Radiation therapy improves treatment Radiation therapy improves treatment outcome in patients with outcome in patients with

diffuse large B-cell lymphomadiffuse large B-cell lymphoma

Luigi Marcheselli, Raffaella Marcheselli, Alessia Bari, Eliana Valentina Liardo, Luigi Marcheselli, Raffaella Marcheselli, Alessia Bari, Eliana Valentina Liardo, Fortunato Morabito, Luca Baldini, Maura Brugiatelli, Francesco Merli, Nicola Di Fortunato Morabito, Luca Baldini, Maura Brugiatelli, Francesco Merli, Nicola Di

Renzo, and Stefano SacchiRenzo, and Stefano Sacchi

Diffuse large B-cell lymphoma (DLBCL) is the most Diffuse large B-cell lymphoma (DLBCL) is the most frequently occurring subtype of non-Hodgkin’s lymphoma frequently occurring subtype of non-Hodgkin’s lymphoma (NHL) and constitutes 30% to 40% of all adult NHLs(NHL) and constitutes 30% to 40% of all adult NHLs

For more than 20 years, combination chemotherapy with For more than 20 years, combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard treatment for prednisone (CHOP) has been the standard treatment for these patientsthese patients

NCCN Giudelines Version 3.2011Non-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 30-36 Gy; for PR after CHT 40-50 Gy

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

PATIENTS AND METHODS (1)PATIENTS AND METHODS (1)

Cases were retrieved from the Gruppo Italiano Studio Linfomi (GISL) Cases were retrieved from the Gruppo Italiano Studio Linfomi (GISL) archive. Patients were included in this study if they fulfilled the archive. Patients were included in this study if they fulfilled the following criteria: following criteria:

histologically confirmed diagnosis of DLBCL CD 20+, previously histologically confirmed diagnosis of DLBCL CD 20+, previously untreated; untreated;

age >18 years;age >18 years; no primary central nervous system involvement; no primary central nervous system involvement; no human immunodeficiency virus, hepatitis B virus, or hepatitis C no human immunodeficiency virus, hepatitis B virus, or hepatitis C

virus infection; virus infection; no severe coincident illnesses; no severe coincident illnesses; availability of data on clinical and laboratory characteristics, availability of data on clinical and laboratory characteristics,

treatments, outcome, and follow-up treatments, outcome, and follow-up

Patients included in this retrospective study were enrolled in two GISL Patients included in this retrospective study were enrolled in two GISL clinical trials (Anzinter3, and LA05)clinical trials (Anzinter3, and LA05)

All patients were treated with R-CHOP with or without IFRT at GISL All patients were treated with R-CHOP with or without IFRT at GISL sites. sites.

All patients included in these trials completed six cycles of CHT. All patients included in these trials completed six cycles of CHT.

At completion of CHT, consolidative or adjuvant IFRT was allowed, at At completion of CHT, consolidative or adjuvant IFRT was allowed, at the treating physician’s discretion, in patients who had obtained the treating physician’s discretion, in patients who had obtained complete (CR) or partial (PR) remission, because the trial protocols complete (CR) or partial (PR) remission, because the trial protocols did not specify how RT was to be used. did not specify how RT was to be used.

It is assumed that IFRT was more likely to be given to patients with It is assumed that IFRT was more likely to be given to patients with previously bulky disease, diseases with extranodal involvement, and previously bulky disease, diseases with extranodal involvement, and diseases that failed to achieve CR upon CHT.diseases that failed to achieve CR upon CHT.

PATIENTS AND METHODS (2)PATIENTS AND METHODS (2)

RESULTSRESULTS

216 patients with a median216 patients with a median follow-up of 30 months were enrolled in the follow-up of 30 months were enrolled in the two GISL protocols between 2003 and 2007two GISL protocols between 2003 and 2007

34 patients (16%) received 34 patients (16%) received 6 cycles of R-CHOP or obtained less than 6 cycles of R-CHOP or obtained less than a PR and were excluded from the studya PR and were excluded from the study

The remaining The remaining 182182 patients, of which 153 (84%) obtained CR and 29 patients, of which 153 (84%) obtained CR and 29 (16%) PR, were the target cohort of our study(16%) PR, were the target cohort of our study

