In their retrospective analysis of German High-Grade Non-Hodgkin Lymphoma Study Group trials reported in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post, Held and colleagues assessed the effects of rituximab (Rituxan) and radiotherapy in patients with aggressive B-cell lymphoma and skeletal involvement.1 The analysis, which included nine consecutive studies in which patients with diffuse large B-cell lymphoma received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHEOP (CHOP and etoposide) -like regimens with or without rituximab, suggested that radiotherapy but not the addition of rituximab to chemotherapy was associated with improved outcome.
Key Findings
For the 231 patients with vs 2,583 patients without skeletal involvement who were treated without rituximab, there was no difference in 3-year event-free survival (55% vs 59%, P = .341) or overall survival (69% vs 75%, P = .070). For the 61 patients with and 965 patients without skeletal involvement who were treated with rituximab, those with skeletal involvement had worse 3-year event-free survival (57% vs 72%, P = .002) and borderline worse 3-year event-free survival (74% vs 82%, P = .055).
The analysis of radiotherapy was restricted to 161 patients with skeletal involvement who had complete or partial response after immunotherapy/chemotherapy, because patients with less than partial response went on to receive salvage chemotherapy. Compared with 29 patients not receiving radiotherapy to sites of skeletal involvement, the 133 who received radiotherapy had better 3-year event-free survival (75% vs 36%, P < .001) and marginally better 3-year event-free survival (86% vs 71%, P = .064).
These findings led the authors to conclude, “Rituximab failed to improve the outcome of patients with diffuse large B-cell lymphoma with skeletal involvement, although our data suggest a beneficial effect of radiotherapy to sites of skeletal involvement.”
Precisely why outcomes of patients with skeletal involvement are not improved by the addition of rituximab is unclear. Perhaps rituximab, a relatively big molecule, has difficulty obtaining appropriate biodistribution to bony sites of involvement. Perhaps these findings are not “real” and simply statistical noise based on the relatively small numbers. There were only 61 patients in the data set who had bony involvement and who received R-CHOP.
I suggest that these observations be viewed as hypothesis-generating rather than as definitive. In the meantime, I will continue to include rituximab in my diffuse large B-cell lymphoma patients who have bony involvement.
Experiment Within the Experiment
The dramatic improvement in outcomes for patients who received post–rituximab/chemotherapy radiation is an interesting observation. It is important to note that the radiation vs no radiation observation is not the result of random assignment. Rather, the protocols suggested that all patients with bony involvement receive consolidation radiation therapy, but it was merely a suggestion. As a result, an experiment within the experiment emerged, and 133 patients received radiation while 29 did not. Because there may have been biases built into the recommendation to receive radiation, this observation should also be viewed as hypothesis-generating.
The authors suggest that positron-emission tomography (PET) imaging post-therapy may be a useful tool to sort out who benefits from radiation post–rituximab/chemotherapy.It might, and it should be studied prospectively. Because of issues with bone remodeling post-therapy and potential for false-positive PET scans, this will need to be done very carefully.
The authors have generated a provocative publication, with results that fly in the face of commonly held beliefs regarding the benefit of rituximab and the role of radiation in advanced-stage diffuse large B-cell lymphoma. ■
Dr. Kahl is Skoronski Chair of Lymphoma Research and Associate Professor, University of Wisconsin School of Medicine and Public Health, and Associate Director for Clinical Research, UW Carbone Cancer Center, Madison.
Disclosure: Dr. Kahl is on the advisory board and receives research funding from Genentech and Roche.
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