Late Effects from Childhood�/�Adolescent Hodgkin Lymphoma Therapy
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
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 chemotherapy regimens utilize lower doses of alkylating agents. Hybrid regimens allow for lower doses of anthracycline and bleomycin as well. Thus, much of the late effects literature is not necessarily applicable to patients receiving modern therapy. (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.)
In general, the use of combined chemotherapy and low-dose involved-field radiation therapy (LD-IFRT) broadens the spectrum of potential toxicities, while reducing the severity of individual drug-related or radiation-related toxicities. Current approaches use chemotherapy with or without LD-IFRT. The volume of radiation and the intensity/duration of chemotherapy are determined by prognostic factors at presentation, including presence of constitutional symptoms, disease stage, and bulk.
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.[2,3] 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), 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. 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 cyclophosphamide (i.e., COPP [cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine]), chlorambucil, or nitrogen mustard (MOPP).
The Society for Paediatric Oncology and Haematology (GPOH-95) utilized OEPA for two cycles for all males. 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, and only rare patients had elevated levels following gonadotropin-releasing hormone stimulation. Basal levels of FSH, however, were elevated in 27.5% and 36.4% of 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 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 (four to six 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. The concern for male fertility is also being addressed in the GPOH 2003 trial by replacing procarbazine with dacarbazine (COPDIC).