In this issue of Blood, Castellino and colleagues investigate morbidity and mortality in a cohort of long-term survivors of Hodgkin lymphoma (HL) from the Childhood Cancer Survivor Study. They observe frequent and serious late sequelae of therapy occurring even after 20 years of follow-up; their findings highlight the need to consider long-term implications when selecting therapeutic strategies for young patients with curable lymphomas.
The unprecedented advancement and success in the treatment of childhood and adolescent hematologic malignancies over the past decades is tempered by the fact that many survivors develop secondary life-threatening complications. The extent of the spectrum of secondary malignancies and cardiac toxicities has only recently been realized. The predominant culprit of these complications has been radiation therapy.1-3 Long-term survivors of HL are a group of people who are particularly devastated by late effects of therapy due to a “perfect storm”-type combination of factors: (1) HL is predominantly a disease of adolescents and young adults; (2) high cure rates mean that survivors can live for many decades after therapy; and (3) nodular sclerosis, the most common subtype, preferentially afflicts young women and frequently with mediastinal involvement, which has historically been treated with radiation therapy. Therefore, this interaction of disease characteristics with historical management strategies has led to the extremely high rates of solid tumors—particularly breast cancer—and ischemic heart disease in this population of survivors.
Castellino and colleagues herein report on morbidity and mortality in 2742 survivors of HL from the Childhood Cancer Survivor Study.4 Although some other groups have specifically investigated HL survivorship, this is the largest available cohort and, thus, is an important and invaluable resource for studying and realizing the late effects of therapy in this population. In addition, this cohort is mature in that all patients were treated before 1986. Despite excellent survival rates in the early years after therapy, the authors observe that beyond 10 years, there is significant excess mortality from secondary malignancies and cardiovascular disease with no plateau despite longer follow-up. Furthermore, at 20 years after initial treatment for HL, the excess death risk from cardiovascular disease rivals that from solid tumors.
As discussed and highlighted by the authors, although women with breast cancer do not appear to have an excess risk of mortality, the scale of breast cancer morbidity in these survivors is remarkable (cumulative incidence at 30 years after diagnosis is 18.3%) and should not be underemphasized. In fact, breast cancer, cardiovascular disease, and thyroid cancer were the principal morbidities identified in this report and as 94% of patients received supra-diaphragmatic radiation, it is probable that radiation therapy was causative in most cases. Although Castellino and colleagues identify a radiation dose > 30 Gy as a risk factor for overall mortality, it is important to realize that lower doses of radiation were linked to morbidity and are not benign in terms of long-term sequelae. In addition, a recent survivorship report evaluated the long-term outcome of pediatric patients with HL who received low-dose radiation and demonstrated that secondary tumors occurred with similar frequency and latency as in studies where HL patients received high-dose radiation.5
Although we have made significant advances in the treatment of HL over the past 20 years and have moved on from using high-dose extended-field radiation, much progress remains to be made. The lessons of this report are clear—it is critical to consider the long-term toxicity of treatment when selecting therapy for newly diagnosed patients. Moreover, it is important to continue to develop and evaluate novel targeted therapies that maintain high cure rates while obviating the need for combination radiation and chemotherapy that may cause these unacceptable long-term effects. Immune-based therapies using monoclonal antibodies and tumor-specific T cells are examples of targeted approaches already being evaluated in clinical trials for patients with HL, which offer the promise of tumor-specific killing while sparing bystander organs.6,7 Hence, a vision for the future of HL therapy could be that targeted therapies are combined and used upfront with carefully selected regimens so that sobering reports such as this one will be tales of the past.
Conflict-of-interest disclosure: The authors declare no competing financial interests. ■
