The case for chemotherapy alone for limited-stage Hodgkin's lymphoma.

In “The Case for Combined-Modality Therapy for LimitedStage Hodgkin’s Disease,” [1] authors Hill-Kayser, Plastaras, Tochner, and Glatstein provide a detailed, instructive, and informative discussion of the insights into the management of Hodgkin’s lymphoma that can be derived from the recently published National Cancer Institute of Canada Clinical Trials Group (NCIC CTG)/Eastern Cooperative Oncology Group (ECOG) Hodgkin’s Disease.6 (HD.6) study comparing radiation-based treatment with chemotherapy alone for limitedstage Hodgkin’s lymphoma [2]. Unfortunately, much of their discussion focuses on the control arm when the study’s real value, that is, what is most relevant for the management of patients in 2012, lies in what was achieved in the experimental arm. To understand the most important lessons learned from the HD.6 study, attention should dwell on the remarkably good outcomes that followed initial treatment with chemotherapy alone—the best outcomes ever reported for limited-stage Hodgkin’s lymphoma. The experimental arm of the HD.6 study called for patients with limited-stage Hodgkin’s lymphoma (stages IA or IIA and low bulk [ 10 cm], excluding highly favorable stage IA nodular sclerosing or lymphocyte predominant subtypes) to be treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone [3]). ABVD was chosen because it was the most effective, well-tolerated, multiagent chemotherapy regimen for Hodgkin’s lymphoma available in the early 1990s when the HD.6 trial was designed [4]. This selection of chemotherapy regimen has stood the test of time, and ABVD is still the widely acknowledged chemotherapy of choice for limited-stage Hodgkin’s lymphoma in 2012. With a median follow-up duration 11 years, the estimated 12-year overall survival rate for patients assigned to the experimental ABVD alone arm of the HD.6 trial was 94%. No other trial examining treatment strategies for limited-stage Hodgkin’s lymphoma has ever reported better results. The most appropriate benchmark is the German Hodgkin Study Group (GHSG) HD10 study [5], which showed that brief ABVD (either two or four cycles) plus involved-field radiation (either 20 Gy or 30 Gy), for a more favorable subset of patients with limited-stage Hodgkin’s lymphoma than was enrolled in the NCIC CTG/ ECOG HD.6 study, produced a 95% overall survival rate at 8 years. Thus, the strategy of ABVD alone, as given in the HD.6 study, matched or exceeded the strategy of combined-modality treatment when one focuses on the most clinically relevant outcome, the overall survival rate. Hill-Kayser and her colleagues are correct in noting that the control arm of the HD.6 study, which employed wide-field radiation, is outmoded and has appropriately been abandoned. However, that observation is irrelevant. The HD.6 study demonstrated not that inclusion of radiation in the primary treatment of limited-stage Hodgkin’s lymphoma is bad, but that it is unnecessary. When comparing two different treatment approaches for an imminently curable disease such as Hodgkin’s lymphoma, it is important to consider the full picture, including the effectiveness of primary treatment, secondary treatment, and toxicity. As shown in Figure 1, the primary treatment outcome, which is best characterized by such endpoints as the progression-free survival interval or time to progression, may not be the most appropriate measure of the overall strategy. If reliably curative secondary treatment is available, as is true for Hodgkin’s lymphoma, then one must measure the relative merits of primary treatment using outcomes that reflect overall treatment, such as the overall survival time or freedom from second treatment failure rate. In the case of limited-stage Hodgkin’s lymphoma,