The clinical characteristics of The clinical characteristics of these 182 patients were as these 182 patients were as follows: follows:

median age, 69 yearsmedian age, 69 years51% male51% male65% stage III-IV65% stage III-IV5% PS 5% PS 1 1 73% IPI 73% IPI 1 126% bulky disease 26% bulky disease

Comparisons between the Comparisons between the characteristics of patients who characteristics of patients who received IFRT and those who received IFRT and those who did not, showed that did not, showed that younger patients, patients with bulky disease, and patients with stage I–II disease received IFRT more frequently; these differences these differences were statistically significantwere statistically significant

After chemotherapy, 40 (After chemotherapy, 40 (22%22%) ) of 182 patients who achieved of 182 patients who achieved CR or PR CR or PR were treated withwere treated with consolidative (31 patients) or consolidative (31 patients) or adjuvant (9 patients) adjuvant (9 patients) IFRTIFRT..

IFRT was delivered to 21 of 63 IFRT was delivered to 21 of 63 ((33%33%) patients with ) patients with stage I–IIstage I–II disease and 19 of 119 (disease and 19 of 119 (16%16%) ) patients with patients with stage III–IVstage III–IV diseasedisease

Extra-nodal sites were Extra-nodal sites were irradiated in 20% of patientsirradiated in 20% of patients

The median dose delivered was The median dose delivered was 34 Gy (range 20–40 Gy) 34 Gy (range 20–40 Gy)

We do not have information We do not have information about the criteria used by about the criteria used by physicians when deciding to physicians when deciding to use IFRT and dose. use IFRT and dose.

The comparison between survival outcome of the 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 with the outcome of the 142 non-irradiated patients showed a 5-year OS of 86% and 74% respectively (showed a 5-year OS of 86% and 74% respectively (pp=0.118), and an =0.118), and an EFS of 85% and 56% respectively (p=0.021) EFS of 85% and 56% respectively (p=0.021)

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

DISCUSSION (1)DISCUSSION (1)

Whether the administration of RT after chemotherapy is of benefit in Whether the administration of RT after chemotherapy is of benefit in DLBCL patients has not been completely resolved, in part due to DLBCL patients has not been completely resolved, in part due to conflicting results from several trials. conflicting results from several trials.

Recognizing the lack of definitive evidence, the National Recognizing the lack of definitive evidence, the National Comprehensive Cancer Network (NCCN) guidelines recommend Comprehensive Cancer Network (NCCN) guidelines recommend three cycles of R-CHOP plus IFRT for early-stage, non-bulky 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-disease, but also allow the administration of six to eight cycles of R-CHOP with or without IFRT. CHOP with or without IFRT.

DISCUSSION (2)DISCUSSION (2)

Our retrospective study showed that IFRT delivered after Our retrospective study showed that IFRT delivered after six cycles of R-CHOP was associated with improved six cycles of R-CHOP was associated with improved EFS. EFS.

In our group of patients, we collected information regarding In our group of patients, we collected information regarding the site of irradiation and dose. Criteria used by the site of irradiation and dose. Criteria used by physicians to decide whether to use IFRT remain unclear physicians to decide whether to use IFRT remain unclear because of the retrospective nature of the study. because of the retrospective nature of the study.

Finally, we believe that our results strongly support the Finally, we believe that our results strongly support the hypothesis that hypothesis that IFRT has a clinically useful role, even in IFRT has a clinically useful role, even in the R erathe R era. .

CONCLUSIONCONCLUSION

In conclusion, the role of RT in the treatment of DLBCL, at In conclusion, the role of RT in the treatment of DLBCL, at either early or advanced stages, is still unclear. either early or advanced stages, is still unclear.

The introduction of new treatments and technologies must The introduction of new treatments and technologies must be taken into account to define the value of RT. be taken into account to define the value of RT.

Only a program of prospective randomized clinical trials Only a program of prospective randomized clinical trials can produce a high quality data and address questions can produce a high quality data and address questions about which DLBCL patients are most likely to benefit about which DLBCL patients are most likely to benefit from IFRT. from IFRT.

Stefano Sacchi

Samantha PozziAlessia Bari Eliana Liardo

Monica CivalleroMaria Cosenza

Raffaella MarcheselliLuigi Marcheselli

….GRAZIE PER L’ATTENZIONE