Doxorubicin, bleomycin, vinblastine, and dacarbazine alone in treatment of favorable, limited-stage Hodgkin's lymphoma: do we really have robust data?

TO THE EDITOR: Canellos et al recently reported that six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is an effective and safe treatment for favorable, limited-stage Hodgkin’s lymphoma (HL) based on a retrospective review, including 71 patients from a single institution. The European Organisation for Research and Treatment of Cancer H8F trial was the first trial to demonstrate that higher rates of freedom from recurrence may translate into an overall survival (OS) benefit at 10 years. Therefore, in long-term follow-up, the possibility of poorer survival as a result of higher recurrence rates is of concern when chemotherapy (CT) is given alone. Despite this concern, several trials investigated the impact of singlemodality treatment with CT on clinical outcome in an attempt to reduce treatment-related toxicity. Importantly, most trials evaluating CT with or without radiotherapy (RT) had methodologic limitations. The Spanish trial cited in the discussion is a nonrandomized study including stage I, IIA, and IIB patients. The National Cancer Institute of Canada Clinical Trials Group and Eastern Cooperative Oncology Group study compared four to six cycles of ABVD (the number of cycles was response adapted after the first two cycles) with subtotal nodal RT, which is no longer considered as a standard therapeutic option in HL. Patients were stratified into favorableand unfavorable-risk cohorts before random assignment, and ultimately, 276 of 399 patients had unfavorable features. The unfavorable-risk cohort received two cycles of ABVD in addition to subtotal nodal RT. Thus, indeed, the trial compared CT with combined-modality treatment. With a median follow-up of 4.2 years, there was no OS difference between the CT and RT arms. In a subset analysis comparing patients stratified into the unfavorable cohort, freedom from progression (FFP) was superior in patients assigned to combined-modality treatment. It should be noted that FFP was not the primary objective of the trial. The Memorial Sloan-Kettering Cancer Center trial was an underpowered single-institution phase II study including a more heterogeneous group of patients with stages I, IIA, IIB, and IIIA HL that compared six cycles of ABVD with modified extended-field RT. There was an absolute 5% difference in FFP between the groups, with a P value of . 08. The authors suggested that a possible significant benefit might be masked by the low number of patients. The Indian trial included patients with all stages of HL and suggested a superior outcome in the combined treatment arm compared with the CTalone arm in the overall analysis, with a median follow-up time of 63 months. The results of the European Organisation for Research and Treatment of Cancer–Groupe d’Etude des Lymphomes de l’Adulte H9F trial are noteworthy with respect to the role of RT in favorable limited-stage HL. This trial randomly assigned 783 patients to address two important issues in the management of favorable early-stage HL. The dose of RT in patients who achieved complete remission (CR)/unconfirmed complete remission (CRu) after CT and the need for involved-field RT (IFRT) after CT were assessed in a randomized fashion. Patients who achieved CR/CRu after six cycles of epirubicin, vinblastine, bleomycin, and prednisone were randomly assigned to RT arms (36 v 20 Gy) or to a no RT arm. Seventy-seven percent of patients had CR/CRu after six cycles epirubicin, vinblastine, bleomycin, and prednisone, which was above the stopping rule value of 70%. The trial was closed as a result of significantly lower 5-year relapse-free survival rate in the no RT arm compared with the RT arms (70% v 86 v 89% for no RT, IFRT 36 Gy, and IFRT 20 Gy, respectively; P .001). Of note, the failure of the no RT arm might also be a result of the CT regimen used. This question is going to be answered in the H10 trial, which will also assess early CR after two cycles of ABVD with positron emission tomography scan. There was no difference in the OS, as expected with a short median follow-up time of 37 months. Nevertheless, it is important to note that these results are derived from a randomized trial, and thus, the level of evidence is higher than a retrospective study or an underpowered prospective trial. The results reported by Canellos et al could be considered important for hypothesis generating. Currently, CT combined with IFRT remains the preferred treatment option for patients with favorable limited-stage HL. The retrospective studies always have the possibility of selection bias, as stated by the authors. The low number of patients despite a long treatment period (1992 to 2008) from a single center suggests a difficult treatment decision-making process for recommending a nonstandard treatment option. Moreover, the study population includes stage IIB patients (15%), which is not consistent with the title of the article. Favorable limited-stage HL has a good prognosis; therefore, an optimal balance between efficacy and long-term toxicity is crucial. Improved imaging techniques and advances in RT technology have led to considerable progress in RT over the years. ABVD followed by IFRT based on modern RT principles has been shown to lower both acute and late treatment-related toxicities. In conclusion, we think that the results from this retrospective analysis should be interpreted with caution because such definitive conclusions based on retrospective analyses might be misleading for the oncology community, especially if they are published in prestigious journals like Journal of Clinical Oncology, which is read by all oncologists worldwide. The conclusion might be interpreted as six cycles of ABVD alone is the standard treatment option, and this treatment might be adopted by those who are not familiar with treatment of HL. Finally, we also believe that some patients with favorable early-stage disease might benefit from a response-adapted treatment strategy without RT; however, this strategy must be proven within the scope of prospective randomized clinical trials.