomyopathy, Arrhythmia, Subclinical left ventricular dysfunction, Valve dysfunction.
• Cancers: Almost all, high doses with sarcomas
• Chemotherapy Agents: Anthracyclines
• Radiation: Total Body, Whole lung, Mantle etc
• Risk Factors: Obesity, Congenital Heart Disease,
Isometric exercise, Smoking, Illicit drug use.
Children’s Oncology Group; www.survivorshipguidelines.org

Periodic Evaluation
• History (yearly): SOB, DOE, Orthopnea, Chest pain, Palpitations, if <25 yrs abdominal symptoms
• Physical (yearly): Cardiac murmur, S3/S4,
Increased P2 sound, Pericardial rub, Rales, JVD
Screening
• ECHO or MUGA baseline at entry into LTFU then at intervals. EKG baseline at entry into LTFU then as clinically indicated
Children’s Oncology Group; www.survivorshipguidelines.org

Age at Treatment Radiation with Potential
Impact to the Heart
Anthracycline Dose Recommended
Frequency
< 1 year old
1-4 years old
Yes
No
Yes
No
Any
<200 mg/m2
≥200 mg/m2
Any
<100 mg/m2
≥100 to <300 mg/m2
≥300 mg/m2
<300 mg/m2
Every year
Every 2 years
Every year
Every year
Every 5 years
Every 2 years
Every year
Every 2 years ≥5 years old Yes
No
≥300 mg/m2
<200mg/m2
≥200 to <300 mg/m2
≥300 mg/m2
Any age with decrease in serial function Every year
Every year
Every 5 years
Every 2 years
Every year
Children’s Oncology Group; www.survivorshipguidelines.org

Late Effect: Pulmonary fibrosis, interstitial pneumonitis
• Cancers: Hodgkin’s, germ cell tumors, BMT
• Chemotherapy Agents: Bleomycin, Busulfan
• Radiation: Whole lung, Total Body, Mediastinal etc
• Other: Chronic GVHD
• Risk Factors: Younger age at tx, higher doses, radiation dose ≥ 10Gy, smoking
Children’s Oncology Group; www.survivorshipguidelines.org

Periodic Evaluation
• History (yearly): Cough, SOB, DOE, Wheezing
• Physical (yearly): Pulmonary exam
Screening
• Chest x-ray and Pulmonary function testing
(including DLCO and spirometry): Baseline at entry into long term follow-up. Repeat as clinically indicated if abnormal or if progressive dysfunction.
Children’s Oncology Group; www.survivorshipguidelines.org

Diagnosis: Philadelphia + acute biphenotypic leukemia diagnosed at age 11; 2 x relapsed on therapy 10/14/1993 after two courses (paused for infection) & 1/1994 (after 2 courses of salvage therapy).
Date of Diagnosis: 5/1993 Date of Bone Marrow Transplant: 3/27/1994
Chemotherapy exposures (cumulative dose): Anthracycline (430 mg/m2), Cytoxan (2 gram/m2), Vincristine (12mg/m2), Steroids (prednisone and dexamethasone), Cytarabine
(10.3 gram/m2), Asparginase, 6-mercaptopurine, 6-thioguanine, Etoposide (800 mg/m2),
Fludarabine (41mg/m2) and Intrathecal methotrexate and cytarabine. BMT preparative chemotherapy: Thiotepa (900 mg/m2) and Etoposide (1.5 gram/m2).
Radiation Therapy: Cranial 1800 cGy (1993); TBI 1200 cGy (1994)
Surgeries: Thyroid cyst removed (1984); Cholecystectomy; Appendectomy (1995); multiple central lines; Bilateral hip total arthoplasty (2007); Left knee total arthroplasty (2007);
Manipulation of left knee arthoplasty (2008). Fracture repair & plating of right distal radius
(2009); Multiple dental extractions (2012 & 2013)
Blood Product Exposure/year: 1993
On therapy complications: Multiple episodes of sepsis and bacteremia, clostridium cellulitis of hip, leg, and perineum, veno-occlusive disease, septic arthritis, acute graft-versus-host disease, multiple compression fractures of the spine, hepatic abscesses, GI bleed, seizures.
Off therapy complications: Chronic graft-versus-host disease, osteonecrosis of bilateral hips and left knee, fracture of right wrist, hyperlipidemia, ovarian failure (OCPs to be prescribed once triglycerides are controled), growth failure without GH treatment, sub clinical hypothyroidism, vitamin D deficiency, cholecystitis, osteoporosis, dry eye, diabetes type 2
(controled) and excessive dental caries. Alteration in body image

Late Effect: Reduced Bone Mineral Density,
Osteonecrosis
• Cancers: ALL, osteosarcoma
• Chemotherapy Agents: Steroids, HD Methotrexate
• Radiation: Any
• Other: Bone marrow transplant
• Risk Factor: Younger age, lower weight, growth hormone deficiency, hypogonadism/delayed puberty, inadequate vitamin D or calcium intake, smoking
Children’s Oncology Group; www.survivorshipguidelines.org

