Male Gonadal Toxicity
Female Infertility
Thyroid Abnormalities
Cardiac Toxicity
Secondary Malignancies

Children and adolescent survivors of Hodgkin lymphoma are at risk for numerous late complications of treatment. Alkylating agents and etoposide have been associated with acute myeloid leukemia (AML) and myelodysplastic syndromes. Doxorubicin can lead to cardiomyopathy and bleomycin can cause pulmonary fibrosis. Steroid use can produce avascular necrosis. Radiation therapy can lead to thyroid dysfunction, most commonly compensated hypothyroidism, increased risk for myocardial atherosclerotic heart disease, and is associated with solid tumor development in radiation fields. The therapy for pediatric Hodgkin lymphoma has changed dramatically over the past 20 years. High-dose radiation therapy is no longer utilized and current chemotherapy regimens utilize lower doses of alkylating agents. Hybrid regimens allow for lower doses of anthracycline and bleomycin as well. Thus, much of the current late effects literature is not necessarily applicable to patients receiving modern therapy. (Refer to the PDQ Late Effects of Treatment for Childhood Cancer summary for a full discussion of the late effects of cancer treatment in children and adolescents.)

Male gonadal toxicity is a complex issue in Hodgkin lymphoma. Gonadal toxicity may manifest as infertility; lack of sexual development; small, atrophic testicles; and sexual dysfunction. Infertility caused by azoospermia is the most common manifestation of gonadal toxicity. Some pubertal male patients will have impaired spermatogenesis before they begin therapy.[1,2] The prepubertal testicle is likely equally or slightly less sensitive to chemotherapy compared with the pubertal testicle. Chemotherapy regimens that include no alkylating agents such as ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine), DBVE (doxorubicin, bleomycin, vincristine, etoposide), OEPA (vincristine [Oncovin], etoposide, prednisone, doxorubicin [Adriamycin]), or VAMP (vincristine, doxorubicin [Adriamycin], methotrexate, prednisone) are not associated with male infertility. Until recently, most male patients received chemotherapy regimens that included alkylating agents. Many regimens included more than one alkylating agent, usually procarbazine in conjunction with either cyclophosphamide (i.e., COPP [cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine]), chlorambucil, or nitrogen mustard (MOPP).

The German Pediatric Oncology and Hematology Group Hodgkin Study (GPOH-95) utilized OEPA for two cycles for all males.[3] Males with advanced-stage disease received an additional two or four cycles of COPP (each cycle, 1,500 mg/m² of procarbazine and 1,000 mg/m² of cyclophosphamide). Males receiving only two cycles of OEPA had normal basal levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and only rare patients had elevated levels following gonadotropin-releasing hormone (GnRH) stimulation. Basal levels of FSH, however, were elevated in 27.5% and 36.4% in patients receiving two and four COPP cycles, respectively. Stimulated FSH levels were abnormal in 83.3% and 66.7% of patients receiving two and four COPP cycles, respectively. Semen analysis was not performed in this study. Four cycles of COPP/ABV as given in the recently completed Children’s Cancer Group (CCG) study have a higher alkylator dose compared with two cycles of COPP as given in the German trial (CCG: cyclophosphamide 2,400 mg/m² and procarbazine 4,200 mg/m² versus GPOH: cyclophosphamide 2,000 mg/m² and procarbazine 3,000 mg/m²). In a small study of 11 male patients with Hodgkin lymphoma who received COPP/ABV chemotherapy (4 to 6 cycles), nine patients were azoospermic. One of the patients who was normospermatic received only a 400 mg/m² cumulative procarbazine dose because of an allergic reaction.[4] The concern for male fertility is also being addressed in the German GPOH 2003 trial by replacing procarbazine with dacarbazine (COPDIC).[5]

A regimen used by the former Pediatric Oncology Group (POG) included cyclophosphamide but no procarbazine (ABVE-PC). In this regimen, cyclophosphamide was given at 800 mg/m²/course for three to five cycles. A few studies have evaluated male fertility following cyclophosphamide-containing regimens given to children and young adults with sarcomas and other cancers.[6-8] The studies have suggested that the incidence of sterility will be low if the cyclophosphamide dose is less than 4.0 g/m². The level of inhibin B in blood seems to be inversely correlated with FSH levels.[9] Some patients with normal FSH levels may have azoospermia on semen analysis.

There are few published data concerning the incidence of ovarian failure following chemotherapy for female children and young adults with Hodgkin lymphoma. It appears that the ovaries of children and adolescents are less sensitive to the effects of alkylating agents than are the ovaries of older women. Most females will attain menses (prepubertal at treatment) or regain normal menses (pubertal at treatment) unless pelvic radiation therapy is given without oophoropexy. The incidence of early menopause in young female survivors of Hodgkin lymphoma is currently being studied, and may be as high as 37%.[10,11] A small study of patients treated with ABVD, suggests that there is no effect on fertility.[12] Another study of 12 female childhood Hodgkin lymphoma survivors showed that VAMP chemotherapy and low dose involved-field radiation seems to have a minimal impact on female fertility as 14 healthy babies were born to these women.[13]

