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.)
|Health Effects||Predisposing Therapy||Clinical Manifestations|
|Oral/dental||Any chemotherapy in a patient who has not developed permanent dentition||Dental maldevelopment (tooth/root agenesis, microdontia, root thinning and shortening, enamel dysplasia)|
|Radiation impacting oral cavity and salivary glands||Salivary gland dysfunction|
|Accelerated dental decay|
|Thyroid||Radiation impacting thyroid gland||Hypothyroidism|
|Cardiovascular||Radiation impacting cardiovascular structures||Subclinical left ventricular dysfunction|
|Heart valve dysfunction|
|Coronary, carotid, subclavian vascular disease|
|Anthracycline chemotherapy||Subclinical left ventricular dysfunction|
|Congestive heart failure|
|Pulmonary||Radiation impacting the lungs||Subclinical pulmonary dysfunction|
|Musculoskeletal||Radiation of musculoskeletal tissues in any patient who is not skeletally mature||Growth impairment|
|Glucocorticosteroids||Bone mineral density deficit|
|Reproductive||Alkylating agent chemotherapy||Hypogonadism|
|Immune||Splenectomy||Overwhelming post-splenectomy sepsis|
|Subsequent neoplasm or disease||Alkylating agent chemotherapy||Myelodysplasia/acute myeloid leukemia|
|Epipodophyllotoxins||Myelodysplasia/acute myeloid leukemia|
|Radiation||Solid 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.[5-7]
- 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]
Female Gonadal Toxicity
- Because ovarian hormone production is linked to the maturation of primordial follicles, depletion of follicles by alkylating agent chemotherapy can potentially affect both fertility and ovarian hormone production.
- Because of their greater complement of primordial follicles, the ovaries of young and adolescent girls are less sensitive to the effects of alkylating agents than are the ovaries of older women. In general, girls maintain ovarian function at higher cumulative alkylating agent doses compared with the germ cell function maintained in boys.
- Most females treated with contemporary risk-adapted therapy will attain menses (if prepubertal at treatment) or regain normal menses (if pubertal at treatment) unless pelvic radiation therapy is given without oophoropexy.
- Ovarian transposition to a lateral or medial region from the planned radiation volume may preserve ovarian function in young and adolescent girls who require pelvic radiation therapy for lymphoma.
- The risk of acute ovarian failure and premature menopause is substantial if treatment includes combined-modality therapy with alkylating agent chemotherapy and abdominal or pelvic radiation or dose-intensive alkylating agents for myeloablative conditioning before hematopoietic cell transplantation.[12,13]
- In the Childhood Cancer Survivor Study (CCSS), investigators observed that Hodgkin lymphoma survivors were among the highest risk groups for acute ovarian failure and early menopause. In this cohort, the cumulative incidence of nonsurgical premature menopause among survivors treated with alkylating agents and abdominal or pelvic radiation approached 30%.[12,13]
- In a large study of 1,700 women treated between the ages of 15 and 40 years, there was a high incidence (60%) of premature ovarian failure after alkylating chemotherapy with no excess risk of premature ovarian failure following nonalkylating chemotherapy. Among women who developed premature ovarian failure, 22% had previously had one or more children.
- Abnormalities of the thyroid gland, including hypothyroidism, hyperthyroidism, and thyroid neoplasms have been reported to occur at a higher rate among survivors of Hodgkin lymphoma compared with the general population.
- Risk factors for hypothyroidism include increasing dose of radiation, female gender, and older age at diagnosis.[15-17] CCSS investigators reported a 20-year actuarial risk of 30% of developing hypothyroidism in Hodgkin survivors treated with 3,500 cGy to 4,499 cGy and 50% for subjects whose thyroid received 4,500 cGy or more.
- Hypothyroidism develops most often in the first 5 years after treatment, but new cases have been reported to emerge more than 20 years after the diagnosis.
- Hyperthyroidism has been observed after treatment for Hodgkin lymphoma with a clinical picture similar to that of Graves disease. Higher radiation dose has been associated with greater risk of hyperthyroidism.
- Thyroid neoplasms, both benign and malignant, have been reported with increased frequency following neck irradiation. The incidence of nodules varies substantially across studies (2%–65%) depending on the length of follow-up and detection methods used.[15-17] Risk factors for the development of thyroid nodules in Hodgkin lymphoma survivors reported by CCSS include time since diagnosis greater than 10 years (relative risk [RR], 4.8; 95% confidence interval [CI], 3.0–7.8), female gender (RR, 4.0; 95% CI, 2.5– 6.7), and radiation dose to thyroid greater than 25 Gy (RR, 2.9; 95% CI, 1.4–6.9).
Hodgkin lymphoma survivors exposed to doxorubicin or thoracic radiation therapy are at risk for long-term cardiac toxicity. The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. The pathogenesis of injury differs, however, with radiation primarily affecting the fine vasculature of the heart, and anthracyclines directly damaging myocytes.[19,20]
Radiation-associated cardiovascular toxicity
- Late effects of radiation to the heart include the following:[21-24]
- Delayed pericarditis.
