Radiation therapy improves treatment outcome in patients with diffuse large B-cell lymphoma Luigi Marcheselli, Raffaella Marcheselli, Alessia Bari, Eliana Valentina Liardo, Fortunato Morabito, Luca Baldini, Maura Brugiatelli, Francesco Merli, Nicola Di Renzo, and Stefano Sacchi

Diffuse large B-cell lymphoma (DLBCL) is the most frequently occurring subtype of non-Hodgkin’s lymphoma (NHL) and constitutes 30% to 40% of all adult NHLs For more than 20 years, combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard treatment for these patients

NCCN Giudelines Version Non-Hodgkin’s Lymphomas PRINCIPLES OF RADIATION THERAPY   Field: Involved-Field or Reduced IF   For Extranodal sites: Organ involvement, Bone/Spine Involvement   For Nodal sites: IF, RT consolidation after CHT limited to the originally involved nodes   Dose: consolidation in DLBCL following CR to CHT Gy; for PR after CHT Gy

The issue of whether the administration of RT after chemotherapy (CHT) is beneficial to patients with DLBCL remains unresolved. Therefore, the aim of this study was to determine whether RT was of benefit in our set of patients.

PATIENTS AND METHODS (1) Cases were retrieved from the Gruppo Italiano Studio Linfomi (GISL) archive. Patients were included in this study if they fulfilled the following criteria:  histologically confirmed diagnosis of DLBCL CD 20+, previously untreated;  age >18 years;  no primary central nervous system involvement;  no human immunodeficiency virus, hepatitis B virus, or hepatitis C virus infection;  no severe coincident illnesses;  availability of data on clinical and laboratory characteristics, treatments, outcome, and follow-up Patients included in this retrospective study were enrolled in two GISL clinical trials (Anzinter3, and LA05)

All patients were treated with R-CHOP with or without IFRT at GISL sites. All patients included in these trials completed six cycles of CHT. At completion of CHT, consolidative or adjuvant IFRT was allowed, at the treating physician’s discretion, in patients who had obtained complete (CR) or partial (PR) remission, because the trial protocols did not specify how RT was to be used. It is assumed that IFRT was more likely to be given to patients with previously bulky disease, diseases with extranodal involvement, and diseases that failed to achieve CR upon CHT. PATIENTS AND METHODS (2)

RESULTS 216 patients with a median follow-up of 30 months were enrolled in the two GISL protocols between 2003 and patients (16%) received  6 cycles of R-CHOP or obtained less than a PR and were excluded from the study The remaining 182 patients, of which 153 (84%) obtained CR and 29 (16%) PR, were the target cohort of our study

The clinical characteristics of these 182 patients were as follows: median age, 69 years 51% male 65% stage III-IV 5% PS  1 73% IPI  1 26% bulky disease Comparisons between the characteristics of patients who received IFRT and those who did not, showed that these differences were statistically significant The clinical characteristics of these 182 patients were as follows: median age, 69 years 51% male 65% stage III-IV 5% PS  1 73% IPI  1 26% bulky disease Comparisons between the characteristics of patients who received IFRT and those who did not, showed that younger patients, patients with bulky disease, and patients with stage I–II disease received IFRT more frequently; these differences were statistically significant

After chemotherapy, 40 (22%) of 182 patients who achieved CR or PR were treated with consolidative (31 patients) or adjuvant (9 patients) IFRT. IFRT was delivered to 21 of 63 (33%) patients with stage I–II disease and 19 of 119 (16%) patients with stage III–IV disease IFRT was delivered to 21 of 63 (33%) patients with stage I–II disease and 19 of 119 (16%) patients with stage III–IV disease Extra-nodal sites were irradiated in 20% of patients The median dose delivered was 34 Gy (range 20–40 Gy) We do not have information about the criteria used by physicians when deciding to use IFRT and dose.

The comparison between survival outcome of the with the outcome of the 142 non-irradiated patients showed a 5-year OS of 86% and 74% respectively (p=0.118), and an EFS of 85% and 56% respectively (p=0.021) The comparison between survival outcome of the 40 patients who obtained CR or PR and who were treated with consolidative or adjuvant IFRT with the outcome of the 142 non-irradiated patients showed a 5-year OS of 86% and 74% respectively (p=0.118), and an EFS of 85% and 56% respectively (p=0.021)

When the 31 of 153 patients who and were treated with consolidative IFRT were considered, the comparison with the 122 non-irradiated patients showed a 5-year OS of 91% and 79%, respectively (p=0.141), and an EFS of 88% and 59%, respectively (p=0.035) When the 31 of 153 patients who obtained CR and were treated with consolidative IFRT were considered, the comparison with the 122 non-irradiated patients showed a 5-year OS of 91% and 79%, respectively (p=0.141), and an EFS of 88% and 59%, respectively (p=0.035)

Univariate analysis showed that a poorer EFS was associated with increasing age, Ann Arbor (AA) stage III–IV, PS >1, and LDH > UNL, whereas a reduction of risk was associated with IFRT treatment. We observed the same results for both cohorts (182 patients with CR/PR and 153 patients with CR after chemotherapy) under examination. In multivariate analysis, IFRT had a favorable effect for both the 182 patients with CR/PR (p=0.044) and the 153 patients with CR (p=0.037). In addition to IFRT, increasing age and stage III–IV remained the principal variables associated with EFS. The results of uni- and multivariate analyses for EFS are reported in Table III

DISCUSSION (1) Whether the administration of RT after chemotherapy is of benefit in DLBCL patients has not been completely resolved, in part due to conflicting results from several trials. Recognizing the lack of definitive evidence, the National Comprehensive Cancer Network (NCCN) guidelines recommend three cycles of R-CHOP plus IFRT for early-stage, non-bulky disease, but also allow the administration of six to eight cycles of R- CHOP with or without IFRT.

DISCUSSION (2) Our retrospective study showed that IFRT delivered after six cycles of R-CHOP was associated with improved EFS. In our group of patients, we collected information regarding the site of irradiation and dose. Criteria used by physicians to decide whether to use IFRT remain unclear because of the retrospective nature of the study. Finally, we believe that our results strongly support the hypothesis that IFRT has a clinically useful role, even in the R era.

CONCLUSION In conclusion, the role of RT in the treatment of DLBCL, at either early or advanced stages, is still unclear. The introduction of new treatments and technologies must be taken into account to define the value of RT. Only a program of prospective randomized clinical trials can produce a high quality data and address questions about which DLBCL patients are most likely to benefit from IFRT.

Stefano Sacchi Samantha Pozzi Alessia Bari Eliana Liardo Monica Civallero Maria Cosenza Raffaella Marcheselli Luigi Marcheselli ….GRAZIE PER L’ATTENZIONE