Radiotherapy after immunochemotherapy improves outcomes in patients with primary mediastinal large B‐cell lymphoma

Primary mediastinal B‐cell lymphoma is a rare and unique type of non‐Hodgkin's lymphoma that develops more frequently in younger patients and women. The combination of immunochemotherapy and radiotherapy (RT) has been suggested as the primary treatment choice. However, no consensus has been reached. Thus, we carried out an open‐label clinical trial. Patients with complete response after six cycles of immunochemotherapy were randomized to receive or not receive RT (control group).


INTRODUCTION
Primary mediastinal large B-cell lymphoma (PMBCL) has specific pathological features and clinical presentation. It develops more frequently in younger patients (age <40 years) and women, and generally involves bulky disease (tumor mass >10 cm) in the mediastinum.
Although there are multiple therapeutic approaches, to date, there has been no clear consensus regarding the best treatment. [1][2][3] Initial studies with standard regimens for diffuse large B-cell lymphoma most studies, OS was again extremely poor. 4,5 A recent series with dose-intense regimens obtained positive outcomes in these groups of patients; however, most studies included a small sample size and short follow-up period. [6][7][8][9][10][11][12][13] Additionally, some reports showed that the addition of rituximab (RCHOP) can improve the results; however, these were retrospective analyses or had a small number of patients, precluding definitive conclusions. 14,15 The efficacy of radiotherapy (RT) in PMBCL with bulky disease is controversial, and some studies have shown no clear advantage on OS. 1,13,14 However, these studies were carried out in the pre-rituximab era, and no controlled studies have been performed. Thus, no consensus has been reached so far on the best treatment for this group of patients. [8][9][10][11][12][13][14][15][16] Recently, Dunleavy et al. used dose-adjusted etoposide, prednisone, vincristine,cyclophosphamide, doxorubicin (EPOCH) chemotherapy and reported improved OS, 17 but subsequent studies did not confirm these results. 18,19 Furthermore, severe acute toxicities, in some cases grade 4, often requiring hospitalization that increase the cost of treatment, without improving the outcomes, were observed. At our institution, we previously showed, in a small controlled clinical trial, that the use of RT as adjuvant treatment in patients with complete response (CR) after chemotherapy improves progression-free survival (PFS) and OS 4 ; however, the trial was carried out before the introduction of rituximab. Thus, we carried out an open-label clinical trial to examine the effects of adjuvant RT in patients with CR after receiving immunochemotherapy. if hematological tests showed a granulocyte count >1.5 × 10 9 and a platelet count >100 × 10 9 . After six cycles, patients were carefully evaluated, which included computed tomography of the thorax.

Between
Response criteria were assessed according to international standard criteria at the initiation of the study. 19 Patients who achieved CR were randomized in a sequential and consecutive proportion 1:1 to receive or not receive RT (control group). The mean time to RT after initial treatment was 2-6 weeks (median 4.9 weeks). RT comprises 30 Gy in 20 fractions, in 4 weeks, delivered to the middle plane of the mediastinum, using megavoltage parallel-oppose field to the involved regions, with an adequate safety margin. The study was carried out in compliance with the Declaration of Helsinki, and approved by our institutional review board (HO-2004/2). All patients provided written informed consent to participate in the study.

RESULTS
A total of 463 patients were initially treated with RCHOP; all received the planned six cycles. Given that the hematological toxicities were grade I or II, no reduction in doses was necessary. A total of 324 patients (69%; 95% confidence interval [CI] 59-74%) achieved CR. Of these, 164 received RT and 160 did not. Table 1 shows the clinical and laboratory characteristics of the enrolled patients. No statistical differences were observed between the two groups. The median follow-up duration in the study was 98.8 months (range 69-138 months). The pattern of relapse is presented in Table 2. Relapse occurred statistically more often in patients who did not receive RT compared with those who did receive RT.
The 5-year PFS in the actuarial curves was 84% (95% CI 77-90%) in the RT group, which was statistically greater than that in the control group (67%, 95% CI 60-76%; P < 0.01). OS was also statistically higher in the RT group (86%, 95% CI 79-96%) than in the control group (68%, 95% CI 60-74%; P < 0.001). Toxicity secondary to RT was minimal and well controlled. A total of 17 patients developed cutaneous grade I lesions, and three patients had dysphagia for 2 weeks, but they continued to eat. To date, no evidence of cardiac toxicity or second neoplasm and acute leukemia has been observed. The univariate analysis showed that age, sex, and tumor size were not significantly different, and only RT showed a statistically significant difference (data not shown).

DISCUSSION
In this group of patients with newly diagnosed PMBCL and adverse prognostic factors, such as bulky disease, we assessed the effect of consolidative RT on the outcome of patients who were initially treated with RCHOP and achieved CR after six cycles of immunochemotherapy. We observed improvements in the outcomes, with longer PFS  23 Furthermore, in the present study, we did not observe any evidence of late cardiac or lung toxicities.
In the present study, which to our knowledge is the first controlled clinical trial of RT, we observed that RT is important in the treatment of PMBCL because, given that relapse occurs more frequently in bulky disease, we showed better PFS and OS in patients who received RT compared with those in patients who did not receive RT, without severe toxicities. Furthermore, the use of rituximab did not preclude the use of RT in this patient setting. In a recent retrospective study, it was proposed that stem cell transplant could be beneficial, but the number of patients was small, and the follow-up period was extremely short to draw definitive conclusions. 24

CONCLUSION
Adjuvant RT is useful, and leads to increased PFS and OS compared with RCHOP therapy alone. We suggest that RT should be considered in the initial treatment of these patients.

ACKNOWLEDGMENT
The work did not receive external grants or funding, and was carried out with the resources of the Instituto Mexicano del Seguro Social.