Consolidation radiotherapy in the treatment of advanced Hodgkin's disease: is it dead?

For almost 5 years, the March 1998 issue of The Journal of Clinical Oncology has been sitting on my desk as a reminder to write a rebuttal to “A Meta-Analysis of Chemotherapy Versus Combined Modality Treatment Trials in Hodgkin’s disease” (1). That analysis concluded that combined modality therapy (CMT) was of little value overall in advanced Hodgkin’s disease (HD). Thanks to the editors of the International Journal of Radiation Oncology, Biology, Physics for inviting this editorial and overcoming my inertia. Apologies to those readers who have seen similar thoughts in a recent prior editorial. Let’s set the stage with a brief historical review. HD was considered generally incurable until the 1960s, when the pioneering work of Vera Peters, Henry Kaplan, and Eric Easson all independently demonstrated long-term survival without disease for early stage HD treated with radiotherapy (RT) alone. This was followed in the 1970s by the introduction of combination chemotherapy (CT) for advanced disease. Although RT cured the majority of patients with localized disease, CT had a 40–50% success rate in advanced HD. It was therefore logical to attempt to combine the two in advanced HD to improve results. The rationale was fourfold: (1) HD is exquisitely sensitive to RT (the best drug for HD to paraphrase Richard Hoppe); (2) after CT, HD tends to relapse at sites of initial involvement (note the original articles reporting this never distinguished between bulk and nonbulk disease in this regard); (3) CT works best against small numbers of malignant cells; and (4) when a complete response (CR) is obtained with CT, one cannot distinguish at present between cure (all cells killed) and a two log kill with persistence of subclinical disease. We therefore proposed, a number of years ago, a treatment program whereby, after a CT-induced CR, RT would be administered to the sites at greatest risk for relapse, namely all the clinically involved sites of diagnosis and only those sites. Only a modest dose was thought to be necessary (15–25 Gy), because CT was having some effect (the patients were in CR). Additionally, this dose could be safely administered to parenchymal organs and to nodal areas and was unlikely to have significant long-term toxicity. A number of Phase II trials followed, by us and other groups, which demonstrated a reduction in relapse rate of CR patients from 30–50% with CT alone to 10–15% with the addition of RT and a corresponding modest improvement in survival (2). The next step was confirmatory Phase III trials; here is where difficulties began. The treatment protocol was complex and the concepts foreign to many radiation oncologists. The notion of using such low doses was against conventional wisdom of the time, and whole-organ irradiation was worrisome. The resultant Phase III trial designs varied widely—often only nodal RT was used, fields were not limited to involved sites, and RT doses were higher (35–40 Gy). Quality assurance was highly variable, often with little review of the RT to be certain the doses and field designs were appropriate and administered as intended. An additional variable was the chemotherapy. When testing the value of consolidation RT, it would seem selfevident that one should pick the best CT program and then compare that best program alone to the same with the addition of RT (call this design A). Many studies, however, decided to compare one chemotherapy program plus RT to a different CT program, either more cycles of the same drugs or the addition of other drugs (call this design B), making interpretation of results problematic. Consider now the 1998 meta-analysis referred to previously, published by the International Database on Hodgkin’s Disease Overview Study Group (1). Data on 1740 patients treated on 14 Phase III trials were analyzed. These 14 trials included 16 comparisons: 8 compared the same CT program with and without consolidation RT, whereas 8 compared one CT program plus RT vs. a different CT program alone. These two design types were referred to by the authors as the additional RT design and the parallel