The largest database for thyroid abnormalities is that of the Childhood Cancer Survivor Study. The cohort of 13,674 patients included 1,791 survivors of childhood Hodgkin lymphoma.[14] For patients with full data, 92 patients received chemotherapy alone, and 1,210 patients received radiation therapy (with or without chemotherapy). Only 15% of patients receiving radiation had doses less than 20 Gy. By self-report, hypothyroidism occurred within 20 years from diagnosis in 7.6% of unirradiated patients, 30% of those receiving less than 35 Gy and 50% of those receiving more than 35 Gy. Although no thyroid cancers were noted in patients receiving less than 25 Gy, overall, there was an 18-fold increased risk of thyroid cancer in survivors of pediatric Hodgkin lymphoma. The risk of hypothyroidism in white patients is 2.5 times the risk in black patients.[15] In a study of 47 survivors of pediatric Hodgkin lymphoma who received neck irradiation (22.5–40Gy), ultrasonography revealed atrophy in 45 patients and goiters in two patients. Twenty patients had a focal abnormality (15 multiple, 5 solitary). Five patients had a lesion larger than 1 cm. Ten patients underwent surgery, and five patients had thyroid carcinoma diagnosed.[16]

Hodgkin lymphoma survivors exposed to doxorubicin or thoracic radiation therapy are at risk for long-term cardiac toxicity. The risks to the heart are related to cumulative anthracycline dose, method of administration, 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, latency period, and gender.

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.[17] Late effects of radiation to the heart include:[18-20]

• Delayed pericarditis.
• Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
• Myopathy.
• Coronary artery disease (CAD).
• Functional valve injury.
• Conduction defects.

In a study of 635 patients treated for childhood Hodgkin lymphoma, the actuarial risk of pericarditis requiring pericardiectomy was 4% at 17 years posttreatment (occurring only in children treated with higher radiation doses). Only 12 patients died of cardiac disease, including seven deaths from acute myocardial infarction; however, these deaths occurred only in children treated with 42 Gy to 45 Gy. Among children treated with 15 Gy to 26 Gy, none developed radiation-associated cardiac problems.[21] Cardiac radiation using sophisticated treatment planning and careful blocking to doses 25 Gy or less is generally safe, and 40 Gy may be administered to small cardiac regions. The risk of delayed CAD after lower radiation doses, however, requires additional study of patients followed for longer periods of time to definitively ascertain lifetime risk. Nontherapeutic risk factors for CAD such as family history, obesity, hypertension, smoking, diabetes, and hypercholesterolemia are likely to impact the frequency of disease.[19] Increased risk of doxorubicin-related cardiomyopathy is associated with female sex, cumulative doses higher than 200 mg/m² to 300 mg/m², younger age at time of exposure, and increased time from exposure.[22-37]

Prevention or amelioration of anthracycline-induced cardiomyopathy is of utmost importance because the continued usage of anthracyclines is required in cancer therapy. Dexrazoxane (DZR) is a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent. Studies to date of cancer survivors treated with anthracyclines have not demonstrated the benefit of enalapril in preventing progressive cardiac toxicity.[38,39] Dexrazoxane has been shown to prevent cardiac toxicity in adults and children treated with anthracyclines,[40-44]however, the use of dexrazoxane in combination with etoposide in treating children with Hodgkin lymphoma remains controversial.[45,46] Studies suggest that dexrazoxane is safe and it does not interfere with chemotherapeutic efficacy. There is a single-study experience suggesting that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity; however, at this time, this should not preclude treatment with dexrazoxane.[45,46]

In two closed POG therapeutic phase III studies for Hodgkin lymphoma,[47,48] myocardial toxicity is being measured clinically and sequentially over time by echocardiography and electrocardiography, as well as by the determination of levels of cardiac troponin T, a protein that is elevated after myocardial damage.[40,49-53]

A number of series evaluating the incidence of malignancies in survivors of childhood and adolescent Hodgkin lymphoma have been published.[54-60] Most cover a span of approximately 30 years (1960–1990). Many of the patients included in these series received high-dose radiation therapy and high-dose alkylating agent chemotherapy regimens, which are no longer utilized. In a large study of 1,380 long-term survivors of childhood Hodgkin lymphoma, there was an 18.5-fold increased risk of developing a second cancer compared to the general population. The cumulative incidence of developing a second cancer was 10.6% at 20 years and 26.3% at 30 years.[60] 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 Gy 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 8-fold increase in risk for females who received 40 Gy. Female patients treated with both radiation therapy and alkylating agent chemotherapy have a lower relative risk for developing breast cancer than women receiving radiation therapy alone.[61] Secondary hematologic malignancy (most commonly AML and myelodysplasia) is related to the use of alkylating agents, anthracycline, and etoposide,[62] and there remains controversy about the risk of treatment-related AML (tAML) in Hodgkin lymphoma patients receiving dexrazoxane concurrent with etoposide.[45,46] Second solid tumors are seen in patients receiving radiation are consistently noted. In one study, there was a significantly higher rate of second malignancies in females, which remained when breast cancer cases were censored. In a study from the Netherlands, relative risk for a second malignancy was 4.9, 6.7, and 12.8 for patients diagnosed at ages 31 to 40 years, 21 to 30 years and younger than 20 years, respectively.[55] Patients treated for recurrence of Hodgkin lymphoma had a higher rate of second malignancy than did patients in continuous first remission. The latency period for a hematologic malignancy (median, 3.2 years) was significantly shorter than that for a second solid tumor (median, 14.3 years).[56] In one study, 40 of 43 (83%) second solid tumors arose in areas that had received at least 35 Gy of radiation.[58]

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