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Cancer Therapy Late Effects, Pediatric


Basics


Description


The majority of children diagnosed with cancer will reach adulthood. Childhood cancer survivors require unique medical follow-up. Risks of late effects depend on the treatments received as well as the type and site of cancer. The Children's Oncology Group's long-term follow-up guidelines serve as the basis for many of the recommendations in this chapter.  

Epidemiology


  • Long-term survival into adulthood for a child diagnosed with cancer is nearly 80%.
  • Among adults treated for childhood cancer:
    • Nearly 2/3 of survivors will develop one or more chronic health condition.
    • Nearly 1/3 of survivors will experience severe or life-threatening complications during adulthood.
  • Approximately 270,000 childhood cancer survivors live in the United States.
  • These numbers will continue to grow as new cancer therapies become available and more children survive.

Risk Factors


Late effects of cancer therapy are influenced by tumor-related treatment and host-related factors.  

Pathophysiology


Risk of organ dysfunction is related to primary cancer location and treatment used. See detailed systems-based evaluations in the following sections.  

Diagnosis


History


It is essential for the primary care physician to obtain a thorough cancer treatment summary, including the following:  
  • Date of diagnosis/age at diagnosis
  • Type of cancer, stage, histology
  • Site of primary tumor and metastatic sites
  • Relapse(s) and date(s)
  • Treatment modalities
    • Significant surgical procedures
    • Treatment protocol(s)
    • Chemotherapy
      • Drugs and cumulative dosages
      • Age of first anthracycline therapy
    • Radiation therapy (XRT)
      • Type
      • Site/dose
      • Total/boost doses
    • Hematopoietic stem cell transplant (HSCT)
      • Type and date of transplant
      • Source: bone marrow, cord blood, or peripheral blood stem cells
      • Conditioning regimen
    • Immunotherapy: types/cumulative doses

Physical Exam


Annual physical exam of the entire body with particular attention to organ systems as listed in the following sections  

Screening Tests & Interpretation (By at-Risk Organ System)


Bladder Toxicity
  • Chronic infections
    • Risk factors: cystectomy
  • Hemorrhagic cystitis
    • Risk factors: ≥30 Gy XRT to spine, flank, abdomen, pelvis, bladder, or total body irradiation (TBI)
  • Bladder fibrosis and hemorrhagic cystitis
    • Risk factors: cyclophosphamide, ifosfamide
  • Urinary incontinence or tract obstruction
    • Risk factors: pelvic surgery, hysterectomy
  • Screen with annual urinalysis and detailed voiding history.

Bone Toxicity
  • Decreased bone mineral density, osteopenia, osteonecrosis, increased risk of fractures
    • Risk factors: corticosteroids, methotrexate, ≥40 Gy XRT to any field, or HSCT
    • Evaluate bone density with DEXA scan.
  • Scoliosis or kyphosis
    • Risk factors: spine or thoracic surgery, XRT to spine, chest, lungs, or abdomen
    • Spine exam annually until growth is complete
  • Bone growth failure
    • Risk factors: XRT to any field, especially cranium, spine, trunk, or TBI
    • Measure height, weight, sitting height yearly.

Cardiovascular Toxicity
  • Cardiomyopathy, left ventricular dysfunction, and arrhythmias
    • Risk factors: anthracyclines (daunorubicin, doxorubicin/Adriamycin, epirubicin, idarubicin, mitoxantrone) and/or XRT to the thorax or abdomen
    • Frequency of echocardiogram (ECHO)/multigated acquisition (MUGA) depends on cumulative dose of anthracyclines, age at first dose, and field of XRT (involving heart).
    • Consider close monitoring during pregnancy.
  • Carotid artery or subclavian artery disease
    • Risk factors: ≥40 Gy XRT to head, neck, chest, lungs, or TBI
    • Examine for carotid bruits or diminished carotid/brachial/radial pulses.
  • Thrombosis at prior central venous catheter site
    • Inspect site for pain/swelling
  • Dyslipidemia
    • Risk factors: TBI
    • Screen with fasting lipid panel every 2 years.
  • Vasospastic attacks (Raynaud phenomenon)
    • Risk factors: vincristine or vinblastine