- Pancarditis including pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
- Coronary artery disease.
- Functional valve injury.
- Conduction defects.
The risks to the heart are related to the amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, and latency period.
- Modern radiation techniques allow a reduction in the volume of cardiac tissue incidentally exposed to higher radiation doses. It is anticipated that this will reduce the risk of adverse cardiac events.
Selected studies evaluating cardiovascular toxicity associated with radiation
(Refer to the Cardiovascular Disease in Select Cancer Subgroups: Hodgkin lymphoma section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for information on studies evaluating cardiovascular toxicity associated with radiation.)
Anthracycline-related cardiac toxicity
- Late complications related to anthracycline injury include subclinical left ventricular dysfunction, cardiomyopathy, and congestive heart failure.
- Increased risk of doxorubicin-related cardiomyopathy is associated with female gender, cumulative doses higher than 200 mg/m2 to 300 mg/m2, younger age at time of exposure, and increased time from exposure.
- Prevention or amelioration of anthracycline-induced cardiomyopathy is of utmost importance because the continued usage of anthracyclines is required in cancer therapy in more than one-half of children with newly diagnosed cancer.[26,27]
- Dexrazoxane (a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent) has been shown to prevent heart damage in adults and children treated with anthracyclines. Studies suggest that dexrazoxane is safe and does not interfere with chemotherapeutic efficacy.
- Studies of cancer survivors treated with anthracyclines have not demonstrated the benefit of enalapril in preventing progressive cardiac toxicity.[29,30]
- A number of series evaluating the incidence of subsequent neoplasms in survivors of childhood and adolescent Hodgkin lymphoma have been published.[31-39] Many of the patients included in these series received high-dose radiation therapy and high-dose alkylating agent chemotherapy regimens, which are no longer used.
- Subsequent neoplasms comprise two distinct groups: chemotherapy-related myelodysplasia/acute myeloid leukemia (AML) and solid neoplasms that are predominately radiation related.[40,41]
- Secondary hematological malignancy (most commonly AML and myelodysplasia) is related to the use of alkylating agents, anthracycline, and etoposide and exhibit a brief latency period (<3 years from the primary cancer). This excess risk is largely related to cases of myelodysplasia and secondary AML. A single-study experience suggests that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity. Clinical trials using dexrazoxane in childhood leukemia have not observed an excess risk of subsequent neoplasms.[43-45]
- Chemotherapy-related myelodysplasia/AML are less prevalent following contemporary therapy because of the restriction of cumulative alkylating agent doses.[46,47]
- Solid neoplasms most often involve the skin, breast, thyroid, gastrointestinal tract, and lung with risk increasing with radiation dose.
- The risk of a secondary solid tumor escalates with the passage of time after diagnosis of Hodgkin lymphoma, with a latency of 20 years or more.
- Breast cancer is the most common therapy-related solid subsequent neoplasm after Hodgkin lymphoma. The absolute excess risk ranges from 18.6 to 79 per 10,000 person-years, and the cumulative incidence ranges from 12% to 26%, 25 to 30 years after radiation exposure. [37,48-50]
- High risk of breast cancer has been found to increase as early as 8 years from radiation exposure, and it continues to increase with time from exposure. The median age at diagnosis of breast cancer is 36 years, at least 25 years earlier than what is observed in the general population.
- The cumulative incidence of breast cancer by age 40 to 45 years ranges from 13% to 20%, compared with a 1% risk for women in the general population.[37,48,50,51] This risk is similar to what is observed for women with a BRCA gene mutation, where, by age 40 years, the cumulative incidence of breast cancer ranges from 10% to 19%.
- The risk for breast cancer in female survivors of Hodgkin lymphoma is directly related to the dose of radiation therapy received over a range from 4 to 40 Gy. There is a 3.2-fold increase in the risk of developing breast cancer for females who received 4 Gy and an eightfold increase in risk for females who received 40 Gy. Female patients treated with both radiation therapy and alkylating agent chemotherapy have a lower RR for developing breast cancer than women receiving radiation therapy alone.[38,54] CCSS investigators also demonstrated that breast cancer risk associated with breast irradiation was sharply reduced among women who received 5 Gy or more to the ovaries. The protective effect of alkylating chemotherapy and ovarian radiation is believed to be mediated through induction of premature menopause, suggesting that hormone stimulation contributes to the development of radiation-induced breast cancer.
- Female survivors of Hodgkin lymphoma who develop breast cancer have a sevenfold increase in rate of death, even when adjusted for stage, compared with patients who develop breast cancer de novo. These survivors also have a twofold increase in the rate of death from cardiac disease.
- A study of women survivors who received chest radiation for Hodgkin lymphoma showed that one of the most important factors in obtaining mammograms per guidelines was recommendation from their treating physician. Standard guidelines for routine breast screening are available. The COG guidelines recommend annual screening mammograms for women beginning 8 years after treatment or at age 25 years, whichever is later.
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