Periodic Evaluation
• History (yearly): Fracture history, joint pain
• Physical (yearly): No specific
Screening
• Bone Density Evaluation: Baseline at long term follow-up and than as clinically indicated (baseline is age dependent).
• Vitamin D levels
Children’s Oncology Group; www.survivorshipguidelines.org

Late Effect: Hypothyroidism, Thyroid nodules,
Thyroid cancer
• Cancers: Hodgkin’s, Brain tumors, BMT
• Chemotherapy Agents: None
• Radiation: Cranial, Spine, Supraclavicular, Chest,
Mantle, Mediastinal, Total Body
• Risk Factors: Female, Radiation doses ≥ 10 Gy,
Thyroid directly in field
Children’s Oncology Group; www.survivorshipguidelines.org

Periodic Evaluation
• History (yearly): Fatigue, Weight gain, Cold intolerance, Constipation, Dry skin, Brittle Hair,
Depressed mood.
• Physical (yearly): Height, Weight, Hair and skin, thyroid exam
Screening
• TSH and free F4 yearly. May need more frequently during periods of rapid growth
Children’s Oncology Group; www.survivorshipguidelines.org

Diagnosis: Stage IV Adrenal Neuroblastoma (Age 3 years)
Date of Diagnosis: 11/1993 Date of Bone Marrow Transplant: Auto, July 1994 (CHLA)
Protocol: CCG 3891 Regimen: B - Bone marrow transplant
Chemotherapy exposures (cumulative dose): Carboplatin (1 g/m2); Cisplatin (300 mg/m2);
Etoposide (1.64 g/m2); Doxorubicin (150 mg/m2); Cyclophosphamide (9 g/m2); Melphalan
(210 mg/m2); Retinoic Acid.
Radiation Therapy: 999 cGy TBI (1994); 2000 cGy to the sphenoid sinus, right shoulder, right hip, right tibia, left tibia (1994); 1000 cGy to the abdomen (1994); MIBG 330 mCU (8/1995).
Surgeries: Subtotal resection of left adrenal mass (1994); Left sphenoid sinus sinusotomy
(1994); Line placement x 2 (1994 & 1995); Resection of anterior abdominal wall fibromatosis
(1995); Resection of chest wall keloid and detached retina repair (1997); Left cataract removal and lens implant (2003); YAG laser capsulotomy left eye (2004); Left tonsillectomy (path of mass = lymphoid follicular hyperplasia) and right tonsil biopsy (2005); Bilateral tibia-fibula osteotomy (2006).
Blood Products/year: None on file, presume 1993
Problem List from History: Hypothyroid; Short Stature; Gonadal failure; Cataracts and retinal detachment.
Neuropsych testing: (2001) Intellectually in the "bright normal to superior range". Susceptible to distraction.

Late Effect: Growth Abnormalities (isolated limb or global)
• Chemotherapy Agents: ? intrathecals
• Radiation: Cranial, Spine, Total Body, any bone
• Risk Factors: Younger age, higher radiation doses
Children’s Oncology Group; www.survivorshipguidelines.org

Periodic Evaluation
• History (every 6 months until growth complete):
Assessment of nutritional status
• Physical (every 6 months until sexually mature):
Height, Weight, BMI and Tanner Stage
Screening
• Plot and follow growth curves carefully. If there is one risk factor and cross one height percentile line refer to endocrine.
Children’s Oncology Group; www.survivorshipguidelines.org

Late Effect: Cataracts
• Cancers: ALL, BMT, Brain tumors
• Chemotherapy Agents: Busulfan, Steroids
• Radiation: Cranial, Total Body
• Risk Factors: Radiation dose ≥10 Gy. TBI ≥ 5 Gy.
Combination therapy.
Children’s Oncology Group; www.survivorshipguidelines.org

Periodic Evaluation
• History (yearly): Visual changes (decreased acuity, halos, diplopia)
• Physical (yearly): Eye exam (visual acuity, fundoscopic exam for lens opacity)
Screening
• Yearly evaluation by ophthalmologist for those who received TBI or ≥ 30 Gy radiation
• Evaluation every 3 years for everyone else
Children’s Oncology Group; www.survivorshipguidelines.org

Diagnosis: Acute lymphoblastic leukemia, high risk for age, slow early response, diagnosed at 11 years old, finished planned chemo 5/2003; Myelodysplastic syndrome with monosomy 7 diagnosed August 2003.
Date of Diagnosis: 1/2001 Date of Bone Marrow Transplant : 11/2003 –
MUD marrow
Chemotherapy exposures (cumulative dose): Anthracycline (300 mg/m2); cytoxan (10 grams/m2); including SCT dose); thiopurines, vincristine, steroids, cytarabine, asparaginase, methotrexate, Busulfan (16 mg/kg); fludarabine (160 mg/m2). Grade 1 GVHD off immunosuppression since Oct 2004;
Radiation Therapy: Cranial prophylaxis 1800 cGy
Surgeries: Central line x 2, Cholecystectomy (2003), Sinus irrigation (2004)
Blood Products/year: 2001
Problem List from History: Ovarian failure; Acne; Gastroesophageal reflux;
Recurrent vaginal yeast infections.
Neuropsych testing: (7/2009) FS IQ 107; Attention issues

