Treatment for Early-Stage Hodgkin Lymphoma: Has Radiotherapy Had Its Day?
Authors: John Radford
Journal: Journal of Clinical Oncology (2012)

The article by Meyer et al that was published recently in the New England Journal of Medicine has ignited an important debate around the optimal choice of treatment in early-stage classical Hodgkin lymphoma. This issue distills down to a single question: Are the risks of radiotherapy in this group, where there is a high expectation of cure, such that chemotherapy alone is the better option? In the 1960s and 1970s, patients with clinical stage IA or IIA Hodgkin lymphoma that was apparently confined to the thorax, axillae, or neck underwent a staging laparotomy with lymph node and liver biopsies and a splenectomy. If histologic assessment confirmed absence of disease below the diaphragm, mantle field radiotherapy to include all nodal stations above the diaphragm was recommended. This approach resulted in prolonged disease-free survival in a significant number of patients and represented a major step forward. However, what soon came to light was recurrence of the disease outside of the radiation field in some patients as a result of a surgical sampling error or false-negative histologic assessment of biopsy specimens taken at the staging laparotomy. This led to studies of adjuvant chemotherapy that were designed to determine whether a combined-modality approach could prevent recurrence in patients with seemingly early-stage Hodgkin lymphoma. A clear benefit for patients receiving adjuvant treatment was observed in terms of progression-free survival, but there was no survival advantage because patients who developed recurrent disease after radiotherapy alone were efficiently treated with chemotherapy as salvage treatment. Furthermore, the benefit of fewer relapses after combined-modality therapy was at the expense of everyone who received the highly emetogenic mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy or a close variant at a time when antiemetic medication was in its infancy. It also became evident that MOPP and its relations caused permanent azoospermia in a high proportion of males and premature menopause in females, and a much smaller but still concerning incidence of acute leukemia or myelodysplasia in both sexes. These studies highlighted the benefits of chemotherapy in terms of disease control, but they also identified undesirable longterm consequences of treatment in addition to the immediate toxicity with which patients were already well acquainted. The replacement of MOPP with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as the first-line choice of chemotherapy provided some reassurance in terms of the incidence of infertility, acute leukemia, and myelodysplasia, but the inclusion of doxorubicin in ABVD replaced these late treatment effects with cardiotoxicity. Of course, it is not only chemotherapy that is responsible for eroding the quality and duration of survival after treatment for Hodgkin lymphoma. The consequences of radiotherapy in terms of increased risk of second cancers and cardiovascular disease have become increasingly recognized during the last two decades, and this has produced a move toward smaller radiation fields and doses. But are these changes sufficient to minimize the late toxicity of radiation? Would it be better to abandon radiotherapy altogether in this setting and replace it with chemotherapy? This brings us to the article by Meyer et al. Here the results of a randomized clinical trial run by NCIC and the Eastern Cooperative Oncology Group (ECOG) involving 405 patients with previously untreated, nonbulky stage IA and IIA Hodgkin lymphoma are described. Trial participants were randomly assigned to receive either four or six cycles of ABVD chemotherapy alone or a treatment approach that incorporated subtotal nodal irradiation (STNI). For participants allocated to the radiotherapy arm, treatment was further decided on the basis of risk profile: for those with a favorable risk profile, STNI was given alone, and for those with an unfavorable risk profile, STNI was preceded by two cycles of ABVD. The target volume of radiation in the STNI-treated group included all supradiaphragmatic nodal stations (mantle field), the spleen, and para-aortic lymph nodes with 35 Gy of radiation that was administered in 20 fractions. The primary end point was overall survival at 12 years. Thetrialwas initiated in1994andthisanalysiswasperformedaftera median of 11.3 years of follow-up. Overall survival was superior in the ABVD-alone arm of the trial, in which there were 12 deaths compared with 24 deaths in the STNI arm (94% v 87%; P .04). Of crucial importance, deaths in the ABVD arm included six as a result of Hodgkin lymphoma or early treatment toxicity and six as a result of other causes (four second cancers and two cardiac). In the STNI arm, there were four deaths as a result of Hodgkin lymphoma or early treatment toxicity and 20 as a result of other causes (10 second cancers, two cardiac, three infective, and five other). Freedom from disease progression was 87% in the ABVD-alone group and 92% in the STNI group (P .05), and the authors concluded that overall survival was better in the chemotherapy-alone group because of a higher incidence of deaths as a result of other causes in those receiving STNI. Many of the excess deaths in the STNI arm of this trial can be attributed to late treatment toxicity, but five deaths categorized as JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 30 NUMBER 31 NOVEMBER 1 2012