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Late Effects from Childhood / Adolescent Hodgkin Lymphoma Therapy

    Children and adolescent survivors of Hodgkin lymphoma are at risk for numerous late complications of treatment related to radiation, specific chemotherapeutic exposures, and surgical staging. Adverse treatment effects may impact oral/dental health; musculoskeletal growth and development; endocrine, reproductive, cardiovascular and pulmonary function; and risk of secondary carcinogenesis. In the past 30 to 40 years, pediatric Hodgkin lymphoma therapy has changed dramatically to proactively limit exposure to radiation and chemotherapeutic agents, such as anthracyclines, alkylating agents, and bleomycin. When counseling individual patients about the risk for specific treatment complications, the era of treatment should be considered.

    The following table summarizes late health effects observed in Hodgkin lymphoma survivors followed by a limited discussion of the common late effects. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)

    Table 8. Treatment Complications Observed in Hodgkin Lymphoma Survivors

    Health EffectsPredisposing TherapyClinical Manifestations
    Oral/dentalAny chemotherapy in a patient who has not developed permanent dentitionDental maldevelopment (tooth/root agenesis, microdontia, root thinning and shortening, enamel dysplasia)
    Radiation impacting oral cavity and salivary glandsSalivary gland dysfunction
    Xerostomia
    Accelerated dental decay
    Periodontal disease
    ThyroidRadiation impacting thyroid glandHypothyroidism
    Hyperthyroidism
    Thyroid nodules
    CardiovascularRadiation impacting cardiovascular structuresSubclinical left ventricular dysfunction
    Cardiomyopathy
    Pericarditis
    Heart valve dysfunction
    Conduction disorder
    Coronary, carotid, subclavian vascular disease
    Myocardial infarction
    Stroke
    Anthracycline chemotherapySubclinical left ventricular dysfunction
    Cardiomyopathy
    Congestive heart failure
    PulmonaryRadiation impacting the lungsSubclinical pulmonary dysfunction
    BleomycinPulmonary fibrosis
    MusculoskeletalRadiation of musculoskeletal tissues in any patient who is not skeletally matureGrowth impairment
    GlucocorticosteroidsBone mineral density deficit
    Osteonecrosis
    ReproductiveAlkylating agent chemotherapyHypogonadism
    Gonadal irradiationInfertility
    ImmuneSplenectomyOverwhelming post-splenectomy sepsis
    Subsequent neoplasm or diseaseAlkylating agent chemotherapyMyelodysplasia/acute myeloid leukemia
    EpipodophyllotoxinsMyelodysplasia/acute myeloid leukemia
    RadiationSolid benign and malignant neoplasms

    Male Gonadal Toxicity

    • Gonadal radiation and alkylating agent chemotherapy may produce testicular Leydig cell or germ cell dysfunction with risk related to cumulative dose of both modalities.
    • Hypoandrogenism associated with Leydig cell dysfunction may manifest as lack of sexual development; small, atrophic testicles; and sexual dysfunction. Hypoandrogenism also increases the risk of osteoporosis and metabolic disorders associated with chronic disease.[1,2]
    • Infertility caused by azoospermia is the most common manifestation of gonadal toxicity. Some pubertal male patients will have impaired spermatogenesis before they begin therapy.[3,4]
    • The prepubertal testicle is likely equally or slightly less sensitive to chemotherapy compared with the pubertal testicle. Pubertal status is not protective of chemotherapy-associated gonadal toxicity.[5,6]
    • Testicular Leydig cells are relatively resistant to treatment toxicity compared with testicular germ cells. Survivors who are azoospermic after gonadal toxic therapy may maintain adequate testosterone production.[5,6,7]
    • Chemotherapy regimens that include no alkylating agents such as ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine), ABVE (doxorubicin [Adriamycin], bleomycin, vincristine, etoposide), OEPA (vincristine [Oncovin], etoposide, prednisone, doxorubicin [Adriamycin]), or VAMP (vincristine, doxorubicin [Adriamycin], methotrexate, prednisone) are not associated with male infertility.
    • Chemotherapy regimens including more than one alkylating agent, usually procarbazine in conjunction with cyclophosphamide (i.e., COPP [cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine]), chlorambucil, or nitrogen mustard (MOPP) confer a high risk of permanent azoospermia if treatment exceeds three cycles.[8,9]
    • Investigations evaluating germ cell function in relation to single alkylating agent exposure suggest that the incidence of permanent azoospermia will be low if the cyclophosphamide dose is less than 7.5 g/m2.[6,10]
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