Role of Radiation Therapy in Localized Aggressive Lymphoma

To date, there have been four randomized trials, including the Groupe d’Etudes des Lymphomes de l’Adulte (GELA) LNH 93-4 trial reported by Bonnet et al in this issue of the Journal of Clinical Oncology, that compare chemotherapy alone to chemotherapy followed by radiation for patients with stage I-II aggressive lymphoma. Although these four trials appeared to address a similar question in a group of patients with localized disease, each of these trials differed in patient characteristics, study design, and number of cycles or type of chemotherapy administered to the treatment arms. These factors, along with the strengths and caveats of each individual trial, need to be taken into consideration in the interpretation of the trials’ results. One trial, the Southwest Oncology Group (SWOG) 8736 trial, was designed to address the question of whether the addition of involved-field radiation therapy allows the use of less chemotherapy. At its initial publication, the answer appeared to be affirmative, in that not only did the addition of radiation therapy allow the use of three cycles instead of eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), but there was also a significant 5-year progression-free and overall survival benefitwithcombined-modalitytherapyusingabbreviatedchemotherapy compared with a prolonged course of chemotherapy alone. In addition, there were more life-threatening events, including left ventricular dysfunction and cardiac deaths, in patients who received eight cycles of chemotherapy compared with patients who received three cycles of chemotherapy followed by radiation therapy. However, updated results of this trial, reported in abstract form, show that there were no longer differences in failure-free survival and overall survival between the two treatment arms. This was largely due to late relapses and lymphoma deaths after 5 years in patients who received abbreviated chemotherapy followed by radiation therapy. These findings suggest that three cycles of CHOP is inadequate systemic therapy, despite the fact that this trial included a relatively favorable group of patients. In this trial, half of the patients were younger than 60 years, two thirds of the patients had stage I disease, and patients with bulky stage II disease were excluded. A second such trial, GELA LNH 93-1, which was conducted in patients with stage I-II mostly low-risk aggressive lymphoma, had a similar design comparing aggressive chemotherapy alone with abbreviated chemotherapy followed by radiation therapy. Patients in this trial were all age 60 years or younger, with normal lactate dehydrogenase (LDH) levels and performance status, and two thirds of the patients had stage I disease. The comparison arms were dose-intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) plus sequential consolidation (a regimen originally developed for patients with poor-risk disease, which had been shown to be superior to eight cycles of CHOP), compared with three cycles of CHOP plus involved-field radiation therapy. Not surprisingly, patients randomly assigned to receive ACVBP, which has a theoretical dose-intensity of at least 150% of that delivered by three cycles of CHOP, had significantly higher 5-year event-free and overall survival rates. Although the addition of radiation therapy after three cycles of CHOP reduced relapses at initial sites of disease, it was not enough to overcome the excessive distant relapses after the abbreviated therapy. Although the SWOG 8736 and GELA LNH 93-1 trials have often been quoted to refute the role of radiation therapy in patients with localized aggressive lymphoma, the results of these trials essentially showed that radiation therapy cannot be used to replace inferior and inadequate chemotherapy. There is, however, a subgroup of patients for whom three cycles of chemotherapy followed by radiation therapy may be adequate, namely, patients with a stage-adjusted international prognostic index (IPI) of 0 (patient characteristics: age 60, normal LDH, performance status of 0-1, and stage I disease). In a subsequent analysis of the SWOG 8736 trial, patients without any stage-adjusted IPI risk factors had a 5-year overall survival rate of 94% after three cycles of CHOP and radiation therapy. However, in those patients with one or more risk factors, the 5-year overall survival was only 70% after the same treatment. These findings are consistent with the long-term results of the British Columbia group reported by Shenkier et al. In that study, patients with localized aggressive lymphoma received three cycles of CHOP-like chemotherapy followed by radiation therapy. Among those patients with a stage-adjusted IPI of 0, the 5and 10-year disease-specific survival rates were 98% and 95%, respectively, and the 5and 10-year overall survival rates were 97% and 90%, respectively. The third trial conducted by the Eastern Oncology Group (ECOG) used the same chemotherapy regimen in the two comparison arms, and is therefore positioned to directly address the role of radiation therapy. This study included less favorable patients, in that all stage I patients had bulky or extranodal disease and patients JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 7 MARCH 1 2007