Is there a role for consolidative radiation therapy for aggressive B-cell lymphoma in the rituximab era?

Randomized trials have compared chemotherapy alone versus combined modality therapy in patients with aggressive non-Hodgkin lymphoma [1–7], with most of the trials focusing on patients with early-stage disease [1,3,4,5,6,7]. However, there are limitations associated with these trials. Two of the trials used abbreviated chemotherapy in the radiotherapy-containing arms [5–7], and are thus more suited to address alternatives to intensive chemotherapy alone in patients with a favorable prognosis, rather than to isolate the benefit of radiation therapy (RT) after chemotherapy. Other shortfalls of the available trials include inadequate chemotherapy [2], limited power [4], poor compliance to assigned treatment arms [4], and suboptimal radiotherapy quality control [3,8]. Perhaps the most relevant limitation of published trials is that they were conducted in the pre-rituximab era. With the availability of more effective systemic therapy and improvement in distant disease control, improved local control may translate into disease-specific and overall survival benefit, as has been shown in other cancer types [9–11]. Conversely, it is possible that the anti-lymphoma effect of rituximab may itself enhance local control sufficiently that RT is rendered unnecessary. In recent years, studies are becoming available examining the role of consolidative RT after rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). In this issue of Leukemia and Lymphoma, Marcheselli et al. report the results for 182 patients with diffuse large B-cell lymphoma (DLBCL) who received at least six cycles of R-CHOP on two Gruppo Italiano Studio Linfomi (GISL) protocols, with 40 (22%) of the patients also treated with consolidative RT at the discretion of the treating physician [12]. The irradiated patients were significantly younger, and more likely to have bulky disease and/or stages I–II disease. On multivariable analysis controlling for known risk factors, patients who received consolidative RT had a significantly better event-free survival (EFS) (hazard ratio [HR] 0.33; 95% confidence interval [CI] 0.11–0.97), and this benefit was also significant in the subset of patients who achieved a complete response to chemotherapy (HR 0.24; 95% CI 0.06–0.92). These findings are consistent with the results of a larger study from the M. D. Anderson Cancer Center where the addition of consolidative RT in patients with DLBCL treated with at least six cycles of R-CHOP, after adjusting for prognostic imbalances [13], yielded significantly superior progression-free survival (PFS) (HR 0.19; 95% CI 0.10–0.38) and overall survival (HR 0.32; 95% CI 0.17–0.51) results. Similar to the Italian study, a significant difference was observed even among patients who had achieved a complete response to chemotherapy. A study from the German High-Grade Non-Hodgkin-Lymphoma Study Group (DSHNHL) focusing on elderly patients who received R-CHOP, on the other hand [14], did not find an overall benefit to the addition of consolidative RT. However, there was a significant EFS benefit in patients with initially bulky disease (defined as >7.5 cm) with a partial response to chemotherapy.

The above studies, despite attempts to control for prognostic differences between the irradiated and non-irradiated cohorts, are limited by the retrospective study designs. The DSHNHL is conducting a prospective randomized trial in patients with stage I–IV aggressive B-cell lymphoma, aged 18–60, with age-adjusted International Prognostic Index (AA-IPI) of 1, or AA-IPI of 0 with bulky disease (>7.5 cm). Patients with non-bulky disease are randomized to R-CHOP-21 alone versus R-CHOP-14 alone. Patients with bulky disease and/or extranodal disease are randomized to one of four arms: R-CHOP-21 alone, R-CHOP-14 alone, R-CHOP-21 followed by radiation therapy if a complete response (CR) is achieved, and R-CHOP-14 followed by radiation therapy if a CR is achieved. The results, when available, will clarify the role of RT in selected patients in the rituximab era. Areas for further investigation specifically on consolidative RT after chemotherapy for aggressive non-Hodgkin lymphoma include: adapting the decision on RT according to the functional imaging response to chemotherapy; identifying the optimal radiation dose based on the initial disease extent and response to chemotherapy; exploring field size reduction from involved-field to involved-node radiation therapy, as has been studied in Hodgkin lymphoma [15]; and investigating novel radiation therapy techniques such as intensity modulated radiation therapy to improve targeting while limiting doses to normal structures. The identification of the subgroup of patients who would benefit from improved local control with RT in the rituximab era while adopting modern RT techniques in these patients will help enhance the therapeutic ratio of consolidative RT for DLBCL.

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