Alert
Anthracycline, antibiotics and XRT to the heart/chest/lungs/neck increases risk of cardiovascular disease; at-risk patients require detailed history, exam, and frequent ECHO/MUGA screening.  
Dermatologic Toxicity
  • Skin cancer, dysplastic nevi, fibrosis, alopecia, telangiectasias, nail/pigmentation changes
    • Risk factors: any XRT, HSCT with chronic graft-versus-host disease (cGVHD)
    • Encourage monthly self-skin exams.

Endocrine Toxicity
  • Thyroid dysfunction, nodules, and cancer
    • Risk factors: XRT to neck, head, spine, mediastinum, TBI, or therapeutic systemic metaiodobenzylguanidine (MIBG)
    • Thyroid exam and TSH/free T4 annually
  • Growth hormone deficiency
    • Risk factors: XRT to cranium or TBI
    • Height, weight, BMI, Tanner stage every 6 months until mature, then annually
    • If at risk: insulin-like growth factor (IGF)-1, IGF-2, and IGFBP-3
  • Central adrenal insufficiency
    • Risk factors: ≥30 Gy XRT to cranium, TBI
    • Screen: annual endocrinology visit
  • Hyperprolactinemia
    • Risk factors: ≥40 Gy XRT to cranium, TBI
    • If symptomatic, screen with prolactin level
  • Hypopituitarism
    • Risk factors: neurosurgery of brain, ≥30 Gy XRT to cranium, TBI
    • Screening labs: cortisol, prolactin, testosterone/estradiol, IGF-1, TSH, FSH, LH
  • Obesity
    • Risk factors: XRT to cranium, brain neurosurgery
    • Height, weight, BMI, BP annually

Gastrointestinal Toxicity
  • Esophageal stricture
    • Risk factors: ≥30 Gy XRT to spine, neck, chest, lung, mediastinum, mantle, abdomen, TBI or HSCT with cGVHD
  • Cholelithiasis
    • Risk factors: ≥30 Gy XRT to abdomen, flank, liver, kidneys, TBI
  • Strictures, fistula, chronic enterocolitis
    • Risk factors: ≥30 Gy XRT to neck, chest, spine, abdomen, liver, kidneys, pelvis, TBI
  • Bowel obstruction/adhesions
    • Risk factors: laparotomy or ≥30 Gy XRT to abdomen, pelvis, or spine
  • Fecal incontinence
    • Risk factors: pelvic or spinal cord surgery, cystectomy

Hepatic Toxicity
  • Chronic hepatitis C
    • Risk factor: blood products prior to 1993
    • Screen with Hep C antibody, PCR if positive
  • Hepatic dysfunction
    • Risk factors: methotrexate, mercaptopurine (6-MP), thioguanine (6-TG), HSCT
  • Veno-occlusive disease
    • Risk factors: mercaptopurine or thioguanine
  • Baseline: ALT/AST/bili; ferritin after HSCT

Neurologic Toxicity
  • Peripheral neuropathy
    • Risk factors: cisplatin, carboplatin, vincristine, or vinblastine
  • Cerebrovascular complications
    • Risk factors: ≥18 Gy XRT to cranium or TBI
  • Neurocognitive difficulties
    • Risk factors: brain neurosurgery, methotrexate, high-dose IV cytarabine, XRT to cranium, TBI
  • Seizures, motor/sensory deficits, or hydrocephalus following brain neurosurgery
  • Clinical leukoencephalopathy following methotrexate, high-dose IV cytarabine, or XRT to cranium or TBI
  • Neuropathic pain risk following amputation
  • Neurogenic bowel/bladder, incontinence, sexual dysfunction risk after spinal cord neurosurgery

Ophthalmologic Toxicity
  • Cataracts/ocular issues
    • Risk factors: corticosteroids, busulfan, XRT to orbit/eye, cranium, or TBI
    • Annual funduscopic and visual acuity exams
    • Annual ophthalmologist exam as indicated

