Radiation Therapy After R-CHOP for Diffuse Large B-Cell Lymphoma: The Gain Remains

It is hard to imagine that, less than two decades ago, the acronyms IPI (International Prognostic Index), FDG-PET ([F]fluorodeoxyglucose positron emission tomography), WHO classification, and even R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) were not part of the lymphoma language. But in contrast to these advances, we are still employing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) after almost four decades (now enhanced with the anti-CD20 antibody rituximab) as our basic chemotherapy for diffuse large B-cell lymphoma (DLBCL), and we keep debating the need for consolidative involved-field radiotherapy (IFRT) for patients with stage I and II disease. Clearly, the issue of treatment consolidation after R-CHOP with IFRT, or alternatively with more chemotherapy, has not been resolved. In an attempt to satisfy all opinions, the National Comprehensive Cancer Network (NCCN) guidelines recommend three cycles of R-CHOP IFRT for early-stage, nonbulky disease but also allow the administration of six to eight cycles of R-CHOP with or without IFRT. The latter is also the NCCN recommendation for bulky disease. This variety of options in the NCCN guidelines may make everybody happy, but it could be confusing to the nonexpert. In reality, many oncologists simply extend the chemotherapy course and omit radiotherapy (RT). The shorter chemotherapy followed by RT approach for early-stage disease is solidly based on the results of the benchmark, randomized trial published in 1998 by the Southwest Oncology Group (SWOG) that clearly showed that three cycles of CHOP IFRT was a safer and significantly more effective treatment than eight cycles of CHOP alone. The SWOG study did not secure the use of combined modality in localized disease for long. For some chemotherapists, the better safety profile of short CHOP IFRT and its survival advantage, which lasts for almost a decade in patients with a median age of 60 years, still did not justify keeping RT in the program. Moreover, given that all randomized trials in early-stage DLBCL were done in the pre-R, pre-IPI, pre–positron emission tomography (PET) era, it was suggested that the magic of R or a PET conversion will make RT irrelevant. This hypothesis has not been tested yet. Unfortunately, randomized studies in earlystage DLBCL that will incorporate R, IPI, and PET and will also examine the likely advantage of modern, better targeted, safer, and lower-dosage, consolidative RT are not coming to a theater near you anytime soon. The retrospective work published in this issue from the M. D. Anderson Cancer Center (MDACC) on the benefit of consolidative RT in patients with DLBCL treated with R-CHOP is important. Still, it is not the ideal study to fully settle the role of RT in early-stage disease simply because it is not a prospective, randomized trial. Yet it reflects a common reality: different experts in a large cancer center exercising different approaches to the use of RT in early-stage DLBCL. At MDACC, over the last decade, 103 (54%) of 190 stage I and II patients received IFRT. In stages III and IV, where IFRT is not commonly used, 39 (14%) of 279 MDACC patients still received RT; 59% of those had bulky disease. In each of the groups, patients who received RT had a significantly better outcome. Several features of the study helped to avoid some of the concerns that tarnish the previous randomized studies that tested the role of RT. First, all patients in the MDACC study were treated with R-CHOP and not with CHOP alone. Second, they all received six to eight cycles of chemotherapy, averting the concern that three cycles of CHOP are not sufficient as systemic treatment for patients with stage-modified IPI more than 1. The study also incorporated IPI, and often FDG-PET, data into the analysis. To overcome common concerns of retrospective data, the researchers examined in several ways the impact on outcome of adding IFRT, including analyzing all patients, evaluating patients with earlystage and advanced-stage disease separately, scrutinizing all subgroup permutations, and using multivariate statistics and matched-cohort comparison. Each method of analysis used by the MDACC researchers indicated that patients who received consolidative RT experienced a significantly better outcome than those who did not. Quite impressively, the five-year overall survival (OS) and progression-free survival (PFS) for stage I and II disease treated with RT were 92% and 82%, respectively; whereas without RT, OS and PFS were 73% (P .0007) and 68% (P .0003), respectively. For stage III and IV disease, the minority of patients who received RT had five-year OS and PFS of 89% and 76% compared with 66% (P .008) and 55% (P .003), respectively, for those not receiving RT. It remains unclear what criteria were used to select those patients with advanced-stage disease to receive RT and how the sites for RT were determined. The data are strong in the early-stage category in which more than half of patients received RT, and there is no apparent selection bias in favor of RT patients. Although this is not a randomized study, the data are solid and are well in line with the randomized studies in the United States. Now, the burden of proof for not using RT in early-stage disease is on those who still do not believe that RT should be used in DLBCL after complete response (CR) to chemotherapy. Perhaps before designing a new prospective study to determine the role of RT in early-stage disease, we should examine the strengths and flaws of the available studies. They have not completely resolved the controversy concerning using RT but may provide us with some clues and principles. It is not disputed that DLBCL is almost always a systemic disease, even when this is not apparent clinically at presentation. In almost one third of patients, DLBCL presents in only one or two sites, and in some, it persists locally after chemotherapy or (without RT) tends to relapse in the same original site. Furthermore, the responsiveness of DLBCL to RT was well established before the advent of effective chemotherapy, when RT was used alone in localized aggressive lymphomas. For example, a study of early-stage non-Hodgkin’s lymphoma from Princess Margaret Hospital (Toronto, Canada) showed that, in a cohort of clinically staged patients Editorials