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Childhood Hodgkin Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Late Effects from Childhood / Adolescent Hodgkin Lymphoma Therapy

Table 8. Treatment Complications Observed in Hodgkin Lymphoma Survivors continued...

Cardiac Toxicity

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:[21,22,23,24]
    • Delayed pericarditis.
    • Pancarditis including pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
    • Cardiomyopathy.
    • Coronary artery disease.[24]
    • 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.[25]
  • 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.[28] 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]

Subsequent Neoplasms

  • A number of series evaluating the incidence of subsequent neoplasms in survivors of childhood and adolescent Hodgkin lymphoma have been published.[31,32,33,34,35,36,37,38,39] 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).[42] 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.[43] Clinical trials using dexrazoxane in childhood leukemia have not observed an excess risk of subsequent neoplasms.[43,44,45]
  • Chemotherapy-related myelodysplasia/AML are less prevalent following contemporary therapy because of the restriction of cumulative alkylating agent doses.
  • Solid neoplasms most often involve the skin, breast, thyroid, gastrointestinal tract, and lung with risk increasing with radiation dose.[38]
  • 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. [37,46,47,48]
  • 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.[37]
  • 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.[37,46,48,49] 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%.[50]
  • 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.[51] 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.[38,52] 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.[53] 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.[54]
  • 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.[55]
  • 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.[56]

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Last Updated: February 25, 2014
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