Finding the Balance in Pediatric Hodgkin's Lymphoma

It is difficult to improve on a 90% cure rate, which is the wonderful place in which we find ourselves today with pediatric Hodgkin’s lymphoma (HL). Large numbers of children and adolescents with HL worldwide are now being cured with risk-based combined-modality therapy. Five-year data points for assessment of event-free (EFS) and overall survival (OS) are commonly used in cooperative group studies to evaluate outcome. However, for diseases in which we truly achieve cures, such as HL, we must look beyond 5 years to know the true impact of our treatment and management. In Journal of Clinical Oncology, Wolden et al report mature data from the large CCG (Children’s Cancer Group) 5942 study, which enrolled 826 patients, including a projected 10-year EFS of 83.5% and OS of 92.5%. These truly remarkable and firm data are worthy of praise. We now have 40 years of experience with the model of combined-modality therapy using multiagent chemotherapy and involved-field radiation therapy (IFRT), which has consistently achieved the 90% cure rate. This success has challenged us to ask how we can better refine therapy to avoid any unintended consequences, such as untoward costs of survival. At Stanford University, having the longest experience with high-dose, extended-field radiation to cure HL, we were mindful of treatment-induced toxicities involving soft tissue and bone growth and development in prepubertal children, endocrine and cardiopulmonary dysfunction, sterility, and secondary carcinogenesis. We then introduced lower radiation doses delivered in smaller volumes in combination with aggressive chemotherapy programs to minimize radiation-associated problems. However, we gradually discovered late effects from multiagent chemotherapy, including infertility in boys, cardiac and pulmonary dysfunction, neuropathy, and leukemia. Soon it became clear that the optimal treatment would be a package of risk-based therapy, combining the most effective agents, used for a limited number of cycles in short durations, along with low doses of radiation delivered in small treatment volumes. This approach has set the standard of treatment for children with HL worldwide. Gradually investigators have asked if we could optimize the therapy even further. They feared the radiation-associated effects and questioned if some children could be cured without the radiation component of the combination therapy. Thus, CCG 5942 was designed to answer this question by investigating, in a prospective randomized fashion, whether children achieving a complete response (CR) to initial chemotherapy could be cured without radiotherapy. The study was stopped early when an interim analysis demonstrated relapses occurring among the nonirradiated cohort. However, would this change with more mature data? There are important lessons to learn from this wellwritten report: First, not all children are suitable for a study asking this question, because not all children will achieve a good result from the treatment. In this study, 19% of children had either progression of disease while undergoing initial chemotherapy and were taken off study or experienced only a partial response to chemotherapy and were then assigned to receive radiation therapy. Furthermore, some children did not receive the treatment they were assigned or randomly assigned to receive. Second, 77% achieved a CR to chemotherapy and were then eligible for the randomized portion of the study. However, only 60% of the children were actually randomly assigned to IFRT or no radiation and hence formed the cohort for an as-treated analysis. For these patients, once again, we see that the addition of IFRT to chemotherapy improved 10-year EFS and OS, but the comparisons are most obvious and hence significant for EFS, not OS. Third, a large majority of the untoward events that were observed represented relapse or progression of HL, not toxicity from the treatment. Thus, the culprit still remains HL. However, treatment toxicity does enter into the discussion of outcome, because salvage therapy after first or subsequent relapses of disease involves much more aggressive therapy, which carries with it many more early and late adverse effects and is not always successful. Relapse of HL in children is commonly managed with stem-cell transplantation. OS after high-dose chemotherapy and stem-cell transplantation for refractory or relapsed HL in children at 5 years is only approximately 68%. We have learned that in children with treatable and curable disease, we must look at the impact of overall therapy, because we need to know not just whether the treatment was successful as measured by EFS, but also the overall price of the late effects of treatment experienced by those who survive. Our goal must be cure with the initial treatment, but we must also be concerned with quality of life and our patients’ ability to lead normal and productive lives. The statistical significance of IFRT plus chemotherapy for the patients in clinical group one (100% v 89%) is important. However, it does not follow that there is no improvement from IFRT added to chemotherapy for children in clinical groups two and three, because this study was not powered for such a subset analysis. Thus, this study suffers from the small numbers of children achieving a CR to initial chemotherapy, who were eligible for random assignment. This is especially true for the clinical group two and three cohorts, in which fewer patients achieved a CR with chemotherapy alone.