Treatment of advanced Hodgkin lymphoma: the more things change, the more they stay the same.

As wise people at least as far back as Heraclitus (fifth century BC) have observed, change is the only constant. Change is the vehicle through which we make progress. But progress is not the inevitable product of change. Some changes lead to improvement, some lead to decline, and some produce no perceptible improvement or decline. John F. Kennedy said, “There is nothing more certain and unchanging than uncertainty and change.” The most effective treatment for advanced Hodgkin lymphoma since the 1960s has been combination chemotherapy. The current treatment of choice is a four-drug combination—doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)—that was developed and first reported 37 years ago. The first effective therapies for this disease—nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) and ABVD—took this disease from incurable to curable in nearly 75% of patients, an authentic quantum leap in efficacy. However, since then, genuine progress has been ephemeral—here today, gone tomorrow. A new regimen will be developed and touted. Then it will be compared with the standard ABVD and found to be no better. The latest of the new-and-improved treatments to follow this fateful path is Stanford V, a regimen involving doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone. Widely hailed for its brief duration of treatment and apparently high level of activity, Stanford V was elevated to the status of acceptable primary treatment primarily on the basis of phase II data. An initial phase III study comparing Stanford V to ABVD and a 10-drug regimen found that ABVD was superior to Stanford V; however, the Stanford V regimen was not administered in that study as its developers had intended. Modifying a regimen without supporting data seems to be a common affliction in Hodgkin lymphoma clinical trials. The authors’ goal of limiting exposure to radiation therapy because of its late fatal toxic effects was laudable. However, we really do not need more data to convince us that a regimen might not work as well if not administered as intended. A randomized trial from the United Kingdom compared ABVD with Stanford V. Fewer patients randomly assigned to ABVD received radiation therapy (53% v 73% on Stanford V), but with a median follow-up of 4.3 years, the 5-year progression-free and overall survival rates were not different between the arms. Of course, the rates of late complications cannot be assessed at this early time point. In the article that accompanies this editorial, Gordon et al report results from a large Intergroup study assessing Stanford V versus ABVD. In this study, ABVD was administered together with radiation therapy only in 41% of patients, primarily those with large mediastinal masses; in contrast, 75% of Stanford V–treated patients received combined-modality therapy. Because of the efficacy of salvage therapy in this disease, failure-free survival was chosen as the primary end point rather than overall survival. The study accrued nearly 800 evaluable patients and is reported with a median follow-up of 6.4 years. Failure-free survival for patients on the ABVD arm was 74%; for patients on Stanford V, failure-free survival was 71%. From the United Kingdom and North American Intergroup studies, it seems safe to conclude that Stanford V does not cure more patients with advanced Hodgkin lymphoma than does ABVD. The question, then, becomes this: does Stanford V have any advantages over ABVD that would make it a more desirable choice for primary treatment? Stanford V is administered for a shorter duration and provides lower cumulative doses of doxorubicin and bleomycin than does ABVD. By contrast, ABVD does not contain alkylating agents and reduces the need for radiation therapy compared with Stanford V. The presence of both alkylating agents and radiation therapy in the Stanford V regimen is of concern, even though the creators of this regimen hoped that lower doses of both carcinogenic agents would somehow fall below an imaginary threshold for carcinogenicity. We anxiously await long-term follow-up of patients on these two large studies to assess fertility, cardiac and pulmonary complications, and second malignancies. More attention needs to be paid to collecting data on quality of life and late illnesses in patients cured of Hodgkin lymphoma. The evidence that Stanford V is not an improvement over ABVD answers one major current question in the treatment of advanced Hodgkin lymphoma. Other questions include is radiation therapy needed and if so, who should receive it?; is there a role for midcycle positron emission tomography (PET) scanning in treatment planning and if so, what is it?; what about escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)?; and is there any prospect for new effective therapies that might actually be an improvement over ABVD?