Table 9. Treatment Complications Observed in Hodgkin Lymphoma Survivors continued...
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). 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.[43,44,45]
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. [37,48,49,50]
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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