Ototoxicity
  • Hearing loss, vertigo, or tinnitus
    • Risk factors: cisplatin, carboplatin: myeloablative or any does <1 year; XRT > 30 Gy to ear, cranium, or TBI
    • Baseline audiogram (annually if loss detected)
    • Otoscopic exam annually

Oral Toxicity
  • Tooth enamel dysplasia and root/tooth agenesis or root thinning/shortening
    • Risk factors: any chemotherapy (particularly at a young age), XRT to head/neck
  • Xerostomia or salivary gland dysfunction
    • Risk factors: head/neck XRT or cGVHD
  • Osteoradionecrosis
    • Risk factors: ≥40 Gy XRT to head, neck, TBI
  • Oral exam annually; dental cleaning and exam every 6 months

Pulmonary Toxicity
  • Fibrosis, dyspnea, decreased lung function
    • Risk factors: bleomycin, busulfan, carmustine, lomustine, XRT to chest or lungs, or TBI
    • If at risk, obtain baseline pulmonary function testing, and as clinically indicated

Psychosocial Disorders
  • Neurocognitive, educational, or vocational difficulties
    • Risk factors: any treatment, especially methotrexate, high-dose cytarabine, brain neurosurgery or XRT to head or TBI
    • Educational/vocational assessment annually
    • Formal neuropsychological evaluation as indicated
  • Posttraumatic stress, depression, anxiety, risky behaviors, body image disturbance
    • Risk factors: any cancer treatment
    • Assess mental health at each clinic visit.

Renal Toxicity
  • Hypertension or renal dysfunction
    • Risk factors: nephrectomy or carboplatin, cisplatin, ifosfamide, methotrexate, or XRT to liver, kidneys, flank, abdomen, TBI, or HSCT
  • Hydronephrosis, dysfunctional voiding, vesicoureteral reflux
    • Risk factors: cyclophosphamide, ifosfamide, ≥30 Gy XRT to abdomen, flank, or pelvis
  • Urinary incontinence or tract obstruction
    • Risk factor: pelvic surgery
  • Baseline: BUN/Cr, Na/K/Cl/CO2, Mg, Phos, Ca
  • Annual UA and BP if at risk or after nephrectomy

Reproductive Toxicity
  • Gonadal dysfunction: infertility, azoospermia, oligospermia, hypogonadism, delayed or arrested puberty, sexual dysfunction, early menopause
    • Risk factors: spinal neurosurgery, orchiectomy, alkylating agents (busulfan, carmustine, chlorambucil, cyclophosphamide, ifosfamide, lomustine, mechlorethamine, melphalan, procarbazine, thiotepa), carboplatin, cisplatin, dacarbazine, temozolomide, XRT to gonads, pelvis, abdomen, cranium, or TBI
    • Assess Tanner stage yearly until mature.
    • Males: Screen with FSH/LH/testosterone at 14 years or if symptomatic and semen analysis as requested.
    • Females: Screen with FSH/LH/estradiol at 13 years or with delayed puberty/amenorrhea/irregular menses/estrogen deficiency symptoms.

