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Cancer Therapy Late Effects, Pediatric

Basics

Description

- 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

- Hematopoietic stem cell transplant (HSCT) - Type and date of transplant - Source: bone marrow, cord blood, or peripheral blood stem cells - Conditioning regimen

- 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.

- Bone growth failure - Risk factors: XRT to any field, especially cranium, spine, trunk, or TBI - Measure height, weight, sitting height yearly.

- 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.

- 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

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 modalitiesSignificant surgical proceduresTreatment protocol(s)ChemotherapyDrugs and cumulative dosagesAge of first anthracycline therapyRadiation therapy (XRT)TypeSite/doseTotal/boost dosesHematopoietic stem cell transplant (HSCT)Type and date of transplantSource: bone marrow, cord blood, or peripheral blood stem cellsConditioning regimenImmunotherapy: 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
  • Hemorrhagic cystitisRisk factors: ≥30 Gy XRT to spine, flank, abdomen, pelvis, bladder, or total body irradiation (TBI)
  • Bladder fibrosis and hemorrhagic cystitisRisk factors: cyclophosphamide, ifosfamide
  • Urinary incontinence or tract obstructionRisk factors: pelvic surgery, hysterectomy
  • Screen with annual urinalysis and detailed voiding history.

Bone Toxicity

  • Decreased bone mineral density, osteopenia, osteonecrosis, increased risk of fracturesRisk factors: corticosteroids, methotrexate, ≥40 Gy XRT to any field, or HSCTEvaluate bone density with DEXA scan.
  • Scoliosis or kyphosisRisk factors: spine or thoracic surgery, XRT to spine, chest, lungs, or abdomenSpine exam annually until growth is complete
  • Bone growth failureRisk factors: XRT to any field, especially cranium, spine, trunk, or TBIMeasure height, weight, sitting height yearly.

Cardiovascular Toxicity

  • Cardiomyopathy, left ventricular dysfunction, and arrhythmiasRisk factors: anthracyclines (daunorubicin, doxorubicin/Adriamycin, epirubicin, idarubicin, mitoxantrone) and/or XRT to the thorax or abdomenFrequency 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 diseaseRisk factors: ≥40 Gy XRT to head, neck, chest, lungs, or TBIExamine for carotid bruits or diminished carotid/brachial/radial pulses.
  • Thrombosis at prior central venous catheter siteInspect site for pain/swelling
  • DyslipidemiaRisk factors: TBIScreen 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 changesRisk factors: any XRT, HSCT with chronic graft-versus-host disease (cGVHD)Encourage monthly self-skin exams.

Endocrine Toxicity

  • Thyroid dysfunction, nodules, and cancerRisk factors: XRT to neck, head, spine, mediastinum, TBI, or therapeutic systemic metaiodobenzylguanidine (MIBG)Thyroid exam and TSH/free T4 annually
  • Growth hormone deficiencyRisk factors: XRT to cranium or TBIHeight, weight, BMI, Tanner stage every 6 months until mature, then annuallyIf at risk: insulin-like growth factor (IGF)-1, IGF-2, and IGFBP-3
  • Central adrenal insufficiencyRisk factors: ≥30 Gy XRT to cranium, TBIScreen: annual endocrinology visit
  • HyperprolactinemiaRisk factors: ≥40 Gy XRT to cranium, TBIIf symptomatic, screen with prolactin level
  • HypopituitarismRisk factors: neurosurgery of brain, ≥30 Gy XRT to cranium, TBIScreening labs: cortisol, prolactin, testosterone/estradiol, IGF-1, TSH, FSH, LH
  • ObesityRisk factors: XRT to cranium, brain neurosurgeryHeight, weight, BMI, BP annually

Gastrointestinal Toxicity

  • Esophageal strictureRisk factors: ≥30 Gy XRT to spine, neck, chest, lung, mediastinum, mantle, abdomen, TBI or HSCT with cGVHD
  • CholelithiasisRisk factors: ≥30 Gy XRT to abdomen, flank, liver, kidneys, TBI
  • Strictures, fistula, chronic enterocolitisRisk factors: ≥30 Gy XRT to neck, chest, spine, abdomen, liver, kidneys, pelvis, TBI
  • Bowel obstruction/adhesionsRisk factors: laparotomy or ≥30 Gy XRT to abdomen, pelvis, or spine
  • Fecal incontinenceRisk factors: pelvic or spinal cord surgery, cystectomy

Hepatic Toxicity

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

Neurologic Toxicity

  • Peripheral neuropathyRisk factors: cisplatin, carboplatin, vincristine, or vinblastine
  • Cerebrovascular complicationsRisk factors: ≥18 Gy XRT to cranium or TBI
  • Neurocognitive difficultiesRisk 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 issuesRisk factors: corticosteroids, busulfan, XRT to orbit/eye, cranium, or TBIAnnual funduscopic and visual acuity examsAnnual ophthalmologist exam as indicated

Ototoxicity

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

Oral Toxicity

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

Pulmonary Toxicity

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

Psychosocial Disorders

  • Neurocognitive, educational, or vocational difficultiesRisk factors: any treatment, especially methotrexate, high-dose cytarabine, brain neurosurgery or XRT to head or TBIEducational/vocational assessment annuallyFormal neuropsychological evaluation as indicated
  • Posttraumatic stress, depression, anxiety, risky behaviors, body image disturbanceRisk factors: any cancer treatmentAssess mental health at each clinic visit.

Renal Toxicity

  • Hypertension or renal dysfunctionRisk factors: nephrectomy or carboplatin, cisplatin, ifosfamide, methotrexate, or XRT to liver, kidneys, flank, abdomen, TBI, or HSCT
  • Hydronephrosis, dysfunctional voiding, vesicoureteral refluxRisk factors: cyclophosphamide, ifosfamide, ≥30 Gy XRT to abdomen, flank, or pelvis
  • Urinary incontinence or tract obstructionRisk 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 menopauseRisk 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 TBIAssess 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, temozolomideTopoisomerase 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 cancerRisk factors: cyclophosphamide, XRT to bladder, prostate, abdomen, pelvis, vagina, flank, inguinal region, or sacral/whole spineObtain annual detailed voiding history.
  • Bone cancer in any XRT fieldPerform annual inspection/palpation of the bones/soft tissues/skin in XRT field.
  • Brain tumorsRisk factors: XRT to cranium or TBIPerform annual neurologic exam.
  • Breast cancerRisk factors: XRT to chest, lungs, mediastinum, axilla, mantle, or TBIAnnual 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 cancerRisk factors: ≥30 Gy XRT to spine, liver, kidneys, flank, abdomen, pelvis, or TBIPerform 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 cancerRisk factors: any XRTPerform annual dermatologic exam in XRT field.Encourage monthly self-skin exams.
  • Thyroid cancerRisk factors: XRT to cranium, neck, spine, supraclavicular, mediastinum, mantle, chest, lungs, or TBIPerform 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/