Late Effect: Delayed puberty, oligo/ azospermia, premature menopause, infertility
• Cancers: Sarcomas, Hodgkin’s, BMT
• Chemotherapy Agents: Alkylating agents
• Radiation: Cranial, radiation to ovary or testes
• Risk Factors: Higher cumulative doses of alkylators combine with radiation, smoking
Children’s Oncology Group; www.survivorshipguidelines.org

Periodic Evaluation
• History (yearly): Puberty (onset, tempo), Sexual function, Medications impacting sexual function
• Physical (yearly): Tanner Staging, Testicular volume until sexually mature for boys
Screening
• FSH, LH, Estradiol/Testosterone: At age 13
(girls)/14 (boys) and as indicated for signs of gonadal deficiency. Sexual function.
• Semen analysis
Children’s Oncology Group; www.survivorshipguidelines.org

Late Effect: Deficits in executive function, attention, memory, processing speed, visual-motor integration
• Chemotherapy agents: Cytarabine (high dose),
Methotrexate (IT and high dose),
• Radiation: Cranial, Total Body
• Risk Factors: Younger age, female, CNS leukemia/ lymphoma, CNS-directed therapy, Radiation
Children’s Oncology Group; www.survivorshipguidelines.org

Periodic Evaluation
• History (yearly): Educational and/or vocational progress
Screening
• Referral for formal neuropsychological evaluation: Baseline at entry into long term follow-up then as indicated
Children’s Oncology Group; www.survivorshipguidelines.org

AML/MDS:
– Chemotherapy Agents: Anthracyclines,
Etoposide
– Other: Bone marrow transplant
Skin Cancer:
– Radiation: Skin in any field
Soft Tissue Cancer (Bone, Brain, Thyroid, Breast,
GI, Muscle):
– Radiation: Any tissue in the field
Children’s Oncology Group; www.survivorshipguidelines.org

Robison LL et al. 2009

Robison LL et al. 2009

• AML: CBC every year for 10 years (ongoing for BMT)
• Skin Cancer: Yearly dermatologic exam
• Soft Tissue Cancer: Yearly exam
• Breast Cancer: Mammogram beginning 8 years after radiation or at age 25 years (later date). Breast
MRI yearly in addition to mammography.
• Colorectal Cancer: Colonscopy every 5 years
(minimum) beginning at 10 years after radiation or age 35 years (later date).
Children’s Oncology Group; www.survivorshipguidelines.org

Comprehensive Survivorship Program
• Access to risk-based recommendations
• Access to multi-disciplinary consultation and instruction regarding issues
• Education regarding future screening
• Communication with providers

• Multi-disciplinary clinics on Fridays
– Program Coordinator: Kitt Swartz
– Medical Director: Sue Lindemulder
– Nurse Practitioner: Kelly Anderson
– Psychologist: Michael Harris & Debbie Dwelle
– Social Worker: Sue Best
– Educational Specialist: Kerri Russell
– Dental Support: Dental residents
– Neuro-oncologist: Stacy Nicholson
– Orthopedic Surgeons: Ivan Krajbich and James Hayden
– Oncology Nurse: Katie Loomis

• Most children will survive their cancer.
• Survivors are at risk for medical and psychosocial late effects and need lifelong monitoring
• Education for patients and providers with regard to screening for late effects is important to maintain future health
• There are many tools and resources to assist with the care of these patients

Chow EF et al. Risk of Thyroid Dysfunction and Subsequent Thyroid Cancer Among
Survivors of Acute Lymphoblastic Leukemia: A report from the Childhood
Cancer Survivor Study. Pediatr Blood Cancer (2009). 53: 432-437.
Hudson MM et al. Clinical Ascertainment of Health Outcomes Among Adults
Treated for Childhood Cancer. JAMA (2013). 309(22): 2371-2381.
Nathan PC et al. Medical Care in Long-Term Survivors of Childhood Cancer: A Report
From the Childhood Cancer Survivor Study. J Clin Oncol (2008). 26(27): 4401-
4409.
Oeffinger KC et al. Chronic Health Conditions in Adult Survivors of Childhood
Cancer. NEJM (2006). 355(15): 1572-1582.
Robison LL et al. Treatment-associated subsequent neoplasms among long-term survivors of childhood cancer: The Childhood Cancer Survivor Study experience.
Pediatr Radiol (2009). 39(Suppl 1): S32-S37 .