Response: Early-stage Hodgkin lymphoma

Response: Dr. Zubizarreta’s and Dr. Raslawski’s commentary contributes to the collective findings of previously published contemporary trials for favorable risk pediatric Hodgkin disease [1–7]. These studies uniformly indicate that many children with favorable presentations of Hodgkin lymphoma can be cured with chemotherapy alone. Our understanding of late therapy-related complications underscores the benefits of avoiding radiation in very young children, in particular. However, similar to other reports delineating treatment results after combination chemotherapy alone [1,6], Dr. Zubizarreta and Dr. Raslawski focus on relatively early treatment outcomes (within first 5–10 years) and fail to provide information about long-term toxicity. Late treatment effects anticipated after four cycles of COPP/ABV include cardiopulmonary and gonadal dysfunction and secondary leukemogenesis. Substituting cyclophosphamide for mechlorethamine in the MOPP combination and limiting alkylating agent exposure to 4 months should confer a negligible risk of secondary acute myeloid leukemia [8]. Similarly, the restricted cumulative doses of anthracycline and bleomycin should be associated with a low risk of cardiopulmonary toxicity, although long-term data establishing safety of low-dose anthracycline treatment in very young children are not yet available [9,10]. Finally, previous German multicenter studies indicate that gonadal dysfunction after four cycles of COPP is still a potential risk for boys, but its impact on long-term fertility has not been established [11]. Treatment with four cycles of ABVD eliminates the potential risk of gonadal dysfunction and leukemogenesis, but provides a slightly higher cumulative anthracycline and bleomycin dosage compared to the COPP/ABV hybrid regimen. For very young children with favorable risk disease, the risk of life-threatening toxicity should be extremely low with the cumulative chemotherapy doses delivered in four cycles of COPP/ABV or ABVD. However, clinicians should note that treatment efficacy is based on an estimated event-free survival at a median follow-up of only 36 months. Similarly, we also do not have long-term treatment outcome data for chemotherapy alone using limited cycles of ABVD derivative therapy like VAMP (currently under study by our consortium), VBVP, or DBVE. The excellent results previously reported using these combinations have been in the context of combined modality therapy [2,4,7]. Thus, there is a potential risk of compromising disease control by eliminating a potentially critical modality in these effective regimens. The exception to this is the more mature results (5-year event-free survival) of the German multicenter combination using the dose-intensive OEPA or OPPA lends stronger support for treatment with restricted cycles of chemotherapy alone for favorable Hodgkin lymphoma [3]. Our knowledge deficits regarding the biologic behavior of Hodgkin disease undoubtedly results in over-treatment of some children that contributes to long-term toxicity. One approach to avoid radiation-associated morbidity is to accept a lower event-free survival with frontline chemotherapy alone and let children who need radiation to optimize long-term outcomes declare themselves by failure. The disadvantage of this approach is the excess mortality and morbidity conferred by salvage therapy [12,13]. My preference is to study this issue in the context of a prospective clinical trial in which well-defined data regarding treatment response, outcomes and morbidity are uniformly collected to facilitate characterization of patients at risk for treatment failure and at risk for unacceptable treatment toxicity.