Subsequent Neoplasms
  • Increased risk varies by host factors, primary cancer therapy, and environmental exposures.
  • The Childhood Cancer Survivor Study reported a 30-year cumulative incidence of 20.5%.
  • The risk of subsequent neoplasms (SNs) remains elevated for more than 30 years following primary cancer diagnosis.
  • Patients with genetic cancer predisposition syndromes are at increased risk of SNs.
  • 80% of SNs are solid tumors and demonstrate a strong relationship with ionizing radiation.
  • Blood cancer: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and therapy-related myelodysplastic syndrome (t-MDS)
    • Risk factors: alkylating agents, anthracyclines, carboplatin, cisplatin, dacarbazine, temozolomide
    • Topoisomerase II inhibitor-associated AML occurs 6 months to 3 years after exposure.
    • Alkylating agent-associated t-MDS/AML occurs 3-5 years after exposure.
    • Screen with annual complete blood count with differential for 10 years following treatment.
    • Perform dermatologic exam for petechiae, purpura, and pallor at each visit.
  • Bladder cancer
    • Risk factors: cyclophosphamide, XRT to bladder, prostate, abdomen, pelvis, vagina, flank, inguinal region, or sacral/whole spine
    • Obtain annual detailed voiding history.
  • Bone cancer in any XRT field
    • Perform annual inspection/palpation of the bones/soft tissues/skin in XRT field.
  • Brain tumors
    • Risk factors: XRT to cranium or TBI
    • Perform annual neurologic exam.
  • Breast cancer
    • Risk factors: XRT to chest, lungs, mediastinum, axilla, mantle, or TBI
    • Annual breast exam from puberty to age 25 years; after age 25 years, perform every 6 months
    • ≥20 Gy XRT: annual mammogram and breast MRI beginning at age 25 or 8 years post XRT (whichever is last); 10-19 Gy XRT: consider testing
  • Colorectal cancer
    • Risk factors: ≥30 Gy XRT to spine, liver, kidneys, flank, abdomen, pelvis, or TBI
    • Perform colonoscopy at age 35 years or 10 years after XRT (whichever is last), every 5 years.
    • Familial adenomatous polyposis (FAP), start colonoscopy at 21 years; hereditary nonpolysis colorectal cancer (HNPCC), start at puberty
  • Skin cancer
    • Risk factors: any XRT
    • Perform annual dermatologic exam in XRT field.
    • Encourage monthly self-skin exams.
  • Thyroid cancer
    • Risk factors: XRT to cranium, neck, spine, supraclavicular, mediastinum, mantle, chest, lungs, or TBI
    • Perform annual thyroid exam.

Treatment


Treatment depends on long-term effects; see previous discussion for organ system-specific follow-up care.  

Ongoing Care


  • Regular visits with primary care provider and oncologist or long-term follow-up program
  • Dental exams and cleanings every 6 months
  • Promptly assess signs or symptoms of SNs.
  • Assess psychosocial functioning at each visit.
  • Maintain health insurance coverage.
  • Immunizations may require updates.

Alert


  • Reimmunize after chemotherapy per oncologist and using Centers for Disease Control and Prevention (CDC) guidelines.
  • Psychosocial assessment of the patient should be performed at each clinic visit.

Additional Reading


  • 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.  [View Abstract]
  • Centers for Disease Control and Prevention. Immunization schedules. http://www.cdc.gov/vaccines/schedules/. Accessed February 5, 2015.
  • Children's Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. http://www.survivorshipguidelines.org/. Accessed February 5, 2015.
  • Oeffinger  KC, Mertens  AC, Sklar  CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med.  2006;355(15):1572-1582.  [View Abstract]

Codes


ICD09


  • 909.5 Late effect of adverse effect of drug, medicinal or biological substance
  • V10 Personal history of malignant neoplasm
  • V87.41 Personal history of antineoplastic chemotherapy
  • 909.2 Late effect of radiation

ICD10


  • T88.7XXS Unspecified adverse effect of drug or medicament, sequela
  • Z85 Personal history of malignant neoplasm
  • Z92.21 Personal history of antineoplastic chemotherapy
  • Z92.3 Personal history of irradiation

SNOMED


  • 423661009 Complication of chemotherapy
  • 266987004 History of malignant neoplasm (situation)
  • 161653008 history of - chemotherapy (situation)
  • 212904005 Radiation therapy complication (disorder)
  • 269191009 Late effect of medical and surgical care complication (disorder)

FAQ


  • Q: Who is considered a cancer "survivor"?
  • A: Anyone from time of cancer diagnosis until end of life. Many long-term follow-up clinics specialize in patients who are 2 years post cancer therapy.
  • Q: Where can I find the latest long-term follow-up guidelines for childhood cancer survivors?
  • A: http://www.survivorshipguidelines.org/
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