Second cancers following Hodgkin's lymphoma: radiation therapy once more.

Although it had been known for some time that radiation therapy (RT) was carcinogenic, there were few reports documenting an increase in second malignant neoplasms (SMN) in children with cancer in 1988, when Ekert et al. [1] published the results of treating children and adolescents with Hodgkin’s lymphoma (HL) with chemotherapy alone. Omitting RT was truly courageous, and since the results were no less effective than those following treatment with protocols in which RT had been used, treatment with chemotherapy alone in young people with HL was common in Australia after 1986. Consequently, a large cohort of survivors who were treated between 1960 and 1999 with chemotherapy alone and did not receive RT now exists in Australia. This permits comparison between the risks of SMN in this unique cohort with those of survivors treated with RT. In this issue, Barbaro et al. [2] report significant differences in the incidence of solid SMN at 30 years between the cohort of 63 survivors who were treated with RT (25%) and the 79 treated with chemotherapy alone (5%) [2]. Patients treated with RT were five times more likely to develop SMN than those given chemotherapy alone. Other large cohorts of HL survivors, composed largely of children treated with RT, have reported similar risks: 23.5% of the 1400 survivors in the Late Effects Study Group and 18% of the almost 14 000 survivors in the Childhood Cancer Survivor Study [3, 4]. Of the 14 SMN, 5 were thyroid cancers, and all but one developed following RT. Radiation is a known thyroid carcinogen, especially in children [5]. Also not surprising were the other tumors that have been reported following HL, usually in RT fields, including condrosarcoma, salivary gland adenocarcinoma, lung cancer, rectal adenocarcinoma and nonHodgkin’s lymphoma. There was no difference in SMN incidence between patients who received RT doses of <25 Gy or >25 Gy. The primitive neuroectodermal tumor that developed in a sciatic nerve 3 years after radiation and the Kaposi sarcoma diagnosed 8 years after HL are unusual. What is interesting is the absence of secondary breast cancers, especially since it is the most common solid neoplasm reported following RT in other survivors of HL. The short follow-up, median not quite 20 years, cannot be the entire explanation since the median follow-up in other large cohorts for breast cancer after RT for Hodgkin lymphoma is also 20 years [3–6]. It should be noted that patients in this Australian cohort were all <15 years of age at diagnosis, while those in the other large cohorts were older. The short follow-up likely can explain the absence of gastrointestinal and genitourinary cancers as second cancers reported recently from the large cohort of UK childhood cancer survivors treated with RT [7]. Most patients in both the RT and non-RT groups were treated with several alkylating agents, including chlorambucil, a highly leukemogenic agent. It is not surprising, therefore, that three patients developed hematologic malignancies, one after RT and chemotherapy and two following chemotherapy alone. As expected, these occurred before 5 years, which was the earliest latent period for the solid tumors. Two patients developed melanoma, but since there is scant evidence for ionizing radiation in the etiology of melanoma, one wonders whether they were exposed to the Australian sun in the first two decades of life and whether this risk of melanoma exceeds that of age-matched individuals in the general population. Curiously, one patient in the cohort survived without chemotherapy or RT. This analysis has the benefit of being population-based, of including detailed treatment information, and of having histopathologic confirmation of SMN. The RT and non-RT groups were comparable with regard to sex, age and stage at diagnosis, B-symptoms, use of chemotherapy and number of cycles. And, not unexpectedly, there was no difference in survival. However, there was a significant difference in the follow-up time: median was 230 months in the RT group and 174 months in the non-RT group. To compensate for this, the authors censored the analysis at 170 months of follow-up, and there remained a significant difference in SMN between the RT and non-RT groups with regard to SMN. Although second cancers are among the most serious late effects of treatment of childhood cancer, especially HL, they are not the only complications that increase survivors’ morbidity and mortality; heart disease is a major source of morbidity and mortality in survivors of childhood and adolescent cancer [9]. When chemotherapy began to be used widely to treat lymphoma, alkylating agents, such as nitrogen mustard, cyclophosphamide and procarbazine, were the main agents. In addition to increasing the risk of secondary leukemia, these agents were found to cause infertility in men. A successful regimen, ABVD, included the effective anthracycline doxorubicin and it became the standard in many centers. It continues to be used in most multi-agent chemotherapy regimens and, together with RT, anthracyclines have been shown to increase the risk of congestive heart failure and coronary artery disease in survivors. The recommendation by the Institute of Medicine that survivors of childhood cancer are followed regularly is especially important here [10]. Cardiac, pulmonary, endocrine e d it o ri a l