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The Pediatric Perspective on Cancer Survivorship. Sue Lindemulder, MD, MCR Medical Director , Childhood Cancer Survivorship Program September 12, 2013. Objectives. After this presentation, participants should be able to: - PowerPoint PPT Presentation
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The Pediatric Perspective on Cancer Survivorship
Sue Lindemulder, MD, MCRMedical Director, Childhood Cancer Survivorship Program
September 12, 2013
Objectives
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
Background
Majority of children with cancer become long term survivors
Majority of childhood cancer survivors have late effects
Approximately 80% will be Survivors
Childhood Cancer Survivor Study
• 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
Childhood Cancer Survivor Study
• 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
CCSS: Percentage with Late Effects
Oeffinger KC et al. 2006
CCSS: Type of Late Effects
Oeffinger KC et al. 2006
CCSS: Timing of Late Effects
Oeffinger KC et al. 2006
St Jude Lifetime Cohort Study
• 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%)
SJLIFE: Effect of Screening
CCSS: Survivors and Medical Care
Nathan PC et al. 2008.
Putting a Face on Survivorship
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
Cancer Treatment Summary
Cardiac Toxicity
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
Cardiac ToxicityPeriodic 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
Cardiac Toxicity Screening GuidelinesAge at Treatment Radiation with Potential
Impact to the HeartAnthracycline Dose Recommended
Frequency
< 1 year old Yes Any Every year
No<200 mg/m2 Every 2 years
≥200 mg/m2 Every year
1-4 years old Yes Any Every year
No<100 mg/m2 Every 5 years
≥100 to <300 mg/m2 Every 2 years
≥300 mg/m2 Every year
≥5 years old Yes <300 mg/m2 Every 2 years
≥300 mg/m2 Every year
No <200mg/m2 Every 5 years
≥200 to <300 mg/m2 Every 2 years
≥300 mg/m2 Every year
Any age with decrease in serial function Every year
Children’s Oncology Group; www.survivorshipguidelines.org
Pulmonary Toxicity
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
Pulmonary Toxicity
Periodic Evaluation• History (yearly): Cough, SOB, DOE, Wheezing• Physical (yearly): Pulmonary examScreening• 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
Meet Jessica
Jessica’s Cancer Treatment Summary
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
Bone ToxicityLate 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
Bone Toxicity
Periodic Evaluation• History (yearly): Fracture history, joint pain• Physical (yearly): No specificScreening• 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
Endocrine Toxicity: Thyroid
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
Endocrine Toxicity: ThyroidPeriodic 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
Meet Brady
Brady’s Cancer Treatment Summary
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.
Brady’s Growth Chart
Growth Abnormalities
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
Growth AbnormalitiesPeriodic 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
Warning! Decreased Velocity!
Eye Toxicity
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
Eye ToxicityPeriodic 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
Meet Leah
Leah’s Cancer Treatment SummaryDiagnosis: 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
Endocrine Toxicity: Gonadal Function
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
Endocrine Toxicity: Gonadal Function
Periodic Evaluation• History (yearly): Puberty (onset, tempo), Sexual
function, Medications impacting sexual function• Physical (yearly): Tanner Staging, Testicular
volume until sexually mature for boysScreening• 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
Neurocognitive Function
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
Neurocognitive Function
Periodic Evaluation• History (yearly): Educational and/or
vocational progressScreening• Referral for formal neuropsychological
evaluation: Baseline at entry into long term follow-up then as indicated
Children’s Oncology Group; www.survivorshipguidelines.org
Risk for All?
Second CancersAML/MDS:
– Chemotherapy Agents: Anthracyclines, Etoposide
– Other: Bone marrow transplantSkin Cancer:
– Radiation: Skin in any fieldSoft Tissue Cancer (Bone, Brain, Thyroid,
Breast, GI, Muscle):– Radiation: Any tissue in the field
Children’s Oncology Group; www.survivorshipguidelines.org
When are they at Risk?
Robison LL et al. 2009
Does the Risk Ever End?
Robison LL et al. 2009
Second Cancers: Screening• 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
Tools to Assist Medical Providers
Tools for Providers and Patients
Comprehensive Survivorship Program• Access to risk-based recommendations• Access to multi-disciplinary consultation and
instruction regarding issues• Education regarding future screening• Communication with providers
Doernbecher Childhood Cancer Survivorship Program
• 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
Conclusions
• 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
Thank you for Your Attention!
References
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.